Immune system

The immune system is made up of a complex network of cells, chemicals, tissues, organs, and the substances they make that helps your body fight infections and other diseases. The immune system includes white blood cells and organs and tissues of the lymph system, such as the thymus, spleen, tonsils, lymph nodes, lymph vessels, and bone marrow (see Figures 1 and 2 below). The immune system must recognize foreign invaders and abnormal cells (Table 1) and distinguish them from the body’s healthy cells. An underactive or overactive immune system can cause health issues. For example, autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, happen when the body mounts an immune response against its own tissues instead of a foreign invader. In addition, allergies occur when an individual’s immune system reacts to substances in the environment that are tolerated by most people. Underactivity of the immune system or immunodeficiency, can increase your risk of infection. You may be born with an immunodeficiency (known as primary immunodeficiency or inborn errors of immunity), or acquire it from a medical treatment or another disease (known as secondary immunodeficiency). Primary immunodeficiency are a group of more than 450 rare, chronic conditions in which part of the body’s immune system is missing or does not function correctly. Primary immunodeficiencies are caused by hereditary genetic defects and can affect anyone, regardless of age, gender, or ethnicity ¹. Because the most important function of the immune system is to protect against infection, children and adults with primary immunodeficiency commonly experience increased susceptibility to infection. The infections may be in the skin, sinuses, throat, ears, lungs, brain or spinal cord, or in the urinary or intestinal tracts. Increased susceptibility to infection may show up as repeated infections, infections that are unusually hard to cure or unusually severe infections (requires hospitalization or intravenous antibiotics).

The immune system is constantly working to protect your body from infections, injury, cancers and diseases. The immune system recognizes invaders such as bacteria, viruses and fungi as well as abnormal cells. It mounts an immune response to help the body fight the invasion. When harmful microbes (tiny particles) enter and invade your body, the body produces white blood cells to fight the infection. The white blood cells identify the microbe, produce antibodies (immunoglobulins or or gamma-globulins) to fight it, and help other immune responses to occur. They also ‘remember’ the attack. There are five major classes of antibodies (IgG, IgA, IgM, IgD, and IgE). IgG has four different subclasses (IgG1, IgG2, IgG3, IgG4). IgA has two subclasses (IgA1 and IgA2). Antibodies of the IgA class are produced near mucus membranes and find their way into secretions such as tears, intestines, bile, saliva and mucus, where they protect against infection in the respiratory tract and intestines. Antibodies of the IgM class are the first antibodies formed in response to infection. They are important in protection during the early days of an infection. Antibodies of the IgE class are responsible for allergic reactions. IgD is expressed on mature B cells along with IgM and may play some role in helping B cells differentiate into plasma cells. Recently, studies have suggested that IgD may be important in the gut homeostasis by binding to mast cells and basophils to react against pathogenic bacteria in the gut.

Antibodies protect the body against infection in a number of different ways. For example, some microorganisms, such as viruses, must attach to body cells before they can cause an infection, but antibodies bound to the surface of a virus can interfere with the virus’ ability to attach to the host cell. In addition, antibodies attached to the surface of some microorganisms can cause the activation of a group of proteins called the complement system that can directly kill some bacteria. Antibody-coated bacteria are also much easier for neutrophils to ingest and kill than bacteria that are not coated with antibodies. All of these actions of antibodies prevent microorganisms from successfully invading body tissues and causing serious infections.

The immune response is split into two functional divisions: innate and acquired immunity.

1. Innate immunity is the first line of defense against foreign invaders. Innate immunity involves immediate, nonspecific responses to pathogens.
2. Acquired immunity also called adaptive immunity, is the second line of defense against foreign invaders. Acquired immunity involves a complex, targeted response to a specific pathogen. Exposure to a pathogen stimulates the production of certain immune cells that mark the pathogen for destruction. Upon first exposure, it takes several days or weeks to develop the acquired immune response, but the involved immune cells “remember” the encounter and respond quickly upon subsequent exposure to the same pathogen.

The components of the innate and acquired immune systems communicate and work together to protect your body from infection and disease (Table 2).

Major organs of the Immune System (Figure 1):

• Thymus: The thymus is an organ located in the upper chest where T cells mature. First, lymphocytes (a type of white blood cell) that are destined to become T cells leave the bone marrow and find their way to the thymus where they are then “educated” to become mature T cells.
• Liver: The liver is the major organ responsible for producing proteins of the complement system. In addition, it contains large numbers of phagocytic cells (a specific type of white blood cell) that ingest bacteria in the blood as it passes through the liver.
• Bone Marrow: The bone marrow is the location where all cells of the immune system begin their development from stem cells.
• Tonsils: Tonsils are collections of lymphocytes in the throat.
• Lymph Nodes: Lymph nodes are collections of B cells and T cells throughout the body. Cells congregate in lymph nodes to communicate with each other. Lymph nodes can become swollen when they are fighting an infection.
• Spleen: The spleen is a collection of B cells, T cells, and monocytes. It serves to filter the blood and provide a site for invaders/germs and cells of the immune system to interact.
• Blood: Blood is contained within the circulatory system that carries cells and proteins of the immune system from one part of the body to another.

The cells that are involved in the immune system (Figure 2):

• Granulocytes include basophils, eosinophils, and neutrophils. Basophils and eosinophils are important for host defense against parasites. They also are involved in allergic reactions.
• Neutrophils (also known as polymorphonuclear cells, PMNs or granulocytes), the most numerous innate immune cell (the most numerous of all the types of white blood cells), patrol for problems by circulating in the bloodstream. Neutrophils or polymorphonuclear leukocytes are found in the bloodstream and can migrate into sites of infection within a matter of minutes. These cells, like the other cells in the immune system, develop from hematopoietic stem cells in the bone marrow. Neutrophils can phagocytose, or ingest, bacteria, degrading them inside special compartments called vesicles. Neutrophils increase in number in the bloodstream during infection and are in large part responsible for the elevated white blood cell count seen with some infections. They are the cells that leave the bloodstream and accumulate in the tissues during the first few hours of an infection and are responsible for the formation of pus. Their major role is to ingest bacteria or fungi and kill them. Their killing strategy relies on ingesting the infecting organisms in specialized pockets within the cell. Neutrophils contain toxic chemicals that fuse with the bacteria-containing pockets to kill the bacteria. Neutrophils have little role in the defense against viruses.
• Monocytes, which develop into macrophages, also patrol and respond to problems. Monocytes make up 5 to 10% of the white blood cells. They also line the walls of blood vessels in organs like the liver and spleen where they capture microorganisms in the blood as they pass by. When monocytes leave the bloodstream and enter the tissues, they change shape and size and become macrophages. Macrophages, “big eater” in Greek, are named for their ability to ingest and degrade bacteria. Macrophages are essential for killing fungi and the class of bacteria to which tuberculosis belongs (mycobacteria). Like neutrophils, macrophages ingest microbes and deliver toxic chemicals directly to the foreign invader to kill it. Macrophages live longer than neutrophils and are especially important for slow growing or chronic infections. Macrophages can be influenced by T cells and often collaborate with T cells in killing microorganisms. Macrophages also have important non-immune functions, such as recycling dead cells, like red blood cells, and clearing away cellular debris. These “housekeeping” functions occur without activation of an immune response. Upon activation, monocytes and macrophages coordinate an immune response by notifying other immune cells of the problem.
• B cells (B lymphocytes) and often named on lab reports as CD19 or CD20 cells: These lymphocytes arise in the bone marrow from stem cells. When B cells encounter foreign germs (antigens), they respond by maturing into another cell type called plasma cells. Plasma cells are the mature B cells (mature B lymphocytes) that actually produce the antibodies (also known as immunoglobulins or gamma-globulins) and are located in the spleen and lymph nodes throughout the body. B cells can also mature into memory cells, which allows a rapid response if the same infection is encountered again. The long life of plasma cells enables your body to retain immunity to viruses and bacteria that infected you many years ago. For example, once you have been fully immunized with live vaccine strains of measles virus, you will almost never catch it because your body retain the plasma cells and antibodies for many years and these antibodies prevent infection.
• T cells sometimes called T lymphocytes and often named in lab reports as CD3 cells, are another type of immune cell. Some T cells directly attack cells infected with viruses, and others act as regulators of the immune system. Each T cell reacts with one specific antigen, just as each antibody molecule reacts with one specific antigen. In fact, T cells have molecules on their surfaces that are similar to antibodies. The variety of different T cells is also so extensive that the body has T cells that can react against virtually any antigen. T cells have different abilities to recognize antigen and are varied in their function. There are killer or cytotoxic T cells (often denoted in lab reports as CD8 T cells), helper T cells (often denoted in lab reports as CD4 T cells), and regulatory T cells. Each has a different role to play in the immune system.
• Cytotoxic T cells (CD8+ T cells or Killer T cells): These lymphocytes mature in the thymus and are responsible for killing cells infected with viruses. Killer T cells protect the body from certain bacteria and viruses that have the ability to survive and even reproduce within the body’s own cells. The killer T cell must migrate to the site of infection and directly bind to its target to ensure its destruction. In addition to fighting germs, killer T cells also recognize and respond to foreign tissues in the body, such as a transplanted kidney. When T cells are fighting infections, they grow and divide, making more T cells.
• Helper T cells (CD4+ T-cell): Helper T cells assist B cells to produce antibodies and assist killer T cells in their attack on foreign substances.
• Regulatory T cells. Regulatory T cells suppress or turn off the T cells when an infection is controlled and they are no longer needed. Regulatory T cells act as the thermostat of the lymphocyte system to keep it turned on just enough—not too much and not too little. Without regulatory T cells, the immune system would keep working even after an infection has been treated. Without regulatory T cells, there is the potential for the body to overreact to the infection.
• Plasma cells: These cells develop from B cells (B lymphocytes) and are the cells that make immunoglobulin (antibodies).
• Mast cells also are important for defense against parasites. Mast cells are found in tissues and can mediate allergic reactions by releasing inflammatory chemicals like histamine.
• Dendritic cells (DC) also known as antigen-presenting cells (APCs), instruct T cells on what to attack. Dendritic cells (DC) also can develop from monocytes. Antigens are molecules from pathogens, host cells, and allergens that may be recognized by adaptive immune cells. APCs like DCs are responsible for processing large molecules into “readable” fragments (antigens) recognized by adaptive B or T cells. However, antigens alone cannot activate T cells. They must be presented with the appropriate major histocompatiblity complex (MHC) expressed on the APC. MHC provides a checkpoint and helps immune cells distinguish between host and foreign cells.
• Natural killer (NK) cells have features of both innate and adaptive immunity. They are important for recognizing and killing virus-infected cells or tumor cells. Natural killer (NK) cells are so named because they easily kill cells infected with viruses. They are said to be natural killer cells as they are always ready to fight and do not require the same thymus education that T cells require. NK cells are derived from the bone marrow and are present in relatively low numbers in the bloodstream and in tissues. They are important in defending against viruses and possibly preventing cancer as well. They contain intracellular compartments chemicals called cytotoxic granules, which are filled with proteins that can form holes in the target cell and also cause apoptosis, the process for programmed cell death. NK cells kill virus-infected cells by injecting them with a killer potion of chemicals called cytotoxic granules. It is important to distinguish between apoptosis and other forms of cell death like necrosis. Apoptosis, unlike necrosis, does not release danger signals that can lead to greater immune activation and inflammation. Through apoptosis, immune cells can discreetly remove infected cells and limit bystander damage. NK cells are particularly important in the defense against herpes viruses. This family of viruses includes the traditional cold sore form of herpes (herpes simplex) as well as Epstein-Barr virus (the cause of infectious mononucleosis or mono) and the varicella virus (the cause of chickenpox and shingles). Recently, researchers have shown in mouse models that NK cells, like adaptive cells, can be retained as memory cells and respond to subsequent infections by the same pathogen.

The immune system relies on an adequate supply of nutrients for its baseline functions as well as for ramping up its activity when necessary ², ³, ⁴, ⁵, ⁶, ⁷. It is well established that malnutrition (protein-energy malnutrition and obesity) and deficiencies in one or more micronutrients (vitamins and nutritionally essential minerals) diminish immune function. In most instances, correcting the nutrient deficiency restores the affected immune functions. At a minimum, getting the recommended dietary allowance (RDA) for vitamin C and vitamin D is necessary for the immune system to function properly; there is some evidence that intakes above the current RDA (recommended dietary allowance) for these vitamins may be of further benefit ⁸. Because supplementation with iron can have unwanted side effects in those with preexisting infections, especially malaria, routine iron supplementation should be accompanied by malaria detection and treatment strategies ⁸. The long-chain Omega-3 Polyunsaturated Fatty Acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have potent anti-inflammatory effects, especially in individuals with chronic or acute inflammation ⁸. Increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumption increases the EPA and DHA content of immune cell membranes, mainly by displacing the long-chain Omega-6 Polyunsaturated Fatty Acids (PUFA) arachidonic acid and becoming the substrate for the enzymes that synthesize eicosanoids. EPA and DHA also give rise to anti-inflammatory compounds that “turn off” the inflammatory response. In chronic inflammatory states (e.g., rheumatoid arthritis, atherosclerosis), eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplements have been shown to reduce symptoms of rheumatoid arthritis and the risk of cardiac events. However, the dose of EPA plus DHA that is optimal for immune function in healthy individuals is not yet established. Ingestion of at least 500 mg/day of EPA plus DHA is recommended by the International Society for the Study of Fatty Acids and Lipids ⁹ and the American Heart Association recommends eating one to two servings of seafood per week to reduce your risk of some heart problems, especially if you consume the seafood in place of less healthy foods ¹⁰. For people with heart disease, the American Heart Association recommends consuming about 1 g per day EPA plus DHA, preferably from oily fish, but supplements are an option under the guidance of a health care provider ¹¹. The AHA does not recommend omega-3 supplements for people who do not have a high risk of cardiovascular disease ¹². The Linus Pauling Institute recommends that generally healthy adults eat fish twice weekly, which provides approximately 500 mg/day of EPA plus DHA; for those who do not regularly consume fish, consider taking a two-gram fish oil supplement several times a week in consultation with a physician ⁸. Higher daily intakes may be recommended for the treatment of specific disorders.

Table 1.  The Immune System responds to Foreign Invaders and Abnormal Cells

Table 2. Functional Divisions and Components of the Immune Response

Figure 1. Immune system

Figure 2. Cells of the immune system

Footnote: The cells of the immune system originate in the bone marrow from pluripotent hematopoietic stem cells. Pluripotent hematopoietic stem cells give rise to a common lymphoid progenitor, which gives rise to all of the major lymphoid cell types (T‐cells, B‐cells, and Natural killer [NK] cells) or a common myeloid progenitor, which gives rise to all of the major myeloid cell types (neutrophils, eosinophils, basophils, dendritic cells (DCs), mast cells, and monocytes/macrophages) as well as the erythrocytes and megakaryocytes (which generate platelets).

Figure 3. Factors that influence the immune response

Figure 4. Vitamins and minerals for immune system

Footnotes: Vitamins and minerals have key roles at every stage of the immune response ¹³. This schematic summarizes important components and processes that are involved in different aspects of the innate and adaptive immune responses. The circles highlight those micronutrients that are known to affect these responses. The significant overlap between micronutrients and processes indicates the importance of multiple micronutrients in supporting proper function of the immune system.

Abbreviations: APCs = antigen-presenting cells; C3 = complement component 3; CRP = C-reactive protein; Cu = copper; Fe = iron; IFNs = interferons; Igs = immunoglobulins; ILs = interleukins; GI = gastrointestinal; GM-CSF = granulocyte-macrophage colony stimulating factor; MAC = membrane attack complex; MCP-1 = monocyte chemoattractant protein-1; Mg = magnesium; MHCs = major histocompatibility complexes; NK = natural killer; NO = nitric oxide; ROS = reactive oxygen species; Se = selenium; TLRs = toll-like receptors; TNF = tumor-necrosis factors; Zn = zinc

How does the immune system work?

The immune system involves many parts of your body. Each part plays a role in recognizing foreign microbes, communicating with other parts of your body, and working to fight the infection. Parts of the immune system are:

• Skin – The skin is usually the first line of defense against microbes. Skin cells produce and secrete important antimicrobial proteins, and immune cells can be found in specific layers of skin.
• Bone marrow – helps produce immune cells. The bone marrow contains stems cells that can develop into a variety of cell types. The common myeloid progenitor stem cell in the bone marrow is the precursor to innate immune cells—neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells, and macrophages—that are important first-line responders to infection. The common lymphoid progenitor stem cell leads to adaptive immune cells—B cells and T cells—that are responsible for mounting responses to specific microbes based on previous encounters (immunological memory). Natural killer (NK) cells also are derived from the common lymphoid progenitor and share features of both innate and adaptive immune cells, as they provide immediate defenses like innate cells but also may be retained as memory cells like adaptive cells. B, T, and NK cells also are called lymphocytes.
• Bloodstream: Immune cells constantly circulate throughout the bloodstream, patrolling for problems. When blood tests are used to monitor white blood cells, another term for immune cells, a snapshot of the immune system is taken. If a cell type is either scarce or overabundant in the bloodstream, this may reflect a problem.
• The thymus, a small gland in your upper chest where some immune T cells mature.
• Lymphatic system is a network of of tiny vessels which allows immune cells to travel between tissues and the bloodstream. The lymphatic system contains lymphocytes (white blood cells; mostly T cells and B cells), which try to recognize any bacteria, viruses or other foreign substances in the body and fight them. They are carried in a milky fluid called lymph. Immune cells are carried through the lymphatic system and converge in lymph nodes, which are found throughout the body.
• Lymph nodes, small lumps in the groin, armpit, around the neck and elsewhere that help the lymphatic system to communicate. Lymph nodes are a communication hub where immune cells sample information brought in from the body. They can become swollen when the body mounts an immune response. For instance, if adaptive immune cells in the lymph node recognize pieces of a microbe brought in from a distant area, they will activate, replicate, and leave the lymph node to circulate and address the pathogen. Thus, doctors may check patients for swollen lymph nodes, which may indicate an active immune response.
• The spleen is an organ under the ribs behind the stomach on the left that processes information from the blood. While it is not directly connected to the lymphatic system, it is important for processing information from the bloodstream. Immune cells are enriched in specific areas of the spleen, and upon recognizing blood-borne pathogens, they will activate and respond accordingly.
• Mucous membranes, like the lining of the inside of your mouth are prime entry points for pathogens, and specialized immune hubs are strategically located in mucosal tissues like the respiratory tract and gut. For instance, Peyer’s patches are important areas in the small intestine where immune cells can access samples from the gastrointestinal tract.​

Immune organs

The organ systems involved in the immune response are primarily lymphoid organs which include, spleen, thymus, bone marrow, lymph nodes, tonsils, and liver. The lymphoid organ system classifies according to the following ¹⁴:

1. Primary lymphoid organs (thymus and bone marrow), where T and B cells first express antigen receptors and become mature functionally.
2. Secondary lymphoid organs like the spleen, tonsils, lymph nodes, the cutaneous and mucosal immune system; this is where B and T lymphocytes recognize foreign antigens and develop appropriate immune responses.

All immune cells originate in the bone marrow, deriving from hematopoietic stem cells, but an important set of immune cells (T lymphocytes) undergo maturation in an organ known as the thymus. The thymus and bone marrow are known as primary lymphoid tissues. T lymphocytes mature in the thymus, where these cells reach a stage of functional competence while B lymphocytes mature in the bone marrow the site of generation of all circulating blood cells. Excessive release of cytokines stimulated by these organisms can cause tissue damage, such as endotoxin shock syndrome.

Secondary lymphoid tissues, namely the lymph nodes, spleen and mucosa-associated lymphoid tissues (MALT) are important sites for generating adaptive immune responses and contain the lymphocytes (key adaptive cells). The lymphatic system is a system of vessels draining fluid (derived from blood plasma) from body tissues. Lymph nodes, that house lymphocytes, are positioned along draining lymph vessels, and monitor the lymph for signs of infection. MALT tissues are important in mucosal immune responses, and reflect the particular importance of the gut and airways in immune defence. The spleen essentially serves as a ‘lymph node’ for the blood.

Immune cells communication

Immune cells communicate in a number of ways, either by cell-to-cell contact or through secreted signaling molecules. Receptors and ligands are fundamental for cellular communication.

• Receptors are protein structures that may be expressed on the surface of a cell or in intracellular compartments. The molecules that activate receptors are called ligands, which may be free-floating or membrane-bound.
• Ligand-receptor interaction leads to a series of events inside the cell involving networks of intracellular molecules that relay the message. By altering the expression and density of various receptors and ligands, immune cells can dispatch specific instructions tailored to the situation at hand.

Cytokines are small proteins with diverse functions. In immunity, there are several categories of cytokines important for immune cell growth, activation, and function.

• Colony-stimulating factors are essential for cell development and differentiation.
• Interferons (IFNs) are necessary for immune-cell activation. Type I interferons mediate antiviral immune responses, and type II interferon is important for antibacterial responses.
• Interleukins (ILs), which come in over 30 varieties, provide context-specific instructions, with activating or inhibitory responses.
• Chemokines are made in specific locations of the body or at a site of infection to attract immune cells. Different chemokines will recruit different immune cells to the site needed.
• Tumor necrosis factor (TNF) family of cytokines stimulates immune-cell proliferation and activation. They are critical for activating inflammatory responses, and as such, TNF blockers are used to treat a variety of disorders, including some autoimmune diseases.

Toll-like receptors (TLRs) are expressed on innate immune cells, like macrophages and dendritic cells. They are located on the cell surface or in intracellular compartments because microbes may be found in the body or inside infected cells. TLRs recognize general microbial patterns, and they are essential for innate immune-cell activation and inflammatory responses.

B-cell receptors (BCRs) and T-cell receptors (TCRs) are expressed on adaptive immune cells. They are both found on the cell surface, but BCRs also are secreted as antibodies to neutralize pathogens. The genes for BCRs and TCRs are randomly rearranged at specific cell-maturation stages, resulting in unique receptors that may potentially recognize anything. Random generation of receptors allows the immune system to respond to unforeseen problems. They also explain why memory B or T cells are highly specific and, upon re-encountering their specific pathogen, can immediately induce a neutralizing immune response.

Major histocompatibility complex (MHC) or human leukocyte antigen (HLA), proteins serve two general roles.

Major histocompatibility complex (MHC) proteins function as carriers to present antigens on cell surfaces. MHC class I proteins are essential for presenting viral antigens and are expressed by nearly all cell types, except red blood cells. Any cell infected by a virus has the ability to signal the problem through MHC class I proteins. In response, CD8+ T cells (also called CTLs) will recognize and kill infected cells. MHC class II proteins are generally only expressed by antigen-presenting cells like dendritic cells and macrophages. MHC class II proteins are important for presenting antigens to CD4+ T cells. MHC class II antigens are varied and include both pathogen- and host-derived molecules.

MHC proteins also signal whether a cell is a host cell or a foreign cell. They are very diverse, and every person has a unique set of MHC proteins inherited from his or her parents. As such, there are similarities in MHC proteins between family members. Immune cells use MHC to determine whether or not a cell is friendly. In organ transplantation, the MHC or HLA proteins of donors and recipients are matched to lower the risk of transplant rejection, which occurs when the recipient’s immune system attacks the donor tissue or organ. In stem cell or bone marrow transplantation, improper MHC or HLA matching can result in graft-versus-host disease, which occurs when the donor cells attack the recipient’s body.

Complement refers to a unique process that clears away pathogens or dying cells and also activates immune cells. Complement consists of a series of proteins found in the blood that form a membrane-attack complex. Complement proteins are only activated by enzymes when a problem, like an infection, occurs. Activated complement proteins stick to a pathogen, recruiting and activating additional complement proteins, which assemble in a specific order to form a round pore or hole. Complement literally punches small holes into the pathogen, creating leaks that lead to cell death. Complement proteins also serve as signaling molecules that alert immune cells and recruit them to the problem area.

Best vitamins for immune system

Through experimental research and studies of people with immune deficiencies, a number of vitamins (A, B6, B12, folate, C, D and E) and trace elements (zinc, copper, selenium, iron) have been demonstrated to have key roles in supporting the human immune system and reducing risk of infections ¹⁵. Other essential nutrients including other vitamins and trace elements, amino acids and fatty acids are also important in this regard. All of the nutrients named above have roles in supporting antibacterial and antiviral defences but zinc and selenium seem to be particularly important for the latter.

Table 3. Vitamins and minerals that affect the immune system

Abbreviations: IFN = Interferon; IL= interleukin; NK = natural killer; Th = T-helper; TNF = tumor necrosis factor

Table 4. Important dietary sources of nutrients that support the immune system

Table 5. Results of multiple scientific studies (meta-analyses) on micronutrients and respiratory infections

List of foods containing Vitamins and Minerals that Affect the Immune System

Vitamin A

Vitamin A is name of a group of fat-soluble vitamin (retinoids, including retinol, retinal, and retinyl esters) ³⁵, ³⁶, ³⁷, that is naturally present in many foods.

Vitamin A is important for normal vision, gene expression, the immune system, embryonic development, growth, and reproduction. Vitamin A also helps the heart, lungs, kidneys, and other organs work properly ³⁸.

There are two different types of vitamin A ³⁹.

1. The first type, preformed vitamin A (retinol and its esterified form, retinyl ester), is found in meat (especially liver), poultry, fish, and dairy products.
2. The second type, provitamin A carotenoids (beta-carotene, alpha-carotene and beta-cryptoxanthin), is found in fruits, vegetables, and other plant-based products (oily fruits and red palm oil). The most common type of provitamin A carotenoids in foods and dietary supplements is beta-carotene (β-carotene). The body converts these plant pigments into vitamin A.

There are a number of reviews of the role of vitamin A and its metabolites (eg, 9-cis-retinoic acid) in immunity and in host susceptibility to infection ⁴⁰. Vitamin A is important for normal differentiation of epithelial tissue and for immune cell maturation and function. Thus, vitamin A deficiency is associated with impaired barrier function, altered immune responses and increased susceptibility to a range of infections. Vitamin A-deficient mice show breakdown of the gut barrier and impaired mucus secretion (due to loss of mucus-producing goblet cells), both of which would facilitate entry of pathogens. Many aspects of innate immunity, in addition to barrier function, are modulated by vitamin A and its metabolites. Vitamin A controls neutrophil maturation and in vitamin A deficiency blood neutrophil numbers are increased, but they have impaired phagocytic function. Therefore, the ability of neutrophils to ingest and kill bacteria is impaired. Vitamin A also supports phagocytic activity and oxidative burst of macrophages, so promoting bacterial killing. Natural killer cell activity is diminished by vitamin A deficiency, which would impair antiviral defences. The impact of vitamin A on acquired immunity is less clear and may depend on the exact setting and the vitamin A metabolite involved. Vitamin A controls dendritic cell and CD4+ T lymphocyte maturation and its deficiency alters the balance between T helper 1 and T helper 2 lymphocytes. Studies in experimental model systems indicate that the vitamin A metabolite 9-cis retinoic acid enhances T helper 1 responses. Retinoic acid promotes movement (homing) of T lymphocytes to the gut-associated lymphoid tissue. Interestingly, some gut-associated immune cells are able to synthesise retinoic acid. Retinoic acid is required for CD8+ T lymphocyte survival and proliferation and for normal functioning of B lymphocytes including antibody generation. Thus, vitamin A deficiency can impair the response to vaccination, as discussed elsewhere ⁴¹. In support of this, vitamin A-deficient Indonesian children provided with vitamin A showed a higher antibody response to tetanus vaccination than seen in vitamin A-deficient children ⁴². Vitamin A deficiency predisposes to respiratory infections, diarrhoea and severe measles. Systematic reviews and meta-analyses of trials in children with vitamin A report reduced all-cause mortality ²², reduced incidence, morbidity and mortality from measles ²² and from infant diarrhoea ²² and improved symptoms in acute pneumonia ²³.

You can get recommended amounts of vitamin A by eating a variety of foods, including the following:

• Beef liver and other organ meats (but these foods are also high in cholesterol, so limit the amount you eat).
• Some types of fish, such as salmon.
• Green leafy vegetables and other green, orange, and yellow vegetables, such as broccoli, carrots, and squash.
• Fruits, including cantaloupe, apricots, and mangos.
• Dairy products, which are among the major sources of vitamin A for Americans.
• Fortified breakfast cereals.

Table 4 suggests many dietary sources of vitamin A. The foods from animal sources contain primarily preformed vitamin A, the plant-based foods have provitamin A, and the foods with a mixture of ingredients from animals and plants contain both preformed vitamin A and provitamin A.

Table 6. Selected Food Sources of Vitamin A

Footnote: *DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin A is 5,000 IU for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Beta Carotene

Beta-carotene is a red-orange pigment found in plants and fruits, especially carrots and colorful vegetables. It is the yellow/orange pigment that gives vegetables and fruits their rich colors.

Carotene is an orange photosynthetic pigment important for photosynthesis. It is responsible for the orange color of the carrot and many other fruits and vegetables. It contributes to photosynthesis by transmitting the light energy it absorbs to chlorophyll. Chemically, carotene is a terpene. It is the dimer of retinol (vitamin A) and comes in two primary forms: alpha- and beta-carotene. Gamma-, delta- and epsilon-carotene also exist. Carotene can be stored in the liver and converted to vitamin A as needed.

Beta-carotene in itself is not an essential nutrient, but vitamin A is.

Beta-carotene is a carotenoid that is a precursor of vitamin A and the human body converts beta-carotene into vitamin A (retinol). We need vitamin A for healthy skin and mucus membranes, our immune system, and good eye health and vision.

Beta-carotene, like all carotenoids, is an antioxidant. An antioxidant is a substance that inhibits the oxidation of other molecules; it protects the body from free radicals.

Free radicals damage cells through oxidation. Eventually, the damage caused by free radicals can cause several chronic illnesses.

Several studies have shown that antioxidants through diet help people’s immune systems, protect against free radicals, and lower the risk of developing cancer and heart disease.

Some studies have suggested that those who consume at least four daily servings of beta-carotene rich fruits and/or vegetables have a lower risk of developing cancer or heart disease.

Beta-carotene may also slow down cognitive decline. Men who have been taking beta-carotene supplements for 15 or more years are considerably less likely to experience cognitive decline than other males, researchers from Harvard Medical School reported in Archives of Internal Medicine.

B-group vitamins

There is a recent comprehensive review of B vitamins and immunity ⁴⁴. B vitamins are involved in intestinal immune regulation, thus contributing to gut barrier function. Folic acid (vitamin B9) deficiency in animals causes thymus and spleen atrophy, and decreases circulating T lymphocyte numbers. Spleen lymphocyte proliferation is also reduced but the phagocytic and bactericidal capacity of neutrophils appears unchanged. In contrast, vitamin B12 deficiency decreases phagocytic and bacterial killing capacity of neutrophils, while vitamin B6 deficiency causes thymus and spleen atrophy, low blood T lymphocyte numbers and impaired lymphocyte proliferation and T lymphocyte-mediated immune responses. Vitamins B6 and B12 and folate all support the activity of natural killer cells and CD8+ cytotoxic T lymphocytes, effects which would be important in antiviral defence. Patients with vitamin B12 deficiency had low blood numbers of CD8+ T lymphocytes and low natural killer cell activity ⁴⁵. In a study in healthy older humans ⁴⁶, a vitamin B6-deficient diet for 21 days resulted in a decreased percentage and total number of circulating lymphocytes, and a decrease in T and B lymphocyte proliferation and IL-2 production. Repletion over 21 days using vitamin B6 at levels below those recommended did not return immune function to starting values, while repletion at the recommended intake (22.5 µg/kg body weight per day, which would be 1.575 mg/day in a 70 kg individual) did ⁴⁶. Providing excess vitamin B6 (33.75 µg/kg body weight per day, which would be 2.362 mg/day in a 70 kg individual) for 4 days caused a further increase in lymphocyte proliferation and IL-2 production.

Thiamin (Vitamin B1)

Thiamin (or thiamine) is one of the water-soluble B vitamins. It is also known as vitamin B1. Thiamin is naturally present in some foods, added to some food products, and available as a dietary supplement. This vitamin plays a critical role in energy metabolism and, therefore, in the growth, development, and function of cells ⁴⁷.

Thiamin (also called vitamin B1) helps turn the food you eat into the energy you need. Thiamin is important for the growth, development, and function of the cells in your body.

Table 7. Selected Food Sources of Thiamine (vitamin B1)

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for thiamine is 1.5 mg for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Vitamin B2 (Riboflavin)

Riboflavin also called vitamin B2 is one of the B vitamins, which are all water soluble and it’s important for the growth, development, and function of the cells in your body. It also helps turn the food you eat into the energy you need.

More than 90% of dietary riboflavin is in the form of flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN); the remaining 10% is comprised of the free form and glycosides or esters ⁴⁹, ⁵⁰. Most riboflavin is absorbed in the proximal small intestine ⁵¹. The body absorbs little riboflavin from single doses beyond 27 mg and stores only small amounts of riboflavin in the liver, heart, and kidneys. When excess amounts are consumed, they are either not absorbed or the small amount that is absorbed is excreted in urine ⁵⁰.

Bacteria in the large intestine produce free riboflavin that can be absorbed by the large intestine in amounts that depend on the diet. More riboflavin is produced after ingestion of vegetable-based than meat-based foods ⁴⁹.

Riboflavin is yellow and naturally fluorescent when exposed to ultraviolet light ⁵². Moreover, ultraviolet and visible light can rapidly inactivate riboflavin and its derivatives. Because of this sensitivity, lengthy light therapy to treat jaundice in newborns or skin disorders can lead to riboflavin deficiency. The risk of riboflavin loss from exposure to light is the reason why milk is not typically stored in glass containers ⁵⁰, ⁵³.

Table 8. Selected Food Sources of Riboflavin (vitamin B2)

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for riboflavin is 1.7 mg for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Vitamin B6 (Pyridoxine)

Vitamin B6 includes a group of closely related compounds: pyridoxine, pyridoxal, and pyridoxamine. Substantial proportions of the naturally occurring pyridoxine in fruits, vegetables, and grains exist in glycosylated forms that exhibit reduced bioavailability ⁵⁴. The body needs vitamin B6 for more than 100 enzyme reactions involved in metabolism. They are metabolized in the body to pyridoxal phosphate, which acts as a coenzyme in many important reactions in blood, CNS, and skin metabolism. Vitamin B6 is important in heme and nucleic acid biosynthesis and in lipid, carbohydrate, and amino acid metabolism. Vitamin B6 is also involved in brain development during pregnancy and infancy as well as immune function.

Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism. Both pyridoxal 5’ phosphate and pyridoxamine 5’ phosphate are involved in amino acid metabolism, and pyridoxal 5’ phosphate is also involved in the metabolism of one-carbon units, carbohydrates, and lipids ⁵⁴. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood ⁵⁴. Vitamin B6 is involved in gluconeogenesis and glycogenolysis, immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation ⁵⁴.

The human body absorbs vitamin B6 in the jejunum. Phosphorylated forms of the vitamin are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion ⁵⁵.

Table 9. Selected Food Sources of Vitamin B6 (Pyridoxine)

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin B6 is 2 mg for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin B6 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Vitamin B12 (Cyanocobalamin)

Vitamin B12 is also known as Cyanocobalamin is a nutrient that helps keep the body’s nerve and blood cells healthy and helps make DNA, the genetic material in all cells. Vitamin B12 also helps prevent a type of anemia called megaloblastic anemia that makes people tired and weak.

Vitamin B12 is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and a prescription medication. Vitamin B12 exists in several forms and contains the mineral cobalt ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, so compounds with vitamin B12 activity are collectively called “cobalamins”. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 that are active in human metabolism ⁶⁰.

Two steps are required for the body to absorb vitamin B12 from food.

• First, food-bound vitamin B12 is released in the stomach’s acid environment (hydrochloric acid and and gastric protease in the stomach separate vitamin B12 from the protein to which vitamin B12 is attached in food) and is bound to R protein (haptocorrin) ⁶⁰. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and thus, does not require this separation step.
• Second, pancreatic enzymes cleave this B12 complex (B12-R protein) in the small intestine. After cleavage, intrinsic factor (a protein made by the stomach), secreted by parietal cells in the gastric mucosa, binds with the free vitamin B12. Intrinsic factor is required for absorption of vitamin B12, which takes place in the terminal ileum ⁶⁰, ⁶¹. Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12) ⁶². Some people have pernicious anemia, a condition where they cannot make intrinsic factor. As a result, they have trouble absorbing vitamin B12 from all foods and dietary supplements.

Several food sources of vitamin B12 are listed in Table 10.

Table 10. Selected Food Sources of Vitamin B12

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers determine the level of various nutrients in a standard serving of food in relation to their approximate requirement for it. The DV for vitamin B12 is 6.0 mcg. However, the FDA does not require food labels to list vitamin B12 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Folate (Vitamin B9)

Folate is also known vitamin B9 (Folacin, Folic Acid, Pteroylglutamic acid) that is naturally present in many foods. Folic Acid is a form of folate that is manufactured and used in dietary supplements and fortified foods ⁶³. Everyone needs folic acid. Our bodies need folate to make DNA and other genetic material. Folate is also needed for the body’s cells to divide.

Folic acid and folate also help your body make healthy new red blood cells. Red blood cells carry oxygen to all the parts of your body. If your body does not make enough red blood cells, you can develop anemia. Anemia happens when your blood cannot carry enough oxygen to your body, which makes you pale, tired, or weak. Also, if you do not get enough folic acid, you could develop a type of anemia called folate-deficiency anemia ⁶⁴.

Folate-deficiency anemia is most common during pregnancy. Other causes of folate-deficiency anemia include alcoholism and certain medicines to treat seizures, anxiety, or arthritis.

In women and pregnant mothers, folic acid is very important because it can help prevent some major birth defects of the baby’s brain and spine (anencephaly and spina bifida) ⁶⁵.

Every woman needs folic acid every day, whether she’s planning to get pregnant or not, for the healthy new cells the body makes daily. Think about the skin, hair, and nails. These – and other parts of the body – make new cells each day.

Centers for Disease Control and Prevention (CDC) urges women to take 400 mcg of folic acid every day, starting at least one month before getting pregnant and while she is pregnant, to help prevent major birth defects of the baby’s brain and spine.

Folate is naturally present in many foods and food companies add folic acid to other foods, including bread, cereal, and pasta. You can get recommended amounts by eating a variety of foods, including the following:

• Leafy Green Vegetables (especially asparagus, Brussels sprouts, and dark green leafy vegetables such as spinach and mustard greens).
• Fruits and fruit juices (especially oranges and orange juice).
• Nuts, beans, and peas (such as peanuts, black-eyed peas, and kidney beans).
• Grains (including whole grains; fortified cold cereals; enriched flour products such as bread, bagels, cornmeal, and pasta; and rice).
• Folic acid is added to many grain-based products, enriched breads, cereals and corn masa flour (used to make corn tortillas and tamales, for example). To find out whether folic acid has been added to a food, check the product label.

Beef liver is high in folate but is also high in cholesterol, so limit the amount you eat. Only small amounts of folate are found in other animal foods like meats, poultry, seafood, eggs, and dairy products.

Table 11. Selected Food Sources of Folate and Folic Acid

Footnote: * DV = Daily Value. The FDA developed DVs to help consumers compare the nutrient contents of products within the context of a total diet. The DV for folate is 400 mcg for adults and children aged 4 and older. However, the FDA does not require food labels to list folate content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

† Fortified with folic acid as part of the folate fortification program.

Vitamin C

Vitamin C also known as ascorbic acid or ascorbate, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Vitamin C is synthesized from D-glucose or D-galactose by many plants and animals. However, humans lack the enzyme L-gulonolactone oxidase required for ascorbic acid synthesis and must obtain vitamin C through food or supplements ⁶⁶, ⁶⁷. Vitamin C is found in many fruits and vegetables, including citrus fruits, tomatoes, potatoes, red and green peppers, kiwifruit, broccoli, strawberries, brussels sprouts, and cantaloupe. In the body, vitamin C acts as an antioxidant, helping to protect cells from the damage caused by free radicals. Free radicals are compounds formed when our bodies convert the food we eat into energy. People are also exposed to free radicals in the environment from cigarette smoke, air pollution, and ultraviolet light from the sun.

The Recommended Dietary Allowance (RDA; average daily level of intake sufficient to meet the nutrient requirement of 97–98% healthy individuals) for vitamin C ranges from 15 to 115 mg for infants and children (depending on age) and from 75 to 120 mg for nonsmoking adults; people who smoke need 35 mg more per day ⁶⁸. The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter ⁶⁹. Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.

Vitamin C plays a role in collagen, carnitine, hormone, and amino acid formation. It is essential for wound healing and facilitates recovery from burns. Vitamin C is also an antioxidant, supports immune function, and facilitates the absorption of iron ⁷⁰. Vitamin C also plays an important role in both innate and adaptive immunity, probably because of its antioxidant effects, antimicrobial and antiviral actions, and effects on immune system modulators ⁷¹. Vitamin C helps maintain epithelial integrity, enhance the differentiation and proliferation of B cells and T cells, enhance phagocytosis, normalize cytokine production, and decrease histamine levels ⁷². Vitamin C might also inhibit viral replication ⁷³.

Vitamin C deficiency impairs immune function and increases susceptibility to infections ⁷². Some research suggests that supplemental vitamin C enhances immune function ⁷⁴, but its effects might vary depending on an individual’s vitamin C status ⁷⁵.

Vitamin C deficiency is uncommon in the United States, affecting only about 7% of individuals aged 6 years and older ⁷⁶. People who smoke and those whose diets include a limited variety of foods (such as some older adults and people with alcohol or drug use disorders) are more likely than others to obtain insufficient amounts of vitamin C ⁷⁴.

High-Dose vitamin C, when taken by intravenous (IV) infusion, vitamin C can reach much higher levels in the blood than when it is taken by mouth. Studies suggest that these higher levels of vitamin C may cause the death of cancer cells in the laboratory. Surveys of healthcare practitioners at United States complementary and alternative medicine conferences in recent years have shown that high-dose IV vitamin C is frequently given to patients as a treatment for infections, fatigue, and cancers, including breast cancer ⁷⁷.

There are reviews of the role of vitamin C in immunity and in host susceptibility to infection ⁷⁸. Vitamin C is required for collagen biosynthesis and is vital for maintaining epithelial integrity. Vitamin C also has roles in several aspects of immunity, including leucocyte migration to sites of infection, phagocytosis and bacterial killing, natural killer cell activity, T lymphocyte function (especially of CD8+ cytotoxic T lymphocytes) and antibody production. Jacob et al ⁷⁹ showed that a vitamin C-deficient diet in healthy young adult humans decreased mononuclear cell vitamin C content by 50% and decreased the T lymphocyte-mediated immune responses to recall antigens. Vitamin C deficiency in animal models increases susceptibility to a variety of infections ⁷⁸. People deficient in vitamin C are susceptible to severe respiratory infections such as pneumonia. A meta-analysis ²⁴ reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with low dietary intakes. Vitamin C supplementation has also been shown to decrease the duration and severity of upper respiratory tract infections, such as the common cold, especially in people under enhanced physical stress ²⁵.

Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism ⁶⁷, ⁸⁰. Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant ⁸¹ and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E) ⁸². Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function ⁸² and improves the absorption of nonheme iron ⁸³, the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility ⁶⁷, ⁸⁰, ⁸², ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷.

Table 12. Selected Food Sources of Vitamin C

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin C is 60 mg for adults and children aged 4 and older. The FDA requires all food labels to list the percent DV for vitamin C. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Vitamin D

Vitamin D is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation ⁸⁸. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol ⁸⁹.

Vitamin D is a nutrient found in some foods that is needed for health and to maintain strong bones. It does so by helping the body absorb calcium (one of bone’s main building blocks) from food and supplements. People who get too little vitamin D may develop soft, thin, and brittle bones, a condition known as rickets in children and osteomalacia in adults.

Vitamin D is important to the body in many other ways as well. Muscles need it to move, for example, nerves need it to carry messages between the brain and every body part, and the immune system needs vitamin D to fight off invading bacteria and viruses. Together with calcium, vitamin D also helps protect older adults from osteoporosis. Vitamin D is found in cells throughout the body.

Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts ⁸⁹, ⁹⁰. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults ⁸⁹. Together with calcium, vitamin D also helps protect older adults from osteoporosis.

Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation ⁸⁹, ⁹¹, ⁹². Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D ⁸⁹. Many cells have vitamin D receptors, and some convert 25(OH)D to 1,25(OH)2D.

There are a number of reviews of the role of vitamin D and its metabolites in immunity and in host susceptibility to infection ⁹³. The active form of vitamin D (1,25-dihydroxyvitamin D3) is referred to here as vitamin D. Vitamin D receptors have been identified in most immune cells and some cells of the immune system can synthesise the active form of vitamin D from its precursor, suggesting that vitamin D is likely to have important immunoregulatory properties. Vitamin D enhances epithelial integrity and induces antimicrobial peptide (eg, cathelicidin) synthesis in epithelial cells and macrophages, directly enhancing host defence ⁹⁴. However, the effects of vitamin D on the cellular components of immunity are rather complex. Vitamin D promotes differentiation of monocytes to macrophages and increases phagocytosis, superoxide production and bacterial killing by innate immune cells. It also promotes antigen processing by dendritic cells although antigen presentation may be impaired. Vitamin D is also reported to inhibit T-cell proliferation and production of cytokines by T helper 1 lymphocytes and of antibodies by B lymphocytes, highlighting the paradoxical nature of its effects. Effects on T helper 2 responses are not clear and vitamin D seems to increase number of regulatory T lymphocytes. Vitamin D seems to have little impact on CD8+ T lymphocytes. A systematic review and meta-analysis of the influence of vitamin D status on influenza vaccination (nine studies involving 2367 individuals) found lower seroprotection rates to influenza A virus subtype H3N2 and to influenza B virus in those who were vitamin D deficient ⁹⁵. Berry et al ⁹⁶ described an inverse linear relationship between vitamin D levels and respiratory tract infections in a cross-sectional study of 6789 British adults. In agreement with this, data from the US Third National Health and Nutrition Examination Survey which included 18 883 adults showed an independent inverse association between serum 25(OH)-vitamin D and recent upper respiratory tract infection ⁹⁷. Other studies also report that individuals with low vitamin D status have a higher risk of viral respiratory tract infections ⁹⁸. Supplementation of Japanese schoolchildren with vitamin D for 4 months during winter decreased the risk of influenza by about 40% ⁹⁹. Meta-analyses have concluded that vitamin D supplementation can reduce the risk of respiratory tract infections ²⁹, ²⁸.

Table 13. Selected Food Sources of Vitamin D

Footnotes: * IUs = International Units. ** DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents among products within the context of a total daily diet. The DV for vitamin D is currently set at 400 IU for adults and children age 4 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Vitamin E

Naturally occurring vitamin E exists in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) that have varying levels of biological activity ¹⁰⁰. Alpha- (or α-) tocopherol is the only form that is recognized to meet human requirements, but beta-, gamma-, and delta-tocopherols, 4 tocotrienols, and several stereoisomers may also have important biologic activity. These compounds act as antioxidants, which prevent lipid peroxidation of polyunsaturated fatty acids in cellular membranes ¹⁰¹.

Serum concentrations of vitamin E (alpha-tocopherol) depend on the liver, which takes up the nutrient after the various forms are absorbed from the small intestine.

Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

Antioxidants protect cells from the damaging effects of free radicals, which are molecules that contain an unshared electron. Free radicals damage cells and might contribute to the development of cardiovascular disease and cancer ¹⁰². Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species. The body forms reactive oxygen species endogenously when it converts food to energy, and antioxidants might protect cells from the damaging effects of reactive oxygen species. The body is also exposed to free radicals from environmental exposures, such as cigarette smoke, air pollution, and ultraviolet radiation from the sun. Reactive oxygen species are part of signaling mechanisms among cells.

The body also needs vitamin E to boost its immune system so that it can fight off invading bacteria and viruses. It helps to widen blood vessels and keep blood from clotting within them.

In addition to its activities as an antioxidant, vitamin E is involved in immune function and, as shown primarily by in vitro studies of cells, cell signaling, regulation of gene expression, and other metabolic processes ¹⁰⁰. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes ¹⁰³. Vitamin-E–replete endothelial cells lining the interior surface of blood vessels are better able to resist blood-cell components adhering to this surface. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasing the release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits platelet aggregation ¹⁰³.

There are a number of reviews of the role of vitamin E in immunity and host susceptibility to infection ¹⁰⁴. In laboratory animals, vitamin E deficiency decreases lymphocyte proliferation, natural killer cell activity, specific antibody production following vaccination and phagocytosis by neutrophils. Vitamin E deficiency also increases susceptibility of animals to infectious pathogens. Vitamin E supplementation of the diet of laboratory animals enhances antibody production, lymphocyte proliferation, T helper 1-type cytokine production, natural killer cell activity and macrophage phagocytosis. Vitamin E promotes interaction between dendritic cells and CD4+ T lymphocytes. There is a positive association between plasma vitamin E and cell-mediated immune responses, and a negative association has been demonstrated between plasma vitamin E and the risk of infections in healthy adults over 60 years of age ¹⁰⁵. There appears to be particular benefit of vitamin E supplementation for the elderly ¹⁰⁶. Studies by Meydani et al ¹⁰⁷ demonstrated that vitamin E supplementation at high doses, one study used 800 mg/day ¹⁰⁸ and the other used doses of 60, 200 and 800 mg/day ¹⁰⁷ enhanced T helper 1 cell-mediated immunity (lymphocyte proliferation, IL-2 production) and improved vaccination responses, including to hepatitis B virus. Supplementation of older adults with vitamin E (200 mg/day) improved neutrophil chemotaxis and phagocytosis, natural killer cell activity and mitogen-induced lymphocyte proliferation ¹⁰⁶. Secondary analysis of data from the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study identified that daily vitamin E supplements for 5 to 8 years reduced the incidence of hospital treated, community-acquired pneumonia in smokers ¹⁰⁹. One study reported that vitamin E supplementation (200 IU/day~135 mg/day) for 1 year decreased risk of upper respiratory tract infections in the elderly ¹¹⁰, but another study did not see an effect of supplemental vitamin E (200 mg/day) on the incidence, duration or severity of respiratory infections in an elderly population ¹¹¹.

Table 14. Selected Food Sources of Vitamin E (Alpha-Tocopherol)

Footnote: *DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient content of different foods within the context of a total diet. The DV for vitamin E is 30 IU (approximately 20 mg of natural alpha-tocopherol) for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin E content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Iron

Iron is a mineral that our bodies need for many functions. In the human body, iron is present in all cells and has several vital functions — as a carrier of oxygen to the tissues from the lungs in the form of hemoglobin (Hb), as a facilitator of oxygen use and storage in the muscles as myoglobin, as a transport medium for electrons within the cells in the form of cytochromes, and as an integral part of enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and mortality ¹¹², ¹¹³.

In adults, the recommended dietary allowance of iron is 8 to 11 mg per day for men and 8 to 18 mg for women in whom higher levels are recommended during pregnancy (27 mg per day) ¹¹⁴. Iron is poorly absorbed and body and tissue iron stores are controlled largely by modifying rates of absorption. Adequate amounts of iron are found in most Western diets, with highest levels found in red meats and moderate levels in fish, poultry, green vegetables, cereals and grains (some of which are fortified with iron).

Your body needs the right amount of iron. If you have too little iron, you may develop iron deficiency anemia. Iron deficiency is usually due to loss of iron, predominantly as a result of blood loss in the gastrointestinal tract or from menstruation and is rarely due to deficiency in intake or an inability to absorb enough iron from foods. People at higher risk of having too little iron are young children and women who are pregnant or have periods.

There are a number of reviews of the role of iron in immunity and host susceptibility to infection ¹¹⁵. Iron deficiency induces thymus atrophy, reducing output of naive T lymphocytes, and has multiple effects on immune function in humans. The effects are wide ranging and include impairment of respiratory burst and bacterial killing, natural killer cell activity, T lymphocyte proliferation and production of T helper 1 cytokines. T lymphocyte proliferation was lower by 50% to 60% in iron-deficient than in iron-replete housebound older Canadian women ¹¹⁶. These observations would suggest a clear case for iron deficiency increasing susceptibility to infection. However, the relationship between iron deficiency and susceptibility to infection remains complex ¹¹⁷. Evidence suggests that infections caused by organisms that spend part of their life-cycle intracellularly, such as plasmodia and mycobacteria, may actually be enhanced by iron. In the tropics, in children of all ages, iron at doses above a particular threshold has been associated with increased risk of malaria and other infections, including pneumonia. Thus, iron intervention in malaria-endemic areas is not advised, particularly high doses in the young, those with compromised immunity and during the peak malaria transmission season. There are different explanations for the detrimental effects of iron administration on infections. First, iron overload causes impairment of immune function ¹¹⁸. Second, excess iron favors damaging inflammation. Third, micro-organisms require iron and providing it may favor the growth of the pathogen. Perhaps for the latter reasons several host immune mechanisms have developed for withholding iron from a pathogen ¹¹⁵. In a recent study giving iron (50 mg on each of 4 days a week) to iron-deficient school children in South Africa increased the risk of respiratory infections ¹¹⁹; coadministration of omega-3 fatty acids (500 mg on each of 4 days a week) mitigated the effect of iron. Meta-analysis of studies in Chinese children showed that those with recurrent respiratory tract infection were more likely to have low hair iron ³⁰.

What foods provide iron?

Iron is found naturally in many foods and is added to some fortified food products. You can get recommended amounts of iron by eating a variety of foods, including the following:

• Lean meat, seafood, and poultry.
• Iron-fortified breakfast cereals and breads.
• White beans, lentils, spinach, kidney beans, and peas.
• Nuts and some dried fruits, such as raisins.

Iron in food comes in two forms: heme iron and nonheme iron. Nonheme iron is found in plant foods and iron-fortified food products. Meat, seafood, and poultry have both heme and nonheme iron.

Heme iron has higher bioavailability than nonheme iron, and other dietary components have less effect on the bioavailability of heme than nonheme iron ¹²⁰. The bioavailability of iron is approximately 14% to 18% from mixed diets that include substantial amounts of meat, seafood, and vitamin C (ascorbic acid, which enhances the bioavailability of nonheme iron) and 5% to 12% from vegetarian diets ¹²¹. In addition to ascorbic acid, meat, poultry, and seafood can enhance nonheme iron absorption, whereas phytate (present in grains and beans) and certain polyphenols in some non-animal foods (such as cereals and legumes) have the opposite effect ¹²². Unlike other inhibitors of iron absorption, calcium might reduce the bioavailability of both nonheme and heme iron. However, the effects of enhancers and inhibitors of iron absorption are attenuated by a typical mixed western diet, so they have little effect on most people’s iron status.

Several food sources of iron are listed in Table 15. Some plant-based foods that are good sources of iron, such as spinach, have low iron bioavailability because they contain iron-absorption inhibitors, such as polyphenols ¹²³.

Your body absorbs iron from plant sources better when you eat it with meat, poultry, seafood, and foods that contain vitamin C, like citrus fruits, strawberries, sweet peppers, tomatoes, and broccoli.

Table 15. Selected Food Sources of Iron

Footnote: * DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for iron is 18 mg for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Copper

Copper is an essential mineral that you need to stay healthy. Your body uses copper to carry out many important functions, including making energy, connective tissues, and blood vessels. Copper also helps maintain the nervous, pigmentation, and immune systems, and activates genes. Your body also needs copper for brain development ¹²⁴. In addition, defense against oxidative damage depends mainly on the copper-containing superoxide dismutases ¹²⁵. Copper is a cofactor for several enzymes known as “cuproenzymes” involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis ¹²⁴. One abundant cuproenzyme is ceruloplasmin, which plays a role in iron metabolism and carries more than 95% of the total copper in healthy human plasma ¹²⁶.

There are a number of reviews of the role of copper in immunity and host susceptibility to infection ¹²⁷. Copper itself has antimicrobial properties. Copper supports neutrophil, monocyte and macrophage function and natural killer cell activity. It promotes T lymphocyte responses such as proliferation and IL-2 production. Copper deficiency in animals impairs a range of immune functions and increases susceptibility to bacterial and parasitic challenges. Human studies show that subjects on a low copper diet have decreased lymphocyte proliferation and IL-2 production, with copper administration reversing these effects ¹²⁸. Children with Menke’s syndrome, a rare congenital disease with complete absence of the circulating copper-carrying protein caeruloplasmin, show immune impairments and have increased bacterial infections, diarrhea and pneumonia ¹²⁹. Meta-analysis of studies in Chinese children showed that those with recurrent respiratory tract infection were more likely to have low hair copper ³⁰.

A wide variety of plant and animal foods contain copper, and the average human diet provides approximately 1,400 mcg/day for men and 1,100 mcg/day for women that is primarily absorbed in the upper small intestine ¹³⁰. Almost two-thirds of the body’s copper is located in the skeleton and muscle ¹²⁴.

Only small amounts of copper are typically stored in the body, and the average adult has a total body content of 50–120 mg copper ¹²⁴. Most copper is excreted in bile, and a small amount is excreted in urine. Total fecal losses of copper of biliary origin and nonabsorbed dietary copper are about 1 mg/day ¹²⁴. Copper levels in the body are homeostatically maintained by copper absorption from the intestine and copper release by the liver into bile to provide protection from copper deficiency and toxicity ¹³¹.

Copper status is not routinely assessed in clinical practice, and no biomarkers that accurately and reliably assess copper status have been identified ¹³². Human studies typically measure copper and cuproenzyme activity in plasma and blood cells because individuals with known copper deficiency often have low blood levels of copper and ceruloplasmin ¹³². However, plasma ceruloplasmin and copper levels can be influenced by other factors, such as estrogen status, pregnancy, infection, inflammation, and some cancers ¹³². Normal serum concentrations are 10–25 mcmol/L (63.5–158.9 mcg/dL) for copper and 180–400 mg/L for ceruloplasmin ¹³³.

The amount of copper you need each day depends on your age. Typical diets in the United States meet or exceed the copper recommended dietary allowance (RDA), which is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals. Mean dietary intakes of copper from foods range from 800 to 1,000 mcg per day for children aged 2–19 ¹³⁴. In adults aged 20 and older, average daily intakes of copper from food are 1,400 mcg for men and 1,100 mcg for women. Total intakes from supplements and foods are 900 to 1,100 mcg/day for children and 1,400 to 1,700 mcg/day for adults aged 20 and over.

Copper deficiency is uncommon in humans ¹³². Based on studies in animals and humans, the effects of copper deficiency include anemia, hypopigmentation, hypercholesterolemia, connective tissue disorders, osteoporosis and other bone defects, abnormal lipid metabolism, ataxia, and increased risk of infection ¹³⁵.

Copper is available in dietary supplements containing only copper, in supplements containing copper in combination with other ingredients, and in many multivitamin/multimineral products ¹³⁶. These supplements contain many different forms of copper, including cupric oxide, cupric sulfate, copper amino acid chelates, and copper gluconate. To date, no studies have compared the bioavailability of copper from these and other forms ¹³⁷. The amount of copper in dietary supplements typically ranges from a few micrograms to 15 mg (about 17 times the daily value [DV] for copper) ¹³⁶.

Table 16. Selected Food Sources of Copper

Footnote: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for copper is 0.9 mg (900 mcg) for adults and children age 4 years and older [13]. The FDA does not require food labels to list copper content unless copper has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Selenium

Selenium is a trace element that is naturally present in many foods, added to others, and available as a dietary supplement. Selenium, which is nutritionally essential for humans, is a constituent of more than two dozen selenoproteins that play critical roles in reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection ¹³⁸.

Selenium exists in two forms:

• inorganic (selenate and selenite) and
• organic (selenomethionine and selenocysteine) ¹³⁹.

Both forms can be good dietary sources of selenium ¹⁴⁰. Soils contain inorganic selenites and selenates that plants accumulate and convert to organic forms, mostly selenocysteine and selenomethionine and their methylated derivatives.

Selenium is found naturally in many foods. The amount of selenium in plant foods depends on the amount of selenium in the soil where they were grown. The amount of selenium in animal products depends on the selenium content of the foods that the animals ate. You can get recommended amounts of selenium by eating a variety of foods, including the following:

• Seafood
• Meat, poultry, eggs, and dairy products
• Breads, cereals, and other grain products.

Selenium is important for reproduction, thyroid gland function, DNA production, and protecting the body from damage caused by free radicals and from infection ¹⁴¹, ¹⁴². Selenium is incorporated into selenoproteins that have a wide range of pleiotropic effects, ranging from antioxidant and anti-inflammatory effects to the production of active thyroid hormone ¹⁴³. In the past 10 years, the discovery of disease-associated polymorphisms in selenoprotein genes has drawn attention to the relevance of selenoproteins to health. Low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline. Higher selenium status or selenium supplementation has antiviral effects, is essential for successful male and female reproduction, and reduces the risk of autoimmune thyroid disease. Prospective studies have generally shown some benefit of higher selenium status on the risk of prostate, lung, colorectal, and bladder cancers, but findings from trials have been mixed, which probably emphasises the fact that supplementation will confer benefit only if intake of a nutrient is inadequate. Supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes. The crucial factor that needs to be emphasised with regard to the health effects of selenium is the inextricable U-shaped link with status; whereas additional selenium intake may benefit people with low status, those with adequate-to-high status might be affected adversely and should not take selenium supplements.

There are a number of reviews of the role of selenium in immunity and host susceptibility to infection ¹⁴⁴. Selenium deficiency in laboratory animals adversely affects several components of both innate and acquired immunity, including T and B lymphocyte function including antibody production and increases susceptibility to infections. Lower selenium concentrations in humans have been linked with diminished natural killer cell activity and increased mycobacterial disease. Selenium deficiency was shown to permit mutations of coxsackievirus, polio virus and murine influenza virus increasing virulence ¹⁴⁵. These latter observations suggest that poor selenium status could result in the emergence of more pathogenic strains of virus, thereby increasing the risks and burdens associated with viral infection. Selenium supplementation (100 to 300 µg/day depending on the study) has been shown to improve various aspects of immune function in humans ¹⁴⁶, including in the elderly ¹⁴⁷. Selenium supplementation (50 or 100 µg/day) in adults in the UK with low selenium status improved some aspects of their immune response to a poliovirus vaccine ¹⁴⁸.

Table 17. Selected Food Sources of Selenium

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for selenium is 70 mcg for adults and children aged 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient. The U.S. Department of Agriculture’s (USDA’s) Nutrient Database Web site ¹⁴⁹ lists the nutrient content of many foods and provides a comprehensive list of foods containing selenium arranged by nutrient content and by food name.

Zinc

Zinc is involved in numerous aspects of cellular metabolism. It is required for the catalytic activity of approximately 100 enzymes, including many nicotinamide adenine dinucleotide (NADH) dehydrogenases, RNA and DNA polymerases, and DNA transcription factors as well as alkaline phosphatase, superoxide dismutase, and carbonic anhydrase ¹⁵⁰, ¹⁵¹ and it plays a role in immune function ¹⁵², ¹⁵³, protein synthesis ¹⁵³, wound healing ¹⁵⁴, DNA synthesis ¹⁵¹, ¹⁵³ and cell division ¹⁵³. Zinc also supports normal growth and development during pregnancy, childhood, and adolescence ¹⁵⁵, ¹⁵⁶, ¹⁵⁷ and is required for proper sense of taste and smell ¹⁵⁸. A daily intake of zinc is required to maintain a steady state because the body has no specialized zinc storage system ¹⁵⁹.

Most Americans get enough zinc from the foods they eat.

There are a number of reviews of the role of zinc in immunity and host susceptibility to infection ¹⁶⁰. Of note, Read et al ¹⁶¹ have recently provided a very insightful evaluation of the role of zinc in antiviral immunity. Zinc inhibits the RNA polymerase required by RNA viruses, like coronaviruses, to replicate ¹⁶², suggesting that zinc may play a key role in host defence against RNA viruses. In vitro replication of influenza virus was inhibited by the zinc ionophore pyrrolidine dithiocarbamate ¹⁶³ and there are indications that zinc might inhibit replication of SARS-associated coronavirus (SARS-CoV) in vitro ¹⁶⁴. In addition, as discussed by Read et al ¹⁶¹, the zinc-binding metallothioneins seem to play an important role in antiviral defence ¹⁶⁵. Zinc deficiency has a marked impact on bone marrow, decreasing the number immune precursor cells, with reduced output of naive B lymphocytes and causes thymic atrophy, reducing output of naive T lymphocytes. Therefore, zinc is important in maintaining T and B lymphocyte numbers. Zinc deficiency impairs many aspects of innate immunity, including phagocytosis, respiratory burst and natural killer cell activity. Zinc also supports the release of neutrophil extracellular traps that capture microbes ¹⁶⁶. There are also marked effects of zinc deficiency on acquired immunity. Circulating CD4+ T lymphocyte numbers and function (eg, IL-2 and IFN-γ production) are decreased and there is a disturbance in favour of T helper 2 cells. Likewise, B lymphocyte numbers and antibody production are decreased in zinc deficiency. Zinc supports proliferation of CD8+ cytotoxic T lymphocytes, key cells in antiviral defence. Many of the in vitro immune effects of zinc are prevented by zinc chelation ¹⁶⁷. Moderate or mild zinc deficiency or experimental zinc deficiency in humans result in decreased natural killer cell activity, T lymphocyte proliferation, IL-2 production and cell-mediated immune responses which can all be corrected by zinc repletion ¹⁶⁸. In patients with zinc deficiency related to sickle cell disease, natural killer cell activity is decreased, but can be returned to normal by zinc supplementation ¹⁶⁹. Patients with the zinc malabsorption syndrome acrodermatitis enteropathica display severe immune impairments ¹⁷⁰ and increased susceptibility to bacterial, viral and fungal infections. Zinc supplementation (30 mg/day) increased T lymphocyte proliferation in elderly care home residents in the USA, an effect mainly due to an increase in numbers of T lymphocytes ¹⁷¹. The wide ranging impact of zinc deficiency on immune components is an important contributor to the increased susceptibility to infections, especially lower respiratory tract infection and diarrhoea, seen in zinc deficiency. Correcting zinc deficiency lowers the likelihood of diarrhea and of respiratory and skin infections, although some studies fail to show benefit of zinc supplementation in respiratory disease ¹⁷². Meta-analysis of studies in Chinese children showed that those with recurrent respiratory tract infection were more likely to have low hair zinc ³⁰. Recent systematic reviews and meta-analyses of trials with zinc report shorter duration of common cold in adults ³¹, reduced incidence and prevalence of pneumonia in children ³³ and reduced mortality when given to adults with severe pneumonia ³⁴.

Table 18. Selected Food Sources of Zinc

Footnote: * DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents of products within the context of a total diet. The DV for zinc is 15 mg for adults and children age 4 and older. Food labels, however, are not required to list zinc content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Magnesium

Magnesium (Mg) is an abundant mineral in your body that your body needs to stay healthy and is naturally present in many foods, added to other food products, available as a dietary supplement, and present in some medicines (such as antacids and laxatives) ¹⁷³. Magnesium is important for many processes in your body, including regulating muscle and nerve function, energy production, blood sugar levels, and blood pressure and making protein, bone, and DNA. Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation ¹⁷⁴, ¹⁷⁵, ¹⁷⁶, ¹⁷⁷, ¹⁷⁸. Low magnesium levels (hypomagnesemia) don’t cause symptoms in the short term. However, chronically low magnesium levels can increase your risk of high blood pressure, heart disease, type 2 diabetes and osteoporosis ¹⁷⁹.

Magnesium is required for energy production, oxidative phosphorylation, and glycolysis ¹⁸⁰. It contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm ¹⁷⁶. Many people don’t get enough magnesium in their diets. However, before you reach for a supplement, though, you should know that just a few servings of magnesium-rich foods a day can meet your need for this important nutrient.

An adult body contains approximately 25 g magnesium, with 50% to 60% present in the bones and most of the rest in soft tissues ¹⁸¹. Less than 1% of total magnesium is in blood serum, and these levels are kept under tight control through its absorption, reservoir, and excretion process by various organs such as the gut, bone, and kidney ¹⁸². Besides these organs, several hormones, namely vitamin D, parathyroid hormone, and estrogen, are involved in the regulation of normal level of magnesium ¹⁸³. Normal serum magnesium concentrations range between 0.75 and 0.95 millimoles (mmol)/L ¹⁷⁴, ¹⁸⁴. Hypomagnesemia is defined as a serum magnesium level less than 0.75 mmol/L ¹⁸⁵. Magnesium homeostasis is largely controlled by the kidney, which typically excretes about 120 mg magnesium into the urine each day ¹⁷⁵. Urinary excretion is reduced when magnesium status is low ¹⁷⁴. Hypomagnesemia is characterized by tetany (involuntary contraction of muscles), convulsion (seizures), and cardiac arrhythmia ¹⁸⁶. Clinical and preclinical studies revealed that the magnesium level is found to be low in various pathological conditions such as migraine, diabetes, osteoporosis, asthma, preeclampsia, cardiovascular diseases and its correction is an important treatment strategy for these conditions ¹⁸⁷, ¹⁸⁸, ¹⁸⁹, ¹⁹⁰, ¹⁹¹.

The diets of many people in the United States provide less than the recommended amounts of magnesium. Men older than 70 and teenage girls and boys are most likely to have low intakes of magnesium. When the amount of magnesium people get from food and dietary supplements is combined, however, total intakes of magnesium are generally above recommended amounts.

Assessing magnesium status is difficult because most magnesium is inside cells or in bone ¹⁷⁶. The most commonly used and readily available method for assessing magnesium status is measurement of serum magnesium concentration, even though serum levels have little correlation with total body magnesium levels or concentrations in specific tissues ¹⁸⁵. Other methods for assessing magnesium status include measuring magnesium concentrations in erythrocytes, saliva, and urine; measuring ionized magnesium concentrations in blood, plasma, or serum; and conducting a magnesium-loading (or “tolerance”) test. No single method is considered satisfactory ¹⁹². Some experts ¹⁸¹ but not others ¹⁷⁶ consider the tolerance test (in which urinary magnesium is measured after parenteral infusion of a dose of magnesium) to be the best method to assess magnesium status in adults. To comprehensively evaluate magnesium status, both laboratory tests and a clinical assessment might be required ¹⁸⁵.

Magnesium is important in acquired immunity via regulating lymphocyte growth ¹⁹³. An in vitro study (test tube study) carried out in chicken B cell line DT40 revealed that the removal of magnesium channel, TRPM7, results in cell death and can be partially corrected by magnesium supplementation ¹⁹⁴. Mutation in a magnesium transporter, MagT1, is reported in patients with X-linked immunodeficiency diseases, Epstein–Barr virus infection, and neoplasia ¹⁹⁵. Low CD4+ T cells and defective activation of T-lymphocytes are due to the decreased magnesium influx, which fails to activate PLCγ1 ¹⁹⁶. The importance of magnesium for CD4+ activation is also evident from reported studies conducted in asthma patients ¹⁹⁷. However, further studies are essential to conclude the effect of magnesium on T cell signaling.

Magnesium has an important role in synthesizing and releasing immune cells and other associated processes like cell adhesion and phagocytosis ¹⁹⁸. Magnesium acts as a natural calcium antagonist, the molecular basis for inflammatory response could be the result of modulation of intracellular calcium concentration ¹⁹⁹. Besides, magnesium acts as a cofactor for the synthesis of immunoglobulin, CI 3 convertase, antibody-dependent cytolysis, macrophage responses to lymphocyte, IgM lymphocyte binding, T helper B cell adherence, substance P binding with lymphoblast, and binding of antigen to macrophage ²⁰⁰, ²⁰¹. Magnesium deficiency affects various immune functions like the decline in NK cell level, monocytes and T cell ratio, increased oxidative stress after strenuous exercise, and elevated cytokine IL-6 level and inflammatory events. Deficiency of magnesium may be prone to recurrent bacterial and fungal infection ²⁰². Many studies have demonstrated that in humans, a moderate or subclinical magnesium deficiency can induce chronic low-grade inflammation or exacerbate inflammatory stress caused by other factors ²⁰³. This low-grade inflammation increases the secretion of pro-inflammatory cytokines, which stimulate the resorption of bone by the induction of the differentiation of osteoclasts from their precursors ²⁰⁴. The ability of magnesium to decrease the inflammatory response and oxidative stress, as well as improving lung inflammation, possibly by inhibiting IL-6 pathway, NF-κB pathway, and L-type calcium channels ²⁰⁵, has raised the hypothesis of a possible magnesium supplementation in the prevention and treatment of COVID-19 patients, as suggested in the recent papers by Tang et al ²⁰⁶ and Iotti ²⁰⁷. Based Tang et al ²⁰⁸ basic and clinical research study, it is evident that magnesium effectively treats respiratory diseases like asthma and pneumonia because of its anti-inflammatory, antioxidant, and smooth muscle relaxant properties. A substantial decrease in the need for oxygen or intensive treatment assistance is reported in elderly COVID-19 patients upon the intake of vitamin D, magnesium, and vitamin B12 in combination ²⁰⁹. Iran’s clinical trial registry ²¹⁰ confirmed that magnesium sulphate inhalation is effective in improving respiratory symptoms such as shortness of breath, cough and oxygen saturation in COVID-19 patients.

Magnesium deficient animal model exhibits inflammation as the first noticeable change with elevated levels of pro-inflammatory mediators like TNFα with declined anti-inflammatory cytokine levels ²¹¹, ²⁰¹. The activation of immune cells like monocyte, macrophages, and polymorphonuclear cells are involved in the release of inflammatory mediators like cytokine, free radical and eicosanoids ²⁰¹. Administration of magnesium reduces leukocyte activation and oxidative damage to peripheral blood lymphocyte DNA in athletes and sedentary young men ¹⁹. Thus, magnesium is an important factor for optimum immune cell functioning by regulating the proliferation and function of lymphocytes ¹⁹⁸. In vitro studies also prove the role of magnesium in reducing leukocyte activation through its calcium antagonistic action ²⁰⁰. Magnesium deficiency results in the stress condition that activate the sympathetic system and hypothalamic-pituitary axis causes fat accumulation and release of neuropeptides; results in the immune response followed by inflammatory cascades ²¹².

Magnesium can inhibit cytokine storm and hyper oxidative stress in COVID-19 patients through various mechanisms such as its antioxidant, immune-modulatory, and anti-inflammatory activities ²¹³.

Table 19. Magnesium Rich Foods

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for magnesium is 400 mg for adults and children aged 4 and older. However, the FDA does not require food labels to list magnesium content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

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Anemia of prematurity

Anemia of prematurity means that a baby born early (prematurely) does not have enough red blood cells. Red blood cells carry oxygen to the body. Preterm infants with birth weight <1.0 kg (commonly designated as extremely low birth weight or ELBW, infants) have completed ≤29 weeks of gestation, and nearly all will need red blood cell (RBC) transfusions during the first weeks of life. Every week in the United States, approximately 10,000 infants are born prematurely (ie, <37 weeks of gestation), with 600 (6%) of these preterm infants being extremely low birth weight ¹. Approximately 90% of extremely low birth weight neonates will receive at least one red blood cell transfusion ².

All babies have some anemia (decrease in hemoglobin concentration) when they are born. In healthy term infants, the nadir hemoglobin value rarely falls below 10 g/dL at an age of 10 to 12 weeks ³. This is normal and is called “physiological anemia of infancy”. For the term infant, a physiologic and usually asymptomatic anemia is observed 8-12 weeks after birth. But in premature babies, the number of red blood cells may decrease faster and go lower than in full-term babies. This may happen because:

• A premature baby may not make enough red blood cells.
• A premature baby may need tests that require blood samples. It may be hard for the baby to produce enough red blood cells to make up for the blood that’s taken out and used in the tests.
• A baby’s red blood cells don’t live as long as an older child’s red blood cells.

Anemia of prematurity is an exaggerated, pathologic response of the preterm infant to this transition. Anemia of prematurity is a normocytic, normochromic, hyporegenerative anemia characterized by a low serum erythropoietin (EPO) level, often despite a remarkably reduced hemoglobin concentration ⁴. Nutritional deficiencies of iron, vitamin E, vitamin B-12, and folate may exaggerate the degree of anemia, as may blood loss and/or a reduced red cell life span.

The anemia of prematurity is caused by untimely birth occurring before placental iron transport and fetal erythropoiesis are complete, by phlebotomy blood losses taken for laboratory testing, by low plasma levels of erythropoietin due to both diminished production and accelerated catabolism, by rapid body growth and need for commensurate increase in red cell volume/mass, and by disorders causing red blood cell losses due to bleeding and/or hemolysis ³.

The risk of anemia of prematurity is inversely related to gestational maturity and birthweight ⁴. As many as half of infants of less than 32 weeks gestation develop anemia of prematurity. Anemia of prematurity is not typically a significant issue for infants born beyond 32 weeks’ gestation.

Race and sex have no influence on the incidence of anemia of prematurity.

Testosterone is believed to be at least partially responsible for a slightly higher hemoglobin level in male infants at birth, but this effect is of no significance with regard to risk of anemia of prematurity. The nadir of the hemoglobin level is typically observed 4-10 weeks after birth in the tiniest infants, with hemoglobin levels of 8-10 g/dL if birthweight was 1200-1400 grams, or 6-9 g/dL at birth weights of less than 1200 grams and to approximately 7 g/dL in infants with birth weights <1 kg ⁴.

Anemia of prematurity is usually not serious. Anemia of prematurity spontaneously resolves in many premature infants within 3-6 months of birth ⁴. In others, however, medical intervention is required, because the low oxygen levels in a premature infant can make other problems worse, such as heart and lung problems. Most infants with birth weight <1.0 kg are given multiple red blood cell (RBC) transfusions within the first few weeks of life ³.

Red blood cell transfusions are the mainstay of therapy for anemia of prematurity with recombinant human erythropoietin (EPO) largely unused because it fails to substantially diminish red blood cell transfusion needs despite exerting substantial erythropoietic effects on neonatal marrow.

Figure 1. Blood composition

Footnote: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Figure 2. Red blood cells (normal red blood cells)

Anemia of prematurity causes

The three basic mechanisms for the development of anemia of prematurity include:

1. Inadequate red blood cell production,
2. Shortened red blood cell life span,
3. Blood loss.

Taken together, the premature infant is at risk for the development of anemia of prematurity because of limited red blood cell synthesis during rapid growth, a diminished red blood cell life span, and an increased loss of red blood cells.

Inadequate red blood cell production

The first mechanism of anemia is inadequate red blood cell production for the growing premature infant. The location of erythropoietin (EPO) and red blood cell production changes during gestation. Erythropoietin (EPO) synthesis initially occurs in the fetal liver but gradually shifts toward the kidney as gestation advances. By the end of gestation, however, the liver remains the major source of erythropoietin (EPO).

Fetal erythrocytes are produced in the yolk sac during the first few weeks of embryogenesis. The fetal liver becomes more important as gestation advances and, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By about 32 weeks’ gestation, the burden of erythrocyte production in the fetus is shared evenly by liver and bone marrow. By 40 weeks’ gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.

Although erythropoietin (EPO) is not the only erythropoietic growth factor in the fetus, it is the most important. Erythropoietin (EPO) is synthesized in response to anemia and consequent relative tissue hypoxia. The degree of anemia and hypoxia required to stimulate erythropoietin (EPO) production is far greater for the fetal liver than for the fetal kidney. Erythropoietin (EPO) production may not be stimulated until a hemoglobin concentration of 6-7 g/dL is reached. As a result, new red blood cell production in the extremely premature infant, whose liver remains the major site of erythropoietin (EPO) production, is blunted despite what may be marked anemia. In addition, erythropoietin (EPO), whether endogenously produced or exogenously administered, has a larger volume of distribution and is more rapidly eliminated by neonates, resulting in a curtailed time for bone marrow stimulation.

Erythroid progenitors in premature infants are quite responsive to erythropoietin (EPO), but the response may be blunted if iron or other substrate or co-factor stores are insufficient. Another potential problem is that while the infant may respond appropriately to increased erythropoietin (EPO) concentrations with increased reticulocyte counts, rapid growth may prevent the appropriate increase in hemoglobin concentration.

Shortened red blood cell life span or hemolysis

Also important in the development of anemia of prematurity is that the average life span of a neonatal red blood cell is only one half to two thirds that of an adult red blood cell. Cells of the most immature infants may survive only 35-50 days. The shortened red blood cell life span of the neonate is a result of multiple factors, including diminished levels of intracellular adenosine triphosphate (ATP), carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.

Blood loss

Finally, blood loss may contribute to the development of anemia of prematurity. If the neonate is held above the placenta for a time after delivery, fetal-placental transfer of blood may occur. Conversely, delayed cord clamping may lessen the degree of anemia of prematurity ⁵, although a study by Elimian et al ⁶ did not find this to be true. More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. These losses are often 5-10% of the total blood volume.

Anemia of prematurity differential diagnoses

Conditions to consider in the differential diagnosis of anemia of prematurity are those which diminish red cell production, increase red cell destruction, or cause blood loss.

• Acute Anemia
• Birth Trauma
• Chronic Anemia
• Head Trauma
• Hemolytic Disease of the Newborn
• Parvovirus B19 Infection
• Intraventricular Hemorrhage in the Preterm Infant

Conditions that diminish red blood cell synthesis are as follows:

• Bone marrow infiltration
• Bone marrow depression (eg, pancytopenia, drugs)
• Diamond-Blackfan anemia
• Substrate deficiencies (eg, iron, vitamin E, folic acid)
• Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)

Conditions that cause hemolysis are as follows:

• Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)
• Acute systemic infections (leading to disseminated intravascular coagulation)
• Abnormal red blood cells (spherocytosis, elliptocytosis)
• Nonspherocytic hemolytic anemias (eg, G6PD deficiency, kinase and isomerase deficiencies)
• Hemolytic disease of the newborn (Rh, ABO, other major blood-group incompatibilities between mother and fetus)

Conditions that reduce blood volume are as follows:

• Twin-to-twin transfusion syndrome (donor twin)
• Iatrogenic (eg, excessive blood sampling)
• Hemorrhage (eg, gastrointestinal, central nervous system, subcutaneous tissues)

Anemia of prematurity symptoms

Many clinical findings have been attributed to anemia of prematurity, but they are neither specific nor diagnostic. These symptoms may include the following:

• Poor weight gain despite adequate caloric intake
• Cardiorespiratory symptoms such as tachycardia, tachypnea, and flow murmurs
• Decreased activity, lethargy, and difficulty with oral feeding
• Pallor
• Increase in apneic and bradycardic episodes, and worsened periodic breathing
• Metabolic acidemia – Increased lactic acid secondary to increased cellular anaerobic metabolism in relatively hypoxic tissues

Anemia of prematurity diagnosis

The following are useful laboratory studies:

• Complete blood count (CBC) – White blood cell (WBC) and platelet values are normal in anemia of prematurity. Low hemoglobin values, below 10 g/dL, are found. They may descend to a nadir of 6-7 g/dL. Lowest levels are generally observed in the smallest infants. Red blood cell indices are normal (eg, normochromic, normocytic) for age.
• Reticulocyte count – The reticulocyte count is low when the degree of anemia is considered, as a result of the low levels of erythropoietin (EPO). Conversely, an elevated reticulocyte count is not consistent with the diagnosis of anemia of prematurity.
• Peripheral blood smear – Red blood cell morphology should be normal. Red blood cell precursors may appear to be more prominent.
• Maternal and infant blood typing; direct antibody test (Coombs) – The direct Coombs test result may be coincidentally positive. Despite this, it is important to ensure an immune-mediated hemolytic process related to maternal-fetal blood group incompatibility (hemolytic disease of the newborn) is not present.
• Serum bilirubin – An elevated serum bilirubin level should suggest other possible explanations for the anemia. These would include hemolytic entities, such as G-6-PD deficiency or other kinase/isomerase/enzyme deficiencies, or more common causes such as infection or hemolytic disease of the newborn.
• Lactic acid – Elevated lactic acid levels have been suggested by some to be useful as an aid to determine the need for transfusion.

Anemia of prematurity treatment

Medical treatment options are blood transfusion(s), recombinant erythropoietin (EPO) treatment, and observation.

Observation may be the best course of action for infants who are asymptomatic, not acutely ill, and are receiving adequate nutrition. Adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to blunt the expected decline in hemoglobin levels in the premature infant. Periodic measurements of the hematocrit level in infants with anemia of prematurity are necessary after hospital discharge. Once a steady increase in the hematocrit level has been established, only routine checks are required.

Packed red blood cell transfusions

Packed red blood cell transfusions are the mainstay of therapy for anemia of prematurity. The frequency of blood transfusion varies with gestational age, degree of illness, and, interestingly, the hospital evaluated. Unfortunately, there is considerable disagreement about the indication, timing, and efficacy of packed red blood cell transfusion.

Guidelines for transfusing red blood cells to preterm neonates are controversial, and practices vary greatly ⁷. This lack of a universal approach stems from limited knowledge of the cellular and molecular biology of erythropoiesis during the perinatal period, an incomplete understanding of infant physiological/adaptive responses to anemia, and contrary/controversial transfusion practice guidelines as based on results of randomized clinical trials and expert opinions. Generally, red blood cell transfusions are given to maintain a level of blood hemoglobin or hematocrit believed to be optimal for each neonate’s clinical condition. Guidelines for red blood cell transfusions, judged to be reasonable by most neonatologists to treat the anaemia of prematurity, are listed by Table 1. These guidelines are very general, and it is important that terms such as “severe” and “symptomatic” be defined to fit local transfusion practices/policies. Importantly, guidelines are not mandates for red blood cell transfusions that must be followed; they simply suggest situations when an red blood cell transfusion would be judged to be reasonable/acceptable.

The decision to give a transfusion should not be made lightly, because significant infectious, hematologic, immunologic, and metabolic complications are possible. Late-onset necrotizing enterocolitis has been reported in stable-growing premature infants electively transfused for anemia of prematurity ⁸. Transfusions also transiently decrease erythropoiesis and EPO levels. There is also agreement that the number of transfusions, as well as the number of donor exposures, should be reduced as much as possible.

Clinical trials designed to determine the efficacy of blood transfusions in relieving symptoms ascribed to anemia of prematurity have produced conflicting results ⁹. Improved growth has been an inconsistent finding. While some studies have demonstrated a decrease in apneic episodes after blood transfusion, others have found similar results with simple crystalloid volume expansion.

Subjective improvement in activity, decreased lethargy, and improved feeding have been described in some studies. Blood transfusions have been documented to decrease lactic acid levels in otherwise healthy preterm infants who are anemic. Blood transfusions have reduced tachycardia in anemic infants who are transfused.

Some medical professionals have suggested using lactate levels as an aid in determining the need for transfusion.

Table 1. Allogeneic red blood cell transfusions for the anemia of prematurity

Transfuse to maintain the blood hematocrit per each clinical situation:

• > 40% (35 to 45% ^*) for severe cardiopulmonary disease
• > 30% for moderate cardiopulmonary disease
• > 30% for major surgery
• >25% (20 to 25% ^*) for symptomatic anemia
• > 20% for asymptomatic anemia

*Reflects practices that vary among neonatologists. Thus, any value within range is acceptable for local practices.

Reducing the number of transfusions

Studies from individual centers have documented a marked decrease in the administration of packed red blood cell transfusions in the past decades, even before the use of EPO became more frequent. This decrease in transfusions is almost certainly multifactorial in origin. Adoption of standardized transfusion protocols that take various factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia, are acknowledged as an important factor in this reduction. A restricted transfusion protocol may decrease the number of transfusions while also decreasing the hematocrit at discharge ¹⁰.

A 2011 study ¹¹ evaluated 41 preterm infants with birth weights of 500-1300 g who were enrolled in a clinical trial that compared high and low hematocrit thresholds for transfusion. A rise in systemic oxygen transport and a decrease in lactic acid after transfusion was noted in both groups; however, oxygen consumption did not change significantly in either group. In the low hematocrit group only, cardiac output and fractional oxygen extraction fell after transfusion, which shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anemia. The results demonstrate that infants with low hematocrit thresholds may benefit from transfusion, while transfusion in those with high hematocrit thresholds may provide no acute physiological benefit ¹¹.

The Premature Infant in Need of Transfusion study ¹² showed that transfusing infants to maintain higher hemoglobin level (8.5-13.5 g/dL) conferred no benefit in terms of mortality, severe morbidity, or apnea intervention compared with infants transfused to maintain a low hemoglobin levels (7.5-11.5 g/dL).

These findings differ from the Iowa study, which found less parenchymal brain hemorrhage, periventricular leukomalacia, and apnea in infants whose transfusion criteria was not restricted and whose hemoglobin level was higher. Clearly, no universally accepted guidelines for transfusion in infants with anemia of prematurity are available at this time, and clinicians must determine their individual standardized transfusion practices.

Anemia of prematurity guidelines

No universally accepted guidelines for transfusion in infants with anemia of prematurity are available at this time, and clinicians must determine their individual standardized transfusion practices.

As an example, note the Children’s Hospital of Wisconsin Transfusion Committee guidelines for consideration:

• An infant with a hemoglobin (Hb) level of less than 8 g/dL may be transfused at the discretion of the attending physician
• A stable infant with a hemoglobin level of 8-10 g/dL without clinical symptoms or other exceptions listed below may be transfused
• An infant with a hemoglobin level of 11-13 g/dL without a supplemental oxygen or continuous positive airway pressure (CPAP) requirement, apnea/bradycardia, significant tachycardia or tachypnea, or other exceptions listed below should not be transfused
• An infant with a hemoglobin level of more than 13 g/dL without an oxygen requirement of more than 40% by hood, CPAP, or ventilator; hypotension that requires pressor medication; major surgery; or other exceptions listed below should not be transfused
• An infant with a hemoglobin level of more than 15 g/dL without cyanotic heart disease, extracorporeal membrane oxygenation (ECMO) therapy, regional oxygen saturations less than 50%, or hypotension that requires pressor medications should not be transfused
• An infant with a history of massive blood loss may be transfused at the discretion of the attending physician

It is of obvious importance to discuss with the family their child’s need for transfusion and to obtain consent before the transfusion. It is also important to discuss with parents the normal course of anemia, the criteria for and risks associated with transfusions, and the advantages and disadvantages of erythropoietin (EPO) administration. Also necessary is consideration of the family’s religious beliefs regarding transfusions.

Reducing the number of donor exposures

Reducing the number of donor exposures is also important. Preservatives and additive systems allow blood to be stored safely for as long as 35-42 days. This can be accomplished by using packed red blood cells stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization and thus limit exposure to the single donor of that unit. Concerns that stored blood might increase serum potassium levels are unfounded if the transfused volume is low.

Complications

Potential complications of transfusion include the following:

• Infection (eg, hepatitis, cytomegalovirus [CMV], human immunodeficiency virus [HIV], syphilis)
• Fluid overload and electrolyte imbalances
• Exposure to plasticizers
• Hemolysis
• Posttransfusion graft versus host disease

An important tool in reducing at least one of these transfusion risks is to use all available screening techniques for infection. The risk of cytomegalovirus (CMV) transmission can be dramatically reduced by use of CMV-safe blood. This can be accomplished by using CMV serology–negative cells, along with blood processed through leukocyte-reduction filters or inverted spin technique. These methods also reduce other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica) by yielding a leukocyte-poor suspension of packed red blood cells. The American Red Cross now provides exclusively leukocyte-reduced blood to hospitals in the United States.

Recombinant Erythropoietin treatment

Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO and supplemental iron with a brisk reticulocytosis. Subcutaneous administration of EPO may be preferred, as intravenous administration has increased urinary losses. Although EPO cannot prevent early transfusions, modest decreases in the frequency of late packed red blood cell transfusions have been documented. Additional iron supplementation is necessary during exogenous EPO treatment.

Trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with very low birth weight (VLBW) are capable of responding to EPO with a reticulocytosis.

Studies and a Cochrane Neonatal Systemic review suggest an association between exogenous EPO administration and retinopathy of prematurity ¹³.

Yasmeen et al ¹⁴ studied 60 preterm low birth weight infants and concluded that short-term recombinant human erythropoietin with iron and folic acid was effective in preventing anemia of prematurity.

EPO with iron does not adversely affect growth or developmental outcomes, but the impact on the number of transfusions a premature infant receives ranges from nonexistent to small.

At this time, no agreement regarding the safety, timing, dosing, route, or duration of therapy has been established. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not universally accepted as a standard therapy for an infant with anemia of prematurity.

Anemia of prematurity prognosis

Spontaneous recovery of mild anemia of prematurity may occur 3-6 months after birth. In more severe, symptomatic cases, medical intervention may be required.

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12. Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006 Sep. 149(3):301-307.
13. Suk KK, Dunbar JA, Liu A, et al. Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model. J AAPOS. 2008 Jun. 12(3):233-8.
14. Yasmeen BH, Chowdhury MA, Hoque MM, Hossain MM, Jahan R, Akhtar S. Effect of short-term recombinant human erythropoietin therapy in the prevention of anemia of prematurity in very low birth weight neonates. Bangladesh Med Res Counc Bull. 2012 Dec. 38(3):119-23.

What is L-Glutamine

L-glutamine is in a class of medications called amino acids. It works by helping to prevent damage to red blood cells. L-glutamine is a non-essential branched-chain amino acid that is present abundantly throughout the body and is involved in many metabolic processes ¹. L-glutamine is an important non-toxic nitrogen carrier in the body and an essential component of diet, especially dairy products, fish and green leafy vegetables ². L-glutamine participates in a variety of physiological functions, and is a major fuel source of enterocytes (intestine or gut cells) and is a substrate for gluconeogenesis (glucose formation) in the kidney, lymphocytes (white blood cells) and monocytes (white blood cells). L-glutamine is also a nutrient in muscle protein metabolism in response to infection, inflammation and muscle trauma ³. Because of glutamine’s importance as a nitrogen carrier and respiratory fuel for enterocytes of the gut and other rapidly proliferating cells, including lymphocytes and fibroblasts, glutamine can be considered as a conditionally essential amino acid ⁴. Although there are no known drug interactions with glutamine, physiological antagonism may occur with lactulose when given to treat high ammonia levels in liver failures. In some patients, glutamate may lead to brain excitation, and in patients with seizure, may make the drug less effective.

L-glutamine is used by doctors as prescription medicine to reduce the frequency of painful episodes (crises) in adults and children 5 years of age and older with sickle cell anemia (an inherited blood disorder in which the red blood cells are abnormally shaped [shaped like a sickle] and cannot bring enough oxygen to all parts of the body) ⁵. And L-glutamine is often prescribed to treat short bowel syndrome (short gut syndrome). Glutamine is used together with human growth hormone and a specialized diet to treat short bowel syndrome. This medicine is available only with your doctor’s prescription.

• L-glutamine has Pregnancy Category C: Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

• Breast Feeding: There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

In addition to L-glutamine usage in sickle cell anemia and short bowel syndrome, L-glutamine supplement may have an important role in the prevention of gastrointestinal, neurologic and, possibly, cardiac complications of cancer therapy ². The influence of glutamine on body homeostasis is protean (able to do many different things, versatile). States of physiologic stress, including those resulting from the treatment of malignant disease, are characterized by a relative deficiency of glutamine. These complications often negatively affect the quality of life and may also lead to changes in therapy, which potentially alter efficacy. L-glutamine may also improve the therapeutic index of both chemotherapy and radiation, increasing cytotoxicity while concurrently protecting against toxicity. However, the current evidence is not sufficient to recommend its regular use. Further studies of glutamine supplementation in these areas is warranted and multicentric, placebo-controlled phase III studies are needed to evaluate the role of L-glutamine for the prevention of mucositis, neurotoxicity and cardiotoxicity, and for the prevention of hepatic venoocclusive disease in patients undergoing hematopoietic cell transplantation before any definitive recommendation can be made.

Figure 1. L-Glutamine

What does L-glutamine do?

Glutamine is a major component of tissue of the skeletal muscle, which is the main site for the synthesis and storage of L-glutamine. When the supply of glutamine in plasma is inadequate to meet the demand, glutamine synthesis occurs in skeletal muscle and liver. Glutamine is transported to the neurons and, by the enzyme glutaminase, is converted to glutamate – the potential excitotoxin. L-glutamine accounts for 30–35% of the amino acid nitrogen in the plasma. It contains two ammonia groups, one from its precursor, glutamate, and the other from free ammonia in the bloodstream. Glutamine plays an important role to prevent fluctuations in the levels of ammonia in blood by acting as a “nitrogen shuttle.” It does so by acting as a buffer, accepting and then releasing excess ammonia when needed to form other amino acids, amino sugars, nucleotides and urea. This capacity to accept and donate nitrogen makes glutamine the major vehicle for nitrogen transfer among tissues. Glutamine is one of the three amino acids involved in glutathione synthesis. Glutathione synthesis, an important intracellular antioxidant and hepatic detoxifier, is comprised of glutamic acid, cysteine and glycine ⁶. Glutamine is one of the most important substrates for ammoniagenesis in the gut and the kidney due to its important role in the regulation of acid–base homeostasis ⁷. It decomposes readily to yield ammonia and glutamate or via intramolecular catalysis to pyroglutamate. Deamidation of glutamine via the enzyme glutaminase produces glutamate, a precursor of gamma-amino butyric acid. The transfer of the amide nitrogen from glutamine via the amido transferase reaction is involved in the biosynthesis of purines and pyrimidines and in the production of hexosamines. Glutamine via glutamate is converted to α-ketoglutarate, an integral component of the citric acid cycle. It is a component of the antioxidant glutathione synthesis and of the polyglutamated folic acid. The cyclization of glutamate produces proline, an amino acid important for the synthesis of collagen and connective tissue. However, excess glutamine in a protein is of pathological importance, and a number of neurodegenerative diseases have been found to be due to a CAG expansion that causes expansion of glutamine repeats in affected proteins (CAA and CAG codons are responsible for the insertion of glutamine from its transfer RNA with its anti-codon triplet into the genetically determined position of the coded polypeptide chain). This leads to abnormal protein folding ⁸ and neuronal diseases ⁹.

Glutamine is involved in many metabolic processes in the body. Glutamine is converted to glucose when more glucose is required by the body as an energy source. Glutamine also plays a part in maintaining proper blood glucose levels and the right pH range. It is also used by white blood cells and is important for immune function. Glutamine assists in maintaining the proper acid/alkaline balance in the body, and is the basis of the building blocks for the synthesis of RNA and deoxyribonucleic acid (DNA). Glutamine regulates the expression of certain genes, including those that govern certain protective enzymes, and helps regulate the biosynthesis of DNA and RNA. Construction of DNA is dependent on adequate amounts of glutamine. It also increases the body’s ability to secrete human growth hormone, which assists in metabolizing body fat and helps to support new muscle tissue growth. The glutamic acid–glutamine interconversion is of central importance to the regulation of the levels of toxic ammonia in the body, and thus among all the amino acids of blood plasma, glutamine has the highest concentration.

L-glutamine benefits

Glutamine is one of the most common plasma amino acids, and its concentration often decreases post-operatively ¹⁰, during sepsis ¹¹ and after multiple trauma ¹² or major burns ¹³, similar to a fall in the concentrations of many other amino acids, electrolytes, minerals and trace elements; therefore, it seems prudent to give glutamine supplementation in all these conditions ¹⁴.

Short Bowel Syndrome

Short bowel syndrome is a group of problems related to poor absorption of nutrients. Short bowel syndrome typically occurs in people who have:

• had at least half of their small intestine removed and sometimes all or part of their large intestine removed
• significant damage of the small intestine
• poor motility, or movement, inside the intestines

Short bowel syndrome may be mild, moderate, or severe, depending on how well the small intestine is working.

People with short bowel syndrome cannot absorb enough water, vitamins, minerals, protein, fat, calories, and other nutrients from food. What nutrients the small intestine has trouble absorbing depends on which section of the small intestine has been damaged or removed.

What causes Short Bowel Syndrome ?

The main cause of short bowel syndrome is surgery to remove a portion of the small intestine. This surgery can treat intestinal diseases, injuries, or birth defects.

Some children are born with an abnormally short small intestine or with part of their bowel missing, which can cause short bowel syndrome. In infants, short bowel syndrome most commonly occurs following surgery to treat necrotizing enterocolitis, a condition in which part of the tissue in the intestines is destroyed ¹⁵.

Short bowel syndrome may also occur following surgery to treat conditions such as:

• cancer and damage to the intestines caused by cancer treatment
• Crohn’s disease, a disorder that causes inflammation, or swelling, and irritation of any part of the digestive tract
• gastroschisis, which occurs when the intestines stick out of the body through one side of the umbilical cord
• internal hernia, which occurs when the small intestine is displaced into pockets in the abdominal lining
• intestinal atresia, which occurs when a part of the intestines doesn’t form completely
• intestinal injury from loss of blood flow due to a blocked blood vessel
• intestinal injury from trauma
• intussusception, in which one section of either the large or small intestine folds into itself, much like a collapsible telescope
• meconium ileus, which occurs when the meconium, a newborn’s first stool, is thicker and stickier than normal and blocks the ileum
• midgut volvulus, which occurs when blood supply to the middle of the small intestine is completely cut off
• omphalocele, which occurs when the intestines, liver, or other organs stick out through the navel, or belly button

Even if a person does not have surgery, disease or injury can damage the small intestine.

How common is Short Bowel Syndrome ?

Short bowel syndrome is a rare condition. Each year, short bowel syndrome affects about three out of every million people ¹⁵.

What are the signs and symptoms of Short Bowel Syndrome ?

The main symptom of short bowel syndrome is diarrhea—loose, watery stools. Diarrhea can lead to dehydration, malnutrition, and weight loss. Dehydration means the body lacks enough fluid and electrolytes—chemicals in salts, including sodium, potassium, and chloride—to work properly. Malnutrition is a condition that develops when the body does not get the right amount of vitamins, minerals, and nutrients it needs to maintain healthy tissues and organ function. Loose stools contain more fluid and electrolytes than solid stools. These problems can be severe and can be life threatening without proper treatment.

Other signs and symptoms may include:

• bloating
• cramping
• fatigue, or feeling tired
• foul-smelling stool
• heartburn
• too much gas
• vomiting
• weakness

People with short bowel syndrome are also more likely to develop food allergies and sensitivities, such as lactose intolerance. Lactose intolerance is a condition in which people have digestive symptoms—such as bloating, diarrhea, and gas—after eating or drinking milk or milk products.

What are the complications of Short Bowel Syndrome ?

The complications of short bowel syndrome may include

• malnutrition
• peptic ulcers—sores on the lining of the stomach or duodenum caused by too much gastric acid
• kidney stones—solid pieces of material that form in the kidneys
• small intestinal bacterial overgrowth—a condition in which abnormally large numbers of bacteria grow in the small intestine

How is Short Bowel Syndrome treated ?

A health care provider will recommend treatment for short bowel syndrome based on a patient’s nutritional needs. Treatment may include

• nutritional support
• medications
• surgery
• intestinal transplant

Nutritional Support

The main treatment for short bowel syndrome is nutritional support, which may include the following:

• Oral rehydration. Adults should drink water, sports drinks, sodas without caffeine, and salty broths. Children should drink oral rehydration solutions—special drinks that contain salts and minerals to prevent dehydration—such as Pedialyte, Naturalyte, Infalyte, and CeraLyte, which are sold in most grocery stores and drugstores.
• Parenteral nutrition. This treatment delivers fluids, electrolytes, and liquid vitamins and minerals into the bloodstream through an intravenous (IV) tube—a tube placed into a vein. Health care providers give parenteral nutrition to people who cannot or should not get their nutrition or enough fluids through eating.
• Enteral nutrition. This treatment delivers liquid food to the stomach or small intestine through a feeding tube—a small, soft, plastic tube placed through the nose or mouth into the stomach. Gallstones—small, pebble like substances that develop in the gallbladder—are a complication of enteral nutrition.
• Vitamin and mineral supplements. A person may need to take vitamin and mineral supplements during or after parenteral or enteral nutrition.
• Special diet. A health care provider can recommend a specific diet plan for the patient that may include:
  • small, frequent feedings
  • avoiding foods that can cause diarrhea, such as foods high in sugar, protein, and fiber
  • avoiding high-fat foods.

Bone marrow transplant

Bone marrow transplant is a sophisticated procedure consisting of the administration of high-dose chemoradiotherapy followed by intravenous infusion of hemopoietic stem cells to re-establish marrow function when the bone marrow is damaged or defective. Bone marrow transplant is used in the treatment of solid tumors, hematological diseases and autoimmune disorders. Glutamine has protein-anabolic effects and has shown a clear reduction of complications in patients undergoing bone marrow transplant who exhibit post-transplant body protein wasting, gut mucosal injury leading to mucositis of gastrointestinal tract, acute graft versus host disease and immunodeficiency. Studies indicate that enteral and parenteral glutamine supplementation is well tolerated and potentially efficacious after high-dose chemotherapy or bone marrow transplant for cancer treatment. Although not all studies demonstrate benefits, sufficient data has been published to suggest that this nutrient should be considered as adjunctive metabolic support of some individuals undergoing marrow transplant ¹⁶. However, bone marrow transplant is a rapidly evolving clinical procedure with regard to the conditioning and supportive protocols used. Thus, additional randomized, double-blind, controlled clinical trials are indicated to define the efficacy of glutamine with current bone marrow transplant regimens ¹⁷.

Glutamine and Cancer

Numerous studies on glutamine metabolism in cancer indicate that many tumors are avid glutamine consumers in vivo and in vitro. As a consequence of progressive tumor growth, host glutamine depletion develops and becomes a hallmark. This glutamine depletion occurs in part because the tumor behaves as a “glutamine trap” and also because of cytokine-mediated alterations in glutamine metabolism in host tissues. Animal and human studies that have investigated the use of glutamine-supplemented nutrition in the host with cancer suggest that pharmacologic doses of dietary glutamine may be beneficial. Understanding the control of glutamine metabolism in the tumor-bearing host not only improves the knowledge of metabolic regulation in the patient with cancer but also leads to improved nutritional support regimens targeted to benefit the host.

Glutamine supplementation in chemotherapy

The results of glutamine supplementation and oncology in animals and humans are conflicting ¹⁸. In vitro (test tube) studies reveal an increase in cellular growth with glutamine supplementation ¹⁹. While in vivo (animal) studies show the opposite effect, i.e. reduction in tumor growth ²⁰. Glutamine uptake in patients with colon cancer, regardless of tumor size and cell type, is comparable to uptake in patients with healthy intestinal tissue ²¹, also enteral diet containing glutamine increase muscle glutamine in rats by 60% without increasing tumor growth or tumor glutamine use ²². Glutamine supplementation in rats receiving methotrexate chemotherapy causes reduction in methotrexate-induced side-effects, including mucositis, and improved survival is observed ²³. Mucosal ulceration in rats subjected to abdominal radiation is also prevented ²⁴.

GLUTAMINE: ROLE IN INCREASING SELECTIVITY OF CHEMOTHERAPEUTIC AGENTS

Chemotherapy doses are limited by toxicity to normal tissues. Intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione synthesis content ²⁵. The effects of oral glutamine on tumor and host glutathione synthesis metabolism and response to methotrexate have been studied in rat models of sarcoma as well as in human patients with inflammatory breast cancer. Feeding the glutamine-enriched diets to rats receiving methotrexate decreases tumor glutathione synthesis while increasing or maintaining host glutathione synthesis stores ²⁶. Diminished glutathione synthesis levels in tumor cells increases susceptibility to chemotherapy. Significantly decreased glutathione synthesis content in tumor cells in the glutamine-supplemented group correlates with enhanced tumor volume loss ²⁷. These data suggest that oral glutamine supplementation will enhance the selectivity of antitumor drugs by protecting normal tissues from and possibly sensitizing tumor cells to radiation-induced and chemotherapy treatment-related injury ²⁸.

GLYCYL-GLUTAMINE-DIPEPTIDE IN THE PARENTERAL NUTRITION OF PATIENTS WITH ACUTE LEUKEMIA UNDERGOING INTENSIVE CHEMOTHERAPY

The effects of parenteral glycyl-glutamine supplementation in patients with acute leukemia receiving intensive conventional chemotherapy was evaluated in a randomized, double-blind, controlled study that compared a standard glutamine-free parenteral nutrition with a glycyl-glutamine-supplemented parenteral nutrition containing 20 g of glutamine. There was significant faster neutrophil recovery in the group that received glutamine supplementation along with high-dose cytarabine chemotherapy as compared with those patients receiving cytarabine regimen alone. There was no significant difference in the recovery of CD4+ or CD8+ lymphocytes or monocyte activation between the two groups. The authors concluded that there is a possible role of glutamine in the stimulation of lymphocyte proliferation ²⁹.

Other Uses of L-glutamine

Possibly Effective for:

• Burns. Administering glutamine through a feeding tube or intravenously (by IV) seems to reduce infections, shorten hospital stays, and improve wound healing in people with burns.
• Critical illness (trauma). There is some evidence that glutamine keeps bacteria from moving out of the intestine and infecting other parts of the body after major injuries. However, not all evidence is consistent. It is not clear if glutamine reduces the risk of death in critically ill people. Some studies suggest that it might reduce the risk of death, while others do not.
• Treating weight loss and intestinal problems in people with HIV/AIDs disease. Taking glutamine by mouth seems to help HIV/AIDS patients absorb food better and gain weight. Doses of 40 grams per day seem to produce the best effect.
• Soreness and swelling inside the mouth, caused by chemotherapy treatments. Some evidence suggests that glutamine reduces soreness and swelling inside the mouth caused by chemotherapy. However, glutamine does not seem to have this effect for all chemotherapy patients. It is not clear which patients are likely to benefit. Some researchers suspect that chemotherapy patients who do not have enough glutamine to start with are most likely to be helped.
• Surgery. Giving glutamine intravenously (by IV) along with intravenous nutrition seems to improve immune function and reduce complications related to infections after major surgery. Also, giving glutamine intravenously (by IV) along with intravenous nutrition after a bone marrow transplant seems to reduce the risk of infection and improve recovery compared to intravenous nutrition alone. However, not all people who undergo major surgery or who receive bone marrow transplants seem to benefit from glutamine.

Possibly Ineffective for ³⁰:

• Athletic performance. Taking glutamine by mouth does not seem to improve athletic performance.
• Crohn’s disease. Taking glutamine by mouth does not seem to improve symptoms of Crohn’s disease.
• Inherited disease that causes stones in the kidneys or bladder (Cystinuria). Taking glutamine by mouth does not seem to improve an inherited condition that causes stones to form in the kidneys or bladder.
• Muscular dystrophy. Research shows that taking glutamine by mouth does not improve muscle strength in children with muscular dystrophy.

Insufficient Evidence for ³⁰:

• Diarrhea caused by drugs used to treat HIV. Early research shows that taking glutamine by mouth reduces the severity of diarrhea in people with HIV who are taking the drug nelfinavir.
• Diarrhea caused by chemotherapy treatments. There is some evidence that glutamine might help to prevent diarrhea after chemotherapy, but not all research findings agree.
• Reducing damage to the immune system during cancer treatment. There is some evidence that glutamine reduces damage to the immune system caused by chemotherapy. However, not all research findings agree.
• Diarrhea. There are inconsistent findings about the effects of glutamine when used to treat diarrhea in children and infants. One early study suggests that taking glutamine by mouth reduces the duration of diarrhea in children. However, taking glutamine by mouth along with conventional rehydration solutions does not appear to have an advantage over rehydration solutions alone.
• Low birth weight. There are inconsistent findings about the effects of glutamine in infants with low to very low birth weight. Some research suggests that using glutamine in feeding tubes decreases infections in some low birth weight infants. However, most research suggests that it does not benefit low birth weight infants.
• Muscle and joint pains caused by the drug paclitaxel (Taxol, used to treat cancer). There is some evidence that glutamine might help to reduce muscle and joint pains caused by paclitaxel.
• Inflammation of the pancreas (pancreatitis). An early study shows that giving glutamine intravenously (by IV) along with intravenous nutrition improves immune function but does not reduce the risk for complications or the amount of time spent in the hospital in people with pancreatitis.
• Nutrition problems after major gut surgery (short bowel syndrome). Researchers have studied whether glutamine combined with growth hormone is effective in treating short bowel syndrome. This combination seems to help some patients become less dependent on tube feeding. However, glutamine alone does not seem to be effective.
• Depression.
• Moodiness.
• Irritability.
• Anxiety.
• Attention deficit-hyperactivity disorder (ADHD).
• Insomnia.
• Stomach ulcers.
• Ulcerative colitis.
• Sickle cell anemia.
• Treating alcoholism.
• Other conditions.

More evidence is needed to rate glutamine for these uses.

When to take L-glutamine supplement

L-glutamine comes as a powder to be mixed with a liquid or soft wet food and taken by mouth twice a day. Take L-glutamine at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take L-glutamine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

You will need to mix the medication powder with 8 ounces (240 ml) of a liquid such as water, milk, or apple juice, or 4 to 6 ounces (120 to 180 ml) of a soft wet food such as applesauce or yogurt right before you take it. The liquid or food must be cold or room temperature. The powder does not need to be completely dissolved in the liquid or food before you take the mixture.

What special precautions should I follow when taking L-glutamine ?

Before taking L-glutamine:

• tell your doctor and pharmacist if you are allergic to L-glutamine, any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking L-glutamine, call your doctor.

What special dietary instructions should I follow when taking L-glutamine ?

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose ?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

L-glutamine dosage

Your doctor will tell you how much L-glutamine medicine to use. Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

For patients using the oral powder for solution:

• Mix a packet of this medicine with water just before using it.
• Take it with a meal or snack every 2 to 3 hours while you are awake. Be sure to drink all of the mixture.
• Do not use the medicine during the night unless your doctor tells you to.

For patients using the oral powder:

• Mix the oral powder with 4 to 6 ounces (oz) of food (eg, applesauce, yogurt) or 8 oz of cold or room temperature beverage (eg, water, milk, or apple juice).
• Complete dissolution of the mixture is not required.
• Be sure to drink or swallow all of the mixture.

Missed dose: Take a dose as soon as you remember. If it is almost time for your next dose, wait until then and take a regular dose. Do not take extra medicine to make up for a missed dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

L-glutamine side effects and safety

Special Precautions & Warnings ³¹:

Children: Glutamine is POSSBILY SAFE when taken by mouth appropriately. Children aged 3 to 18 years should not be given doses that are larger than 0.7 grams per kg of weight daily. Not enough information is known about the safety of higher doses in children.

Pregnancy and breast-feeding: Not enough is known about the use of glutamine during pregnancy and breast-feeding. Stay on the safe side and avoid use.

Cirrhosis: Glutamine could make this condition worse. People with this condition should avoid glutamine supplements.

Severe liver disease with difficulty thinking or confusion (hepatic encephalopathy): Glutamine could make this condition worse. Do not use it.

Monosodium glutamate (MSG) sensitivity (also known as “Chinese restaurant syndrome”): If you are sensitive to MSG, you might also be sensitive to glutamine, because the body converts glutamine to glutamate.

Mania, a mental disorder: Glutamine might cause some mental changes in people with mania. Avoid use.

Seizures: There is some concern that glutamine might increase the likelihood of seizures in some people. Avoid use.

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

L-glutamine common side effects.

Tell your doctor if any of these symptoms are severe or do not go away:

• constipation
• nausea
• headache
• abdominal pain
• cough
• back, leg, feet, hands, or arm pain

L-glutamine may cause other side effects. See your doctor if you have any unusual problems while taking this medication.

Less common side effects

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects.

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What are white blood cells

White blood cells, also called leukocytes (or leucocytes), are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders ¹. All white blood cells are produced and derived from multipotent cells in the bone marrow known as hematopoietic stem cells. Leukocytes are found throughout the body, including the blood and lymphatic system.

Most blood samples are about 45% red blood cells by volume, with the white blood cells and platelets accounting for less than 1% of blood volume. The remaining blood sample, about 55%, is the plasma, a clear, straw-colored liquid (see Figure 1). Blood transports leukocytes to sites of infection. Leukocytes may then leave the bloodstream.

Like red blood cells, white blood cells (leukocytes) have limited life spans, so they must constantly be replaced. Leukocytes develop from hematopoietic stem cells in the red bone marrow (see Figure 2) in response to hormones, much as red blood cells form from precursors upon stimulation from erythropoietin. The hormones that affect leukocyte development fall into two groups—interleukins and colony-stimulating factors (CSFs). Interleukins are numbered, while most colony stimulating factors are named for the cell population they stimulate.

Types of white blood cells

All white blood cells have nuclei, which distinguishes them from the other blood cells, the anucleated red blood cells and platelets. They differ in size, the nature of their cytoplasm, the shape of the nucleus, and their staining characteristics, and they are named for these distinctions. Two pairs of broadest categories classify them either by structure (granulocytes or agranulocytes) or by cell division lineage (myeloid cells or lymphoid cells) (see Figure 3). These broadest categories can be further divided into the five main types: neutrophils, eosinophils, basophils, lymphocytes, and monocytes ². These types are distinguished by their physical and functional characteristics. Monocytes and neutrophils are phagocytic. Further subtypes can be classified; for example, among lymphocytes, there are B cells, T cells, and NK (natural killer) cells.

Normally, five types of white blood cells are in circulating blood. For example, leukocytes with granular cytoplasm are called granulocytes, whereas those without cytoplasmic granules are called agranulocytes (see Figure. 3).

A typical granulocyte is about twice the size of a red blood cell. Members of this group include neutrophils, eosinophils, and basophils. Granulocytes develop in red bone marrow as do red blood cells, but they have short life spans, averaging about 12 hours.

Neutrophils have fine cytoplasmic granules that appear light purple in neutral stain. The nucleus of an older neutrophil is lobed and consists of two to five sections (segments, so these cells are sometimes called segs) connected by thin strands of chromatin (Figure 4). Younger neutrophils are also called bands because their nuclei are C-shaped. Neutrophils account for 54% to 62% of the leukocytes in a typical blood sample from an adult.

Eosinophils contain coarse, uniformly sized cytoplasmic granules that appear deep red in acid stain (Figure 4). The nucleus usually has only two lobes (termed
bilobed). Eosinophils make up 1% to 3% of the total number of circulating leukocytes.

Basophils are similar to eosinophils in size and in the shape of their nuclei, but they have fewer, more irregularly shaped cytoplasmic granules that appear deep
blue in basic stain (Figure 4). Basophils usually account for less than 1% of the circulating leukocytes.

The leukocytes of the agranulocyte group include monocytes and lymphocytes. Monocytes generally arise from red bone marrow. Lymphocytes are formed in the organs of the lymphatic system, as well as in the red bone marrow.

Monocytes, the largest blood cells, are two to three times greater in diameter than red blood cells. Their nuclei are round, kidney-shaped, oval, or lobed. They usually make up 3% to 9% of the leukocytes in a blood sample and live for several weeks or even months.

Lymphocytes are only slightly larger than red blood cells. A typical lymphocyte has a large, round nucleus surrounded by a thin rim of cytoplasm. These cells account for 25% to 33% of circulating leukocytes. Lymphocytes may live for years.

Figure 1. Blood composition

Note: Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Normal Leukocyte Life Cycle and Responses

The life cycle of leukocytes includes development and differentiation, storage in the bone marrow, margination within the vascular spaces, and migration to tissues. Stem cells in the bone marrow produce cell lines of erythroblasts, which become red blood cells; megakaryoblasts, which become platelets; lymphoblasts; and myeloblasts. Lymphoblasts develop into various types of T and B cell lymphocytes. Myeloblasts further differentiate into monocytes and granulocytes, a designation that includes neutrophils, basophils, and eosinophils (Figure 2 and 3). Once white blood cells have matured within the bone marrow, 80% to 90% remain in storage in the bone marrow. This large reserve allows for a rapid increase in the circulating white blood cell count within hours. A relatively small pool (2% to 3%) of leukocytes circulate freely in the peripheral blood ³; the rest stay deposited along the margins of blood vessel walls or in the spleen. Leukocytes spend most of their life span in storage. Once a leukocyte is released into circulation and peripheral tissues, its life span ranges from two to 16 days, depending on the type of cell.

Figure 2. Bone marrow anatomy

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Figure 3. White blood cells development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell

Figure 4. White blood cells development

Figure 5. White blood cells

White Blood Cell Counts

The number of leukocytes in a microliter of human blood, called the white blood cell count (WBCC or WCC), normally is 3,500 to 10,500 per mm³ (3.5 to 10.5 × 10⁹ per L). White blood cell counts are of clinical interest because their number may change in response to abnormal conditions. A total number of white blood cells exceeding 10,500 per mm³ (10.5 × 10⁹ per L) of blood constitutes leukocytosis, indicating acute infection, such as appendicitis. The white blood cell count is greatly elevated in leukemia.

A total white blood cell count below 3,500 per mm³ (<3.5 × 10⁹ per L) of blood is called leukopenia. Such a deficiency may accompany typhoid fever, influenza, measles, mumps, chickenpox, AIDS, or poliomyelitis.

Healthy newborn infants may have a white blood cell count from 13,000 to 38,000 per mm³ (13.0 to 38.0 × 10⁹ per L) at 12 hours of life. By two weeks of age, this decreases to approximately 5,000 to 20,000 per mm³ (5.0 to 20.0 × 10⁹ per L), and gradually declines throughout childhood to reach adult levels of 4,500 to 11,000 per mm³ (4.5 to 11.0 × 10⁹ per L) by about 21 years of age ⁴. There is also a shift from relative lymphocyte to neutrophil predominance from early childhood to the teenage years and adulthood ⁵. During pregnancy, there is a gradual increase in the normal white blood cell count (third trimester 95% upper limit = 13,200 per mm³ [13.2 × 10⁹ per L] and 99% upper limit = 15,900 per mm³ [15.9 × 10⁹ per L]), and a slight shift toward an increased percentage of neutrophils ⁶. In one study of afebrile postpartum patients, the mean white blood cell count was 12,620 per mm³ (12.62 × 10⁹ per L) for women after vaginal deliveries and 12,710 per mm³ (12.71 × 10⁹ per L) after cesarean deliveries. Of note, positive bacterial cultures were not associated with leukocytosis or neutrophilia, making leukocytosis an unreliable discriminator in deciding which postpartum patients require antibiotic therapy ⁷. Patients of black African descent tend to have a lower white blood cell count (by 1,000 per mm3 [1.0 × 10⁹ per L]) and lower absolute neutrophil counts ⁸.

A differential white blood cell count lists percentages of the various types of leukocytes in a blood sample. This test is useful because the relative proportions of white blood cells may change in particular diseases. The number of neutrophils, for instance, usually increases during bacterial infections. Eosinophils may become more abundant during certain parasitic infections and allergic reactions. In AIDS, the number of a type of lymphocyte called T cells drops sharply.

Table 1. White Blood Cell Count Variation with Age and Pregnancy

Differentiation by Type of White Blood Cell

Changes in the normal distribution of types of white blood cells can indicate specific causes of leukocytosis ⁹. Although the differential of the major types of white blood cells is important for evaluating the cause of leukocytosis, it is sometimes helpful to think in terms of absolute, rather than relative, leukopenias and leukocytoses. To calculate the absolute cell count, the total leukocyte count is multiplied by the differential percentage. For example, with a normal white blood cell count of 10,000 per mm³ (10.0 × 10⁹ per L) and an elevated monocyte percentage of 12, the absolute monocyte count is 12% or 0.12 times the white blood cell count of 10,000 per mm³, yielding 1,200 per mm³ (1.2 × 10⁹ per L), which is abnormally elevated.

Table 2. Normal White Blood Cell Distribution

Functions of White Blood Cells

White blood cells protect your body against infection in various ways. Some leukocytes phagocytize (engulfing and destroying bacteria and other foreign material) bacterial cells in the body, and others produce proteins (antibodies) that destroy or disable foreign particles.

Leukocytes can squeeze between the cells that form the walls of the smallest blood vessels. This movement, called diapedesis, allows the white blood cells to leave the circulation. Once outside the blood, they move through interstitial spaces using a form of self propulsion called amoeboid motion.

The most mobile and active phagocytic leukocytes are neutrophils and monocytes. Monocytes leave the bloodstream and specialize further to become macrophages that phagocytize bacteria, dead cells, and other debris in the tissues.

Neutrophils cannot ingest particles much larger than bacterial cells, but monocytes can engulf large objects. Both of these phagocytes contain many lysosomes, which are organelles filled with digestive enzymes that break down organic molecules in captured bacteria, nutrients, and wornout organelles. Neutrophils and monocytes may become so engorged with digestive products and bacterial toxins that they die.

Eosinophils are only weakly phagocytic, but they are attracted to and can kill certain parasites. Eosinophils also help control inflammation and allergic reactions by removing biochemicals associated with these reactions.

Basophils migrate to damaged tissues, where they release heparin, which inhibits blood clotting, and histamine, which promotes inflammation. Basophils also play major roles in certain allergic reactions.

Lymphocytes are important in immunity. Lymphocytes called B cells, for example, produce antibodies that attack specific foreign substances that enter the body.

Phagocytosis

Phagocytosis removes foreign particles from the lymph as it moves from the interstitial spaces to the bloodstream. Phagocytes in the blood vessels and in the tissues of the spleen, liver, or bone marrow remove particles that reach the blood. The blood’s most active phagocytic cells are neutrophils and monocytes. Chemicals released from injured tissues attract these cells by chemotaxis. Neutrophils engulf and digest smaller particles; monocytes phagocytize larger ones.

Monocytes that leave the bloodstream by diapedesis become macrophages. These large cells may be free, or fixed in various tissues. The fixed macrophages can divide and produce new macrophages. Neutrophils, monocytes and macrophages constitute the mononuclear phagocytic system (reticuloendothelial system).

Table 3. White blood cells types and functions

Lymphatic tissue contains lymphocytes, macrophages, and other cells.

The unencapsulated diffuse lymphatic tissue associated with the digestive, respiratory, urinary, and reproductive tracts is called the mucosa-associated lymphoid tissue (MALT). Compact masses of lymphatic tissue compose the tonsils and appendix. Mucosa-associated lymphoid tissue (MALT) aggregates of lymphatic tissue, called Peyer’s patches, are scattered throughout the mucosal lining of the distal portion of the small intestine. The lymphatic organs, including the lymph nodes, thymus, and spleen, are encapsulated lymphatic tissue. A capsule of connective tissue with many fibers encloses each organ.

Lymph Nodes

Lymph nodes contain large numbers of lymphocytes (B cells and T cells) and macrophages that fight invading microorganisms. Masses of B cells and macrophages in the cortex are contained within lymphatic nodules, also called lymphatic follicles, the functional units of the lymph node. The spaces within a node, called lymphatic sinuses, provide a complex network of chambers and channels through which lymph circulates.

Lymph nodes are generally in groups or chains along the paths of the larger lymphatic vessels throughout the body, but are absent in the central nervous system. Figure 5 shows the major locations of lymph nodes.

Lymph nodes have two primary functions: (1) filtering potentially harmful particles from lymph before returning it to the bloodstream, and (2) monitoring body fluids (immune surveillance), a function performed by lymphocytes and macrophages. Along with red bone marrow, the lymph nodes are centers for lymphocyte production. Lymphocytes attack viruses, bacteria, and other parasitic cells that are brought to the lymph nodes by lymph in the lymphatic vessels. Macrophages in the lymph nodes engulf and destroy foreign substances, damaged cells, and cellular debris.

Superficial lymphatic vessels inflamed by bacterial infection appear as red streaks beneath the skin, a condition called lymphangitis. Inflammation of the lymph nodes, called lymphadenitis, often follows. In lymphadenopathy, affected lymph nodes enlarge and may be quite painful.

Figure 5. Locations of major lymph nodes

Thymus

The thymus is a soft, bilobed gland enclosed in a connective tissue capsule and located anterior to the aorta. It is posterior to the upper part of the sternum. The
thymus is usually proportionately larger during infancy and early childhood, but shrinks after puberty and may be quite small in an adult. In elderly people, adipose and connective tissues replace lymphatic tissue in the thymus. In a person aged seventy, the thymus is one-tenth the size it was in that person at the age of ten.

Connective tissues extend inward from the surface of the thymus, subdividing it into lobules. The lobules house many lymphocytes. Most of these cells (thymocytes) are inactive; however, some mature into T lymphocytes (T cells), which leave the thymus and provide immunity. Epithelial cells in the thymus secrete hormones called thymosins, which stimulate maturation of T lymphocytes.

Figure 6. Thymus

Spleen

The spleen, the largest lymphatic organ, is in the upper left portion of the abdominal cavity, just inferior to the diaphragm. It is posterior and lateral to the stomach. The spleen resembles a large lymph node and is subdivided into lobules. However, unlike the lymphatic sinuses of a lymph node, the spaces in the spleen, called venous sinuses, are filled with blood instead of lymph.

The tissues within splenic lobules are of two types (Figure 7). The white pulp is distributed throughout the spleen in tiny islands. This tissue is composed of splenic nodules, which are similar to the lymphatic nodules in lymph nodes and are packed with lymphocytes. The red pulp, which fills the remaining spaces of the lobules, surrounds the venous sinuses. This pulp contains numerous red blood cells, which impart its color, plus many lymphocytes and macrophages.

Blood capillaries in the red pulp are quite permeable. Red blood cells can squeeze through the pores in these capillary walls and enter the venous sinuses. The older, more fragile red blood cells may rupture during this passage, and the resulting cellular debris is removed by phagocytic macrophages in the venous sinuses. These macrophages also engulf and destroy foreign particles, such as bacteria, that may be carried in the blood as it flows through the venous sinuses. Thus, the spleen filters blood much as the lymph nodes filter lymph.

Figure 7. The Spleen

Body Defenses Against Infection

The presence and multiplication of a disease-causing agent, or pathogen, which if unchecked may cause an infection. Pathogens include viruses, bacteria, fungi, and protozoans.

The human body can prevent the entry of pathogens or destroy them if they enter. Some mechanisms are general in that they protect against many types of pathogens, providing innate (nonspecific) defense. These mechanisms include species resistance, mechanical barriers, inflammation, chemical barriers (enzyme action, interferon, and complement), natural killer cells, phagocytosis, and fever.

Other defense mechanisms are very precise, targeting specific pathogens and providing adaptive (specific) defense, or immunity. Specialized  lymphocytes that recognize foreign molecules (nonself antigens) in the body act against the foreign molecules in several ways, including the production of cytokines and antibodies. Innate and adaptive defense mechanisms work together to protect the body against infection. The innate defenses respond quite  rapidly, while adaptive defenses develop more slowly.

Inflammation

Inflammation is a tissue response to injury or infection, producing localized redness, swelling, heat, and pain. The redness is a result of blood vessel dilation that increases blood flow and volume in the affected tissues. This effect, coupled with an increase in the permeability of nearby capillaries and subsequent leakage of protein-rich fluid into tissue spaces, swells tissues (edema). The heat comes as blood enters from deeper body parts, which are warmer than the surface. Pain results from stimulation of nearby pain receptors.

Infected cells release chemicals that attract white blood cells to sites of inflammation. Here the white blood cells phagocytize pathogens. Local heat speeds up phagocytic activity. In bacterial infections, the resulting mass of white blood cells, bacterial cells, and damaged tissue may form a thick fluid called pus.

Fluids that leak out of the capillaries, called exudates, also collect in inflamed tissues. These fluids contain fibrinogen and other blood-clotting factors. Clotting forms a network of fibrin threads in the affected region. Later, fibroblasts may arrive and secrete matrix components until the area is enclosed in a connective  tissue sac. This walling off of the infected area helps inhibit the spread of pathogens and toxins to adjacent tissues.

Chemical Barriers

Lymphocytes and fibroblasts produce hormone like peptides called interferons in response to viruses or tumor cells. Once released from the virus-infected cell, interferon binds to receptors on uninfected cells, stimulating them to synthesize proteins that block replication of a variety of viruses. Thus, interferon’s effect is nonspecific. Interferons also stimulate phagocytosis and enhance the activity of other cells that help resist infections and the growth of tumors.

Complement is a group of proteins, in plasma and other body fluids, that interact in an expanding series of reactions or cascade. Activation of complement stimulates inflammation, attracts phagocytes, and enhances phagocytosis.

Natural Killer (NK) Cells

Natural killer (NK) cells are a small population of lymphocytes. They are different from the lymphocytes (T and B cells) that provide adaptive (specific) defense mechanisms. NK cells defend the body against various viruses and cancer cells by secreting cytolytic (“cell-cutting”) substances called perforins that lyse the cell membrane, destroying the infected cell. NK cells also secrete chemicals that enhance inflammation.

Fever

Fever is body temperature elevated above an individual’s normal temperature due to an elevated setpoint. It is part of the innate defense because as a result of the fever the body becomes inhospitable to certain pathogens. Higher body temperature causes the liver and spleen to sequester iron, which reduces the level of iron in the blood. Because bacteria and fungi require iron for normal metabolism, their growth and reproduction in a fever-ridden body slows and may cease. Also, phagocytic cells attack more vigorously when the temperature rises. For these reasons, low-grade fever of short duration may be a natural response to infection, not a treated symptom.

Immunity

The third line of defense, immunity, is resistance to specific pathogens or to their toxins or metabolic by-products. Lymphocytes and macrophages that recognize and remember specific foreign molecules carry out adaptive immune responses, which include the cellular immune response and the humoral immune response.

Antigens

Antigens are proteins, polysaccharides, glycoproteins, or glycolipids that can elicit an immune response. Before birth, cells inventory the antigens in the body, learning to identify these as “self.” The immune response is to “nonself,” or foreign, antigens, but not normally to self antigens. Receptors on lymphocyte surfaces enable these cells to recognize nonself antigens.

The antigens most effective in eliciting an immune response are large and complex, with few repeating parts. A smaller molecule that cannot by itself stimulate an immune response may combine with a larger molecule, which makes it detectable. Such a small molecule is called a hapten. Stimulated lymphocytes react either to the hapten or to the larger molecule of the combination. Hapten molecules are in drugs such as penicillin, in household and industrial chemicals, in dust particles, and in animal dander.

Lymphocyte Origins

Lymphocyte production begins during fetal development and continues throughout life, with red bone marrow releasing unspecialized precursors to lymphocytes into the circulation. About half of these cells reach the thymus, where they specialize into T lymphocytes, or T cells. After leaving the thymus, some of these T cells constitute 70% to 80% of the circulating lymphocytes in blood. Other T cells reside in lymphatic organs and are particularly abundant in the lymph nodes, thoracic duct, and white pulp of the spleen.

Other lymphocytes remain in the red bone marrow until they differentiate into B lymphocytes, or B cells. The blood distributes B cells, which constitute 20% to 30% of circulating lymphocytes. B cells settle in lymphatic organs along with T cells and are abundant in the lymph nodes, spleen, bone marrow, and intestinal lining. Figure 8 illustrates B cell and T cell production. Table 1 compares the characteristics of T cells and B cells.

Figure 8. Lymphocyte production

T Cells and the Cellular Immune Response

A lymphocyte must be activated before it can respond to an antigen. T cell activation requires that processed fragments of the antigen be attached to the surface of another type of cell, called an antigen-presenting cell (accessory cell). Macrophages, B cells, and several other cell types can be antigen-presenting cells.

T cell activation may occur when a macrophage phagocytizes a bacterium and digests it within a phagolysosome formed by the fusion of the vesicle containing the bacterium (phagosome) and a lysosome. Some of the resulting bacterial antigens are then displayed on the macrophage’s cell membrane near certain protein molecules that are part of a group of proteins called the major histocompatibility complex (MHC). MHC antigens help T cells recognize that a newly displayed antigen is foreign (nonself).

Activated T cells interact directly with antigen-bearing cells. Such cell-to-cell contact is called the cellular immune response, or cell-mediated immunity. T cells (and some macrophages) also synthesize and secrete polypeptides called cytokines that enhance certain cellular responses to antigens. For example, interleukin-1 and interleukin-2 stimulate the synthesis of several other cytokines from other T cells. Additionally, interleukin-1 helps activate T cells, whereas interleukin-2 causes T cells to proliferate. This proliferation increases the number of T cells in a clone, which is a group of genetically identical cells that descend from a single, original cell. Other cytokines, called colony stimulating factors (CSFs), stimulate leukocyte production in red bone marrow and activate macrophages. T cells may also secrete toxins that kill their antigen-bearing target cells, growth-inhibiting factors that prevent target cell growth, or interferon that inhibits the proliferation of viruses and tumor cells. Several types of T cells have distinct functions.

A specialized type of T cell, called a helper T cell, is activated when its antigen receptor combines with a displayed foreign antigen (Figure 9). Once activated, the
helper T cell proliferates and the resulting cells stimulate B cells to produce antibodies that are specific for the displayed antigen.

Another type of T cell is a cytotoxic T cell, which recognizes and combines with nonself antigens that cancerous cells or virally infected cells display on their surfaces near certain MHC proteins. Cytokines from helper T cells activate the cytotoxic T cell. Next, the cytotoxic T cell proliferates. Cytotoxic T cells then bind to the surfaces of antigen-bearing cells, where they release perforin protein that cuts pore like openings in the cell membrane, destroying these cells. In this way, cytotoxic T cells continually monitor the body’s cells, recognizing and eliminating tumor cells and cells infected with viruses. Cytotoxic T cells provide much of the body’s defense against HIV infection.

Some cytotoxic T cells do not respond to a nonself antigen on first exposure, but remain as memory T cells that provide for future immune protection. Upon subsequent exposure to the same antigen, these memory cells immediately divide to yield more cytotoxic T cells and helper T cells, often before symptoms arise.

Figure 9. T-cell activation

B Cells and the Humoral Immune Response

When a B cell encounters an antigen whose molecular shape fits the shape of the B cell’s antigen receptors, it becomes activated. In response to the receptor-antigen combination, the B cell divides repeatedly, expanding its clone. However, most of the time B cell activation requires T cell “help.” When an activated helper T cell encounters a B cell already combined with a foreign antigen identical to the one that activated the helper T cell, the helper T cell releases certain cytokines. These cytokines stimulate the B cell to proliferate, increasing the number of cells in its clone of antibody-producing cells (Figure 10). The cytokines also attract macrophages and leukocytes into inflamed tissues and help keep them there.

Some members of the activated B cell’s clone differentiate further into plasma cells, which produce and secrete large globular proteins called antibodies, also called immunoglobulins. Antibodies are similar in structure to the antigen-receptor molecules on the original B cell’s surface. Body fluids carry antibodies, which then react in various ways to destroy specific antigens or antigen-bearing particles. This antibody-mediated immune response is called the humoral immune response.

An individual’s B cells can produce more than 1,000,000,000 different antibodies, each reacting against a specific antigen. The enormity and diversity of the antibody response defends against many pathogens.

Other members of the activated B cell’s clone differentiate further into memory B cells. Like memory T cells, these memory B cells respond rapidly to subsequent exposure to a specific antigen.

Table 2 summarizes the steps leading to antibody production as a result of B cell and T cell activities.

Table 2. Steps in Antibody Production

Figure 10. B-cell activation

Types of Antibodies

Antibodies (immunoglobulins) are soluble, globular proteins that constitute the gamma globulin fraction of blood plasma proteins (see Blood Plasma). Of the five major types of immunoglobulins, the most abundant are immunoglobulin G, immunoglobulin A, and immunoglobulin M.

Immunoglobulin G (IgG) is in plasma and tissue fluids and is particularly effective against bacteria, viruses, and toxins. It also activates complement.

Immunoglobulin A (IgA) is commonly found in exocrine gland secretions. It is in breast milk, tears, nasal fluid, gastric juice, intestinal juice, bile, and urine.

Immunoglobulin M (IgM) is a type of antibody present in plasma in response to contact with certain antigens in foods or bacteria. The antibodies anti-A and anti-B, described in Blood Donation – Blood Transfusions, are examples of IgM. IgM also activates complement.

Immunoglobulin D (IgD) is found on the surfaces of most B cells, especially those of infants. IgD is important in activating B cells.

Immunoglobulin E (IgE) is found on the surfaces of basophils and mast cells. It is associated with allergic responses.

A newborn does not yet have its own antibodies, but does retain for a while IgG that passed through the placenta from the mother. These maternal antibodies protect the infant against some illnesses to which the mother is immune. As the maternal antibody supply falls, the infant begins to manufacture its own antibodies. The newborn also receives IgA from colostrum, a substance secreted from the mother’s breasts for the first few days after birth, and then from breast milk. Antibodies in colostrum protect against certain digestive and respiratory infections.

Antibody Actions

In general, antibodies react to antigens in three ways. Antibodies directly attack antigens, activate complement, or stimulate localized changes (inflammation) that help prevent the spread of pathogens or cells bearing foreign antigens.

In a direct attack, antibodies combine with antigens, causing them to clump (agglutination) or to form insoluble substances (precipitation). Such actions make it easier for phagocytic cells to recognize and engulf the antigen-bearing agents and eliminate them. In other instances, antibodies cover the toxic portions of antigen molecules and neutralize their effects (neutralization). However, under normal conditions, direct antibody attack is not as important as complement activation in protecting against infection.

When certain IgG or IgM antibodies combine with antigens, they expose reactive sites on antibody molecules. This triggers a series of reactions, leading to activation of the complement proteins, which in turn produce a variety of effects. These include:

• coating the antigen-antibody complexes (opsonization), making the complexes more susceptible to phagocytosis;
• attracting macrophages and neutrophils into the region (chemotaxis);
• rupturing membranes of foreign cells (lysis); agglutination of antigen-bearing cells; and
• neutralization of viruses by altering their molecular structure, making them harmless.

Other proteins promote inflammation, which helps prevent the spread of infectious agents.

Immune Responses

Activation of B cells or T cells after they first encounter the antigens for which they are specialized to react constitutes a primary immune response. During such a response, plasma cells release antibodies (IgM, followed by IgG) into the lymph. The antibodies are transported to the blood and then throughout the body, where they help destroy antigen bearing agents. Production and release of antibodies continues for several weeks.

Following a primary immune response, some of the B cells produced during proliferation of the clone remain dormant as memory cells. If the same antigen is encountered again, the clones of these memory cells enlarge, and they can respond rapidly by producing IgG to the antigen to which they were previously sensitized. These memory B cells, along with the memory cytotoxic T cells, produce a secondary immune response.

As a result of a primary immune response, detectable concentrations of antibodies usually appear in the blood plasma five to ten days after exposure to antigens. If the same type of antigen is encountered later, a secondary immune response may produce the same antibodies within a day or two. Although newly formed antibodies may persist in the body for only a few months or years, memory cells live much longer.

Naturally acquired active immunity occurs when a person exposed to a pathogen develops a disease. Resistance to that pathogen is the result of a primary immune response.

A vaccine is a preparation that produces artificially acquired active immunity. A vaccine might consist of bacteria or viruses that have been killed or weakened so that they cannot cause a serious infection, or only molecules unique to the pathogens. A vaccine might also be a toxoid, which is a toxin from an infectious organism that has been chemically altered to destroy its dangerous effects. Whatever its composition, a vaccine includes the antigens that stimulate a primary immune response, but does not produce symptoms of disease and the associated infections.

Specific vaccines stimulate active immunity against a variety of diseases, including typhoid fever, cholera, whooping cough, diphtheria, tetanus, polio, chickenpox, measles (rubeola), German measles (rubella), mumps, influenza, hepatitis A, hepatitis B, and bacterial pneumonia. A vaccine has eliminated naturally acquired smallpox from the world.

Autoimmunity

The immune response can turn against the body itself. It may become unable to distinguish a particular self antigen from a nonself antigen, producing  autoantibodies and cytotoxic T cells that attack and damage the body’s tissues and organs. This reaction against self is called autoimmunity.

The specific nature of an autoimmune disorder reflects the cell types that are the target of the immune attack. In type 1 (insulin dependent) diabetes mellitus the target is beta cells in the pancreas. The tissues within the joints are targeted in rheumatoid arthritis. In systemic lupus erythematosus the target is DNA and proteins associated with it in the cell nuclei. About 5% of the population has an autoimmune disorder.

Why might the immune response attack body tissues ?

Perhaps a virus, while replicating inside a human cell, takes proteins from the host cell’s surface and incorporates them onto its own surface. When the immune response “learns” the surface of the virus in order to destroy it, it also learns to attack the human cells that normally bear those particular proteins. Another explanation of autoimmunity is that somehow T cells never learn to distinguish self from nonself. A third possible route of autoimmunity is when a nonself antigen coincidentally resembles a self antigen.

What does low white blood cells mean

Low white blood cells or leucopenia is a range of disorders can cause decreases in white blood cells. Leukopenia is characterized by a reduction in the circulating white blood cell count to < 4000/μL ¹¹. The type of white blood cell decreased is usually the neutrophil. In this case the decrease may be called neutropenia or granulocytopenia. Less commonly, a decrease in lymphocytes (called lymphocytopenia or lymphopenia) may be seen.

Neutropenia

Neutropenia is an abnormally low level of neutrophils. Neutrophils are a common type of white blood cell important to fighting off infections — particularly those caused by bacteria and fungal infections ¹². When neutropenia is present, the inflammatory response to such infections is ineffective.

Normal lower limit of the neutrophil count (total white blood cell × % neutrophils and bands) is 1500/μL in whites and is somewhat lower in blacks (about 1200/μL) ¹². Neutrophil counts are not as stable as other cell counts and may vary considerably over short periods, depending on many factors such as activity status, anxiety, infections, and drugs. Thus, several measurements may be needed when determining the severity of neutropenia ¹².

Severity of neutropenia relates to the relative risk of infection and is classified as follows ¹²:

• Mild (1000 to 1500/μL)
• Moderate (500 to 1000/μL)
• Severe (<500/μL)

When neutrophil counts fall to <500/μL, endogenous microbial flora (eg, in the mouth or gut) can cause infections. If the count falls to < 200/μL, inflammatory response may be muted and the usual inflammatory findings of leukocytosis or white blood cells in the urine or at the site of infection may not occur. Acute, severe neutropenia, particularly if another factor (eg, cancer) is present, significantly impairs the immune system and can lead to rapidly fatal infections. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections.

The most frequently occurring infections in patients with profound neutropenia are:

• Cellulitis (infection of subcutaneous connective tissue)
• Furunculosis (boils on the skin)
• Pneumonia (lung infection)
• Septicemia (bacteria in the blood)

Vascular catheters and other puncture sites confer extra risk of skin infections; the most common bacterial causes are coagulase-negative staphylococci and Staphylococcus aureus, but other gram-positive and gram-negative infections also occur. Stomatitis, gingivitis, perirectal inflammation, colitis, sinusitis, paronychia, and otitis media often occur. Patients with prolonged neutropenia after hematopoietic stem cell transplantation or chemotherapy and patients receiving high doses of corticosteroids are predisposed to fungal infections.

Causes of neutropenia

Cancer chemotherapy is probably the most common cause of neutropenia. People with chemotherapy-related neutropenia are prone to infections while they wait for their cell counts to recover.

Neutrophils are manufactured in bone marrow — the spongy tissue inside some of your larger bones. Anything that disrupts neutrophil production can result in neutropenia.

Acute neutropenia (occurring over hours to a few days) can develop as a result of rapid neutrophil use or destruction or due to impaired production.

Chronic neutropenia (lasting months to years) usually arises as a result of reduced production or excessive splenic sequestration.

Neutropenia also may be classified as primary due to an intrinsic defect in marrow myeloid cells or as secondary (due to factors extrinsic to marrow myeloid cells).

Neutropenia can be acquired or intrinsic ¹³. A decrease in levels of neutrophils on lab tests is due to either decreased production of neutrophils or increased removal from the blood ¹⁴.

The following is a list of neutropenia causes due to intrinsic defects in myeloid cells or their precursors:

• Aplastic anemia
• Chronic idiopathic neutropenia, including benign neutropenia
• Cyclic neutropenia
• Myelodysplasia
• Neutropenia associated with dysgammaglobulinemia
• Paroxysmal nocturnal hemoglobinuria
• Severe congenital neutropenia (Kostmann syndrome)
• Syndrome-associated neutropenias (eg, cartilage-hair hypoplasia syndrome, dyskeratosis congenita, glycogen storage disease type IB, warts, hypogammaglobulinemia, infections, myelokathexis [WHIM] syndrome, Shwachman-Diamond syndrome)

The following is a list of causes of secondary neutropenias:

• Alcoholism
• Autoimmune neutropenia, including chronic secondary neutropenia in AIDS
• Bone marrow replacement (eg, due to cancer, myelofibrosis, granuloma, or Gaucher cells)
• Cytotoxic chemotherapy or radiation therapy
• Drug-induced neutropenia – sulfas or other antibiotics, phenothiazenes, benzodiazepines, antithyroids, anticonvulsants, quinine, quinidine, indomethacin, procainamide, thiazides
• Folate deficiency, vitamin B12 deficiency, or severe undernutrition
• Hypersplenism
• Infection
• T cell large granular lymphocyte disease

Symptoms and Signs of Neutropenia

Neutropenia is asymptomatic until infection develops. Fever is often the only indication of infection. Typical signs of inflammation (erythema, swelling, pain, infiltrates, leukocytic reaction) may be muted or absent. Focal symptoms (eg, oral ulcers) may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy as a result of the hypersensitivity.

Neutropenia is usually found when your doctor orders tests for a condition you’re already experiencing. It’s rare for neutropenia to be discovered unexpectedly or by chance.

Talk to your doctor about what your test results mean. Neutropenia and results from other tests might indicate the cause of your illness. Or, your doctor may suggest other tests to further check your condition.

Because neutropenia makes you vulnerable to bacterial and fungal infections, your doctor will probably advise certain precautions. These often include wearing a face mask, avoiding anyone with a cold, and washing your hands regularly and thoroughly.

Some patients with chronic benign neutropenia and neutrophil counts < 200/μL do not experience many serious infections. Patients with cyclic neutropenia or severe congenital neutropenia tend to have episodes of oral ulcers, stomatitis, or pharyngitis and lymph node enlargement during severe neutropenia. Pneumonias and septicemia often occur.

Treatment of neutropenia

• Treatment of associated conditions (eg, infections, stomatitis)
• Sometimes antibiotic prophylaxis
• Myeloid growth factors
• Discontinuation of suspected etiologic agent (eg, drug)
• Sometimes corticosteroids

Acute neutropenia

Suspected infections are always treated immediately. If fever or hypotension is present, serious infection is assumed, and empiric, high-dose, broad-spectrum antibiotics are given IV. Regimen selection is based on the most likely infecting organisms, the antimicrobial susceptibility of pathogens at that particular institution, and the regimen’s potential toxicity. Because of the risk of creating resistant organisms, vancomycin is used only if gram-positive organisms resistant to other drugs are suspected.

Indwelling vascular catheters can usually remain in place even if bacteremia is suspected or documented, but removal is considered if infections involve S. aureus or Bacillus sp, Corynebacterium sp, or Candida sp or if blood cultures are persistently positive despite appropriate antibiotics. Infections caused by coagulase-negative staphylococci generally resolve with antimicrobial therapy alone. Indwelling Foley catheters can also predispose to infections in these patients, and change or removal of the catheter should be considered for persistent urinary infections.

If cultures are positive, antibiotic therapy is adjusted to the results of sensitivity tests. If a patient defervesces within 72 h, antibiotics are continued for at least 7 days and until the patient has no symptoms or signs of infection. When neutropenia is transient (such as that following myelosuppressive chemotherapy), antibiotic therapy is usually continued until the neutrophil count is >500/μL; however, stopping antimicrobials can be considered in selected patients with persistent neutropenia, especially those in whom symptoms and signs of inflammation have resolved, if cultures remain negative.

Fever that persists > 72 h despite antibiotic therapy suggests a nonbacterial cause, infection with a resistant species, a superinfection with a 2nd bacterial species, inadequate serum or tissue levels of the antibiotics, or localized infection, such as an abscess. Neutropenic patients with persistent fever are reassessed every 2 to 4 days with physical examination, cultures, and chest x-ray. If the patient is well except for the presence of fever, the initial antibiotic regimen can be continued, and drug-induced fever should be considered. If the patient is deteriorating, alteration of the antimicrobial regimen is considered.

Fungal infections are the most likely cause of persistent fevers and deterioration. Antifungal therapy is added empirically if unexplained fever persists after 3 to 4 days of broad-spectrum antibiotic therapy. Selection of the specific antifungal drug (eg, fluconazole, caspofungin, voriconazole, posaconazole) depends on the type of risk (eg, duration and severity of neutropenia, past history of fungal infection, persistent fever despite use of narrower spectrum antifungal drug) and should be guided by an infectious disease specialist. If fever persists after 3 wk of empiric therapy (including 2 wk of antifungal therapy) and the neutropenia has resolved, then stopping all antimicrobials can be considered and the cause of fever reevaluated.

For afebrile patients with neutropenia, antibiotic prophylaxis with fluoroquinolones (levofloxacin, ciprofloxacin) is used in some centers for patients who receive chemotherapy regimens that commonly result in neutrophils ≤ 100/µL for > 7 days.. Prophylaxis is usually started by the treating oncologist. Antibiotics are continued until the neutrophil count increases to > 1500/µL. Also, antifungal therapy can be given for afebrile neutropenic patients at higher risk of fungal infection (eg, after hematopoietic stem cell transplantation, intensive chemotherapy for acute myelogenous leukemia or a myelodysplastic disorder, prior fungal infections). Selection of the specific antifungal drug should be guided by an infectious disease specialist. Antibiotic and antifungal prophylaxis is not routinely recommended for afebrile neutropenic patients without risk factors who are anticipated to remain neutropenic for < 7 days on the basis of their specific chemotherapy regimen.

Myeloid growth factors (ie, granulocyte colony-stimulating factor [G-CSF]) are widely used to increase the neutrophil count and to prevent infections in patients with severe neutropenia (eg, after hematopoietic stem cell transplantation and intensive cancer chemotherapy). They are expensive. However, if the risk of febrile neutropenia is ≥ 30% (as assessed by neutrophil count < 500 μL, presence of infection during a previous cycle of chemotherapy, associated comorbid disease, or age > 75), growth factors are indicated. In general, most clinical benefit occurs when the growth factor is administered beginning about 24 h after completion of chemotherapy. Patients with neutropenia caused by an idiosyncratic drug reaction may also benefit from myeloid growth factors, particularly if a delayed recovery is anticipated. The dose for G-CSF (filgrastim) is 5 to 10 mcg/kg sc once/day, and the dose for pegylated G-CSF (pegfilgrastim) is 6 mg sc once per chemotherapy cycle.

Glucocorticoids, anabolic steroids, and vitamins do not stimulate neutrophil production but can affect distribution and destruction. If acute neutropenia is suspected to be drug- or toxin-induced, all potentially etiologic agents are stopped. If neutropenia develops during treatment with a drug known to induce low counts (eg, chloramphenicol), then switching to an alternative antibiotic may be helpful.

Saline or hydrogen peroxide gargles every few hours, liquid oral rinses (containing viscous lidocaine, diphenhydramine, and liquid antacid), anesthetic lozenges (benzocaine 15 mg q 3 or 4 h), or chlorhexidine mouth rinses (1% solution) bid or tid may relieve the discomfort of stomatitis with oropharyngeal ulcerations. Oral or esophageal candidiasis is treated with nystatin (400,000 to 600,000 units oral rinse qid; swallowed if esophagitis is present), clotrimazole troche (10 mg slowly dissolved in the mouth 5 times a day), or systemic antifungal drugs (eg, fluconazole). A semisolid or liquid diet may be necessary during acute stomatitis or esophagitis, and topical analgesics (eg,viscous lidocaine) may be needed to minimize discomfort.

Chronic neutropenia

Neutrophil production in congenital neutropenia, cyclic neutropenia, and idiopathic neutropenia can be increased with administration of G-CSF 1 to 10 mcg/kg sc once/day. Effectiveness can be maintained with daily or intermittent G-CSF for months or years. Long-term G-CSF has also been used in other patients with chronic neutropenia, including those with myelodysplasia, HIV, and autoimmune disorders. In general, neutrophil counts increase, although clinical benefits are less clear, especially for patients who do not have severe neutropenia. For patients with autoimmune disorders or who have had an organ transplant, cyclosporine can also be beneficial.

In some patients with accelerated neutrophil destruction caused by autoimmune disorders, corticosteroids (generally, prednisone 0.5 to 1.0 mg/kg po once/day) can increase blood neutrophils. This increase often can be maintained with alternate-day G-CSF therapy.

Splenectomy has been used in the past to increase the neutrophil count in some patients with splenomegaly and splenic sequestration of neutrophils (eg, Felty syndrome); however,because growth factors and other newer therapies are often effective, splenectomy should be avoided in most patients. However, splenectomy can be considered for patients with persistent painful splenomegaly or with severe neutropenia (ie, <500/μL) and serious problems with infections in whom other treatments have failed. Patients should be vaccinated against infections caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae before splenectomy because splenectomy predisposes patients to infection by encapsulated organisms.

Lymphocytopenia

The normal lymphocyte count in adults is 1000 to 4800/μL; in children < 2 yr, 3000 to 9500/μL. At age 6 yr, the lower limit of normal is 1500/μL.

Lymphocytopenia is a total lymphocyte count of < 1000/μL in adults or < 3000/μL in children < 2 yr ¹⁵.

Both B and T cells are present in the peripheral blood; about 75% of the lymphocytes are T cells and 25% B cells. Because lymphocytes account for only 20 to 40% of the total WBC count, lymphocytopenia may go unnoticed when WBC count is checked without a differential.

Almost 65% of blood T cells are CD4+ T-helper cells. Most patients with lymphocytopenia have a reduced absolute number of T cells, particularly in the number of CD4+ T cells. The average number of CD4+ T-helper cells in adult blood is 1100/μL (range, 300 to 1300/μL), and the average number of cells of the other major T-cell subgroup, CD8+ (suppressor) T cells, is 600/μL (range, 100 to 900/μL).

Lymphocytopenia can be ¹⁵:

• Acquired
• Inherited

Causes of Acquired lymphocytopenia:

• AIDS
• Other infectious disorders, including hepatitis, influenza, TB, typhoid fever, and sepsis
• Dietary deficiency in patients with ethanol abuse, protein-energy undernutrition, or zinc deficiency
• Protein losing enteropathy
• Iatrogenic after use of cytotoxic chemotherapy, glucocorticoids, high-dose psoralen and ultraviolet A radiation therapy, lymphocyte antibody therapy, immunosuppressants, radiation therapy, or thoracic duct drainage
• Systemic disorders with autoimmune features (eg, aplastic anemia, Hodgkin lymphoma, myasthenia gravis, protein-losing enteropathy, RA, chronic kidney disease, sarcoidosis, SLE, thermal injury).

Causes of Inherited lymphocytopenia:

• Aplasia of lymphopoietic stem cells
• Ataxia-telangiectasia
• Cartilage-hair hypoplasia syndrome
• Idiopathic CD4+ T lymphocytopenia
• Immunodeficiency with thymoma
• Severe combined immunodeficiency associated with a defect in the IL-2 receptor gamma-chain, deficiency of adenosine deaminase or purine nucleoside phosphorylase, or an unknown defect
• Wiskott-Aldrich syndrome

Acquired lymphocytopenia

Acquired lymphocytopenia can occur with a number of other disorders. The most common causes include:

• Protein-energy undernutrition
• AIDS and certain other viral infections

Protein-energy undernutrition is the most common cause worldwide.

AIDS is the most common infectious disease causing lymphocytopenia, which arises from destruction of CD4+ T cells infected with HIV. Lymphocytopenia may also reflect impaired lymphocyte production arising from destruction of thymic or lymphoid architecture. In acute viremia due to HIV or other viruses, lymphocytes may undergo accelerated destruction from active infections with the virus, may be trapped in the spleen or lymph nodes, or may migrate to the respiratory tract.

Iatrogenic lymphocytopenia is caused by cytotoxic chemotherapy, radiation therapy, or the administration of antilymphocyte globulin (or other lymphocyte antibodies). Long-term treatment for psoriasis using psoralen and ultraviolet A irradiation may destroy T cells. Glucocorticoids can induce lymphocyte destruction.

Lymphocytopenia may occur with lymphomas, autoimmune diseases such as SLE, rheumatoid arthritis, myasthenia gravis, and protein-losing enteropathy.

Inherited lymphocytopenia

Inherited lymphocytopenia (see Table: Causes of Lymphocytopenia) most commonly occurs in:

• Severe combined immunodeficiency disorder
• Wiskott-Aldrich syndrome

It may occur with inherited immunodeficiency disorders and disorders that involve impaired lymphocyte production. Other inherited disorders, such as Wiskott-Aldrich syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency, may involve accelerated T-cell destruction. In many disorders, antibody production is also deficient.

Symptoms and Signs of Lymphocytopenia

Lymphocytopenia per se generally causes no symptoms. However, findings of an associated disorder may include:

• Absent or diminished tonsils or lymph nodes, indicative of cellular immunodeficiency
• Skin abnormalities (eg, alopecia, eczema, pyoderma, telangiectasia)
• Evidence of hematologic disease (eg, pallor, petechiae, jaundice, mouth ulcers)
• Generalized lymphadenopathy and splenomegaly, which may suggest HIV infection or Hodgkin lymphoma

Lymphocytopenic patients experience recurrent infections or develop infections with unusual organisms. Pneumocystis jirovecii, cytomegalovirus, rubeola, and varicella pneumonias often are fatal. Lymphocytopenia is also a risk factor for the development of cancers and for autoimmune disorders.

Diagnosis of Lymphocytopenia

• Clinical suspicion (repeated or unusual infections)
• Complete blood count with differential
• Measurement of lymphocyte subpopulations and immunoglobulin levels

Lymphocytopenia is suspected in patients with recurrent viral, fungal, or parasitic infections but is usually detected incidentally on a complete blood count. P. jirovecii, cytomegalovirus, rubeola, or varicella pneumonias with lymphocytopenia suggest immunodeficiency. Lymphocyte subpopulations are measured in patients with lymphocytopenia. Measurement of immunoglobulin levels should also be done to evaluate antibody production. Patients with a history of recurrent infections undergo complete laboratory evaluation for immunodeficiency, even if initial screening tests are normal.

Treatment of Lymphocytopenia

• Treatment of associated infections
• Treatment of underlying disorder
• Sometimes IV immune globulin
• Possibly hematopoietic stem cell transplantation

In acquired lymphocytopenias, lymphocytopenia usually remits with removal of the underlying factor or successful treatment of the underlying disorder. IV immune globulin is indicated if patients have chronic IgG deficiency, lymphocytopenia, and recurrent infections. Hematopoietic stem cell transplantation can be considered for all patients with congenital immunodeficiencies and may be curative.

What does increase white blood cells mean ?

A high white blood cell count is also called leukocytosis. A high white blood cell count is an increase in disease-fighting cells in your blood.

The exact threshold for a high white blood cell count varies from one laboratory to another. The normal range for white blood cell counts changes with age and pregnancy (Table 1).  In general, for nonpregnant adults a count of more than 11,000 per mm³ (11.0 × 10⁹ per L) white blood cells (leukocytes) in a microliter of blood is considered a high white blood cell count ¹⁶.

Leukocytosis in the range of approximately 50,000 to 100,000 per mm³ (50.0 to 100.0 × 10⁹ per L) is sometimes referred to as a leukemoid reaction. This level of elevation can occur in some severe infections, such as Clostridium difficile infection, sepsis, organ rejection, or in patients with solid tumors ³. Leukocytosis greater than 100,000 per mm³ is almost always caused by leukemias or myeloproliferative disorders ¹⁷.

The most common type of leukocytosis is neutrophilia (an increase in the absolute number of mature neutrophils to greater than 7,000 per mm³ [7.0 × 10⁹ per L]), which can arise from infections, stressful conditions, chronic inflammation, medication use, and other causes (Table 4) ³, ⁸, ¹⁸, ¹⁹. Lymphocytosis (when lymphocytes make up more than 40% of the white blood cell count or the absolute count is greater than 4,500 per mm³ [4.5 × 10⁹ per L]) can occur in patients with pertussis, syphilis, viral infections, hypersensitivity reactions, and certain subtypes of leukemia or lymphoma. Lymphocytosis is more likely to be benign in children than in adults ⁵. Epstein-Barr virus infection, tuberculosis or fungal disease, autoimmune disease, splenectomy, protozoan or rickettsial infections, and malignancy can cause monocytosis (monocytes make up more than 8% of the white blood cell count or the absolute count is greater than 880 per mm³ [0.88 × 10⁹ per L]) ⁹.

Eosinophilia (eosinophil absolute count greater than 500 per mm³ [0.5 × 10⁹ per L]), although uncommon, may suggest allergic conditions such as asthma, urticaria, atopic dermatitis or eosinophilic esophagitis, drug reactions, dermatologic conditions, malignancies, connective tissue disease, idiopathic hypereosinophilic syndrome, or parasitic infections, including helminths (tissue parasites more than gut-lumen parasites) ²⁰, ²¹. Isolated basophilia (number of basophils greater than 100 per mm³ [0.1 × 10⁹ per L]) is rare and unlikely to cause leukocytosis in isolation, but it can occur with allergic or inflammatory conditions and chronic myelogenous leukemia ²² (Table 5).

A high white blood cell count is usually found when your doctor orders tests to help diagnose a condition you’re already experiencing. It’s rarely an unexpected finding or simply discovered by chance.

Speak to your doctor about what these results mean. A high white blood cell count, along with results from other tests, might already indicate the cause of your illness. Or your doctor may suggest other tests to further evaluate your condition.

Nonmalignant Causes of of Raised White Blood Cell

A reactive leukocytosis, typically in the range of 11,000 to 30,000 per mm³ (11.0 to 30.0 × 10⁹ per L), can arise from a variety of etiologies. Any source of stress can cause a catecholamine-induced demargination of white blood cells, as well as increased release from the bone marrow storage pool. Examples include surgery, exercise, trauma, burns, and emotional stress.9 One study showed an average increase in white blood cells of 2,770 per mm³ (2.77 × 10⁹ per L) peaking on postoperative day 2 after knee or hip arthroplasty.10 Medications known to increase the white blood cell count include corticosteroids, lithium, colony-stimulating factors, beta agonists, and epinephrine. During the recovery phase after hemorrhage or hemolysis, a rebound leukocytosis can occur.

Leukocytosis is one of the hallmarks of infection. In the acute stage of many bacterial infections, there are primarily mature and immature neutrophils; sometimes, as the infection progresses, there is a shift to lymphocyte predominance. The release of less-mature bands and metamyelocytes into the peripheral circulation results in the so-called “left shift” in the white blood cell differential. Of note, some bacterial infections paradoxically cause neutropenias, such as typhoid fever, rickettsial infections, brucellosis, and dengue ³, ²³. Viral infections may cause leukocytosis early in their course, but a sustained leukocytosis is not typical, except for the lymphocytosis in some childhood viral infections.

An elevated white blood cell count is a suggestive, but not definitive, marker of the presence of significant infection. For example, the sensitivity and specificity of an elevated white blood cell count in diagnosing acute appendicitis are 62% and 75%, respectively ²⁴, ²⁵. For diagnosing serious bacterial infections without a source in febrile children, the discriminatory value of leukocytosis is less than that of other biomarkers, such as C-reactive protein or procalcitonin ²⁶. Although a WBC count greater than 12,000 per mm³ (12.0 × 10⁹ per L) is one of the criteria for the systemic inflammatory response syndrome (or sepsis when there is a known infection), leukocytosis alone is a poor predictor of bacteremia and not an indication for obtaining blood cultures ²⁷, ²⁸.

Other acquired causes of leukocytosis include functional asplenia (predominantly lymphocytosis), smoking, and obesity. Patients with a chronic inflammatory condition, such as rheumatoid arthritis, inflammatory bowel disease, or a granulomatous disease, may also exhibit leukocytosis. Genetic causes include hereditary or chronic idiopathic neutrophilia and Down syndrome.

Table 4. Nonmalignant Causes of Neutrophilia

Table 5. Selected Conditions Associated with Elevations in Certain White Blood Cell Types

Causes of high white blood cells

A high white blood cell count usually indicates ¹⁶:

• An increased production of white blood cells to fight an infection
• A reaction to a drug that increases white blood cell production
• A disease of bone marrow, causing abnormally high production of white blood cells
• An immune system disorder that increases white blood cell production

Specific causes of a high white blood cell count include ¹⁶:

• Acute lymphocytic leukemia
• Acute myelogenous leukemia (AML)
• Allergy, especially severe allergic reactions
• Chronic lymphocytic leukemia
• Chronic myelogenous leukemia
• Drugs, such as corticosteroids and epinephrine
• Infections, bacterial or viral
• Myelofibrosis
• Polycythemia vera
• Rheumatoid arthritis
• Smoking
• Stress, such as severe emotional or physical stress
• Tuberculosis
• Whooping cough.

Malignant Causes of Raised White Blood Cells

Leukocytosis may herald a malignant disorder, such as an acute or chronic leukemia or a myeloproliferative disorder, such as polycythemia vera, myelofibrosis, or essential thrombocytosis ³⁰. Many solid tumors may lead to a leukocytosis in the leukemoid range, either through bone marrow involvement or production of granulocyte colony-stimulating or granulocyte-macrophage colony-stimulating factors ³¹. Chronic leukemias are most commonly diagnosed after incidental findings of leukocytosis on complete blood counts in asymptomatic patients. Patients with features suggestive of hematologic malignancies require prompt referral to a hematologist/oncologist (Table 6) ³².

Table 6. Findings Suggestive of Blood Cancers in the Setting of Leukocytosis

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What are red blood cells

Blood transports a variety of materials between interior body cells and those that exchange substances with the external environment. In this way, blood helps maintain stable internal environmental conditions. Blood is composed of formed elements suspended in a fluid extracellular matrix called blood plasma. The “formed elements” include red blood cells, white blood cells, and cell fragments called platelets (Figure 2). Most blood cells form in red marrow within the hollow parts of certain long bones.

Most blood samples are roughly 37% to 49% red blood cells by volume – adult females is 38–46% (average = 42%) and for adult males, it is 40–54% (average = 47). This percentage is called the hematocrit. The white blood cells and platelets account for less than 1% of blood volume. The remaining blood sample, about 55%, is the plasma, a clear, straw-colored liquid. Blood plasma is a complex mixture of water, gases, amino acids, proteins, carbohydrates, lipids, vitamins, hormones, electrolytes, and cellular wastes (see Figure 1).

Blood volume varies with body size, percent adipose tissue, and changes in fluid and electrolyte concentrations. An average-size adult has a blood volume of about 5 liters (5.3 quarts), 4–5 liters in a female and 5–6 liters in a male.

Red blood cell (also called erythrocyte) is biconcave disc without a nucleus. This biconcave shape is an adaptation for transporting the gases oxygen and carbon dioxide. It increases the surface area through which oxygen and carbon dioxide can diffuse into and out of the cell (Figures 4 and 5). The characteristic shape of a red blood cell also places the cell membrane closer to oxygen-carrying hemoglobin (Figure 5) molecules in the cell reducing the distance for diffusion.

Each red blood cell is about one-third hemoglobin by volume. This protein imparts the color of blood. When hemoglobin binds oxygen, the resulting oxyhemoglobin is bright red, and when oxygen is released, the resulting deoxyhemoglobin is darker.

Prolonged oxygen deficiency (hypoxia) causes cyanosis, in which the skin and mucous membranes appear bluish due to an abnormally high blood concentration of deoxyhemoglobin in the superficial blood vessels. Exposure to low temperature may also result in cyanosis by constricting superficial blood vessels. This response to environmental change slows skin blood flow. As a result, more oxygen than usual is removed from the blood flowing through the vessels, increasing the concentration of deoxyhemoglobin.

Note: Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Figure 1. Blood composition

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Red Blood Cell Counts

The number of red blood cells in a microliter (μL or mcL or 1 mm³) of blood is called the red blood cell count (RBCC or RCC). This number varies from time to time even in healthy individuals. However, the typical range for adult males is 4,700,000 to 6,100,000 cells per microliter, and that for adult females is 4,200,000 to 5,400,000 cells per microliter.

The absolute numbers for red blood cell, white blood cell, and platelet counts can vary depending on how they are measured and the instruments used to measure them. For this reason, different sources may present different, but very similar, ranges of normal values.

An increase in the number of circulating red blood cells increases the blood’s oxygen-carrying capacity, much as a decrease in the number of circulating red blood cells decreases the blood’s oxygen-carrying capacity. Changes in this number may affect health. For this reason, red blood cell counts are routinely consulted to help diagnose and evaluate the courses of certain diseases.

Blood Cell Formation

The process of blood cell formation, called hematopoiesis, begins in the yolk sac, which lies outside the human embryo. Later in the fetal development, red blood cells are manufactured (erythropoiesis) in the liver and spleen, and still later they form in bone marrow. After birth, these cells are produced in the red bone marrow.

Bone marrow is a soft, netlike mass of connective tissue within the medullary cavities of long bones, in the irregular spaces of spongy bone, and in the larger central canals of compact bone tissue. It is of two kinds: red and yellow. Red bone marrow functions in the formation of red blood cells (erythrocytes), white blood cells (leukocytes), and blood platelets. The color comes from the oxygen-carrying pigment hemoglobin in the red blood cells.

In an infant, red marrow occupies the cavities of most bones. As a person ages, yellow bone marrow, which stores fat, replaces much of the red marrow. Yellow marrow is not active in blood cell production. In an adult, red marrow is primarily found in the spongy bone of the skull, ribs, breastbone (sternum), collarbones (clavicles), backbones (vertebrae), and hip bones. If the supply of blood cells is deficient, some yellow marrow may become red marrow, which then reverts to yellow marrow when the deficiency is corrected.

Figure 3 illustrates the stages in the formation of red blood cells from hematopoietic stem cells (blood-forming cells), which are also called hemocytoblasts.

Red blood cells have nuclei during their early stages of development but lose their nuclei as the cells mature. Losing the nuclei provides more space for hemoglobin. Because mature red blood cells do not have nuclei, they cannot divide. They use none of the oxygen they carry because they do not have mitochondria. Mature red blood cells produce ATP through glycolysis only.

The average life span of a red blood cell is 120 days. Many of these cells are removed from the circulation each day, and yet the number of cells in the circulating blood remains relatively stable. This observation suggests a homeostatic control of the rate of red blood cell production.

The hormone erythropoietin (EPO) controls the rate of red blood cell formation through negative feedback. The kidneys, and to a lesser extent the liver, release erythropoietin in response to prolonged oxygen deficiency (Figure 6). At high altitudes, for example, where the amount of oxygen in the air is reduced, the blood oxygen level initially decreases. This drop in the blood oxygen level triggers the release of erythropoietin, which travels via the blood to the red bone marrow and stimulates red blood cell production.

After a few days of exposure to high altitudes, many newly formed red blood cells appear in the circulating blood. The increased rate of production continues until the number of erythrocytes in the circulation is sufficient to supply tissues with oxygen. When the availability of oxygen returns to normal, erythropoietin release decreases, and the rate of red blood cell production returns to normal as well. An excessive increase in red blood cells is called polycythemia. This condition increases blood viscosity, slowing blood flow and impairing circulation.

Figure 2. Bone marrow anatomy

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Dietary Factors Affecting Red Blood Cell Production

Availability of B-complex vitamins—vitamin B12 and folic acid—significantly influences red blood cell production. Because these vitamins are required for DNA synthesis, they are necessary for the growth and division of cells. Cell division is frequent in blood-forming (hematopoietic) tissue, so this tissue is especially vulnerable to a deficiency of either of these vitamins.

Hemoglobin synthesis and normal red blood cell production also require iron. The small intestine absorbs iron slowly from food. The body reuses much of the iron released by the decomposition of hemoglobin from damaged red blood cells. Nonetheless, insufficient dietary iron can reduce hemoglobin synthesis.

A deficiency of red blood cells or a reduction in the amount of hemoglobin they contain results in a condition called anemia. This reduces the oxygen-carrying capacity of the blood, and the affected person may appear pale and lack energy. A pregnant woman may have a normal number of red blood cells, but she develops a relative anemia because her plasma volume increases due to fluid retention. This shows up as a decreased hematocrit.

In contrast to anemia, the inherited disorder called hemochromatosis results in the absorption of iron in the small intestine at ten times the normal rate. Iron builds up in organs, to toxic levels. Treatment is periodic blood removal, as often as every week.

Figure 3. Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell

Figure 4. Blood cells

Note: Blood tissue consists of red blood cells, white blood cells, and platelets suspended in plasma. (a) Idealized representation of a sample of blood. (b) Micrograph of a sample of blood (1,000x).

Figure 5. Red blood cells

What is the function of red blood cells

Red blood cells function is to transports oxygen and carbon dioxide. to body tissues by blood flow via circulatory system. Red blood cells take oxygen from the lungs and release it into the cells or tissues. Lipids and proteins make up the cell membrane of red blood cells. Hemoglobin, an iron containing biomolecule, is the rich component of the cytoplasm of red blood cells mainly responsible for the oxygen binding and red color of the erythrocytes (see Figure 6).

Figure 6. Red blood cell formation

Note: Low blood oxygen causes the kidneys and to a lesser degree, the liver to release erythropoietin. Erythropoietin stimulates target cells in the red bone marrow to increase the production of red blood cells, which carry oxygen to tissues.

Destruction of Red Blood Cells

The average life span of red blood cells is about four months (120 days) after which it breaks down. Red blood cells are elastic and flexible, and they readily bend as they pass through small blood vessels. As the cells near the end of their four-month life span, however, they become more fragile. The cells may sustain damage simply passing through capillaries, particularly those in active muscles that must withstand strong forces. Macrophages phagocytize and destroy damaged red blood cells, primarily in the liver and spleen. Macrophages are large, phagocytic, wandering cells. During phagocytosis, the iron from the hemoglobin is retained in the liver and spleen cells and is again used in the formation of red blood cells in the body. About 2-10 million red blood cells are formed and destroyed each second in a normal person.

Hemoglobin molecules liberated from red blood cells break down into their four component polypeptide “globin” chains, each surrounding a heme group. The heme further decomposes into iron and a greenish pigment called biliverdin. The blood may transport the iron, combined with a protein, to the hematopoietic tissue in red bone marrow to be reused in synthesizing new hemoglobin. About 80% of the iron is stored in the liver in the form of an iron-protein complex. Biliverdin eventually is converted to an orange-yellow pigment called bilirubin. Biliverdin and bilirubin are secreted in the bile as bile pigments. Figure 7 summarizes the life cycle of a red blood cell.

In jaundice (yellow discoloration of the skin and the whites of the eyes), accumulation of bilirubin turns the skin and eyes yellowish. Newborns can develop physiologic jaundice a few days after birth. This condition may be the result of immature liver cells that ineffectively secrete bilirubin into the bile. Treatment includes exposure to fluorescent light, which breaks down bilirubin in the tissues, and feedings that promote bowel movements. In hospital nurseries, babies being treated for physiological jaundice lie under “bili lights,” clad only in diapers and protective goggles.

Figure 7. Red blood cell hemoglobin

Figure 8. Lifecycle of a red blood cell

What happens when you have low red blood cells (Anemia)

Anemia is a condition in which your blood has a lower than normal number of red blood cells ¹.

Anemia also can occur if your red blood cells don’t contain enough hemoglobin. Hemoglobin is an iron-rich protein that gives blood its red color. This protein helps red blood cells carry oxygen from the lungs to the rest of the body.

Anemia has three main causes ¹:

1. Blood loss,
2. Lack of red blood cell production, or
3. High rates of red blood cell destruction.

These causes might be the result of diseases, conditions, or other factors.

If you have anemia, your body doesn’t get enough oxygen-rich blood. As a result, you may appear pale, feel tired or weak. You also may have other symptoms, such as shortness of breath, dizziness, or headaches.

Severe or long-lasting anemia can damage your heart, brain, and other organs in your body. Very severe anemia may even cause death ¹.

Many types of anemia can be mild, short term, and easily treated. You can even prevent some types with a healthy diet. Other types can be treated with dietary supplements.

However, certain types of anemia can be severe, long lasting, and even life threatening if not diagnosed and treated.

If you have signs or symptoms of anemia, see your doctor to find out whether you have the condition. Treatment will depend on the cause of the anemia and how severe it is.

There are many types of anemia with specific causes and traits.

Some of these include:

• Aplastic anemia
• Blood loss anemia
• Cooley’s anemia
• Diamond-Blackfan anemia
• Fanconi anemia
• Folate- or folic acid-deficiency anemia
• Hemolytic anemia
• Iron-deficiency anemia
• Pernicious anemia
• Sickle cell anemia
• Thalassemias; Cooley’s anemia is another name for beta thalassemia major

What Causes Anemia ?

The three main causes of anemia are:

1. Blood loss.
2. Lack of red blood cell production.
3. High rates of red blood cell destruction.

For some people, the condition is caused by more than one of these factors.

Blood Loss

Blood loss is the most common cause of anemia, especially iron-deficiency anemia. Blood loss can be short term or persist over time.

Heavy menstrual periods or bleeding in the digestive or urinary tract can cause blood loss. Surgery, trauma, or cancer also can cause blood loss.

If a lot of blood is lost, the body may lose enough red blood cells to cause anemia.

Lack of Red Blood Cell Production

Both acquired and inherited conditions and factors can prevent your body from making enough red blood cells. “Acquired” means you aren’t born with the condition, but you develop it. “Inherited” means your parents passed the gene for the condition on to you.

Acquired conditions and factors that can lead to anemia include poor diet, abnormal hormone levels, some chronic (ongoing) diseases, and pregnancy.

Aplastic anemia also can prevent your body from making enough red blood cells. This condition can be acquired or inherited.

Diet

A diet that lacks iron, folic acid (folate), or vitamin B12 can prevent your body from making enough red blood cells. Your body also needs small amounts of vitamin C, riboflavin, and copper to make red blood cells.

Conditions that make it hard for your body to absorb nutrients also can prevent your body from making enough red blood cells.

Hormones

Your body needs the hormone erythropoietin to make red blood cells. This hormone stimulates the bone marrow to make these cells. A low level of this hormone can lead to anemia.

Diseases and Disease Treatments

Chronic diseases, like kidney disease and cancer, can make it hard for your body to make enough red blood cells.

Some cancer treatments may damage the bone marrow or damage the red blood cells’ ability to carry oxygen. If the bone marrow is damaged, it can’t make red blood cells fast enough to replace the ones that die or are destroyed.

People who have HIV/AIDS may develop anemia due to infections or medicines used to treat their diseases.

Pregnancy

Anemia can occur during pregnancy due to low levels of iron and folic acid and changes in the blood.

During the first 6 months of pregnancy, the fluid portion of a woman’s blood (the plasma) increases faster than the number of red blood cells. This dilutes the blood and can lead to anemia.

Aplastic Anemia

Some infants are born without the ability to make enough red blood cells. This condition is called aplastic anemia. Infants and children who have aplastic anemia often need blood transfusions to increase the number of red blood cells in their blood.

Acquired conditions or factors, such as certain medicines, toxins, and infectious diseases, also can cause aplastic anemia.

High Rates of Red Blood Cell Destruction

Both acquired and inherited conditions and factors can cause your body to destroy too many red blood cells. One example of an acquired condition is an enlarged or diseased spleen.

The spleen is an organ that removes wornout red blood cells from the body. If the spleen is enlarged or diseased, it may remove more red blood cells than normal, causing anemia.

Examples of inherited conditions that can cause your body to destroy too many red blood cells include sickle cell anemia, thalassemias, and lack of certain enzymes. These conditions create defects in the red blood cells that cause them to die faster than healthy red blood cells.

Hemolytic anemia is another example of a condition in which your body destroys too many red blood cells. Inherited or acquired conditions or factors can cause hemolytic anemia. Examples include immune disorders, infections, certain medicines, or reactions to blood transfusions.

Who Is at Risk for Anemia ?

Anemia is a common condition. It occurs in all age, racial, and ethnic groups. Both men and women can have anemia. However, women of childbearing age are at higher risk for the condition because of blood loss from menstruation.

Anemia can develop during pregnancy due to low levels of iron and folic acid (folate) and changes in the blood. During the first 6 months of pregnancy, the fluid portion of a woman’s blood (the plasma) increases faster than the number of red blood cells. This dilutes the blood and can lead to anemia.

During the first year of life, some babies are at risk for anemia because of iron deficiency. At-risk infants include those who are born too early and infants who are fed breast milk only or formula that isn’t fortified with iron. These infants can develop iron deficiency by 6 months of age.

Infants between 1 and 2 years of age also are at risk for anemia. They may not get enough iron in their diets, especially if they drink a lot of cow’s milk. Cow’s milk is low in the iron needed for growth.

Drinking too much cow’s milk may keep an infant or toddler from eating enough iron-rich foods or absorbing enough iron from foods.

Older adults also are at increased risk for anemia. Researchers continue to study how the condition affects older adults. Many of these people have other medical conditions as well.

Major Risk Factors

Factors that raise your risk for anemia include:

• A diet that is low in iron, vitamins, or minerals
• Blood loss from surgery or an injury
• Long-term or serious illnesses, such as kidney disease, cancer, diabetes, rheumatoid arthritis, HIV/AIDS, inflammatory bowel disease (including Crohn’s disease), liver disease, heart failure, and thyroid disease
• Long-term infections
• A family history of inherited anemia, such as sickle cell anemia or thalassemia

What Are the Signs and Symptoms of Anemia ?

The most common symptom of anemia is fatigue (feeling tired or weak). If you have anemia, you may find it hard to find the energy to do normal activities.

Other signs and symptoms of anemia include:

• Shortness of breath
• Dizziness
• Headache
• Coldness in the hands and feet
• Pale skin
• Chest pain

These signs and symptoms can occur because your heart has to work harder to pump oxygen-rich blood through your body.

Mild to moderate anemia may cause very mild symptoms or none at all.

Complications of Anemia

Some people who have anemia may have arrhythmias. Arrhythmias are problems with the rate or rhythm of the heartbeat. Over time, arrhythmias can damage your heart and possibly lead to heart failure.

Anemia also can damage other organs in your body because your blood can’t get enough oxygen to them.

Anemia can weaken people who have cancer or HIV/AIDS. This can make their treatments not work as well.

Anemia also can cause many other health problems. People who have kidney disease and anemia are more likely to have heart problems. With some types of anemia, too little fluid intake or too much loss of fluid in the blood and body can occur. Severe loss of fluid can be life threatening.

How Is Anemia Diagnosed ?

Your doctor will diagnose anemia based on your medical and family histories, a physical exam, and results from tests and procedures.

Because anemia doesn’t always cause symptoms, your doctor may find out you have it while checking for another condition.

Medical and Family Histories

Your doctor may ask whether you have any of the common signs or symptoms of anemia. He or she also may ask whether you’ve had an illness or condition that could cause anemia.

Let your doctor know about any medicines you take, what you typically eat (your diet), and whether you have family members who have anemia or a history of it.

Physical Exam

Your doctor will do a physical exam to find out how severe your anemia is and to check for possible causes. He or she may:

• Listen to your heart for a rapid or irregular heartbeat
• Listen to your lungs for rapid or uneven breathing
• Feel your abdomen to check the size of your liver and spleen

Your doctor also may do a pelvic or rectal exam to check for common sources of blood loss.

Diagnostic Tests and Procedures

You may have various blood tests and other tests or procedures to find out what type of anemia you have and how severe it is.

Complete Blood Count

Often, the first test used to diagnose anemia is a complete blood count (CBC). The CBC measures many parts of your blood.

The test checks your hemoglobin and hematocrit levels. Hemoglobin is the iron-rich protein in red blood cells that carries oxygen to the body. Hematocrit is a measure of how much space red blood cells take up in your blood. A low level of hemoglobin or hematocrit is a sign of anemia.

The normal range of these levels might be lower in certain racial and ethnic populations. Your doctor can explain your test results to you.

The CBC also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal results might be a sign of anemia, another blood disorder, an infection, or another condition.

Finally, the CBC looks at mean corpuscular volume (MCV). MCV is a measure of the average size of your red blood cells and a clue as to the cause of your anemia. In iron-deficiency anemia, for example, red blood cells usually are smaller than normal.

Other Tests and Procedures

If the CBC results show that you have anemia, you may need other tests, such as:

• Hemoglobin electrophoresis. This test looks at the different types of hemoglobin in your blood. The test can help diagnose the type of anemia you have.
• A reticulocyte count. This test measures the number of young red blood cells in your blood. The test shows whether your bone marrow is making red blood cells at the correct rate.
• Tests for the level of iron in your blood and body. These tests include serum iron and serum ferritin tests. Transferrin level and total iron-binding capacity tests also measure iron levels.

Because anemia has many causes, you also might be tested for conditions such as kidney failure, lead poisoning (in children), and vitamin deficiencies (lack of vitamins, such as B12 and folic acid).

If your doctor thinks that you have anemia due to internal bleeding, he or she may suggest several tests to look for the source of the bleeding. A test to check the stool for blood might be done in your doctor’s office or at home. Your doctor can give you a kit to help you get a sample at home. He or she will tell you to bring the sample back to the office or send it to a laboratory.

If blood is found in the stool, you may have other tests to find the source of the bleeding. One such test is endoscopy. For this test, a tube with a tiny camera is used to view the lining of the digestive tract.

Your doctor also may want to do bone marrow tests. These tests show whether your bone marrow is healthy and making enough blood cells.

How Is Anemia Treated ?

Treatment for anemia depends on the type, cause, and severity of the condition. Treatments may include dietary changes or supplements, medicines, procedures, or surgery to treat blood loss.

Goals of Treatment

The goal of treatment is to increase the amount of oxygen that your blood can carry. This is done by raising the red blood cell count and/or hemoglobin level. (Hemoglobin is the iron-rich protein in red blood cells that carries oxygen to the body.)

Another goal is to treat the underlying cause of the anemia.

Dietary Changes and Supplements

Low levels of vitamins or iron in the body can cause some types of anemia. These low levels might be the result of a poor diet or certain diseases or conditions.

To raise your vitamin or iron level, your doctor may ask you to change your diet or take vitamin or iron supplements. Common vitamin supplements are vitamin B12 and folic acid (folate). Vitamin C sometimes is given to help the body absorb iron.

Iron

Your body needs iron to make hemoglobin. Your body can more easily absorb iron from meats than from vegetables or other foods. To treat your anemia, your doctor may suggest eating more meat—especially red meat (such as beef or liver), as well as chicken, turkey, pork, fish, and shellfish.

Nonmeat foods that are good sources of iron include:

• Spinach and other dark green leafy vegetables
• Tofu
• Peas; lentils; white, red, and baked beans; soybeans; and chickpeas
• Dried fruits, such as prunes, raisins, and apricots
• Prune juice
• Iron-fortified cereals and breads

You can look at the Nutrition Facts label on packaged foods to find out how much iron the items contain. The amount is given as a percentage of the total amount of iron you need every day.

Iron also is available as a supplement. It’s usually combined with multivitamins and other minerals that help your body absorb iron.

Doctors may recommend iron supplements for premature infants, infants and young children who drink a lot of cow’s milk, and infants who are fed breast milk only or formula that isn’t fortified with iron.

Large amounts of iron can be harmful, so take iron supplements only as your doctor prescribes.

Vitamin B12

Low levels of vitamin B12 can lead to pernicious anemia. This type of anemia often is treated with vitamin B12 supplements.

Good food sources of vitamin B12 include:

• Breakfast cereals with added vitamin B12
• Meats such as beef, liver, poultry, and fish
• Eggs and dairy products (such as milk, yogurt, and cheese)
• Foods fortified with vitamin B12, such as soy-based beverages and vegetarian burgers

Folic Acid

Folic acid (folate) is a form of vitamin B that’s found in foods. Your body needs folic acid to make and maintain new cells. Folic acid also is very important for pregnant women. It helps them avoid anemia and promotes healthy growth of the fetus.

Good sources of folic acid include:

• Bread, pasta, and rice with added folic acid
• Spinach and other dark green leafy vegetables
• Black-eyed peas and dried beans
• Beef liver
• Eggs
• Bananas, oranges, orange juice, and some other fruits and juices

Vitamin C

Vitamin C helps the body absorb iron. Good sources of vitamin C are vegetables and fruits, especially citrus fruits. Citrus fruits include oranges, grapefruits, tangerines, and similar fruits. Fresh and frozen fruits, vegetables, and juices usually have more vitamin C than canned ones.

If you’re taking medicines, ask your doctor or pharmacist whether you can eat grapefruit or drink grapefruit juice. This fruit can affect the strength of a few medicines and how well they work.

Other fruits rich in vitamin C include kiwi fruit, strawberries, and cantaloupes.

Vegetables rich in vitamin C include broccoli, peppers, Brussels sprouts, tomatoes, cabbage, potatoes, and leafy green vegetables like turnip greens and spinach.

Medicines

Your doctor may prescribe medicines to help your body make more red blood cells or to treat an underlying cause of anemia. Some of these medicines include:

• Antibiotics to treat infections.
• Hormones to treat heavy menstrual bleeding in teenaged and adult women.
• A man-made version of erythropoietin to stimulate your body to make more red blood cells. This hormone has some risks. You and your doctor will decide whether the benefits of this treatment outweigh the risks.
• Medicines to prevent the body’s immune system from destroying its own red blood cells.
• Chelation therapy for lead poisoning. Chelation therapy is used mainly in children. This is because children who have iron-deficiency anemia are at increased risk of lead poisoning.

Procedures

If your anemia is severe, your doctor may recommend a medical procedure. Procedures include blood transfusions and blood and marrow stem cell transplants.

Blood Transfusion

A blood transfusion is a safe, common procedure in which blood is given to you through an intravenous (IV) line in one of your blood vessels. Transfusions require careful matching of donated blood with the recipient’s blood.

For more information, see Blood Transfusion topic below.

Blood and Marrow Stem Cell Transplant

A blood and marrow stem cell transplant replaces your faulty stem cells with healthy ones from another person (a donor). Stem cells are made in the bone marrow. They develop into red and white blood cells and platelets.

During the transplant, which is like a blood transfusion, you get donated stem cells through a tube placed in a vein in your chest. Once the stem cells are in your body, they travel to your bone marrow and begin making new blood cells.

Surgery

If you have serious or life-threatening bleeding that’s causing anemia, you may need surgery. For example, you may need surgery to control ongoing bleeding due to a stomach ulcer or colon cancer.

If your body is destroying red blood cells at a high rate, you may need to have your spleen removed. The spleen is an organ that removes wornout red blood cells from the body. An enlarged or diseased spleen may remove more red blood cells than normal, causing anemia.

What Is Iron-Deficiency Anemia ?

Iron-deficiency anemia is a common, easily treated condition that occurs if you don’t have enough iron in your body. Low iron levels usually are due to blood loss, poor diet, or an inability to absorb enough iron from food ².

Iron-deficiency anemia usually develops over time if your body doesn’t have enough iron to build healthy red blood cells. Without enough iron, your body starts using the iron it has stored. Soon, the stored iron gets used up.

After the stored iron is gone, your body makes fewer red blood cells. The red blood cells it does make have less hemoglobin than normal.

Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and other symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in children, and other complications.

Infants and young children and women are the two groups at highest risk for iron-deficiency anemia.

Doctors usually can successfully treat iron-deficiency anemia. Treatment will depend on the cause and severity of the condition. Treatments may include dietary changes, medicines, and surgery.

Severe iron-deficiency anemia may require treatment in a hospital, blood transfusions, iron injections, or intravenous iron therapy.

What Causes Iron-Deficiency Anemia ?

Not having enough iron in your body causes iron-deficiency anemia. Lack of iron usually is due to blood loss, poor diet, or an inability to absorb enough iron from food.

Blood Loss

When you lose blood, you lose iron. If you don’t have enough iron stored in your body to make up for the lost iron, you’ll develop iron-deficiency anemia.

In women, long or heavy menstrual periods or bleeding fibroids in the uterus may cause low iron levels. Blood loss that occurs during childbirth is another cause of low iron levels in women.

Internal bleeding (bleeding inside the body) also may lead to iron-deficiency anemia. This type of blood loss isn’t always obvious, and it may occur slowly. Some causes of internal bleeding are:

• A bleeding ulcer, colon polyp, or colon cancer
• Regular use of aspirin or other pain medicines, such as nonsteroidal anti-inflammatory drugs (for example, ibuprofen and naproxen)
• Urinary tract bleeding

Blood loss from severe injuries, surgery, or frequent blood drawings also can cause iron-deficiency anemia.

Poor Diet

The best sources of iron are meat, poultry, fish, and iron-fortified foods (foods that have iron added). If you don’t eat these foods regularly, or if you don’t take an iron supplement, you’re more likely to develop iron-deficiency anemia.

Vegetarian diets can provide enough iron if you eat the right foods. For example, good nonmeat sources of iron include iron-fortified breads and cereals, beans, tofu, dried fruits, and spinach and other dark green leafy vegetables.

During some stages of life, such as pregnancy and childhood, it may be hard to get enough iron in your diet. This is because your need for iron increases during these times of growth and development.

Inability To Absorb Enough Iron

Even if you have enough iron in your diet, your body may not be able to absorb it. This can happen if you have intestinal surgery (such as gastric bypass) or a disease of the intestine (such as Crohn’s disease or celiac disease).

Prescription medicines that reduce acid in the stomach also can interfere with iron absorption.

Who Is at Risk for Iron-Deficiency Anemia ?

• Infants and Young Children

Infants and young children need a lot of iron to grow and develop. The iron that full-term infants have stored in their bodies is used up in the first 4 to 6 months of life.

Premature and low-birth-weight babies (weighing less than 5.5 pounds) are at even greater risk for iron-deficiency anemia. These babies don’t have as much iron stored in their bodies as larger, full-term infants.

Iron-fortified baby food or iron supplements, when used properly, can help prevent iron-deficiency anemia in infants and young children. Talk with your child’s doctor about your child’s diet.

Young children who drink a lot of cow’s milk may be at risk for iron-deficiency anemia. Milk is low in iron, and too much milk may take the place of iron-rich foods in the diet. Too much milk also may prevent children’s bodies from absorbing iron from other foods.

Children who have lead in their blood also may be at risk for iron-deficiency anemia. Lead can interfere with the body’s ability to make hemoglobin. Lead may get into the body from breathing in lead dust, eating lead in paint or soil, or drinking water that contains lead.

• Teens

Teens are at risk for iron-deficiency anemia if they’re underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods also are at increased risk for the condition.

• Women

Women of childbearing age are at higher risk for iron-deficiency anemia because of blood loss during their monthly periods. About 1 in 5 women of childbearing age has iron-deficiency anemia.

Pregnant women also are at higher risk for the condition because they need twice as much iron as usual. The extra iron is needed for increased blood volume and for the fetus’ growth.

About half of all pregnant women develop iron-deficiency anemia. The condition can increase a pregnant woman’s risk for a premature or low-birth-weight baby.

• Adults Who Have Internal Bleeding

Adults who have internal bleeding, such as intestinal bleeding, can develop iron-deficiency anemia due to blood loss. Certain conditions, such as colon cancer and bleeding ulcers, can cause blood loss. Some medicines, such as aspirin, also can cause internal bleeding.

• Other At-Risk Groups

People who get kidney dialysis treatment may develop iron-deficiency anemia. This is because blood is lost during dialysis. Also, the kidneys are no longer able to make enough of a hormone that the body needs to produce red blood cells.

People who have gastric bypass surgery also may develop iron-deficiency anemia. This type of surgery can prevent the body from absorbing enough iron.

Certain eating patterns or habits may put you at higher risk for iron-deficiency anemia. This can happen if you:

• Follow a diet that excludes meat and fish, which are the best sources of iron. However, vegetarian diets can provide enough iron if you eat the right foods. For example, good nonmeat sources of iron include iron-fortified breads and cereals, beans, tofu, dried fruits, and spinach and other dark green leafy vegetables.
• Eat poorly because of money, social, health, or other problems.
• Follow a very low-fat diet over a long time. Some higher fat foods, like meat, are the best sources of iron.
• Follow a high-fiber diet. Large amounts of fiber can slow the absorption of iron.

What Are the Signs and Symptoms of Iron-Deficiency Anemia ?

The signs and symptoms of iron-deficiency anemia depend on its severity. Mild to moderate iron-deficiency anemia may have no signs or symptoms.

When signs and symptoms do occur, they can range from mild to severe. Many of the signs and symptoms of iron-deficiency anemia apply to all types of anemia.

• Signs and Symptoms of Anemia

The most common symptom of all types of anemia is fatigue (tiredness). Fatigue occurs because your body doesn’t have enough red blood cells to carry oxygen to its many parts.

Also, the red blood cells your body makes have less hemoglobin than normal. Hemoglobin is an iron-rich protein in red blood cells. It helps red blood cells carry oxygen from the lungs to the rest of the body.

Anemia also can cause shortness of breath, dizziness, headache, coldness in your hands and feet, pale skin, chest pain, weakness, and fatigue (tiredness).

If you don’t have enough hemoglobin-carrying red blood cells, your heart has to work harder to move oxygen-rich blood through your body. This can lead to irregular heartbeats called arrhythmias, a heart murmur, an enlarged heart, or even heart failure.

In infants and young children, signs of anemia include poor appetite, slowed growth and development, and behavioral problems.

• Signs and Symptoms of Iron Deficiency

Signs and symptoms of iron deficiency may include brittle nails, swelling or soreness of the tongue, cracks in the sides of the mouth, an enlarged spleen, and frequent infections.

People who have iron-deficiency anemia may have an unusual craving for nonfood items, such as ice, dirt, paint, or starch. This craving is called pica.

Some people who have iron-deficiency anemia develop restless legs syndrome. Restless legs syndrome is a disorder that causes a strong urge to move the legs. This urge to move often occurs with strange and unpleasant feelings in the legs. People who have restless legs syndrome often have a hard time sleeping.

Iron-deficiency anemia can put children at greater risk for lead poisoning and infections.

Some signs and symptoms of iron-deficiency anemia are related to the condition’s causes. For example, a sign of intestinal bleeding is bright red blood in the stools or black, tarry-looking stools.

Very heavy menstrual bleeding, long periods, or other vaginal bleeding may suggest that a woman is at risk for iron-deficiency anemia.

How Is Iron-Deficiency Anemia Diagnosed ?

Your doctor will diagnose iron-deficiency anemia based on your medical history, a physical exam, and the results from tests and procedures.

Once your doctor knows the cause and severity of the condition, he or she can create a treatment plan for you.

Mild to moderate iron-deficiency anemia may have no signs or symptoms. Thus, you may not know you have it unless your doctor discovers it from a screening test or while checking for other problems.

• Specialists Involved

Primary care doctors often diagnose and treat iron-deficiency anemia. These doctors include pediatricians, family doctors, gynecologists/obstetricians, and internal medicine specialists.

A hematologist (a blood disease specialist), a gastroenterologist (a digestive system specialist), and other specialists also may help treat iron-deficiency anemia.

• Medical History

Your doctor will ask about your signs and symptoms and any past problems you’ve had with anemia or low iron. He or she also may ask about your diet and whether you’re taking any medicines.

If you’re a woman, your doctor may ask whether you might be pregnant.

Physical Exam

Your doctor will do a physical exam to look for signs of iron-deficiency anemia. He or she may:

• Look at your skin, gums, and nail beds to see whether they’re pale
• Listen to your heart for rapid or irregular heartbeats
• Listen to your lungs for rapid or uneven breathing
• Feel your abdomen to check the size of your liver and spleen
• Do a pelvic and rectal exam to check for internal bleeding

Diagnostic Tests and Procedures

Many tests and procedures are used to diagnose iron-deficiency anemia. They can help confirm a diagnosis, look for a cause, and find out how severe the condition is.

Complete Blood Count

Often, the first test used to diagnose anemia is a complete blood count (CBC). The CBC measures many parts of your blood.

This test checks your hemoglobin and hematocrit levels. Hemoglobin is an iron-rich protein in red blood cells that carries oxygen to the body. Hematocrit is a measure of how much space red blood cells take up in your blood. A low level of hemoglobin or hematocrit is a sign of anemia.

The normal range of these levels varies in certain racial and ethnic populations. Your doctor can explain your test results to you.

The CBC also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal results may be a sign of infection, a blood disorder, or another condition.

Finally, the CBC looks at mean corpuscular volume (MCV). MCV is a measure of the average size of your red blood cells. The results may be a clue as to the cause of your anemia. In iron-deficiency anemia, for example, red blood cells usually are smaller than normal.

Other Blood Tests

If the CBC results confirm you have anemia, you may need other blood tests to find out what’s causing the condition, how severe it is, and the best way to treat it.

Reticulocyte count. This test measures the number of reticulocytes in your blood. Reticulocytes are young, immature red blood cells. Over time, reticulocytes become mature red blood cells that carry oxygen throughout your body.

A reticulocyte count shows whether your bone marrow is making red blood cells at the correct rate.

Peripheral smear. For this test, a sample of your blood is examined under a microscope. If you have iron-deficiency anemia, your red blood cells will look smaller and paler than normal.

Tests to measure iron levels. These tests can show how much iron has been used from your body’s stored iron. Tests to measure iron levels include:

• Serum iron. This test measures the amount of iron in your blood. The level of iron in your blood may be normal even if the total amount of iron in your body is low. For this reason, other iron tests also are done.
• Serum ferritin. Ferritin is a protein that helps store iron in your body. A measure of this protein helps your doctor find out how much of your body’s stored iron has been used.
• Transferrin level, or total iron-binding capacity. Transferrin is a protein that carries iron in your blood. Total iron-binding capacity measures how much of the transferrin in your blood isn’t carrying iron. If you have iron-deficiency anemia, you’ll have a high level of transferrin that has no iron.

Other tests. Your doctor also may recommend tests to check your hormone levels, especially your thyroid hormone. You also may have a blood test for a chemical called erythrocyte protoporphyrin. This chemical is a building block for hemoglobin.

Children also may be tested for the level of lead in their blood. Lead can make it hard for the body to produce hemoglobin.

Tests and Procedures for Gastrointestinal Blood Loss

To check whether internal bleeding is causing your iron-deficiency anemia, your doctor may suggest a fecal occult blood test. This test looks for blood in the stools and can detect bleeding in the intestines.

If the test finds blood, you may have other tests and procedures to find the exact spot of the bleeding. These tests and procedures may look for bleeding in the stomach, upper intestines, colon, or pelvic organs.

How Is Iron-Deficiency Anemia Treated ?

Treatment for iron-deficiency anemia will depend on its cause and severity. Treatments may include dietary changes and supplements, medicines, and surgery.

Severe iron-deficiency anemia may require a blood transfusion, iron injections, or intravenous (IV) iron therapy. Treatment may need to be done in a hospital.

The goals of treating iron-deficiency anemia are to treat its underlying cause and restore normal levels of red blood cells, hemoglobin, and iron.

Dietary Changes and Supplements

• Iron

You may need iron supplements to build up your iron levels as quickly as possible. Iron supplements can correct low iron levels within months. Supplements come in pill form or in drops for children.

Large amounts of iron can be harmful, so take iron supplements only as your doctor prescribes. Keep iron supplements out of reach from children. This will prevent them from taking an overdose of iron.

Iron supplements can cause side effects, such as dark stools, stomach irritation, and heartburn. Iron also can cause constipation, so your doctor may suggest that you use a stool softener.

Your doctor may advise you to eat more foods that are rich in iron. The best source of iron is red meat, especially beef and liver. Chicken, turkey, pork, fish, and shellfish also are good sources of iron.

The body tends to absorb iron from meat better than iron from nonmeat foods. However, some nonmeat foods also can help you raise your iron levels. Examples of nonmeat foods that are good sources of iron include:

• Iron-fortified breads and cereals
• Peas; lentils; white, red, and baked beans; soybeans; and chickpeas
• Tofu
• Dried fruits, such as prunes, raisins, and apricots
• Spinach and other dark green leafy vegetables
• Prune juice

The Nutrition Facts labels on packaged foods will show how much iron the items contain. The amount is given as a percentage of the total amount of iron you need every day.

• Vitamin C

Vitamin C helps the body absorb iron. Good sources of vitamin C are vegetables and fruits, especially citrus fruits. Citrus fruits include oranges, grapefruits, tangerines, and similar fruits. Fresh and frozen fruits, vegetables, and juices usually have more vitamin C than canned ones.

If you’re taking medicines, ask your doctor or pharmacist whether you can eat grapefruit or drink grapefruit juice. Grapefruit can affect the strength of a few medicines and how well they work.

Other fruits rich in vitamin C include kiwi fruit, strawberries, and cantaloupes.

Vegetables rich in vitamin C include broccoli, peppers, Brussels sprouts, tomatoes, cabbage, potatoes, and leafy green vegetables like turnip greens and spinach.
Treatment To Stop Bleeding

If blood loss is causing iron-deficiency anemia, treatment will depend on the cause of the bleeding. For example, if you have a bleeding ulcer, your doctor may prescribe antibiotics and other medicines to treat the ulcer.

If a polyp or cancerous tumor in your intestine is causing bleeding, you may need surgery to remove the growth.

If you have heavy menstrual flow, your doctor may prescribe birth control pills to help reduce your monthly blood flow. In some cases, surgery may be advised.

Treatments for Severe Iron-Deficiency Anemia

• Blood Transfusion

If your iron-deficiency anemia is severe, you may get a transfusion of red blood cells. A blood transfusion is a safe, common procedure in which blood is given to you through an IV line in one of your blood vessels. A transfusion requires careful matching of donated blood with the recipient’s blood.

A transfusion of red blood cells will treat your anemia right away. The red blood cells also give a source of iron that your body can reuse. However, a blood transfusion is only a short-term treatment. Your doctor will need to find and treat the cause of your anemia.

Blood transfusions are usually reserved for people whose anemia puts them at a higher risk for heart problems or other severe health issues.

• Iron Therapy

If you have severe anemia, your doctor may recommend iron therapy. For this treatment, iron is injected into a muscle or an IV line in one of your blood vessels.

IV iron therapy presents some safety concerns. It must be done in a hospital or clinic by experienced staff. Iron therapy usually is given to people who need iron long-term but can’t take iron supplements by mouth. This therapy also is given to people who need immediate treatment for iron-deficiency anemia.

What Is Pernicious Anemia ?

Pernicious anemia is a condition in which the body can’t make enough healthy red blood cells because it doesn’t have enough vitamin B12 ³. Without enough vitamin B12, your red blood cells don’t divide normally and are too large. They may have trouble getting out of the bone marrow—a sponge-like tissue inside the bones where blood cells are made.

Pernicious anemia is one of two major types of “macrocystic” or “megaloblastic” (large red blood cell) anemia. These terms refer to anemia in which the red blood cells are larger than normal. The other major type of macrocystic anemia is caused by folic acid deficiency.

Rarely, children are born with an inherited disorder that prevents their bodies from making intrinsic factor. This disorder is called congenital pernicious anemia.

Vitamin B12 deficiency also is called cobalamin deficiency and combined systems disease.

The term “pernicious” means “deadly.” The condition is called pernicious anemia because it often was fatal in the past, before vitamin B12 treatments were available. Now, pernicious anemia usually is easy to treat with vitamin B12 pills or shots.

Vitamin B12 is a nutrient found in some foods. The body needs this nutrient to make healthy red blood cells and to keep its nervous system working properly.

People who have pernicious anemia can’t absorb enough vitamin B12 from food. This is because they lack intrinsic factor, a protein made in the stomach ³. A lack of this protein leads to vitamin B12 deficiency.

Other conditions and factors also can cause vitamin B12 deficiency. Examples include infections, surgery, medicines, and diet. Technically, the term “pernicious anemia” refers to vitamin B12 deficiency due to a lack of intrinsic factor ³. Often though, vitamin B12 deficiency due to other causes also is called pernicious anemia.

Without enough red blood cells to carry oxygen to your body, you may feel tired and weak. Severe or long-lasting pernicious anemia can damage the heart, brain, and other organs in the body ³.

Pernicious anemia also can cause other problems, such as nerve damage, neurological problems (such as memory loss), and digestive tract problems. People who have pernicious anemia also may be at higher risk for weakened bone strength and stomach cancer ³.

With ongoing care and proper treatment, most people who have pernicious anemia can recover, feel well, and live normal lives.

Without treatment, pernicious anemia can lead to serious problems with the heart, nerves, and other parts of the body. Some of these problems may be permanent.

What Causes Pernicious Anemia ?

Pernicious anemia is caused by a lack of intrinsic factor or other causes, such as infections, surgery, medicines, or diet.

Lack of Intrinsic Factor

Intrinsic factor is a protein made in the stomach. It helps your body absorb vitamin B12. In some people, an autoimmune response causes a lack of intrinsic factor.

An autoimmune response occurs if the body’s immune system makes antibodies (proteins) that mistakenly attack and damage the body’s tissues or cells.

In pernicious anemia, the body makes antibodies that attack and destroy the parietal cells. These cells line the stomach and make intrinsic factor. Why this autoimmune response occurs isn’t known.

As a result of this attack, the stomach stops making intrinsic factor. Without intrinsic factor, your body can’t move vitamin B12 through the small intestine, where it’s absorbed. This leads to vitamin B12 deficiency.

A lack of intrinsic factor also can occur if you’ve had part or all of your stomach surgically removed. This type of surgery reduces the number of parietal cells available to make intrinsic factor.

Rarely, children are born with an inherited disorder that prevents their bodies from making intrinsic factor. This disorder is called congenital pernicious anemia.

Other Causes

Pernicious anemia also has other causes, besides a lack of intrinsic factor. Malabsorption in the small intestine and a diet lacking vitamin B12 both can lead to pernicious anemia.

Malabsorption in the Small Intestine

Sometimes pernicious anemia occurs because the body’s small intestine can’t properly absorb vitamin B12. This may be the result of:

• Too many of the wrong kind of bacteria in the small intestine. This is a common cause of pernicious anemia in older adults. The bacteria use up the available vitamin B12 before the small intestine can absorb it.
• Diseases that interfere with vitamin B12 absorption. One example is celiac disease. This is a genetic disorder in which your body can’t tolerate a protein called gluten. Another example is Crohn’s disease, an inflammatory bowel disease. HIV also may interfere with vitamin B12 absorption.
• Certain medicines that alter bacterial growth or prevent the small intestine from properly absorbing vitamin B12. Examples include antibiotics and certain diabetes and seizure medicines.
• Surgical removal of part or all of the small intestine.
• A tapeworm infection. The tapeworm feeds off of the vitamin B12. Eating undercooked, infected fish may cause this type of infection.

Diet Lacking Vitamin B12

Some people get pernicious anemia because they don’t have enough vitamin B12 in their diets. This cause of pernicious anemia is less common than other causes.

Good food sources of vitamin B12 include:

• Breakfast cereals with added vitamin B12
• Meats such as beef, liver, poultry, and fish
• Eggs and dairy products (such as milk, yogurt, and cheese)
• Foods fortified with vitamin B12, such as soy-based beverages and vegetarian burgers

Strict vegetarians who don’t eat any animal or dairy products and don’t take a vitamin B12 supplement are at risk for pernicious anemia.

Breastfed infants of strict vegetarian mothers also are at risk for pernicious anemia. These infants can develop anemia within months of being born. This is because they haven’t had enough time to store vitamin B12 in their bodies. Doctors treat these infants with vitamin B12 supplements.

Other groups, such as the elderly and people who suffer from alcoholism, also may be at risk for pernicious anemia. These people may not get the proper nutrients in their diets.

Who Is at Risk for Pernicious Anemia ?

Pernicious anemia is more common in people of Northern European and African descent than in other ethnic groups.

Older people also are at higher risk for the condition. This is mainly due to a lack of stomach acid and intrinsic factor, which prevents the small intestine from absorbing vitamin B12. As people grow older, they tend to make less stomach acid.

Pernicious anemia also can occur in younger people and other populations. You’re at higher risk for pernicious anemia if you:

• Have a family history of the condition.
• Have had part or all of your stomach surgically removed. The stomach makes intrinsic factor. This protein helps your body absorb vitamin B12.
• Have an autoimmune disorder that involves the endocrine glands, such as Addison’s disease, type 1 diabetes, Graves’ disease, or vitiligo. Research suggests a link may exist between these autoimmune disorders and pernicious anemia that’s caused by an autoimmune response.
• Have had part or all of your small intestine surgically removed. The small intestine is where vitamin B12 is absorbed.
• Have certain intestinal diseases or other disorders that may prevent your body from properly absorbing vitamin B12. Examples include Crohn’s disease, intestinal infections, and HIV.
• Take medicines that prevent your body from properly absorbing vitamin B12. Examples of such medicines include antibiotics and certain seizure medicines.
• Are a strict vegetarian who doesn’t eat any animal or dairy products and doesn’t take a vitamin B12 supplement, or if you eat poorly overall.

What Are the Signs and Symptoms of Pernicious Anemia ?

A lack of vitamin B12 (vitamin B12 deficiency) causes the signs and symptoms of pernicious anemia. Without enough vitamin B12, your body can’t make enough healthy red blood cells, which causes anemia.

Some of the signs and symptoms of pernicious anemia apply to all types of anemia. Other signs and symptoms are specific to a lack of vitamin B12.

• Signs and Symptoms of Anemia

The most common symptom of all types of anemia is fatigue (tiredness). Fatigue occurs because your body doesn’t have enough red blood cells to carry oxygen to its various parts.

A low red blood cell count also can cause shortness of breath, dizziness, headache, coldness in your hands and feet, pale or yellowish skin, and chest pain.

A lack of red blood cells also means that your heart has to work harder to move oxygen-rich blood through your body. This can lead to irregular heartbeats called arrhythmias, heart murmur, an enlarged heart, or even heart failure.

• Signs and Symptoms of Vitamin B12 Deficiency

Vitamin B12 deficiency may lead to nerve damage. This can cause tingling and numbness in your hands and feet, muscle weakness, and loss of reflexes. You also may feel unsteady, lose your balance, and have trouble walking. Vitamin B12 deficiency can cause weakened bones and may lead to hip fractures.

Severe vitamin B12 deficiency can cause neurological problems, such as confusion, dementia, depression, and memory loss.

Other symptoms of vitamin B12 deficiency involve the digestive tract. These symptoms include nausea (feeling sick to your stomach) and vomiting, heartburn, abdominal bloating and gas, constipation or diarrhea, loss of appetite, and weight loss. An enlarged liver is another symptom.

A smooth, thick, red tongue also is a sign of vitamin B12 deficiency and pernicious anemia.

Infants who have vitamin B12 deficiency may have poor reflexes or unusual movements, such as face tremors. They may have trouble feeding due to tongue and throat problems. They also may be irritable. If vitamin B12 deficiency isn’t treated, these infants may have permanent growth problems.

How Is Pernicious Anemia Diagnosed ?

Your doctor will diagnose pernicious anemia based on your medical and family histories, a physical exam, and test results.

Your doctor will want to find out whether the condition is due to a lack of intrinsic factor or another cause. He or she also will want to find out the severity of the condition, so it can be properly treated.

Specialists Involved

Primary care doctors—such as family doctors, internists, and pediatricians (doctors who treat children)—often diagnose and treat pernicious anemia. Other kinds of doctors also may be involved, including:

• A neurologist (nervous system specialist)
• A cardiologist (heart specialist)
• A hematologist (blood disease specialist)
• A gastroenterologist (digestive tract specialist)

Medical and Family Histories

Your doctor may ask about your signs and symptoms. He or she also may ask:

• Whether you’ve had any stomach or intestinal surgeries
• Whether you have any digestive disorders, such as celiac disease or Crohn’s disease
• About your diet and any medicines you take
• Whether you have a family history of anemia or pernicious anemia
• Whether you have a family history of autoimmune disorders (such as Addison’s disease, type 1 diabetes, Graves’ disease, or vitiligo). Research suggests a link may exist between these autoimmune disorders and pernicious anemia that’s caused by an autoimmune response.

Physical Exam

During the physical exam, your doctor may check for pale or yellowish skin and an enlarged liver. He or she may listen to your heart for rapid or irregular heartbeats or a heart murmur.

Your doctor also may check for signs of nerve damage. He or she may want to see how well your muscles, eyes, senses, and reflexes work. Your doctor may ask questions or do tests to check your mental status, coordination, and ability to walk.

Diagnostic Tests and Procedures

Blood tests and procedures can help diagnose pernicious anemia and find out what’s causing it.

• Complete Blood Count

Often, the first test used to diagnose many types of anemia is a complete blood count (CBC). This test measures many parts of your blood. For this test, a small amount of blood is drawn from a vein (usually in your arm) using a needle.

A CBC checks your hemoglobin and hematocrit levels. Hemoglobin is an iron-rich protein that helps red blood cells carry oxygen from the lungs to the rest of the body. Hematocrit is a measure of how much space red blood cells take up in your blood. A low level of hemoglobin or hematocrit is a sign of anemia.

The normal range of these levels may be lower in certain racial and ethnic populations. Your doctor can explain your test results to you.

The CBC also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal results may be a sign of anemia, another blood disorder, an infection, or another condition.

Finally, the CBC looks at mean corpuscular volume (MCV). MCV is a measure of the average size of your red blood cells. MCV can be a clue as to what’s causing your anemia. In pernicious anemia, the red blood cells tend to be larger than normal.

• Other Blood Tests

If the CBC results confirm that you have anemia, you may need other blood tests to find out what type of anemia you have.

A reticulocyte count measures the number of young red blood cells in your blood. The test shows whether your bone marrow is making red blood cells at the correct rate. People who have pernicious anemia have low reticulocyte counts.

Serum folate, iron, and iron-binding capacity tests also can help show whether you have pernicious anemia or another type of anemia.

Another common test, called the Combined Binding Luminescence Test, sometimes gives false results. Scientists are working to develop a more reliable test.

Your doctor may recommend other blood tests to check:

• Your vitamin B12 level. A low level of vitamin B12 in the blood indicates pernicious anemia. However, a falsely normal or high value of vitamin B12 in the blood may occur if antibodies interfere with the test.
• Your homocysteine and methylmalonic acid levels. High levels of these substances in your body are a sign of pernicious anemia.
• For intrinsic factor antibodies and parietal cell antibodies. These antibodies also are a sign of pernicious anemia.

Bone Marrow Tests

Bone marrow tests can show whether your bone marrow is healthy and making enough red blood cells. The two bone marrow tests are aspiration and biopsy.

For aspiration, your doctor removes a small amount of fluid bone marrow through a needle. For a biopsy, your doctor removes a small amount of bone marrow tissue through a larger needle. The samples are then examined under a microscope.

In pernicious anemia, the bone marrow cells that turn into blood cells are larger than normal.

How Is Pernicious Anemia Treated ?

Doctors treat pernicious anemia by replacing the missing vitamin B12 in the body. People who have pernicious anemia may need lifelong treatment.

The goals of treating pernicious anemia include:

• Preventing or treating the anemia and its signs and symptoms
• Preventing or managing complications, such as heart and nerve damage
• Treating the cause of the pernicious anemia (if a cause can be found)

Specific Types of Treatment

Pernicious anemia usually is easy to treat with vitamin B12 shots or pills.

If you have severe pernicious anemia, your doctor may recommend shots first. Shots usually are given in a muscle every day or every week until the level of vitamin B12 in your blood increases. After your vitamin B12 blood level returns to normal, you may get a shot only once a month.

For less severe pernicious anemia, your doctor may recommend large doses of vitamin B12 pills. A vitamin B12 nose gel and spray also are available. These products may be useful for people who have trouble swallowing pills, such as older people who have had strokes.

Your signs and symptoms may begin to improve within a few days after you start treatment. Your doctor may advise you to limit your physical activity until your condition improves.

If your pernicious anemia is caused by something other than a lack of intrinsic factor, you may get treatment for the cause (if a cause can be found). For example, your doctor may prescribe medicines to treat a condition that prevents your body from absorbing vitamin B12.

If medicines are the cause of your pernicious anemia, your doctor may change the type or dose of medicine you take. Infants of strict vegetarian mothers may be given vitamin B12 supplements from birth.

Sickle Cell Disease

The term sickle cell disease describes a group of inherited red blood cell disorders. People with sickle cell disease have abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in their red blood cells ⁴.

Hemoglobin is a protein in red blood cells that carries oxygen throughout the body.

“Inherited” means that the disease is passed by genes from parents to their children. Sickle Cell Disease is not contagious. A person cannot catch it, like a cold or infection, from someone else.

People who have sickle cell disease inherit two abnormal hemoglobin genes, one from each parent. In all forms of sickle cell disease, at least one of the two abnormal genes causes a person’s body to make hemoglobin S. When a person has two hemoglobin S genes, Hemoglobin SS, the disease is called sickle cell anemia. This is the most common and often most severe kind of sickle cell disease.

In the United States, most people with sickle cell disease are of African ancestry or identify themselves as black ⁵.

• About 1 in 13 African American babies is born with sickle cell trait.
• About 1 in every 365 black children is born with sickle cell disease.

There are also many people with this disease who come from Hispanic, southern European, Middle Eastern, or Asian Indian backgrounds.

Approximately 100,000 Americans have sickle cell disease.

Hemoglobin SC disease and hemoglobin Sβ thalassemia are two other common forms of sickle cell disease.

Some Forms of Sickle Cell Disease

• Hemoglobin SS
• Hemoglobin SC
• Hemoglobin Sβ0 thalassemia
• Hemoglobin Sβ+ thalassemia
• Hemoglobin SD
• Hemoglobin SE

Cells in tissues need a steady supply of oxygen to work well. Normally, hemoglobin in red blood cells takes up oxygen in the lungs and carries it to all the tissues of the body.

Red blood cells that contain normal hemoglobin are disc shaped (like a doughnut without a hole). This shape allows the cells to be flexible so that they can move through large and small blood vessels to deliver oxygen.

Sickle hemoglobin is not like normal hemoglobin. It can form stiff rods within the red cell, changing it into a crescent, or sickle shape.

Sickle-shaped cells are not flexible and can stick to vessel walls, causing a blockage that slows or stops the flow of blood. When this happens, oxygen can’t reach nearby tissues.

Figure 9. Sickle cell anemia

The lack of tissue oxygen can cause attacks of sudden, severe pain, called pain crises. These pain attacks can occur without warning, and a person often needs to go to the hospital for effective treatment.

Most children with sickle cell disease are pain free between painful crises, but adolescents and adults may also suffer with chronic ongoing pain.

The red cell sickling and poor oxygen delivery can also cause organ damage. Over a lifetime, sickle cell disease can harm a person’s spleen, brain, eyes, lungs, liver, heart, kidneys, penis, joints, bones, or skin.

Sickle cells can’t change shape easily, so they tend to burst apart or hemolyze. Normal red blood cells live about 90 to 120 days, but sickle cells last only 10 to 20 days.

The body is always making new red blood cells to replace the old cells; however, in sickle cell disease the body may have trouble keeping up with how fast the cells are being destroyed. Because of this, the number of red blood cells is usually lower than normal. This condition, called anemia, can make a person have less energy.

Sickle cell disease is a life-long illness. The severity of the disease varies widely from person to person.

In high-income countries like the United States, the life expectancy of a person with sickle cell disease is now about 40–60 years. In 1973, the average lifespan of a person with sickle cell disease in the United States was only 14 years. Advances in the diagnosis and care of sickle cell disease have made this improvement possible.

At the present time, hematopoietic stem cell transplantation is the only cure for sickle cell disease ⁴. Unfortunately, most people with sickle cell disease are either too old for a transplant or don’t have a relative who is a good enough genetic match for them to act as a donor. A well-matched donor is needed to have the best chance for a successful transplant.

There are effective treatments that can reduce symptoms and prolong life. Early diagnosis and regular medical care to prevent complications also contribute to improved well-being.

What Causes Sickle Cell Disease ?

Abnormal hemoglobin, called hemoglobin S, causes sickle cell disease.

The problem in hemoglobin S is caused by a small defect in the gene that directs the production of the beta globin part of hemoglobin. This small defect in the beta globin gene causes a problem in the beta globin part of hemoglobin, changing the way that hemoglobin works.

How Is Sickle Cell Disease Inherited ?

When the hemoglobin S gene is inherited from only one parent and a normal hemoglobin gene is inherited from the other, a person will have sickle cell trait. People with sickle cell trait are generally healthy.

Only rarely do people with sickle cell trait have complications similar to those seen in people with sickle cell disease. But people with sickle cell trait are carriers of a defective hemoglobin S gene. So, they can pass it on when they have a child.

If the child’s other parent also has sickle cell trait or another abnormal hemoglobin gene (like thalassemia, hemoglobin C, hemoglobin D, hemoglobin E), that child has a chance of having sickle cell disease.

Figure 10. Sickle cell disease inheritance

In the image above, each parent has one hemoglobin A gene and one hemoglobin S gene, and each of their children has:

• A 25 percent chance of inheriting two normal genes: In this case the child does not have sickle cell trait or disease. (Blue)
• A 50 percent chance of inheriting one hemoglobin A gene and one hemoglobin S gene: This child has sickle cell trait. (Purple)
• A 25 percent chance of inheriting two hemoglobin S genes: This child has sickle cell disease. (Red)

It is important to keep in mind that each time this couple has a child, the chances of that child having sickle cell disease remain the same. In other words, if the first-born child has sickle cell disease, there is still a 25 percent chance that the second child will also have the disease. Both boys and girls can inherit sickle cell trait, sickle cell disease, or normal hemoglobin.

If a person wants to know if he or she carries a sickle hemoglobin gene, a doctor can order a blood test to find out.

What Are the Signs and Symptoms of Sickle Cell Disease ?

Early Signs and Symptoms

If a person has sickle cell disease, it is present at birth. But most infants do not have any problems from the disease until they are about 5 or 6 months of age. Every state in the United States, the District of Columbia, and the U.S. territories requires that all newborn babies receive screening for sickle cell disease. When a child has sickle cell disease, parents are notified before the child has symptoms.

Some children with sickle cell disease will start to have problems early on, and some later. Early symptoms of sickle cell disease may include:

• Painful swelling of the hands and feet, known as dactylitis
• Fatigue or fussiness from anemia
• A yellowish color of the skin, known as jaundice, or whites of the eyes, known as icteris, that occurs when a large number of red cells hemolyze

The signs and symptoms of sickle cell disease will vary from person to person and can change over time. Most of the signs and symptoms of sickle cell disease are related to complications of the disease.

Major Complications of Sickle Cell Disease

Acute Pain (Sickle Cell or Vaso-occlusive) Crisis

Pain episodes (crises) can occur without warning when sickle cells block blood flow and decrease oxygen delivery. People describe this pain as sharp, intense, stabbing, or throbbing. Severe crises can be even more uncomfortable than post-surgical pain or childbirth.

Pain can strike almost anywhere in the body and in more than one spot at a time. But the pain often occurs in the

• Lower back
• Legs
• Arms
• Abdomen
• Chest

A crisis can be brought on by

• Illness
• Temperature changes
• Stress
• Dehydration (not drinking enough)
• Being at high altitudes

But often a person does not know what triggers, or causes, the crisis.

Chronic Pain

Many adolescents and adults with sickle cell disease suffer from chronic pain. This kind of pain has been hard for people to describe, but it is usually different from crisis pain or the pain that results from organ damage.

Chronic pain can be severe and can make life difficult. Its cause is not well understood.

Severe Anemia

People with sickle cell disease usually have mild to moderate anemia. At times, however, they can have severe anemia. Severe anemia can be life threatening. Severe anemia in an infant or child with sickle cell disease may be caused by:

• Splenic sequestration crisis

The spleen is an organ that is located in the upper left side of the belly. The spleen filters germs in the blood, breaks up blood cells, and makes a kind of white blood cell. A splenic sequestration crisis occurs when red blood cells get stuck in the spleen, making it enlarge quickly. Since the red blood cells are trapped in the spleen, there are fewer cells to circulate in the blood. This causes severe anemia.

A big spleen may also cause pain in the left side of the belly. A parent can usually palpate or feel the enlarged spleen in the belly of his or her child.

• Aplastic crisis

Aplastic crisis is usually caused by a parvovirus B19 infection, also called fifth disease or slapped cheek syndrome. Parvovirus B19 is a very common infection, but in sickle cell disease it can cause the bone marrow to stop producing new red cells for a while, leading to severe anemia.

Splenic sequestration crisis and aplastic crisis most commonly occur in infants and children with sickle cell disease. Adults with sickle cell disease may also experience episodes of severe anemia, but these usually have other causes.

No matter the cause, severe anemia may lead to symptoms that include:

• Shortness of breath
• Being very tired
• Feeling dizzy
• Having pale skin

Babies and infants with severe anemia may feed poorly and seem very sluggish.

• Infections

The spleen is important for protection against certain kinds of germs. Sickle cells can damage the spleen and weaken or destroy its function early in life.

People with sickle cell disease who have damaged spleens are at risk for serious bacterial infections that can be life-threatening. Some of these bacteria include:

• Pneumococcus
• Hemophilus influenza type B
• Meningococcus
• Salmonella
• Staphylococcus
• Chlamydia
• Mycoplasma pneumoniae

Bacteria can cause:

• Blood infection (septicemia)
• Lung infection (pneumonia)
• Infection of the covering of the brain and spinal cord (meningitis)
• Bone infection (osteomyelitis)

Acute Chest Syndrome

Sickling in blood vessels of the lungs can deprive a person’s lungs of oxygen. When this happens, areas of lung tissue are damaged and cannot exchange oxygen properly. This condition is known as acute chest syndrome. In acute chest syndrome, at least one segment of the lung is damaged.

This condition is very serious and should be treated right away at a hospital.

Acute chest syndrome often starts a few days after a painful crisis begins. A lung infection may accompany acute chest syndrome.

Symptoms may include:

• Chest pain
• Fever
• Shortness of breath
• Rapid breathing
• Cough

Brain Complications

Clinical Stroke

A stroke occurs when blood flow is blocked to a part of the brain. When this happens, brain cells can be damaged or can die. In sickle cell disease, a clinical stroke means that a person shows outward signs that something is wrong. The symptoms depend upon what part of the brain is affected. Symptoms of stroke may include:

• Weakness of an arm or leg on one side of the body
• Trouble speaking, walking, or understanding
• Loss of balance
• Severe headache

As many as 24 percent of people with hemoglobin SS and 10 percent of people with hemoglobin SC may suffer a clinical stroke by age 45.

In children, clinical stroke occurs most commonly between the ages of 2 and 9, but recent prevention strategies have lowered the risk.

When people with sickle cell disease show symptoms of stroke, their families or friends should call your local emergency number right away.

Silent Stroke and Thinking Problems

Brain imaging and tests of thinking (cognitive studies) have shown that children and adults with hemoglobin SS and hemoglobin Sβ0 thalassemia often have signs of silent brain injury, also called silent stroke. Silent brain injury is damage to the brain without showing outward signs of stroke.

This injury is common. Silent brain injury can lead to learning problems or trouble making decisions or holding down a job.

Eye Problems

Sickle cell disease can injure blood vessels in the eye.

The most common site of damage is the retina, where blood vessels can overgrow, get blocked, or bleed. The retina is the light-sensitive layer of tissue that lines the inside of the eye and sends visual messages through the optic nerve to the brain.

Detachment of the retina can occur. When the retina detaches, it is lifted or pulled from its normal position. These problems can cause visual impairment or loss.

Heart Disease

People with sickle cell disease can have problems with blood vessels in the heart and with heart function. The heart can become enlarged. People can also develop pulmonary hypertension.

People with sickle cell disease who have received frequent blood transfusions may also have heart damage from iron overload.

Pulmonary Hypertension

In adolescents and adults, injury to blood vessels in the lungs can make it hard for the heart to pump blood through them. This causes the pressure in lung blood vessels to rise. High pressure in these blood vessels is called pulmonary hypertension. Symptoms may include shortness of breath and fatigue.

When this condition is severe, it has been associated with a higher risk of death.

Kidney Problems

The kidneys are sensitive to the effects of red blood cell sickling.

Sickle cell disease causes the kidneys to have trouble making the urine as concentrated as it should be. This may lead to a need to urinate often and to have bedwetting or uncontrolled urination during the night (nocturnal enuresis). This often starts in childhood. Other problems may include:

• Blood in the urine
• Decreased kidney function
• Kidney disease
• Protein loss in the urine

Priapism

Males with sickle cell disease can have unwanted, sometimes prolonged, painful erections. This condition is called priapism.

Priapism happens when blood flow out of the erect penis is blocked by sickled cells. If it goes on for a long period of time, priapism can cause permanent damage to the penis and lead to impotence.

If priapism lasts for more than 4 hours, emergency medical care should be sought to avoid complications.

Gallstones

When red cells hemolyze, they release hemoglobin. Hemoglobin gets broken down into a substance called bilirubin. Bilirubin can form stones that get stuck in the gallbladder. The gallbladder is a small, sac-shaped organ beneath the liver that helps with digestion. Gallstones are a common problem in sickle cell disease.

Gallstones may be formed early on but may not produce symptoms for years. When symptoms develop, they may include:

• Right-sided upper belly pain
• Nausea
• Vomiting

If problems continue or recur, a person may need surgery to remove the gallbladder.

Liver Complications

There are a number of ways in which the liver may be injured in sickle cell disease.

Sickle cell intrahepatic cholestasis is an uncommon, but severe, form of liver damage that occurs when sickled red cells block blood vessels in the liver. This blockage prevents enough oxygen from reaching liver tissue.

These episodes are usually sudden and may recur. Children often recover, but some adults may have chronic problems that lead to liver failure.

People with sickle cell disease who have received frequent blood transfusions may develop liver damage from iron overload.

Leg Ulcers

Sickle cell ulcers are sores that usually start small and then get larger and larger.

The number of ulcers can vary from one to many. Some ulcers will heal quickly, but others may not heal and may last for long periods of time. Some ulcers come back after healing.

People with sickle cell disease usually don’t get ulcers until after the age of 10.

Joint Complications

Sickling in the bones of the hip and, less commonly, the shoulder joints, knees, and ankles, can decrease oxygen flow and result in severe damage. This damage is a condition called avascular or aseptic necrosis. This disease is usually found in adolescents and adults.

Symptoms include pain and problems with walking and joint movement. A person may need pain medicines, surgery, or joint replacement if symptoms persist.

Delayed Growth and Puberty

Children with sickle cell disease may grow and develop more slowly than their peers because of anemia. They will reach full sexual maturity, but this may be delayed.

Pregnancy

Pregnancies in women with sickle cell disease can be risky for both the mother and the baby.

Mothers may have medical complications including:

• Infections
• Blood clots
• High blood pressure
• Increased pain episodes

They are also at higher risk for:

• Miscarriages
• Premature births
• “Small-for-dates babies” or underweight babies

Mental Health

As in other chronic diseases, people with sickle cell disease may feel sad and frustrated at times. The limitations that sickle cell disease can impose on a person’s daily activities may cause them to feel isolated from others. Sometimes they become depressed.

People with sickle cell disease may also have trouble coping with pain and fatigue, as well as with frequent medical visits and hospitalizations.

How Is Sickle Cell Disease Diagnosed ?

Screening Tests

People who do not know whether they make sickle hemoglobin (hemoglobin S) or another abnormal hemoglobin (such as C, β thalassemia, E) can find out by having their blood tested. This way, they can learn whether they carry a gene (i.e., have the trait) for an abnormal hemoglobin that they could pass on to a child.

When each parent has this information, he or she can be better informed about the chances of having a child with some type of sickle cell disease, such as hemoglobin SS, SC, Sβ thalassemia, or others.

Newborn Screening

When a child has sickle cell disease, it is very important to diagnose it early to better prevent complications.

Every state in the United States, the District of Columbia, and the U.S. territories require that every baby is tested for sickle cell disease as part of a newborn screening program.

In newborn screening programs, blood from a heel prick is collected in “spots” on a special paper. The hemoglobin from this blood is then analyzed in special labs.

Newborn screening results are sent to the doctor who ordered the test and to the child’s primary doctor.

If a baby is found to have sickle cell disease, health providers from a special follow-up newborn screening group contact the family directly to make sure that the parents know the results. The child is always retested to be sure that the diagnosis is correct.

Newborn screening programs also find out whether the baby has an abnormal hemoglobin trait. If so, parents are informed, and counseling is offered.

Remember that when a child has sickle cell trait or sickle cell disease, a future sibling, or the child’s own future child, may be at risk. These possibilities should be discussed with the primary care doctor, a blood specialist called a hematologist, and/or a genetics counselor.

Prenatal Screening

Doctors can also diagnose sickle cell disease before a baby is born. This is done using a sample of amniotic fluid, the liquid in the sac surrounding a growing embryo, or tissue taken from the placenta, the organ that attaches the umbilical cord to the mother’s womb.

Testing before birth can be done as early as 8–10 weeks into the pregnancy. This testing looks for the sickle hemoglobin gene rather than the abnormal hemoglobin.

How Is Sickle Cell Disease Treated ?

Health Maintenance To Prevent Complications

Babies with sickle cell disease should be referred to a doctor or provider group that has experience taking care of people with this disease. The doctor might be a hematologist (a doctor with special training in blood diseases) or an experienced general pediatrician, internist, or family practitioner.

For infants, the first sickle cell disease visit should take place before 8 weeks of age.

If someone was born in a country that doesn’t perform newborn sickle cell disease screening, he or she might be diagnosed with sickle cell disease later in childhood. These people should also be referred as soon as possible for special sickle cell disease care.

All people who have sickle cell disease should see their sickle cell disease care providers regularly. Regularly means every 3 to 12 months, depending on the person’s age. The sickle cell disease doctor or team can help to prevent problems by:

• Examining the person
• Giving medicines and immunizations
• Performing tests
• Educating families about the disease and what to watch out for

Preventing Infection

In sickle cell disease, the spleen doesn’t work properly or doesn’t work at all. This problem makes people with sickle cell disease more likely to get severe infections.

Penicillin

In children with sickle cell disease, taking penicillin two times a day has been shown to reduce the chance of having a severe infection caused by the pneumococcus bacteria. Infants need to take liquid penicillin. Older children can take tablets.

Many doctors will stop prescribing penicillin after a child has reached the age of 5. Some prefer to continue this antibiotic throughout life, particularly if a person has hemoglobin SS or hemoglobin Sβ0 thalassemia, since people with sickle cell disease are still at risk. All people who have had surgical removal of the spleen, called a splenectomy, or a past infection with pneumococcus should keep taking penicillin throughout life.

Immunizations

People with sickle cell diseaseshould receive all recommended childhood vaccines. They should also receive additional vaccines to prevent other infections.

Pneumococcus. Even though all children routinely receive the vaccine against pneumococcus (PCV13), children with sickle cell disease should also receive a second kind of vaccine against pneumococcus (PPSV23). This second vaccine is given after 24 months of age and again 5 years later. Adults with sickle cell disease who have not received any pneumococcal vaccine should get a dose of the PCV13 vaccine. They should later receive the PPSV23 if they have not already received it or it has been more than 5 years since they did. A person should follow these guidelines even if he or she is still taking penicillin.

Influenza. All people with sickle cell disease should receive an influenza shot every year at the start of flu season. This should begin at 6 months of age. Only the inactivated vaccine, which comes as a shot, should be used in people with sickle cell disease.

Meningococcus. A child with sickle cell disease should receive this vaccine (Menactra or Menveo) at 2, 4, 6, and 12–15 months of age. The child should receive a booster vaccine 3 years after this series of shots, then every 5 years after that.

Screening Tests and Evaluations

Height, Weight, Blood Pressure, and Oxygen Saturation

Doctors will monitor height and weight to be sure that a child is growing properly and that a person with sickle cell disease is maintaining a healthy weight.

Doctors will also track a person’s blood pressure. When a person with sickle cell disease has high blood pressure, it needs to be treated promptly because it can increase the risk of stroke.

Oxygen saturation testing provides information about how much oxygen the blood is carrying.

Blood and Urine Testing

People with sickle cell disease need to have frequent lab tests.

Blood tests help to establish a person’s “baseline” for problems like anemia. Blood testing also helps to show whether a person has organ damage, so that it can be treated early.

Urine testing can help to detect early kidney problems or infections.

Transcranial Doppler Ultrasound Screening

Children who have hemoglobin SS or hemoglobin Sβ0 thalassemia and are between the ages of 2 and 16 should have Transcranial Doppler Ultrasound testing once a year.

This study can find out whether a child is at higher risk for stroke. When the test is abnormal, regular blood transfusions can decrease the chances of having a stroke.

The child is awake during the Transcranial Doppler Ultrasound exam. The test does not hurt at all. The Transcranial Doppler Ultrasound machine uses sound waves to measure blood flow like the ultrasound machine used to examine pregnant women.

Eye Examinations

An eye doctor, or ophthalmologist, should examine a person’s eyes every 1—2 years from the age of 10 onwards.

These exams can detect if there are sickle cell disease-related problems of the eye. Regular exams can help doctors find and treat problems early to prevent loss of vision. A person should see his or her doctor right away for any sudden change in vision.

Pulmonary Hypertension

Doctors have different approaches to screening for pulmonary hypertension. This is because studies have not given clear information as to when and how a person should receive the screening. People with sickle cell disease and their caretakers should discuss with their doctor whether screening makes sense for them.

Cognitive Screening

People with sickle cell disease can develop cognitive (thinking) problems that may be hard to notice early in life.

Sometimes these problems are caused by “silent” strokes that can only be seen with magnetic resonance imaging (MRI) of the brain.

People with sickle cell disease should tell their doctors or nurses if they have thinking problems, such as difficulties learning in school, slowed decision making, or trouble organizing their thoughts.

People can be referred for cognitive testing. This testing can identify areas in which a person could use extra help.

Children with sickle cell disease who have thinking problems may qualify for an Individualized Education Program. An Individualized Education Program is a plan that helps students to reach their educational goals. Adults may be able to enroll in vocational rehabilitation programs that can help them with job training.

Education and Guidance

Doctors and other providers will talk with people who have sickle cell disease and their caretakers about complications and also review information at every visit.

Because there are a lot of things to discuss, new topics are often introduced as a child or adult reaches an age when that subject is important to know about.

Doctors and nurses know that there is a lot of information to learn, and they don’t expect people to know everything after one discussion. People with sickle cell disease and their families should not be afraid to ask questions.

Topics that are usually covered include:

• Hours that medical staff are available and contact information to use when people with sickle cell disease or caretakers have questions
• A plan for what to do and where to get care if a person has a fever, pain, or other signs of sickle cell disease complications that need immediate attention
• How sickle cell disease is inherited and the risk of having a child with sickle cell disease
• The importance of regular medical visits, screening tests, and evaluations
• How to recognize and manage pain
• How to palpate (feel) a child’s spleen. Because of the risk of splenic sequestration crisis, caretakers should learn how to palpate a child’s spleen. They should try to feel for the spleen daily and more frequently when the child is ill. If they feel that the spleen is bigger than usual, they should call the care provider.

Transitioning Care

When children with sickle cell disease become adolescents or young adults, they often need to transition from a pediatric care team to an adult care team. This period has been shown to be associated with increased hospital admissions and medical problems. There seem to be many reasons for this.

Some of the increased risk is directly related to the disease. As people with sickle cell disease get older, they often develop more organ damage and more disabilities.

The shift in care usually occurs at the same time that adolescents are undergoing many changes in their emotional, social, and academic lives. The transition to more independent self-management may be difficult, and following treatment plans may become less likely.

When compared with pediatrics, there are often fewer adult sickle cell disease programs available in a given region. This makes it more difficult for a person with sickle cell disease to find appropriate doctors, particularly those with whom they feel comfortable.

To improve use of regular medical care by people with sickle cell disease and to reduce age-related complications, many sickle cell disease teams have developed special programs that the make transition easier. Such programs should involve the pediatric and the adult care teams. They should also start early and continue over several years.

Managing Some Complications of sickle cell disease

Acute Pain

Each person with sickle cell disease should have a home treatment regimen that is best suited to their needs. The providers on the sickle cell disease team usually help a person develop a written, tailored care plan. If possible, the person with sickle cell disease should carry this plan with them when they go to the emergency room.

When an acute crisis is just starting, most doctors will advise the person to drink lots of fluids and to take a non-steroidal anti-inflammatory (NSAID) pain medication, such as ibuprofen. When a person has kidney problems, acetaminophen is often preferred.

If pain persists, many people will find that they need a stronger medicine.

Combining additional interventions, such as massage, relaxation methods, or a heating pad, may also help.

If a person with sickle cell disease cannot control the pain at home, he or she should go to an sickle cell disease day hospital/outpatient unit or an emergency room to receive additional, stronger medicines and intravenous (IV) fluids.

Some people may be able to return home once their pain is under better control. In this case, the doctor may prescribe additional pain medicines for a short course of therapy.

People often need to be admitted to the hospital to fully control an acute pain crisis.

When taken daily, hydroxyurea has been found to decrease the number and severity of pain episodes.

Some patients may have fewer visits to the hospital or hospitalizations due to severe pain, and may have shorter hospital stays for pain crises if they are taking L-glutamine oral powder (Endari) compared to patients who are not taking this medicine. More research is needed to understand how effective L-glutamine oral powder is as a treatment and which patients may benefit from using it.

Chronic Pain

Sometimes chronic pain results from a complication, such as a leg ulcer or aseptic necrosis of the hip. In this case, doctors try to treat the complication causing the pain.

While chronic pain is common in adults with sickle cell disease, the cause is often poorly understood. Taking pain medicines daily may help to decrease the pain. Some examples of these medicines include:

• NSAID drugs, such as ibuprofen
• Duloxetine
• Gabapentin
• Amitriptyline
• Strong pain medicines, such as opiates

Other approaches, such as massage, heat, or acupuncture may be helpful in some cases. Chronic pain often comes with feelings of depression and anxiety. Supportive counseling and, sometimes, antidepressant medicines may help.

Severe Anemia

People should see their doctors or go to a hospital right away if they develop anemia symptoms from a splenic sequestration crisis or an aplastic crisis. These conditions can be life-threatening, and the person will need careful monitoring and treatment in the hospital. A person also usually needs a blood transfusion.

People with sickle cell disease and symptoms of severe anemia from other causes should also see a doctor right away.

Some patients may have fewer hospital visits due to sickle cell crises, including splenic sequestration, if they are taking L-glutamine oral powder compared to patients who are not taking this medicine. More research is needed to understand how effective L-glutamine oral powder is as a treatment and which patients may benefit from using it.

Infections

Fever is a medical emergency in sickle cell disease. All caretakers of infants and children with sickle cell disease should take their child to their doctor or go to a hospital right away when their child has a fever. Adults with sickle cell disease should also seek care for fever or other signs of infection.

All children and adults who have sickle cell disease and a fever (over 38.50 C or 101.30 F) must be seen by a doctor and treated with antibiotics right away.

Some people will need to be hospitalized, while others may receive care and follow-up as an outpatient.

Acute Chest Syndrome

People with sickle cell disease and symptoms of acute chest syndrome should see their doctor or go to a hospital right away.

They will need to be admitted to the hospital where they should receive antibiotics and close monitoring. They may need oxygen therapy and a blood transfusion.

When taken daily, the medicine hydroxyurea has been found to decrease the number and severity of acute chest events.

Some patients may have fewer hospital visits due to sickle cell crises, including acute chest syndrome, if they are taking L-glutamine oral powder compared to patients who are not taking this medicine. More research is needed to understand how effective L-glutamine oral powder is as a treatment and which patients may benefit from using it.

Clinical Stroke

People with sickle cell disease who have symptoms of stroke should be brought to the hospital right away by an ambulance. If a person is having symptoms of stroke, someone should call your local emergency number.

Symptoms of stroke may include:

• Weakness of an arm or leg on one side of the body
• Trouble speaking, walking, or understanding
• Loss of balance
• Severe headache

If imaging studies reveal that the person has had an acute stroke, he or she may need an exchange transfusion. This procedure involves slowly removing an amount of the person’s blood and replacing it with blood from a donor who does not have sickle cell disease or sickle cell trait. Afterward, the person may need to receive monthly transfusions or other treatments to help to prevent another stroke.

Silent Stroke and Cognitive Problems

Children and adults with sickle cell disease and cognitive problems may be able to get useful help based upon the results of their testing. For instance, children may qualify for an Individualized Education Program. Adults may be able to enroll in vocational, or job, training programs.

Priapism

Sometimes, a person may be able to relieve priapism by:

• Emptying the bladder by urinating
• Taking medicine
• Increasing fluid intake
• Doing light exercise

If a person has an episode that lasts for 4 hours or more, he should go to the hospital to see a hematologist and urologist.

Some patients may have fewer hospital visits due to sickle cell crises, including priapism, if they are taking L-glutamine oral powder compared to patients who are not taking this medicine. More research is needed to understand how effective L-glutamine oral powder is as a treatment and which patients may benefit from using it.

Pregnancy

Pregnant women with sickle cell disease are at greater risk for problems. They should always see an obstetrician who has experience with sickle cell disease and high-risk pregnancies and deliveries.

The obstetrician should work with a hematologist or primary medical doctor who is well informed about sickle cell disease and its complications.

Pregnant women with sickle cell disease need more frequent medical visits so that their doctors can follow them closely. The doctor may prescribe certain vitamins and will be careful to prescribe pain medicines that are safe for the baby.

A pregnant woman with sickle cell disease may need to have one or more blood transfusions during her pregnancy to treat complications, such as worsening anemia or an increased number of pain or acute chest syndrome events.

Hydroxyurea

Hydroxyurea is an oral medicine that has been shown to reduce or prevent several sickle cell disease complications.

This medicine was studied in patients with sickle cell disease because it was known to increase the amount of fetal hemoglobin (hemoglobin F) in the blood. Increased hemoglobin F provides some protection against the effects of hemoglobin S.

Hydroxyurea was later found to have several other benefits for a person with sickle cell disease, such as decreasing inflammation.

Use in adults. Many studies of adults with hemoglobin SS or hemoglobin Sβ thalassemia showed that hydroxyurea reduced the number of episodes of pain crises and acute chest syndrome. It also improved anemia and decreased the need for transfusions and hospital admissions.
Use in children. Studies in children with severe hemoglobin SS or Sβ thalassemia showed that hydroxyurea reduced the number of vaso-occlusive crises and hospitalizations. A study of very young children (between the ages of 9 and 18 months) with hemoglobin SS or hemoglobin Sβ thalassemia also showed that hydroxyurea decreased the number of episodes of pain and dactylitis.

Who Should Use Hydroxyurea ?

Since hydroxyurea can decrease several complications of sickle cell disease, most experts recommend that children and adults with hemoglobin SS or Sβ0 thalassemia who have frequent painful episodes, recurrent chest crises, or severe anemia take hydroxyurea daily.

Some experts offer hydroxyurea to all infants over 9 months of age and young children with hemoglobin SS or Sβ0 thalassemia, even if they do not have severe clinical problems, to prevent or reduce the chance of complications. There is no information about how safe or effective hydroxyurea is in children under 9 months of age.

Some experts will prescribe hydroxyurea to people with other types of sickle cell disease who have severe, recurrent pain. There is little information available about how effective hydroxyurea is for these types of sickle cell disease.

In all situations, people with sickle cell disease should discuss with their doctors whether or not hydroxyurea is an appropriate medication for them.

Pregnant women should not use hydroxyurea.

How Is Hydroxyurea Taken ?

To work properly, hydroxyurea should be taken by mouth daily at the prescribed dose. When a person does not take it regularly, it will not work as well, or it won’t work at all.

A person with sickle cell disease who is taking hydroxyurea needs careful monitoring. This is particularly true in the early weeks of taking the medicine. Monitoring includes regular blood testing and dose adjustments.

What Are the Risks of Hydroxyurea ?

Hydroxyurea can cause the blood’s white cell count or platelet count to drop. In rare cases, it can worsen anemia. These side effects usually go away quickly if a person stops taking the medication. When a person restarts it, a doctor usually prescribes a lower dose.

Other short-term side effects are less common.

It is still unclear whether hydroxyurea can cause problems later in life in people with sickle cell disease who take it for many years. Studies so far suggest that it does not put people at a higher risk of cancer and does not affect growth in children. But further studies are needed.

Red Blood Cell Transfusions

Doctors may use acute and chronic red blood cell transfusions to treat and prevent certain sickle cell disease complications. The red blood cells in a transfusion have normal hemoglobin in them.

A transfusion helps to raise the number of red blood cells and provides normal red blood cells that are more flexible than red blood cells with sickle hemoglobin. These cells live longer in the circulation. Red blood cell transfusions decrease vaso-occlusion (blockage in the blood vessel) and improve oxygen delivery to the tissues and organs.

Acute Transfusion in sickle cell disease

Doctors use blood transfusions in sickle cell disease for complications that cause severe anemia. They may also use them when a person has an acute stroke, in many cases of acute chest crises, and in multi-organ failure.

A person with sickle cell disease usually receives blood transfusions before surgery to prevent sickle cell disease-related complications afterwards.

Chronic Transfusion

Doctors recommend regular or ongoing blood transfusions for people who have had an acute stroke, since transfusions decrease the chances of having another stroke.

Doctors also recommend chronic blood transfusions for children who have abnormal Transcranial Doppler Ultrasound results because transfusions can reduce the chance of having a first stroke.

Some doctors use this approach to treat complications that do not improve with hydroxyurea. They may also use transfusions in people who have too many side effects from hydroxyurea.

What Are the Risks of Transfusion Therapy ?

Possible complications include:

• Hemolysis
• Iron overload, particularly in people receiving chronic transfusions (can severely impair heart and lung function)
• Infection
• Alloimmunization (can make it hard to find a matching unit of blood for a future transfusion)

All blood banks and hospital personnel have adopted practices to reduce the risk of transfusion problems.

People with sickle cell disease who receive transfusions should be monitored for and immunized against hepatitis. They should also receive regular screenings for iron overload. If a person has iron overload, the doctor will give chelation therapy, a medicine to reduce the amount of iron in the body and the problems that iron overload causes.

Hematopoietic Stem Cell Transplantation

At the present time, hematopoietic stem cell transplantation (HSCT) is the only cure for sickle cell disease. People with sickle cell disease and their families should ask their doctor about this procedure.

What Are Stem Cells ?

Stem cells are special cells that can divide over and over again. After they divide, these cells can go on to become blood red cells, white cells, or platelets.

A person with sickle cell disease has stem cells that make red blood cells that can sickle. People without sickle cell disease have stem cells that make red cells that usually won’t sickle.

What Stem Cells Are Used in hematopoietic stem cell transplantation ?

In hematopoietic stem cell transplantation, stem cells are taken from the bone marrow or blood of a person who does not have sickle cell disease (the donor). The donor, however, may have sickle cell trait.

The donor is often the person’s sister or brother. This is because the safest and most successful transplants use stem cells that are matched for special proteins called HLA antigens. Since these antigens are inherited from parents, a sister or brother is the most likely person to have the same antigens as the person with sickle cell disease.

What Happens During hematopoietic stem cell transplantation ?

First, stem cells are taken from the donor. After this, the person with sickle cell disease (the recipient) is treated with drugs that destroy or reduce his or her own bone marrow stem cells.

The donor stem cells are then injected into the person’s vein. The injected cells will make a home in the recipient’s bone marrow, gradually replacing the recipient’s cells. The new stem cells will make red cells that do not sickle.

Which People Receive hematopoietic stem cell transplantation ?

At the present time, most sickle cell disease transplants are performed in children who have had complications such as strokes, acute chest crises, and recurring pain crises. These transplants usually use a matched donor.

Because only about 1 in 10 children with sickle cell disease has a matched donor without sickle cell disease in their families, the number of people with sickle cell disease who get transplants is low.

Hematopoietic stem cell transplantation is more risky in adults, and that is why most transplants are done in children.

There are several medical centers that are researching new sickle cell disease hematopoietic stem cell transplantation techniques in children and adults who don’t have a matched donor in the family or are older than most recipients. Hopefully, more people with sickle cell disease will be able to receive a transplant in the future, using these new methods.

What Are the Risks ?

Hematopoietic stem cell transplantation is successful in about 85 percent of children when the donor is related and HLA matched. Even with this high success rate, hematopoietic stem cell transplantation still has risks.

Complications can include severe infections, seizures, and other clinical problems. About 5 percent of people have died. Sometimes transplanted cells attack the recipient’s organs (graft versus host disease).

Medicines are given to prevent many of the complications, but they still can happen.

What happens when you have too many red blood cells

Polycythemia vera is a rare blood disease in which your your bone marrow makes too many red blood cells and it also can make too many white blood cells and platelets ⁷. The disease affects people of all ages, but it’s most common in adults who are older than 60. Polycythemia vera is rare in children and young adults. Men are at slightly higher risk for polycythemia vera than women.

The extra red blood cells make your blood thicker than normal. As a result, blood clots can form more easily. These clots can block blood flow through your arteries and veins, which can cause a heart attack or stroke.

Thicker blood also doesn’t flow as quickly to your body as normal blood. Slowed blood flow prevents your organs from getting enough oxygen, which can cause serious problems, such as angina (heart pain) and heart failure. Angina is chest pain or discomfort.

A mutation, or change, in the body’s JAK2 gene is the major cause of polycythemia vera. This gene makes a protein that helps the body produce blood cells. What causes the change in the JAK2 gene isn’t known. Polycythemia vera generally isn’t inherited—that is, passed from parents to children through genes.

Polycythemia vera develops slowly and may not cause symptoms for years. The disease often is found during routine blood tests done for other reasons.

When signs and symptoms are present, they’re the result of the thick blood that occurs with polycythemia vera. This thickness slows the flow of oxygen-rich blood to all parts of your body. Without enough oxygen, many parts of your body won’t work normally.

For example, slower blood flow deprives your arms, legs, lungs, and eyes of the oxygen they need. This can cause headaches, dizziness, itching, and vision problems, such as blurred or double vision.

Polycythemia vera is a serious, chronic (ongoing) disease that can be fatal if not diagnosed and treated. Polycythemia vera has no cure, but treatments can help control the disease and its complications.

Polycythemia vera is treated with procedures, medicines, and other methods. You may need one or more treatments to manage the disease.

What Causes Polycythemia Vera ?

Primary Polycythemia

Polycythemia vera also is known as primary polycythemia. A mutation, or change, in the body’s JAK2 gene is the main cause of polycythemia vera. The JAK2 gene makes a protein that helps the body produce blood cells.

What causes the change in the JAK2 gene isn’t known. Polycythemia vera generally isn’t inherited—that is, passed from parents to children through genes. However, in some families, the JAK2 gene may have a tendency to mutate. Other, unknown genetic factors also may play a role in causing polycythemia vera.

Secondary Polycythemia

Another type of polycythemia, called secondary polycythemia, isn’t related to the JAK2 gene. Long-term exposure to low oxygen levels causes secondary polycythemia.

A lack of oxygen over a long period can cause your body to make more of the hormone erythropoietin (EPO). High levels of EPO can prompt your body to make more red blood cells than normal. This leads to thicker blood, as seen in polycythemia vera.

People who have severe heart or lung disease may develop secondary polycythemia. People who smoke, spend long hours at high altitudes, or are exposed to high levels of carbon monoxide where they work or live also are at risk.

For example, working in an underground parking garage or living in a home with a poorly vented fireplace or furnace can raise your risk for secondary polycythemia.

Rarely, tumors can make and release EPO, or certain blood problems can cause the body to make more EPO.

Sometimes doctors can cure secondary polycythemia—it depends on whether the underlying cause can be stopped, controlled, or cured.

What Are the Signs and Symptoms of Polycythemia Vera ?

Polycythemia vera develops slowly. The disease may not cause signs or symptoms for years.

When signs and symptoms are present, they’re the result of the thick blood that occurs with polycythemia vera. This thickness slows the flow of oxygen-rich blood to all parts of your body. Without enough oxygen, many parts of your body won’t work normally.

The signs and symptoms of polycythemia vera include:

• Headaches, dizziness, and weakness
• Shortness of breath and problems breathing while lying down
• Feelings of pressure or fullness on the left side of the abdomen due to an enlarged spleen (an organ in the abdomen)
• Double or blurred vision and blind spots
• Itching all over (especially after a warm bath), reddened face, and a burning feeling on your skin (especially your hands and feet)
• Bleeding from your gums and heavy bleeding from small cuts
• Unexplained weight loss
• Fatigue (tiredness)
• Excessive sweating
• Very painful swelling in a single joint, usually the big toe (called gouty arthritis)

In rare cases, people who have polycythemia vera may have pain in their bones.

Polycythemia Vera Complications

If you have polycythemia vera, the thickness of your blood and the slowed blood flow can cause serious health problems.

Blood clots are the most serious complication of polycythemia vera. Blood clots can cause a heart attack or stroke. They also can cause your liver and spleen to enlarge. Blood clots in the liver and spleen can cause sudden, intense pain.

Slowed blood flow also prevents enough oxygen-rich blood from reaching your organs. This can lead to angina (chest pain or discomfort) and heart failure. The high levels of red blood cells that polycythemia vera causes can lead to stomach ulcers, gout, or kidney stones.

Some people who have polycythemia vera may develop myelofibrosis. This is a condition in which your bone marrow is replaced with scar tissue. Abnormal bone marrow cells may begin to grow out of control.

This abnormal growth can lead to acute myelogenous leukemia (AML), a cancer of the blood and bone marrow. This disease can worsen very quickly.

How Is Polycythemia Vera Diagnosed ?

Polycythemia vera may not cause signs or symptoms for years. The disease often is found during routine blood tests done for other reasons. If the results of your blood tests aren’t normal, your doctor may want to do more tests.

Your doctor will diagnose polycythemia vera based on your signs and symptoms, your age and overall health, your medical history, a physical exam, and test results.

During the physical exam, your doctor will look for signs of polycythemia vera. He or she will check for an enlarged spleen, red skin on your face, and bleeding from your gums.

If your doctor confirms that you have polycythemia, the next step is to find out whether you have primary polycythemia or secondary polycythemia.

Your medical history and physical exam may confirm which type of polycythemia you have. If not, you may have tests that check the level of the hormone erythropoietin (EPO) in your blood.

People who have polycythemia vera have very low levels of EPO. People who have secondary polycythemia usually have normal or high levels of EPO.

Specialists Involved

If your primary care doctor thinks you have polycythemia vera, he or she may refer you to a hematologist. A hematologist is a doctor who specializes in diagnosing and treating blood diseases and conditions.

Diagnostic Tests

You may have blood tests to diagnose polycythemia vera. These tests include a complete blood count (CBC) and other tests, if necessary.
Complete Blood Count

Often, the first test used to diagnose polycythemia vera is a CBC. The CBC measures many parts of your blood.

This test checks your hemoglobin and hematocrit levels. Hemoglobin is an iron-rich protein that helps red blood cells carry oxygen from the lungs to the rest of the body. Hematocrit is a measure of how much space red blood cells take up in your blood. A high level of hemoglobin or hematocrit may be a sign of polycythemia vera.

The CBC also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal results may be a sign of polycythemia vera, a blood disorder, an infection, or another condition.

In addition to high red blood cell counts, people who have polycythemia vera also may have high white blood cell and/or platelet counts.

Other Blood Tests

Blood smear. For this test, a small sample of blood is drawn from a vein, usually in your arm. The blood sample is examined under a microscope.

A blood smear can show whether you have a higher than normal number of red blood cells. The test also can show abnormal blood cells that are linked to myelofibrosis and other conditions related to polycythemia vera.

Erythropoietin level. This blood test measures the level of EPO in your blood. EPO is a hormone that prompts your bone marrow to make new blood cells. People who have polycythemia vera have very low levels of EPO. People who have secondary polycythemia usually have normal or high levels of EPO.

Bone Marrow Tests

Bone marrow tests can show whether your bone marrow is healthy. These tests also show whether your bone marrow is making normal amounts of blood cells.

The two bone marrow tests are aspiration and biopsy. For aspiration, your doctor removes a small amount of fluid bone marrow through a needle. For a biopsy, your doctor removes a small amount of bone marrow tissue through a larger needle. The samples are then examined under a microscope.

If the tests show that your bone marrow is making too many blood cells, it may be a sign that you have polycythemia vera.

How Is Polycythemia Vera Treated ?

Polycythemia vera doesn’t have a cure. However, treatments can help control the disease and its complications. polycythemia vera is treated with procedures, medicines, and other methods. You may need one or more treatments to manage the disease.

Goals of Treatment

The goals of treating polycythemia vera are to control symptoms and reduce the risk of complications, especially heart attack and stroke. To do this, polycythemia vera treatments reduce the number of red blood cells and the level of hemoglobin (an iron-rich protein) in the blood. This brings the thickness of your blood closer to normal.

Blood with normal thickness flows better through the blood vessels. This reduces the chance that blood clots will form and cause a heart attack or stroke.

Blood with normal thickness also ensures that your body gets enough oxygen. This can help reduce some of the signs and symptoms of polycythemia vera, such as headaches, vision problems, and itching.

Studies show that treating polycythemia vera greatly improves your chances of living longer.

The goal of treating secondary polycythemia is to control its underlying cause, if possible. For example, if the cause is carbon monoxide exposure, the goal is to find the source of the carbon monoxide and fix or remove it.

Treatments To Lower Red Blood Cell Levels

Phlebotomy

Phlebotomy is a procedure that removes some blood from your body. For this procedure, a needle is inserted into one of your veins. Blood from the vein flows through an airtight tube into a sterile container or bag. The process is similar to the process of donating blood.

Phlebotomy reduces your red blood cell count and starts to bring your blood thickness closer to normal.

Typically, a pint (1 unit) of blood is removed each week until your hematocrit level approaches normal. Hematocrit is the measure of how much space red blood cells take up in your blood.

You may need to have phlebotomy done every few months.

Medicines

Your doctor may prescribe medicines to keep your bone marrow from making too many red blood cells. Examples of these medicines include hydroxyurea and interferon-alpha.

Hydroxyurea is a medicine generally used to treat cancer. This medicine can reduce the number of red blood cells and platelets in your blood. As a result, this medicine helps improve your blood flow and bring the thickness of your blood closer to normal.

Interferon-alpha is a substance that your body normally makes. It also can be used to treat polycythemia vera. Interferon-alpha can prompt your immune system to fight overactive bone marrow cells. This helps lower your red blood cell count and keep your blood flow and blood thickness closer to normal.

Radiation Treatment

Radiation treatment can help suppress overactive bone marrow cells. This helps lower your red blood cell count and keep your blood flow and blood thickness closer to normal.

However, radiation treatment can raise your risk of leukemia (blood cancer) and other blood diseases.

Treatments for Symptoms

Aspirin can relieve bone pain and burning feelings in your hands or feet that you may have as a result of polycythemia vera. Aspirin also thins your blood, so it reduces the risk of blood clots.

Aspirin can have side effects, including bleeding in the stomach and intestines. For this reason, take aspirin only as your doctor recommends.

If your polycythemia vera causes itching, your doctor may prescribe medicines to ease the discomfort. Your doctor also may prescribe ultraviolet light treatment to help relieve your itching.

Other ways to reduce itching include:

• Avoiding hot baths. Cooler water can limit irritation to your skin.
• Gently patting yourself dry after bathing. Vigorous rubbing with a towel can irritate your skin.
• Taking starch baths. Add half a box of starch to a tub of lukewarm water. This can help soothe your skin.

Experimental Treatments

Researchers are studying other treatments for polycythemia vera. An experimental treatment for itching involves taking low doses of selective serotonin reuptake inhibitors (SSRIs). This type of medicine is used to treat depression. In clinical trials, SSRIs reduced itching in people who had polycythemia vera.

Imatinib mesylate is a medicine that’s approved for treating leukemia. In clinical trials, this medicine helped reduce the need for phlebotomy in people who had polycythemia vera. This medicine also helped reduce the size of enlarged spleens.

Researchers also are trying to find a treatment that can block or limit the effects of an abnormal JAK2 gene. A mutation, or change, in the JAK2 gene is the major cause of polycythemia vera.

Blood Transfusions

Early attempts to transfer blood from one person to another produced varied results. Sometimes, the recipient improved. Other times, the recipient suffered a blood transfusion reaction in which the red blood cells clumped, obstructing vessels and producing great pain and organ damage.

Eventually scientists determined that blood is of differing types and that only certain combinations of blood types are compatible. These discoveries led to the development of procedures for typing blood. Today, safe transfusions of whole blood depend on two blood tests—“type and cross match.” First the recipient’s ABO blood type and Rh status are determined. Following this, a “cross match” is done of the recipient’s serum with a small amount of the donor’s red blood cells that have the same ABO type and Rh status as the recipient. Compatibility is determined by examining the mixture under a microscope for agglutination, the clumping of red blood cells. Agglutination (“clumping”) is a reaction between antigens and specific antibodies. This is what happens when antigens on mismatched donated red blood cells react with antibodies in plasma.

Blood Antigens and Antibodies

An antigen, is any molecule that triggers an immune response, the body’s reaction to invasion by a foreign substance or organism. When the immune system encounters an antigen not found on the body’s own cells, it will attack, producing antibodies. In a transfusion reaction, antigens (agglutinogens) on the surface of the donated red blood cells react with antibodies (agglutinins) in the plasma of the recipient, resulting in the agglutination of the donated red blood cells.

A mismatched blood transfusion quickly produces telltale signs of agglutination—anxiety, breathing difficulty, facial flushing, headache, and severe pain in the neck, chest, and lumbar area. Red blood cells burst, releasing free hemoglobin. Liver cells and macrophages phagocytize the hemoglobin, converting it to bilirubin, which may sufficiently accumulate to cause the yellow skin of jaundice. Free hemoglobin reaching the kidneys may ultimately cause them to fail.

Only a few of the 32 known antigens on red blood cell membranes can produce serious transfusion reactions. These include the antigens of the ABO group and those of the Rh group. Avoiding the mixture of certain kinds of antigens and antibodies prevents adverse transfusion reactions.

ABO Blood Group

The ABO blood group is based on the presence (or absence) of two major antigens on red blood cell membranes—antigen A and antigen B. A and B antigens are carbohydrates attached to glycolipids projecting from the red blood cell surface. A person’s erythrocytes have on their surfaces one of four antigen combinations: only A, only B, both A and B, or neither A nor B.

A person with only antigen A has type A blood. A person with only antigen B has type B blood. An individual with both antigens A and B has type AB blood. A person with neither antigen A nor B has type O blood. Thus, all people have one of four possible ABO blood types—A, B, AB, or O. The resulting ABO blood type is inherited. It is the consequence of DNA encoding enzymes to synthesize A or B antigens on erythrocytes in one of these four combinations.

• In the United States, the most common ABO blood types are O (47%) and A (41%). Rarer are type B (9%) and type AB (3%). These percentages vary in subpopulations and over time, reflecting changes in the genetic structure of populations.

Antibodies that affect the ABO blood group antigens are present in the plasma about two to eight months following birth, as a result of exposure to foods or microorganisms containing the antigen(s) that are not present on the individual’s red blood cells. Specifically, whenever antigen A is absent in red blood cells, an antibody called anti-A is produced, and whenever antigen B is absent on cells, an antibody called anti-B is produced. Therefore, individuals with type A blood have anti-B antibody in their plasma; those with type B blood have anti-A antibody; those with type AB blood have neither antibody; and those with type O blood have both anti-A and anti-B antibodies (Figure 11 and Table 1). The antibodies anti-A and anti-B are large and do not cross the placenta. Thus, a pregnant woman and her fetus may be of different ABO blood types, but agglutination in the fetus will not occur.

An antibody of one type will react with an antigen of the same type and clump red blood cells; therefore, such combinations must be avoided. The major concern in blood transfusion procedures is that the cells in the donated blood not clump due to antibodies in the recipient’s plasma. For this reason, a person with type A (anti-B) blood must not receive blood of type B or AB, either of which would clump in the presence of anti-B in the recipient’s type A blood. Likewise, a person with type B (anti-A) blood must not receive type A or AB blood, and a person with type O (anti-A and anti-B) blood must not receive type A, B, or AB blood.

Type AB blood does not have anti-A or anti-B antibodies, so an AB person can receive a transfusion of blood of any other type. For this reason, individuals with type AB blood are called universal recipients. However, type A (anti-B) blood, type B (anti-A) blood, and type O (anti-A and anti-B) blood still contain antibodies (either anti-A and/or anti-B) that could agglutinate type AB cells if transfused rapidly.

Consequently, even for AB individuals, using donor blood of the same type as the recipient is best. Type O blood has neither antigen A nor antigen B. Therefore, theoretically this type could be transfused into persons with blood of any other type. Individuals with type O blood are called universal donors. Type O blood, however, does contain both anti-A and anti-B antibodies. If type O blood is given to a person with blood type A, B, or AB, it should be transfused slowly so that the recipient’s larger blood volume will dilute the donor blood, minimizing the chance of an adverse reaction.

Figure 11. ABO Blood Types and Antibodies (different combinations of antigens and antibodies distinguish blood types)

Table 1. Antigens and Antibodies of the ABO Blood Group

Table 2. Preferred and Permissible Blood Types for Transfusions

Rh Blood Group

The Rh (Rhesus) blood group was named after the rhesus monkey in which it was first studied. In humans, this group includes several Rh antigens (factors). The most prevalent of these is antigen D, a transmembrane protein.

If the Rh antigens are present on the red blood cell membranes, the blood is said to be Rh-positive. Conversely, if the red blood cells do not have Rh antigens, the blood is called Rh-negative. The presence (or absence) of Rh antigens is an inherited trait. Anti-Rh antibodies (anti-Rh) form only in Rh-negative individuals in response to the presence of red blood cells with Rh antigens. This happens, for example, if an individual with Rh-negative blood receives a transfusion of Rh-positive blood. The Rh antigens stimulate the recipient to begin producing anti-Rh antibodies. Generally, this initial transfusion has no serious consequences, but if an individual with Rh-negative blood—who is now sensitized to Rh-positive blood—receives another transfusion of Rh-positive blood some months later, the donated red cells are likely to agglutinate.

A similar situation of Rh incompatibility arises when an Rh-negative woman is pregnant with an Rh-positive fetus. Her first pregnancy with an Rh-positive fetus would probably be uneventful. However, if at the time of the infant’s birth (or if a miscarriage occurs) the placental membranes that separated the maternal blood from the fetal blood during the pregnancy tear, some of the infant’s Rh-positive blood cells may enter the maternal circulation. These Rh-positive cells may then stimulate the maternal tissues to produce anti-Rh antibodies. If a woman who has already developed anti-Rh antibodies becomes pregnant with a second Rh-positive fetus, these antibodies, called hemolysins, cross the placental membrane and destroy the fetal red blood cells. The fetus then develops a condition called erythroblastosis fetalis, or hemolytic disease of the fetus and newborn.

Erythroblastosis fetalis is extremely rare today because obstetricians carefully track Rh status. An Rh-negative woman who might carry an Rh-positive fetus is given an injection of a drug called RhoGAM at week 28 of her pregnancy and after delivery of an Rh-positive baby. Rhogam is a preparation of anti-Rh antibodies, which bind to and shield any Rh-positive fetal cells that might contact the woman’s cells and sensitize her immune system. RhoGAM must be given within 72 hours of possible contact with Rh-positive cells—including giving birth, terminating a pregnancy, miscarrying, or undergoing amniocentesis (a prenatal test in which a needle is inserted into the uterus).

1. Anemia. National Heart, Lung and Blood Institute. https://www.nhlbi.nih.gov/health/health-topics/topics/anemia
2. Iron-Deficiency Anemia. National Heart, Lung and Blood Institute. https://www.nhlbi.nih.gov/health-topics/topics/ida
3. Pernicious Anemia. National Heart, Lung and Blood Institute. https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia
4. Sickle Cell Disease. National Heart, Lung and Blood Institute. https://www.nhlbi.nih.gov/health/health-topics/topics/sca
5. Who Is at Risk for Sickle Cell Disease ? National Heart, Lung and Blood Institute. https://www.nhlbi.nih.gov/health/health-topics/topics/sca/atrisk
6. By en:User:Cburnett – Own work in Inkscape, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1840082
7. Polycythemia Vera. National Heart, Lung and Blood Institute. https://www.nhlbi.nih.gov/health/health-topics/topics/poly

What is blood plasma

How much blood you have depends mostly on your size and weight. A man who weighs about 70 kg (about 154 pounds) has about 5 to 6 liters of blood in his body. Blood is 55% blood plasma and about 45% different types of blood cells. Blood is composed of solid particles (red blood cells, white blood cells, and cell fragments called platelets) suspended in a fluid extracellular matrix called blood plasma. Over 99% of the solid particles present in blood are cells that are called red blood cells (erythrocytes) due to their red color. The rest are pale or colorless white blood cells (leukocytes) and platelets (thrombocytes).

The blood plasma is the clear, straw-colored, liquid portion of the blood in which the cells (red blood cells, white blood cells) and platelets are suspended. It is
approximately 92% water and less than 8% is dissolved substances, mostly proteins, a complex mixture of organic and inorganic biochemicals. Functions of plasma include transporting gases, vitamins, and other nutrients; helping to regulate fluid and electrolyte balance; and maintaining a favorable pH. Blood plasma also contain antibodies to fight infections (part of the immune system), glucose, amino acids and the proteins that form blood clots (part of the hemostatic system)..

Blood plasma contains electrolytes that are absorbed from the intestine or released as by-products of cellular metabolism. They include sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate, and sulfate ions. Sodium and chloride ions are the most abundant. Bicarbonate ions are important in maintaining the pH of plasma. Like other plasma constituents, bicarbonate ions are regulated so that their blood concentrations remain relatively stable.

Blood transports a variety of materials between interior body cells and those that exchange substances with the external environment. In this way, blood helps maintain stable internal environmental conditions.

Hemostasis refers to the process that stops bleeding, which is vitally important when blood vessels are damaged. Following an injury to the blood vessels, several actions may help to limit or prevent blood loss. These include vascular spasm, platelet plug formation, and blood coagulation.

Platelets adhere to any rough surface, particularly to the collagen in connective tissue. When a blood vessel breaks, platelets adhere to the collagen underlying the endothelium lining blood vessels. Platelets also adhere to each other, forming a platelet plug in the vascular break. A plug may control blood loss from a small break, but a larger break may require a blood clot to halt bleeding.

Coagulation, the most effective hemostatic mechanism, forms a blood clot in a series of reactions, each one activating the next. Blood coagulation is complex and utilizes many biochemicals called clotting factors. Some of these factors promote coagulation, and others inhibit it. Whether or not blood coagulates depends on the balance between these two groups of factors. Normally, anticoagulants prevail, and the blood does not clot. However, as a result of injury (trauma), biochemicals that favor coagulation may increase in concentration, and the blood may coagulate. The resulting mass is a blood clot, which may block a vascular break and prevent further blood loss. The clear, yellow liquid that remains after the clot forms is called serum. Serum is plasma minus the clotting factors.

Note: Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Figure 1. Blood composition

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Blood Plasma Proteins

Blood plasma proteins are the most abundant of the dissolved substances (solutes) in plasma. These proteins remain in the blood and interstitial fluids, and ordinarily are not used as energy sources. The three main types of blood plasma proteins—albumins, globulins, and fibrinogen—differ in composition and function.

Albumins are the smallest plasma proteins, yet account for about 60% of them by weight. Albumins are synthesized in the liver.

Plasma proteins are too large to pass through the capillary walls, so they are impermeant. They create an osmotic pressure that holds water in the capillaries, despite blood pressure forcing water out of capillaries by filtration. The term colloid osmotic pressure is used to describe this osmotic effect due to the plasma proteins. Because albumins are so plentiful, they are an important determinant of the colloid osmotic pressure of the plasma.

By maintaining the colloid osmotic pressure of plasma, albumins and other plasma proteins help regulate water movement between the blood and the tissues. In doing so, the blood plasma proteins help control blood volume, which, in turn, directly affects blood pressure.

If the concentration of plasma proteins falls, tissues swell. This condition is called edema. As the concentration of plasma proteins drops, so does the colloid osmotic pressure. Water leaves the blood vessels and accumulates in the interstitial spaces, causing swelling. A low plasma protein concentration may result from starvation, a protein-deficient diet, or an impaired liver that cannot synthesize plasma proteins.

Globulins make up about 36% of the plasma proteins. They can be further subdivided into alpha, beta, and gamma globulins. The liver synthesizes alpha and
beta globulins, which have a variety of functions. The globulins transport lipids and fat-soluble vitamins. Lymphatic tissues produce the gamma globulins, which are a type of antibody.

Fibrinogen constitutes about 4% of the plasma proteins, and functions in blood coagulation (clotting). Fibrinogen is synthesized in the liver, fibrinogen is the largest of the plasma proteins.

Plasma products and their uses

Plasma products can be grouped into three main types:

• clotting or coagulation factors
• albumin solutions
• immunoglobulins

Coagulation or clotting factors

Coagulation is the name for the complex process of blood clotting. Clotting factors are proteins that work together with platelets to clot blood.

People need clotting factors for their blood to successfully clot. Missing one or more of these factors leads to blood clotting disorders such as haemophilia and Von Willebrand disease.

In the US, hemophilia is commonly treated with ‘recombinant factors’ that are manufactured in a laboratory and do not come from donated plasma.

Other blood clotting disorders that are treated with coagulation factors made from donated plasma.

Albumin

Albumin is the most common protein in blood plasma. It helps to:

• carry substances around the body
• maintain the right amount of fluid circulating in the body

If the circulation is working properly, vital hormones, cells and enzymes are transported to the right parts of the body to do their job.

If it’s not working properly, the circulatory system starts to break down, with serious consequences such as fluids being retained in the cells.

This can be treated by using human albumin solution which makes sure that the right amount of fluid is circulating in the blood stream.

Albumin can also be used to treat people with some types of liver or kidney disease and patients who have suffered burns.

Immunoglobulins

Immunoglobulins are protective antibodies which are produced by the body to fight against invading viruses or bacteria. There are two different types of immunoglobulins, specific and non-specific.

Specific immunoglobulins

Specific immunoglobulins contain high levels of antibody to a particular illness. These are given to people who have been exposed to a specific infection.

Antidotes to tetanus, rabies, chickenpox and hepatitis are all examples of specific immunoglobulins.

For example, a donor who has had chicken pox will have high levels of chicken pox antibodies. So their plasma would be ideal to treat a child with leukaemia who has been exposed to chicken pox.

Non-specific immunoglobulins

Non-specific immunoglobulins contain a wide variety of antibodies. These are given to people:

• who make faulty antibodies, or can’t make their own antibodies
• who are having treatments for diseases like cancer, where the treatment harms their ability to make antibodies

People with a faulty immune system need these products to live. Over 1,000 donations of plasma contribute to a single dose of an immunoglobulin product that contains all the necessary antibodies.

Table 1 summarizes the characteristics of the blood plasma proteins.

Table 1. Blood plasma proteins

Separating plasma products

Plasma is first tested to be sure it’s safe to use, in the same way that whole blood is tested.

Many chemical and physical processes (e.g., spinning and heat treatments) are then carried out to separate the individual proteins. This is known as the fractionation process.

This process is fully automated and takes up to five days to complete.

Solvent or detergent treatment, dry heat treatment, filtration and pasteurization are also used to kill or remove any viruses that may be present.

The finished products are then tested again to make sure they contain the right biological make-up.

Once processing and testing is complete, the products are labeled, coded and packed, ready to be used by hospitals, clinics and doctors’ surgeries.

The total number of products that can be made with plasma fractionation runs into hundreds.

Blood Plasma Gases and Nutrients

The most important blood gases are oxygen (O2) and carbon dioxide (CO2). Blood plasma also contains a considerable amount of dissolved nitrogen, which ordinarily has no physiological function.

The plasma nutrients include amino acids, simple sugars, nucleotides, and lipids, all absorbed from the digestive tract. For example, blood plasma transports glucose from the small intestine to the liver, where it may be stored as glycogen or converted to fat. If blood glucose concentration drops below the normal range, glycogen may be broken down into glucose.

Blood plasma also carries recently absorbed amino acids to the liver, where they may be used to manufacture proteins, or deaminated and used as an energy source.

Blood plasma lipids include fats (triglycerides), phospholipids, and cholesterol. Because lipids are not water-soluble and plasma is almost 92% water, these lipids are carried in the plasma attached to proteins.

Blood Plasma Nonprotein Nitrogenous Substances

Molecules that contain nitrogen atoms but are not proteins comprise a group called nonprotein nitrogenous substances. In plasma, this group includes amino acids, urea, uric acid, creatine and creatinine. Amino acids come from protein digestion and amino acid absorption. Urea and uric acid are products of protein and nucleic acid catabolism, respectively. Creatinine results from the metabolism of creatine. In the skeletal muscle creatine is part of creatine phosphate in muscle tissue, where it stores energy in phosphate bonds.

Blood Plasma Electrolytes

Blood plasma contains electrolytes that are absorbed from the intestine or released as by-products of cellular metabolism. They include sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate, and sulfate ions. Sodium and chloride ions are the most abundant. Bicarbonate ions are important in maintaining the pH of plasma. Like other plasma constituents, bicarbonate ions are regulated so that their blood concentrations remain relatively stable.

Blood plasma donation

Plasmapheresis is the standard procedure by which blood plasma is separated from whole blood and collected ¹. Blood flows through a single needle placed in an arm vein, into a machine that contains a sterile, disposable plastic kit. The plasma is isolated and channeled out into a special bag, and red blood cells and other parts of the blood are returned to you through the same needle.

Is Plasmapheresis Safe ?

Absolutely. The machine and the procedure have been evaluated and approved by the Food and Drug Administration (FDA), and all plastics and needles coming into contact with you are used once and discarded ¹. At no time during the procedure is the blood being returned to you detached from the needle in your arm, so there is no risk of returning the wrong blood to you.

Who Is Eligible to Participate in the AB Plasma Program ?

Donors must have blood group AB and must be male, because men lack plasma proteins (antibodies) directed against blood cell elements ¹. Otherwise, eligibility for plasmapheresis procedures is the same as that for whole-blood donation. The interval between consecutive group AB plasmapheresis donations at National Institutes of Health Blood Bank is 1 month.

How Long Does Plasmapheresis Take ?

Plasmapheresis procedures take about 40 minutes, but you should allow another 20 minutes for staff to obtain your medical history ¹.

What is blood plasma used for

Blood plasma is the pale yellow liquid part of whole blood. It is enriched in proteins that help fight infection (part of the immune system) and aid the blood in clotting (part of the hemostatic system). AB plasma is plasma collected from blood group AB donors. It is considered “universal donor” plasma because it is suitable for all recipients, regardless of blood group. Due to its value as a transfusion component, it is sometimes referred to as “liquid gold.”

Blood plasma products available in the United States include fresh frozen plasma and thawed plasma that may be stored at 33.8 to 42.8°F (1 to 6°C) for up to five days ². Blood plasma contains all of the coagulation factors. Fresh frozen plasma infusion can be used for reversal of anticoagulant effects. Thawed plasma has lower levels of factors V and VIII and is not indicated in patients with consumption coagulopathy (diffuse intravascular coagulation) ³.

Blood plasma transfusion is recommended in patients with active bleeding and an International Normalized Ratio (INR) greater than 1.6, or before an invasive procedure or surgery if a patient has been anticoagulated ⁴, ⁵. Blood plasma is often inappropriately transfused for correction of a high INR when there is no bleeding. Supportive care can decrease high-normal to slightly elevated INRs (1.3 to 1.6) without transfusion of plasma. Table 2 gives indications for plasma transfusion ⁴, ⁵, ⁶.

Table 2. Indications for Transfusion of Blood Plasma Products

Cryoprecipitate

Cryoprecipitate is prepared by thawing fresh frozen plasma and collecting the precipitate. Cryoprecipitate contains high concentrations of factor VIII and fibrinogen ². Cryoprecipitate is used in cases of hypofibrinogenemia, which most often occurs in the setting of massive hemorrhage or consumptive coagulopathy. Indications for cryoprecipitate transfusion are listed in Table 3 ⁷, ⁸. Each unit will raise the fibrinogen level by 5 to 10 mg per dL (0.15 to 0.29 μmol per L), with the goal of maintaining a fibrinogen level of at least 100 mg per dL (2.94 μmol per L) ⁸. The usual dose in adults is 10 units of pooled cryoprecipitate ³. Recommendations for dosing regimens in neonates vary, ranging from 2 mL of cryoprecipitate per kg to 1 unit of cryoprecipitate (15 to 20 mL) per 7 kg ⁷.

Table 3. Indications for Transfusion of Cryoprecipitate

Blood plasma for patients undergoing surgery on the heart or blood vessels

Cardiovascular surgery includes many types of major surgery on the heart and major blood vessels, including procedures such as: heart valve replacements, coronary artery bypass grafts, aortic aneurysm repairs and corrections or congenital abnormalities of the heart. Cardiovascular surgery is associated with a significant risk of bleeding, with 8% of patients losing more than 2 ml/kg/hour of blood postoperatively ⁹. A number of features make patients undergoing cardiovascular surgery more likely to bleed ¹⁰, ¹¹:

• These patients may be taking drugs that predispose towards bleeding, such as aspirin or clopidogrel.

• Patients undergoing major heart surgery will often require a cardiopulmonary bypass, where a circuit is formed by removing the heart from the circulation by passing a catheter into the aorta and the pulmonary artery while a cardiopulmonary bypass machine circulates blood round the body and ensures that it is adequately oxygenated. Heparin is used to prevent the cardiopulmonary bypass circuit from clotting. Heparin is an anticoagulant and can predispose patients to bleeding. When cardiopulmonary bypass is complete, heparin is neutralised with protamine.

• Hypothermia and acidosis during the procedure may also contribute towards excess bleeding.

• Dilution of clotting factors with administration of intravenous fluid; this is a particular problem in the paediatric setting.

• When acute bleeding develops, clotting factors are consumed, resulting in a coagulopathy and predisposing the patient towards further bleeding.

In some cases these patients will have a clearly defined bleeding risk. They may already be haemorrhaging and, if this is the case, treatments to reduce bleeding would be considered therapeutic. Alternatively they may have abnormal blood results, such as a prolonged prothrombin time, suggesting that clotting factors may be deficient. Lastly, in some cases it may be presumed that a coagulopathy may develop and that prophylactic treatment before this event would reduce the risk of bleeding.

Treatment strategies to reduce bleeding include optimising surgical technique to minimise blood loss; antifibrinolytic agents such as tranexamic acid; careful monitoring and neutralisation of heparin; optimising the management of anticoagulant and antiplatelet drugs; and blood components such as fresh frozen plasma ¹².

Fresh frozen plasma obtained from whole blood from blood donors, is a source of procoagulant factors, including fibrinogen and is used for either the treatment or prophylaxis of bleeding ¹³. Many audits indicate that patients undergoing major cardiac and vascular surgery receive a significant proportion of all clinical plasma transfusions. Some studies have reported wide variation in the use of clinical plasma for cardiac surgery and in critical care among centres within the same country ¹⁴.

Fresh frozen plasma contains a number of factors that help blood to clot. The risk of bleeding in open heart surgery or surgery on the main blood vessels in the body is high. Fresh frozen plasma is sometimes administered to these patients to reduce bleeding. It can be administered prophylactically (to prevent bleeding) or therapeutically (to treat bleeding). However, there are risks of side effects from fresh frozen plasma, such as severe allergic reactions or breathing problems ¹⁵.

However a 2015 Cochrane Review found no evidence for the efficacy of fresh frozen plasma for the prevention of bleeding in heart surgery and it found some evidence of an increased overall need for red cell transfusion in those treated with fresh frozen plasma ¹⁵. There were no reported adverse events due to fresh frozen plasma transfusion. Overall the evidence for the safety and efficacy of prophylactic fresh frozen plasma for cardiac surgery is insufficient. The trials focused on prevention of bleeding and did not address prevention of bleeding for patients with abnormal blood clotting or for the treatment of bleeding patients.

Blood plasma for critically ill patients

Plasma transfusions are a frequently used treatment for critically ill patients, and they are usually prescribed to correct abnormal coagulation tests and to prevent or stop bleeding ¹⁶. Plasma transfusions have been used since 1941 ¹⁷. In 2008, 4,484,000 plasma units were transfused in patients in the United States ¹⁸. More than 10% of critically ill patients, both adults and children, receive a plasma transfusion during their hospital stay, making plasma transfusion a frequently used treatment modality ¹⁹, ²⁰, ²¹. In current practice, plasma transfusions are widely used in critical care; they are administered most often to correct abnormal coagulation tests or to prevent bleeding ²².

In situations in which active bleeding is attributable to a coagulation factor deficiency, plasma transfusions can constitute a life-saving intervention by improving coagulation factor deficit ²³, especially in patients requiring massive transfusion ²⁴. Although plasma transfusions are frequently prescribed for critically ill patients, some of the reasons for their use are not supported by evidence from medical research. Some research has found an association of plasma transfusions with worse outcomes, and other studies have suggested that plasma transfusions do not help to return blood to its normal thickness ²⁵.

Blood plasma for chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy is a disease that causes progressive or relapsing and remitting weakness and numbness. At least one or two cases per 100,000 of the population and may be as high as 8.9 per 100,000 ²⁶. It is probably caused by an autoimmune process. Chronic inflammatory demyelinating polyradiculoneuropathy is an uncommon disease that causes weakness and numbness of the arms and legs. The condition may progress steadily or have periods of worsening and improvement. Although not proven, chronic inflammatory demyelinating polyradiculoneuropathy is generally considered to be an autoimmune disease caused by either humoral or cell-mediated immunity directed against myelin around individual nerve fibres or Schwann cell antigens which have not been identified ²⁷. In severe cases, the disease affects the actual nerve fibres themselves. There has been debate as to whether people with the clinical features of an acquired demyelinating neuropathy and a systemic disease, such as cancer, diabetes mellitus, systemic lupus erythematosus, and other connective tissue diseases should be categorised as having chronic inflammatory demyelinating polyradiculoneuropathy ²⁸.

Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. According to Cochrane systematic reviews, three immune system treatments are known to help. These are corticosteroids (‘steroids’), plasma exchange (which removes and replaces blood plasma), and intravenous immunoglobulin (infusions into a vein of human antibodies). Moderate- to high-quality evidence from two small trials shows that plasma exchange provides significant short-term improvement in disability, clinical impairment, and motor nerve conduction velocity in chronic inflammatory demyelinating polyradiculoneuropathy but rapid deterioration may occur afterwards ²⁹. Adverse events related to difficulty with venous access, use of citrate, and haemodynamic changes are not uncommon.

Blood plasma for generalised myasthenia gravis

Myasthenia gravis is an autoimmune disease caused by antibodies in the blood which attack the junctions (against the nicotinic acetylcholine receptor) between nerves and muscles they stimulate. Less than five per cent of patients have auto-antibodies to a muscle tyrosine kinase. Myasthenia gravis is characterised by weakness and fatigability of voluntary muscle, which changes over time. Acute exacerbations are life-threatening because they can cause swallowing difficulties or respiratory failure. Historically, with treatment – including thymectomy, steroids, and immunosuppressive drugs – after one to 21 (mean 12) years, 6% of patients went into remission, 36% improved, 42% were unchanged, and 2% were worse ³⁰. In recent years, expert opinion has highlighted the greater efficacy of combined immunosuppressive treatments ³¹. A new subtype of myasthenia is associated with autoantibodies to a muscle specific kinase and these antibodies are also pathogenic on passive transfer ³².

Plasma exchange was introduced in 1976 as a short-term therapy for acute exacerbations of myasthenia gravis ³³. It is thought to work because the exchange removes circulating anti-AChR (anti-acetylcholine receptor) antibodies. However, improvement has also been reported in so-called seronegative myasthenia gravis (where no anti-AChR antibodies can be detected) following plasma exchange ³⁴. A symposium held in 1978 ³⁵, and numerous papers have recognised the short-term benefit of plasma exchanges ³⁶. The use of repeated plasma exchange over a long period in refractory myasthenia gravis has also been reported ³⁷. Plasma exchange is used worldwide for the treatment of myasthenia gravis but despite the published case series and the conferences of experts many questions remains unanswered concerning its efficacy for the treatment of chronic, more or less severe, myasthenia gravis as well as of myasthenic exacerbation or crisis and its efficacy in comparison with other treatments. Few randomised controlled trials have been published ³⁸, ³⁹. Plasma exchange removes these circulating auto-antibodies. Many case series suggest that plasma exchange helps to treat myasthenia gravis. However, two Cochrane Reviews 2002 ⁴⁰ and 2003 ⁴¹, both found no adequate randomised controlled trials have been performed to determine whether plasma exchange improves the short- or long-term outcome for chronic myasthenia gravis or myasthenia gravis exacerbation. However, many case series studies convincingly report short-term benefit from plasma exchange in myasthenia gravis, especially in myasthenic exacerbation or crisis. In severe exacerbations of myasthenia gravis one randomised controlled trial did not show a significant difference between plasma exchange and intravenous immunoglobulin. Further research is need to compare plasma exchange with alternative short-term treatments for myasthenic crisis or before thymectomy and to determine the value of long-term plasma exchange for treating myasthenia gravis.

Blood plasma for the prevention of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome is an iatrogenic, serious and potentially fatal complication of ovarian stimulation which affects 1% to 14% of all in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles ⁴². Ovarian hyperstimulation syndrome may be associated with massive ovarian enlargement, extracellular exudate accumulation combined with profound intravascular volume depletion, ascites, hydrothorax, haemoconcentration, liver dysfunction and renal failure ⁴³. It can lead to cancellation of an IVF cycle and prolonged bed rest or hospitalisation, which may have significant emotional, social, and economic impacts ⁴⁴. Ovarian hyperstimulation syndrome can be classified into an early form that is related to the ovarian response and exogenous human chorionic gonadotrophin (hCG) administration, and is detected three to nine days after hCG administration. A late form of ovarian hyperstimulation syndrome, diagnosed 10 to 17 days later, is due to endogenous hCG ⁴⁵ and is categorised as mild, moderate, severe or life-threatening. The aetiology of ovarian hyperstimulation syndrome is not completely clear at this moment; however the syndrome is strongly associated with serum hCG and certain vasoactive substances ⁴⁶ are not elevated during gonadotropin stimulation in in vitro fertilization (IVF) patients developing ovarian hyperstimulation syndrome (OHSS): results of a prospective cohort study with matched controls. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2001;96:196-201. https://www.ncbi.nlm.nih.gov/pubmed/11384807)).

Blood plasma albumin has both osmotic and transport functions. It contributes about 75% of the plasma oncotic pressure and administration of 50 g human albumin solution will draw more than 800 mL of extracellular fluid into the circulation within 15 minutes ⁴⁷. It has been suggested that the binding and transport properties of human albumin play a major role in the prevention of severe ovarian hyperstimulation syndrome, as albumin may result in binding and inactivation of the vasoactive intermediates responsible for the pathogenesis of ovarian hyperstimulation syndrome. The osmotic function is responsible for maintaining the intra-vascular volume in the event of capillary leakage, thus preventing the sequelae of hypovolaemia, ascites and haemoconcentration ⁴⁸. A 2016 Cochrane Review concluded that there is some eEvidence suggesting that the plasma expanders assessed in this review (human albumin, hydroxyethyl starch and mannitol) reduce rates of moderate and severe ovarian hyperstimulation syndrome in women at high risk. Adverse events appear to be uncommon, but were too poorly reported to reach any firm conclusions ⁴⁸.

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Blood donation rules

Blood donation rules and requirements vary a lot between countries. For example, in the the United States (US) you must be at least 17 years old to donate blood at the National Institutes of Health Blood Bank ¹. In Australia the minimum age to donate blood is 16 years with an upper limit of 70 years of age ². In the US there is no upper age limit for donation ¹.

The temperature of blood in the body is 38° C, which is about one degree higher than body temperature ³. How much blood you have depends mostly on your size and weight. A man who weighs about 70 kg (about 154 pounds) has about 5 to 6 liters of blood in his body.

The volume of blood removed during a donation (450 mL ± 10% of blood) represents only about 10% of the total blood mass of a subject weighing 70 Kg.

Blood is 55% blood plasma and about 45% different types of blood cells. The blood plasma is a light yellow liquid. Over 90% of blood plasma is water, while less than 10% is dissolved substances, mostly proteins. Blood plasma also contains electrolytes, vitamins and nutrients such as glucose and amino acids. Over 99% of the solid particles present in blood are cells that are called red blood cells (erythrocytes) due to their red color. The rest are pale or colorless white blood cells (leukocytes) and platelets (thrombocytes).

Note: Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Figure 1. Blood composition

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Blood has three important functions:

• Transportation

The blood transports oxygen from the lungs to the cells of the body, where it is needed for metabolism. The carbon dioxide produced during metabolism is carried back to the lungs by the blood, where it is then exhaled. Blood also provides the cells with nutrients, transports hormones and removes waste products, which the liver, the kidneys or the intestine, for example, then get rid of.

• Regulation

The blood helps to keep certain values of the body in balance. For instance, it makes sure that the right body temperature is maintained. This is done both through blood plasma, which can absorb or give off heat, as well as through the speed at which the blood is flowing. When the blood vessels expand, the blood flows more slowly and this causes heat to be lost. When the environmental temperature is low the blood vessels can contract, so that as little heat as possible is lost. Even the so-called pH value of the blood is kept at a level ideal for the body. The pH value tells us how acidic or alkaline a liquid is. A constant pH value is very important for bodily functions.

• Protection

If a blood vessel is damaged, certain parts of the blood clot together very quickly and make sure that a scrape, for instance, stops bleeding. This is how the body is protected against losing blood. White blood cells and other messenger substances also play an important role in the immune system.

Blood donation eligibility ⁴

You can donate blood if you:

• Are healthy
• Are at least 17 years of age
• Weigh at least 110 pounds (50 kgs). There is no upper weight limit.

The tables below address specific situations affecting donation eligibility.

Table 1. Medical Condition

Medical Condition	Eligibility
Acquired Immune Deficiency Syndrome (AIDS), individuals at high risk and their partners	cannot donate
Colds and flu within 2 days	cannot donate
Diabetes, on or off medication and under control. If well-controlled by diet, oral medication, or insulin, you can donate. *However, the use of insulin made from beef is a cause for permanent deferral.	can donate
Hepatitis or jaundice after age 11	cannot donate
Pregnancy. You cannot donate until six weeks after the conclusion of the pregnancy.	cannot donate
Pregnancy, after delivery, miscarriage, abortion	6-week wait
Menstruation	can donate
Cancer, treatment complete and disease-free; most types	2-year wait

Table 2. Medical Procedures

Medical Procedures	Eligibility
Surgery, without transfusion (except for autologous blood)	can donate
Surgery, with transfusion	1-year wait

Table 3. Vaccinations