What is hypogammaglobulinemia

Hypogammaglobulinemia is a medical condition of abnormally low levels of gamma globulin (low immunoglobulin G, or IgG) or antibodies in your blood ¹, ², ³. Gamma globulins are a class of globulins, identified by their position after serum protein electrophoresis. The most significant gamma globulins are immunoglobulins that act as antibodies, although some immunoglobulins are not gamma globulins, and some gamma globulins are not immunoglobulins. People with hypogammaglobulinemia are at high risk for infections. Hypogammaglobulinemia may be due to certain genetic diseases or to acquired diseases such as HIV. Most patients with hypogammaglobulinemia present with a history of recurrent infections, failure to thrive, autoimmune disease, and more rarely with malignancies (especially leukemias or lymphomas). Among the conditions associated with hypogammaglobulinemia, common variable immunodeficiency (CVI) is the most common disorder associated with antibody deficiency and has a notably high prevalence, affecting one in every 10,000–50,000 live births ⁴.

Hypogammaglobulinemia may be due to a primary immune deficiency (genetic disorders and/or chromosome anomalies) or may be secondary to other disease entities (induced by extrinsic factors – infectious agents, mediators such as corticosteroids and immunosuppressants, chemotherapy, metabolic diseases such as nephrotic syndrome, nutritional disorders, and environmental conditions such as ionizing radiation) ⁵. Primary immunodeficiencies represent a group of approximately 350 diseases resulting from an intrinsic immune system defect due genetic disorders and/or chromosomal anomalies during the development of the immune system ⁶, ⁷, ¹. Secondary causes are usually induced by an external or acquired factor such as a corticosteroid or immunosuppressant drug, nutritional disorders, infections, chemotherapy, malignancy, nephrotic syndrome, other metabolic diseases, and hazardous environmental conditions ⁴. It is important that physicians distinguish between primary and secondary causes of hypogammaglobulinemia to provide appropriate treatment ⁸.

Hypogammaglobulinemia may be asymptomatic if mild or may be associated with a number of clinical entities with varied causes and manifestations if more extreme. IgA (immunoglobulin A) deficiency is a separate diagnosis, but may be a precursor to loss of immunoglobulin G (IgG) or may occur concurrently. The common clinical feature of symptomatic hypogammaglobulinemia is a predisposition toward infections that normally are defended against by antibody responses including but not limited to Streptococcus pneumoniae and Haemophilus influenzae infections. The source of the immunoglobulin deficiency is key, as the treatment will vary by causality.

Hypogammaglobulinemia causes

Hypogammaglobulinemia can cause frequent and recurrent infections of varying severity. Hypogammaglobulinemia may be due to underlying medical conditions or treatments for these conditions. This is termed secondary (acquired) hypogammaglobulinemia and is a much more common reason for recurrent infections in adults. A less common cause is primary (congenital) hypogammaglobulinemia, which typically presents in infancy or early childhood.

Secondary immunodeficiency may be caused by drugs including steroids, cyclophosphamide, azathioprine, mycophenolate, methotrexate, leflunomide, ciclosporin, tacrolimus, and rapamycin, which affect the functions of both T and B lymphocytes. Viral infections can cause immunodeficiency. For example, HIV causes AIDS, which mainly affects CD4+T cells and downregulates cellular immune responses that produce opportunistic infections and cancers, which are threatening to human health ⁹.

Malnutrition is a cause of the secondary deficiency, for example, the protein-energy malnutrition affects cell-mediated immunity and phagocytosis, the ingestion of microorganisms is intact, but the ability of phagocytic cells to kill intracellular organisms is impaired. Nutritional deficiency can result from cancer, burns, chronic renal disease, multiple trauma and chronic infections. Zinc and iron deficiencies have a variety of effects on immunity including a reduction in delayed cutaneous hypersensitivity. Vitamin supplementation (B6 and B12), selenium and copper are also important for a normal function of the immune system ¹⁰.

Primary hypogammaglobulinemia

Primary hypogammaglobulinemia typically denotes inherited abnormalities of the immune system. Primary immunodeficiency can affect T-cells, B-cells, phagocytes (phagocytic cells) or the complement system.

Most primary immune deficiencies are inherited diseases that appear to run in families; examples include X-linked agammaglobulinemia (XLA) and severe combined immunodeficiency (SCID). Other primary immune deficiencies, such as common variable immunodeficiency (CVID), are not as obvious as to whether they are inherited. The causes of the defects are unknown and genetic factors cannot be ruled out.

Recurrent pneumonia caused by extracellular bacteria suggest antibody deficiency. On the other hand, the recurrent fungal infection may be caused by a lack of T lymphocytes.

Severe combined immunodeficiency disorders (SCID) are incompatible with life and affected children usually die within the first 2 years. SCID is more common in the male. It is caused by a gene defect on the X chromosome in more than 50% of cases. The defective gene encodes the gamma chain of the interleukin-2 (IL-2) receptor. This chain forms a molecular part of the receptors for IL-2, IL-4, IL-7, IL-11, IL-15, and IL-21. On the other hand, few cases of SCID are caused by defective genes that encode for adenosine deaminase or nucleoside phosphorylase. Deficiency of these enzymes causes ribonucleotide reductase inhibition leading to a defect in the DNA synthesis and cell replication. Mutation in the genes encoding RAG1 or RAG2 cause an autosomal recessive form of SCID ¹¹.

The DiGeorge anomaly arises from a defect in the third and fourth pharyngeal pouches that causes a developmental abnormality of the thymus. The T-cell defect is variable depending on the severity of the thymic lesion. These infants have partial monosomy of 22q11-pter or 10p.

In the bare leukocyte syndrome, there is a mutation in the gene that encodes for the MHC class II transactivator (CIITA) resulting in the absence of class-II MHC molecule on antigen-presenting cells including macrophages and dendritic cells. A mutation in the gene that encodes for transport associated protein (TAP) results in the lack of class-I MHC molecule expression, which is manifested by a deficiency of CD8+ T lymphocytes.

B-cell Deficiencies

X- linked Agammaglobulinemia (Bruton’s disease)

• First described by Bruton ¹².
• X-linked disorder
• Found in male babies expressed around 5 to 6 months of age (maternal IgG disappears)
• In boys, pre-B cells did not differentiate into mature B lymphocytes
• There is a mutation in the gene that encodes for a tyrosine kinase protein
• Low level of all immunoglobulins (IgG, IgA, IgM, IgD and IgE) is present
• Infants with X-linked agammaglobulinemia suffer from recurrent bacterial infections: otitis media, bronchitis, septicemia, pneumonia, and arthritis, and
• Giardia lamblia causes intestinal malabsorption.
• Intermittent injections of large amounts of IgG keep the patient alive, but a patient may die at a younger age if infection with antibiotic-resistant bacteria occurs.
• Bone marrow transplantation is critical.

Selective Immunoglobulin IgA Deficiencies

• IgA deficiency is more common than other deficiencies of immunoglobulins ¹³.
• These patients are more prone to recurrent sinus and lung infections.
• A malfunctioning in heavy-chain gene switching may cause this problem.
• Treatment should not include gammaglobulin preparations to prevent hypersensitivity reactions.

T-cell Immunodeficiencies

Congenital thymic Aplasia (DiGeorge Syndrome)

• Tetany is present ¹⁴.
• Fungal and viral infections are common.
• A transplant of the fetal thymus is needed to correct this deficiency.

Chronic Mucocutaneous Candidasis

• Selective defect in functioning of T-cells ¹⁵.
• Patient with this disorder usually have a normal T-cell mediated immunity to microorganisms other than Candida.
• B-cells function is normal.
• Disorders affect both genders, and it is inherited.
• Patient in addition to the above will have other disorders like parathyroid deficiencies.
• Antifungals are useful.

Hyper-IgM syndrome

• Hyper-IgM syndrome is characterized by bacterial infections including pneumonia, meningitis, otitis, among others that start in early childhood ¹⁶.
• High levels of IgM.
• Other immunoglobulins are defective.
• Lymphocytes are normal in numbers.
• The gene encoding the CD40 ligand on T lymphocytes is faulty.
• B and T lymphocyte cooperation in the immune response is compromised.
• The failure to interact with CD40 results in an inability of the B cell to switch from the production of IgM to the other classes of antibodies.
• Immunoglobulin therapy is recommended.

Interleukin-12 receptor deficiency

• Mycobacterial infections are frequent due to the lack of the interleukin-12 receptor.
• Treatment involves selective antimicrobials.

T-cell and B-cell Deficiencies

Severe combined immunodeficiency disease (SCID)

• There is a failure of early stem cells to differentiate into T and B lymphocytes ¹⁷.
• Deficiency of the interleukin-2 receptor is the most prevalent.
• Other problems are due to defective genes encoding ZAP-70, Janus kinase 3 and the genes involved in the DNA recombination of immune cells receptors: RAG1 and RAG2.
• Clinically characterized by a variety of infections, including those caused by opportunistic pathogens
• Selective antibiotics, antivirals, and antifungals are available after the pathogen identification.
• Immunosuppressive therapy is not needed after allograft transplantation.

Wiskott-Aldrich syndrome

• Wiskott-Aldrich syndrome is associated with normal T-cell numbers with reduced functions, which get progressively worse ¹⁸.
• IgM concentrations are reduced, but IgG levels are normal.
• Both IgA and IgE levels are elevated.
• These patients have a defective WASP which is involved in actin filament assembly.

Immunodeficiency with ataxia-telangiectasia

• Immunodeficiency with ataxia-telangiectasia is a deficiency of T-cells associated with a lack of coordination of movement (ataxia) and dilation of small blood vessels of the facial area (telangiectasis) ¹⁹.
• T-cells and their functions are diminished to various degrees.
• B-cell numbers and IgM concentrations are normal to low.
• IgG is often reduced, and IgA is considerably reduced.
• There is a high incidence of malignancy, especially leukemias, in these patients.

MHC deficiency (Bare leukocyte syndrome)

• MHC deficiency (Bare leukocyte syndrome) patients have have fewer CD4+ or CD8+ T lymphocytes that predispose to these individuals to be prone to recurrent infections ²⁰.
• Antibody production is affected and predispose to bacteremia.

Complement Deficiencies

Hereditary angioedema

• Hereditary angioedema has an autosomal dominant genetic pattern ²¹.
• Caused by C1 inhibitor deficiency
• Clinically characterized by generalized edema including the one leading to acute suffocation
• Therapy with oxymetholone and danazol can be helpful in correcting the defect.

Recurrent infections

• Frequent infections by extracellular bacteria may be caused by C3 deficiency. C5 deficiency predisposes to viral infections.
• Patients with deficiency of the membrane attack complex (MAC) are particularly susceptible to bacteremia caused by Neisseria species.

Autoimmune diseases

Autoimmune diseases are caused by C2 and C4 deficiencies and mimic systemic lupus erythematosus ²².

Phagocyte Deficiencies

Chronic granulomatous disease

• Chronic granulomatous disease is mostly an X-linked disorder ²³.
• It is clinically characterized by a defective NADPH that interferes with the intracellular ability of neutrophils to kill engulfed bacteria species.
• NAPDH oxidase is required for the generation of peroxidase and superoxides that will kill the organisms.
• The intracellular survival of the organisms leads to the formation of a granuloma, an organized structure consisting of mononuclear cells.
• These granulomas can become large enough to obstruct the stomach, esophagus, or bladder.
• Patients with this disease are very susceptible to opportunistic infection by certain bacteria and fungi especially with Serratia and Burkholderia.
• Nitroblue tetrazolium (NBT) dye reduction test confirms the diagnosis of chronic granulomatous disease and the dichlorofluorescein (DCF) test is also useful.
• Aggressive therapy with wide spectrum antibiotics and antifungal agents is required.

Leukocyte adhesion deficiency syndrome

• Leukocyte adhesion deficiency syndrome is characterized by pyogenic infections including pneumonia and otitis ²⁴.
• It is an autosomal recessive disease, and the faulty gene encodes for an integrin.
• There is an impaired adhesion and defective phagocytosis of bacteria.
• Treatment involves the use of selective antibiotics.

Secondary hypogammaglobulinemia

Secondary hypogammaglobulinemia occurs when the function of the immune system is disrupted secondary to an underlying disease state, medications, surgery or other medical procedure. Radiation, chemotherapy, burns, chronic illness and malignancies can cause secondary immunodeficiency. Infections with the Human Immunodeficiency Virus (HIV) can cause a secondary immunodeficiency known as Acquired Immune Deficiency Syndrome (AIDS). Chemotherapy treatments can cause a secondary immunodeficiency called neutropenia. In leukemia and multiple myeloma, cancerous immune cells crowd out the normal stem cells of the bone marrow. These abnormal cells reduce the number of B-cells and lead to hypogammaglobinemia, another type of secondary immunodeficiency.

There are over 400 known primary immunodeficiencies and the number of secondary immunodeficiencies is also large.

Use of Drugs (Steroids) ²⁵

• Administration of steroids has direct effects on immune cell traffic and functions.
• T cells are more affected than B cells.
• Cytokine synthesis is inhibited.

Nutrient Deficiencies ¹⁰

• They are associated with impaired immune system.
• Affects cell-mediated immunity, antibody production, phagocyte function, complement system and cytokine synthesis.
• Aggravated by infections
• Multiple enzymes with important roles require zinc, iron and other micronutrients.

Obesity

• It may cause impaired immune responses.
• There is altered NK function.
• Cytotoxicity is compromised and the ability of phagocytes to kill microorganisms.

Acquired Immune Deficiency Syndrome (AIDS) ²⁶

• Caused by human immunodeficiency virus (HIV), which is a retrovirus transmitted sexually, perinatally or blood products.
• Immune dysfunction results from the direct effects of HIV and impairment of CD4 T cells.
• HIV proteins may act as superantigens.
• There is decreased responses to antigens and mitogens.
• Interleukin-2 and other cytokines are decreased.
• Infected cells may be killed by HIV-1 specific CD8+ T cells.
• In HIV-1 infection neutralizing antibodies appear to be ineffective in controlling viral replication and infection.

Hypogammaglobulinemia symptoms

Patients with mild hypogammaglobulinemia (slightly low Immunoglobulin) may be asymptomatic, but those with more severe hypogammaglobulinemia usually present with a history of recurrent infections.

The most apparent sign of an immune deficiency disorder is frequent, unusual and recurrent infections that appear excessive.

The number of infections vary in healthy people depending on several factors such as stress level, exposure to children and virulence of common viruses. This makes it harder to assess whether a person is experiencing an excessive number of infections.

The below list was adapted from the Jeffrey Modell Foundation’s 10 Warning Signs of a Primary Immunodeficiency. Individuals who have experienced two or more of the following symptoms may have a primary immunodeficiency:

Adults

• Two or more new ear infections within 1 year
• Two or more new sinus infections within 1 year, in the absence of allergy
• One pneumonia per year (radiographically proven) for more than 1 year
• Chronic diarrhea with weight loss
• Recurrent viral infections (colds, herpes, warts, condyloma)
• Recurrent need for intravenous antibiotics to clear infections
• Recurrent, deep abscesses of the skin, lymph nodes or internal organs
• Persistent thrush or fungal infections on skin or elsewhere
• Infections with normally harmless tuberculosis-like bacteria
• A family history of primary immunodeficiency

Children

• Four or more ear infections within 1 year
• Two or more severe sinus infections within one year
• Two or more months of antibiotic treatment with little effect
• Two or more pneumonias per year
• Insufficient weight gain or growth delay
• Recurrent deep skin or organ abscesses
• Persistent thrush in mouth or fungal infection on skin
• Need for intravenous antibiotics to clear infections
• Two or more deep seated infections
• A family history of a primary immunodeficiency

Clinical history

A detailed clinical history should emphasize the following:

• Symptoms (especially infections)
• Age of onset
• Family history
• Site of infections
• Type of microorganisms
• Recurrent infections
• Gastrointestinal symptoms
• Musculoskeletal symptoms
• Autoimmune and collagen vascular diseases

Physical findings will vary by the cause, but primary hypogammaglobulinemia (associated with a primary immune deficiency) may include the following:

• Growth retardation
• Abnormalities of lymphoid tissue and organs (eg, a paucity of tonsillar tissue, adenoids, and peripheral lymph nodes)
• Developmental abnormalities (eg, of skeleton or chest wall)
• Abnormalities of skin and mucous membranes (eg, scars, rash, or livedo reticularis)
• Ear, nose, and throat abnormalities (eg, tympanic membrane perforation, purulent nasal discharge, cobblestone pattern of pharyngeal mucosa, and nasal exudate)
• Pulmonary abnormalities suggestive of recurrent infections (eg, bronchiectasis and lung fibrosis with rales, rhonchi, and wheezing)
• Cardiovascular abnormalities associated with DiGeorge or CHARGE syndrome

Physical exam findings in secondary hypogammaglobulinemia will vary by cause.

Family history

A family history of frequent infections, persons receiving immunoglobulin, or infants who died at an early age due to infection are all suggestive of immune deficiency.

A positive family history may suggest the diagnosis and guide testing for X-linked agammaglobulinemia, but a negative family history does not exclude X-linked agammaglobulinemia (Bruton agammaglobulinemia; XLA), as new mutations may constitute more than half of the cases in some series ²⁷. The same is true of other X-linked immune deficiencies.

A family history of an infant with severe combined immunodeficiency (SCID) should suggest prompt testing of subsequent infants (although, most infants with severe combined immunodeficiency (SCID) are now detected by newborn screening).

Age of onset

Onset during early childhood suggests an inherited disorder. However, the condition transient hypogammaglobulinemia of infancy, as its name implies, represents a delay in the maturation of the full range of antibody responses, and usually resolves by a few years of age.

Acquired hypogammaglobulinemias may start at any age, depending on the underlying cause.

Type of microorganisms

Antibody deficiency and complement deficiency are associated with recurrent infections with encapsulated bacteria. These most often involve the respiratory tract, including otitis media, and may lead to bronchiectasis in childhood. Giardia lamblia infection is frequently observed in patients with combined variable immunodeficiency (CVID) or IgA deficiency.

Opportunistic infections with viral, fungal, or protozoan pathogens suggest concomitant T-cell deficiency, although some of these pathogens can occasionally cause infections with Common variable immune deficiency (CVID) and X-linked agammaglobulinemia.

Blood product reactions

History of anaphylaxis or other severe reactions following transfusion of blood products may indicate an underlying IgA deficiency, although this is controversial.

Rarely, patients with undetectable IgA antibodies may develop anti-IgA antibodies of the IgE isotype. Once sensitized, these patients may be at risk for anaphylactic reactions if they receive blood products containing IgA. Most patients who have anaphylactic reactions to blood transfusions, however, do not have IgA deficiency, and most patients with IgA deficiency do not develop IgE anti-IgA antibodies.

Recurrent infections

Infections (in decreasing order of occurrence) commonly affect the upper and lower respiratory tracts (eg, sinopulmonary infections, including chronic otitis media, sinusitis, bronchitis/bronchiectasis, pneumonia), gastrointestinal tract (eg, bacterial or parasitic gastroenteritis), skin, joints, and meninges. Septicemia, conjunctivitis, and osteomyelitis are less common.

Encapsulated bacteria such as S pneumoniae, Streptococcus pyogenes, H influenzae, and Staphylococcus aureus are the most common pathogens. Bordetella pertussis may rarely play an important role in respiratory infections.

IgG2 is the predominant isotype of antibodies produced in response to polysaccharides. Thus, occasionally isolated IgG2 deficiency may be as severe as global IgG deficiency in terms of recurrent upper and lower respiratory tract infections with encapsulated bacteria. Isolated IgG3 deficiency may be associated with recurrent sinopulmonary infections with viruses and Moraxella catarrhalis, and with pneumococcal infection, in a few patients.

In pure B-cell disorders, cellular immunity generally is intact, and the frequency of opportunistic fungal and mycobacterial infections is not increased.

In X-linked hyper-IgM syndrome, a T-cell defect is responsible for a lack of B-cell isotype switching. The lack of IgG and IgA are the hallmarks of this disease and patients are at risk for bacterial infections, but fungal and protozoan infections are often responsible for more severe morbidity than bacterial infections since bacterial infections are largely preventable by IgG replacement therapy. In combined B-cell and T-cell disorders, both components of the immune response are defective, which leads to mixed presentation, including increased infections with encapsulated bacteria and infections with fungi, Mycobacterium species, and P carinii. Occasionally, severe and prolonged primary varicella (or zoster), herpes simplex, and cytomegalovirus infections may occur.

Patients with XLA and with autosomal recessive forms of agammaglobulinemia are typically infected with pneumococcal, streptococcal, or staphylococcal organisms and H influenzae. While the upper respiratory system, conjunctivae, and gastrointestinal tract are the usual sites of infection, patients with no antibodies are prone to bacteremia and sepsis as well. Infections are typically seen when patients are younger than 5 years, but the diagnosis in this age of antibiotic availability is often delayed. XLA may occasionally present with neutropenia, since the affected enzyme is also involved in myeloid development ²⁷.

Without IgG replacement, patients with XLA are also susceptible to viral diseases that were common in childhood before widespread immunization, including measles, mumps, rubella, and polio.

The typical invasive bacteria seen in XLA are also found in hyper-IgM syndrome, but these patients can also be susceptible to P jeroveci infection and other opportunistic infections, which may represent the initial presentation of an immunodeficiency.

Although most patients with IgA deficiency are healthy, some patients develop symptoms later in life after an uneventful childhood and early adulthood and can have recurrent upper respiratory tract infections and GI infections. Recurrent or chronic upper and lower respiratory tract infections leading to bronchiectasis, chronic sinusitis or cor pulmonale are not common.

Common variable immune deficiency (CVID) leaves patients prone to the same infections that patients with agammaglobulinemia have with a variable defect in cell mediated immunity. Common variable immune deficiency (CVID) is not one disorder but a variety of defects, and occasional cases of severe abnormalities of cell-mediated immunity have been reported. In these cases, infections with fungi, mycobacteria, and Pneumocystis carinii may be seen, and severe and prolonged primary varicella or herpes zoster, herpes simplex, and cytomegalovirus infections have been reported.

During the first years of their lives, patients with transient hypogammaglobulinemia of infancy may have a high incidence of recurrent upper respiratory or gastrointestinal infections, but they do not usually have life-threatening or opportunistic infections.

Half the patients with Good syndrome (immunodeficiency with thymoma) have cell-mediated immunodeficiency and may present with mucocutaneous candidiasis, cytomegalovirus, herpes zoster, or Pneumocystis carinii.

Patients with disorders of T-cell maturation and/or function, including ADA deficiency, may develop disseminated infection with the attenuated viruses used in live virus vaccines. Such immunizations should be withheld from these infants, and exposure to chicken pox should be avoided.

Non-infectious gastrointestinal symptoms

Malabsorptive enteritis occurs in up to 50% of patients with common variable immune deficiency (CVID).

Gastritis with achlorhydria and pernicious anemia may occur.

Other gastrointestinal diseases, such as sprue-like syndrome, ulcerative colitis, and Crohn disease, have been reported in patients with common variable immune deficiency (CVID) and IgA deficiency.

Chronic cholangitis and hepatitis with Cryptosporidium parvum is often associated with X-linked hyper-IgM syndrome.

Musculoskeletal symptoms

Arthralgia and monoarticular or oligoarticular arthritis of the large joints with sterile effusions occasionally occur. Ureaplasma urealyticum has been implicated in the pathogenesis of “sterile” arthritis.

In many cases, acute septic arthritis may occur after recognized or unrecognized bacteremia.

Autoimmune and collagen vascular diseases

Immune cytopenias are the most common autoimmune manifestation of common variable immune deficiency (CVID).

The incidence of autoimmune and collagen vascular diseases is increased, especially in IgA deficiency. Rheumatoid arthritis, systemic lupus erythematosus without renal disease, autoimmune hepatitis, neutropenia, hemolytic anemia, and endocrinopathies have been described, especially in common variable immune deficiency (CVID) ²⁸.

Pure red cell aplasia, agranulocytosis, and myasthenia gravis have been reported with Good syndrome.

Hypogammaglobulinemia diagnosis

The first step in diagnosing an immune deficiency is a good evaluation. An immune system specialist (immunologist) can help with diagnosis and treatment.

Evaluation of the immune system may include:

• Detailed medical history including detailed family medical history
• Physical exam
• Blood tests
• Vaccines to test the immune response
• Genetic testing

At the time of the evaluation, your doctor will ask questions about your health. Frequent or unusual infections, prolonged diarrhea and poor childhood growth are some symptoms of a possible immune deficiency.

Because some immune deficiencies run in families, you will be asked questions about your family’s health. You will also have a complete checkup.

If your doctor suspects an immune deficiency, a series of blood tests and vaccines may be done.

• Blood tests will show if any part of your immune system is missing or not working properly. For example, blood tests will reveal if there are any cells lacking from a complete immune system or if the cells are present but are not functioning appropriately.
• Vaccines may be given to test your immune system’s response. In the normal immune system, antibodies fighting against the organism in the vaccine are formed in the blood. If antibodies to the vaccine are not found a few weeks after the vaccine is given, you may have an immune deficiency.

Your doctor may order additional tests to confirm the diagnosis.

Laboratory studies that may be helpful include the following:

• Serum immunoglobulin levels (IgA, IgG, and IgM)
• Complete blood count with differential
• Antibody response for recall antigens
• Isohemagglutinins (especially useful if patient already received IV or SC Ig)
• Peripheral blood lymphocyte immunophenotyping
• Evaluation of cellular immunity (cutaneous delayed-type hypersensitivity or mitogen and antigen proliferation)

Imaging studies that may be useful include the following:

• Chest radiography
• High-resolution computed tomography (HRCT) to evaluate for bronchiectasis

The following tests may be considered as circumstances warrant:

• Microarray for DiGeorge (primarily T cell disorder, but T cell disorders will lead to B cell dysfunction if severe) and evaluation for genetic variaqnts of CVID if warranted
• HIV testing (although untreated HIV is classically assciated with hypergammaglobulinemia, late-stage HIV may be assciated with loss of Immunoglobulin)

The following biopsy procedures may also be considered:

• Lymph node biopsy (for rapidly enlarging lymph nodes to rule out infection or malignancy)
• Thymus biopsy (indicated only for thymoma)

The evaluation of patients with suspected hypogammaglobulinemia should include quantitative measurement of serum immunoglobulins. If these levels are normal and a humoral immunodeficiency still is suggested, antibody response to specific antigens (polysaccharide and protein antigens) should be determined ²⁹. The impaired antibody responses to various pathogens in hypogammaglobulinemic states may make serological diagnosis of certain infections (eg, HIV, Epstein-Barr virus [EBV]) difficult. In these patients, nucleic acid detection methods (ie, PCR or reverse PCR) may be the best diagnostic tests for certain viral infections.

Perform serum protein electrophoresis for presumptive diagnosis of hypogammaglobulinemia or monoclonal protein. Quantitative methods using immunodiffusion or nephelometry are used for the precise measurements of each isotype of Ig. Enzyme-linked immunosorbent assay is used for IgE quantitation.

Values must be compared with age-standardized reference ranges.

Common variable immunodeficiency (CVID) is defined by IgG levels less than 2 standard deviations below the mean, with equally low levels of IgA, IgM, or both ²⁹.

Serum IgA is less than 5 mg/dL, with normal IgG and IgM levels, in selective IgA deficiency. levels of IgG2 and IgG4 also may be decreased, especially in patients with sinopulmonary infections.

In hyper-IgM syndromes, IgM may be markedly increased to levels frequently higher than 1000 mg/dL. However, the level of IgM often gradually increases with time and may be normal in children. levels of IgG, IgA, IgE, and the lymphocytes bearing these antibodies are decreased. IgM response to antigens is possible, but IgG and IgA responses are absent or diminished.

Antibody response after immunization

Vaccination-associated antibodies to diphtheria, tetanus toxoid, and Haemophilus influenzae type b (Hib) are normally demonstrable in patients who have received these vaccines, reflecting memory B-cell responses. Neoantigen responses may better reflect a patient’s current ability to mount antibody responses.

Typically, immunization with unconjugated pneumococcal vaccine is used to assess the response to polysaccharides by comparison of pre- and post-immunization titers (generally, a 4-fold rise is considered adequate) ³⁰. Vaccine-induced antibodies should be determined 4-8 weeks after pneumococcal immunization. Pneumococcal immunization should be repeated if the response is inadequate after the first immunization, and remaining titers should be determined 8-12 months later, if impaired immunologic memory is suspected.

Isohemagglutinins

IgM antibodies to A and/or B blood group antigens should be checked if the other tests results are normal and the patient is unable to mount a response to specific antigens. Antibodies to blood group antigens A or B would not be expected to be present if the patient’s blood group is A or B respectively, or AB. These antibodies normally develop in the first year of life in response to ingestion of cross-reacting animal antigens in food.

The production of these antibodies is normal in protein-losing states, in contrast to extremely low levels in X-linked agammaglobulinemia (XLA).

Peripheral blood lymphocyte immunophenotyping

Peripheral B cell levels are variable.

Their number is normal in 75% of patients with common variable immune deficiency (CVID), but their surface phenotype may be immature.

T-lymphocyte number and function are intact in most cases of pure B-cell disorders.

Reversal of the ratio of helper (CD4) to suppressor (CD8) T cells has been reported in common variable immune deficiency (CVID), leading to nonreactive delayed-type hypersensitivity (DTH) test results. In combined T-cell and B-cell disorders, peripheral T cells are absent or decreased, with negative delayed-type hypersensitivity test results.

Evaluation of cellular immunity

Cutaneous delayed-type hypersensitivity

Delayed-type hypersensitivity testing helps evaluate the memory response of cellular immunity to a previously encountered antigen. This test is not reliable in children younger than 1 year, and the response frequently is suppressed following viral and bacterial infections and during or after glucocorticoid therapy.

The test is read by measuring the induration 48-72 hours following administration of mumps skin test antigen or candidal antigen (at 1:100 wt/vol dilution; if no reaction, use 1:10 dilution), tuberculin (0.1 mL containing 2-10 IU of purified protein derivative), and trichophytin (1:30 wt/vol dilution). The test result is considered positive if the induration is greater than 5 mm (or >2 mm in children). Aqueous tetanus toxoid is no longer available for anergy panel testing.

Complete blood count (CBC)

The complete blood count (CBC) may indicate lymphopenia or lymphocytosis, which may be seen with secondary causes of hypogammaglobulinemia (intestinal lymphangiectasia and chronic lymphocytic leukemia [CLL], respectively). The absolute lymphocyte count must be compared to age-specific norms because infants normally have higher counts than older children and adults. Immunophenotypic lymphocyte studies are useful in determining the most likely defect in infants with severe combined immunodeficiency (SCID) and may be required to diagnose chronic lymphocytic leukemia.

Renal studies

Renal disease in which protein loss causes hypogammaglobulinemia is easily diagnosed by quantitation of the total 24-hour urinary protein excretion.
Gastrointestinal studies

Protein-losing enteropathy that causes hypogammaglobulinemia may be more difficult to diagnose. Increased alpha1-antitrypsin (which is not present in normal diet) loss in the stool can be quantified in a 24-hour clearance procedure. Alternatively, a nuclear scan using technetium 99m dextran can be used to diagnose and localize protein-losing enteropathy.

Intestinal lymphangiectasia, which is sometimes considered a subset of protein-losing enteropathies, manifests not only with protein loss but also with lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen. Imaging and endoscopy are useful in diagnosing intestinal lymphangiectasia. However, this is often a “patchy lesion,” and the diagnosis may be difficult.

Imaging Studies

Chest radiograph

In many patients with common variable immune deficiency (CVID) and primary hypogammaglobulinemia, recurrent or chronic infections lead to abnormal findings on chest radiograph, such as interstitial infiltrates, bronchiectasis, emphysema or bullae, and scarring. Chest radiograph findings may be normal despite the presence of structural abnormalities. CVID patients often have hilar adenopathy and/or granulomata. [14]

Although chest radiograph is an appropriate follow-up test for these patients, some argue for the use of high-resolution computed tomography (HRCT) as the criterion standard.

The absence of a thymic shadow is a common finding in patients with SCID. Thymomas may be identified on chest radiograph in patients with Good syndrome.

Cupping and flaring of the costochondral junctions is typical for adenosine deaminase (ADA) deficiency.

High-resolution computed tomography (HRCT) and nuclear scanning

High-resolution computed tomography (HRCT) scans may uncover important lung abnormalities in patients with CVID and primary hypogammaglobulinemia ³¹. These include, but are not limited to, pulmonary fibrosis, bronchiectasis, parenchymal scarring, pleural thickening, and, less commonly, emphysema or parenchymal nodules.

High-resolution computed tomography (HRCT) scans are more sensitive than chest radiograph for detecting asymptomatic structural changes of airways and lung parenchyma that sometimes occur despite appropriate intravenous immunoglobulin (IVIG) therapy ³¹.

Imaging studies of the abdomen may show organomegaly. Splenomegaly may be observed in CVID in the absence of lymphoma or lymphoproliferative disease. Pathologic-appearing para-aortic and other abnormal abdominal lymph nodes may be stable findings in CVID; they should be monitored carefully and may require studies using other modalities (fluorodeoxyglucose positron emission tomography [FDG-PET] and/or biopsy) to rule out malignancy.

Other Tests

Adenosine deaminase (ADA) levels should be measured in patients with SCID. The diagnosis of adenosine deaminase (ADA) deficiency is made by finding adenosine deaminase (ADA) levels less than 1% of the reference range. Cost-benefit analysis dictates that enzyme assays should be checked before genetic analysis. Also in the differential are mutations in purine nucleoside phosphorylase; this should be evaluated along with ADA levels. Tests can be done prenatally on amniotic fluid.

Absent or decreased Wiskott-Aldrich syndrome protein (WASP) can be determined by flow cytometry or western blotting. For Wiskott-Aldrich syndrome (WAS), sequence analysis determines 99% of mutations known to cause the disease entity.

Prenatal diagnosis of X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHM), WAS, and adenosine deaminase (ADA) deficiency can be accomplished by restriction fragment length polymorphism (RFLP) using fetal blood, amniotic cells, or chorionic villus tissue.

The most consistent feature of individuals with X-linked agammaglobulinemia (XLA) is the absence or extreme decrease in the number of B cells (CD19+ cells). The BTK gene contains the mutation.

Umbilical cord blood can be used in the prenatal diagnosis of some of these disorders. B cells are absent in XLA. T cells are absent in X-linked SCID. “Bald” lymphocytes found on scanning electron microscopy is diagnostic of WAS. Red blood cell ADA is decreased in fetuses with ADA deficiency.

Hypogammaglobulinemia treatment

Medications and treatments for immune deficiencies include:

• Antimicrobial therapy to fight and prevent infections
• Immune globulin replacement therapy
• Vaccinations
• Specialized immune globulins
• Hematopoietic cell transplant
• Gene therapy
• Enzyme replacement therapy
• Biologics

Immunoglobulin Replacement Therapy

People who are unable to produce adequate amounts or functional immunoglobulins or antibodies may benefit from replacement therapy with gamma globulins. There are a number of immunoglobulins: IgG, IgA, IgM and IgE. Antibody replacement with gamma globulin replaces IgG in the blood. This can be given both intravenously (IVIG) or under the skin, called subcutaneously (SCIG.)

Gamma globulin is made of pooled antibodies from the blood of healthy people. Antibodies from at least 1,000 donors in each treatment provide protection against a wide variety of foreign invaders. The blood is carefully tested, and discarded if there is evidence of contagious diseases such as hepatitis or HIV. Talk with your doctor if you have any questions or concerns.

Because supplemental IgG therapy (IVIG or SCIG) does not contain IgA or IgM, their protective functions are not replaced. People with immune deficiencies may continue to have trouble with certain types of infections despite supplemental IgG therapy. However, treatment with supplemental IgG and early treatment of infections help many people with immune deficiencies lead active and full lives.

In cases of slightly low immunoglobulin (IgG) where antibody production is intact, watchful waiting is encouraged. Infants with transient hypogammaglobulinemia often have resolution of this finding without intervention. Some individuals will have low immunoglobulin without disruption of ability to produce antibody, and require no intervention.

Replacement therapy with immunoglobulin G (IgG), administered intravenously (IVIG) or subcutaneously (SCIG), is the treatment of choice for most primary immunodeficiency syndromes where very low immunoglobulin is a feature, including the following:

• X-linked agammaglobulinemia (Bruton disease; XLA)
• Common variable immune deficiency (CVID)
• Severe combined immunodeficiency (SCID) prior to stem cell or bone marrow transplantation
• Hyper-IgM
• ADA deficiency
• Wiskott-Aldrich syndrome (WAS)
• Syndromes associated with low immunoglobulin or poor antibody production
• Sometimes specific antibody deficiency

If poor T-cell function is also a part of the immune deficiency (ie, severe combined immune deficiency or combined immune deficiency), stem cell transplant or bone marrow transplant may be the definitive treatment, and may replace B cell function so that IgG replacement is no longer necessary ³².

Treatment of secondary hypogammaglobulinemia is directed at the underlying cause, as follows:

• Intravenous immunoglobulin (IVIg) is not indicated for lymphoproliferative disorders unless immunoglobulin levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions that may accompany these disorders
• If IgG is being lost through the gut or kidney, replacement of IgG will not be effective

Specific Immune Globulins

Pathogen-specific immune globulins may be used in some immunocompromised people for prophylaxis against potentially life-threatening infection from the offending pathogen. Monoclonal antibody treatment against respiratory syncytial virus (RSV) is used to prevent RSV infection in high-risk populations. Specific immune globulins are also used to prevent or treat varicella infections and cytomegalovirus infections.

Antimicrobial therapy

Antimicrobials, such as antibiotics and antifungals, are medications that fight bacterial or fungal infections. They are used when signs of infection are present. It is often difficult to determine whether a pulmonary or sinus infection is caused by bacteria, as viral infections can present with similar signs and symptoms. In these cases, your doctor may perform additional testing, such as imaging (X-ray or CT scan), or obtain cultures of secretions from the infected area to determine the nature of the infectious agent. Cultures can also provide sensitivities of that particular organism to determine the most effective antimicrobial agent.

Antimicrobial therapy may also be used to prevent infections, and may be added as a routine medication that is taken as prophylaxis. Talk with your doctor about the potential side effects of antimicrobials.

Other Treatments

Other treatments are available for some types of immune deficiencies. Bone marrow transplants, hematopoietic cell transplantation, thymus transplantation, gene therapy, enzyme replacement and biologic cytokine inhibitors are examples of other treatments. Researchers in immunology are experimenting with gene therapy and other treatments that will be available in the future.

Hypogammaglobulinemia life expectancy

Hypogammaglobulinemia life expectancy depends on the underlying cause.

Living with hypogammaglobulinemia

People living with immune deficiency can lead active and full lives. The goal of treating an immune deficiency is to help you regain or maintain control of your life. Sometimes a chronic illness can be hard on the whole family. If your immune deficiency is causing family problems, be sure to talk with someone. Your doctor can help you find an expert to talk with. There also may be support groups where you can meet and talk to other people with an immune deficiency. Having an immune deficiency may require treatment with medications that require approval from your insurance company. If you are having problems getting proper coverage for these medications, it is important to tell your doctor. Your doctor may be able to talk with your insurance company and fix these insurance problems. Your doctor is your partner in taking care of your immune deficiency.

For many people this may include:

• Participating in work, school, family and social activities
• Decreasing the number and severity of infections
• Having few, if any, side effects from medications and other treatments
• Feeling good about yourself and your treatment program

Your doctor may prescribe medications or other treatments to make you feel better and to protect you from foreign invaders. Medications and treatments must be chosen for your individual needs and may be adjusted as your needs change.

Preventing Infections

There are things you can do to prevent infection. They include:

• Stay away from people who have a cold or other infection.
• Wash your hands with soap before eating, after outings and after using the bathroom.
• Although hand-washing seems simple, make sure it is effective. Use liquid soap and scrub your hands using plenty of lather for 10-15 seconds. Rinse your hands and dry them completely.
• If a sink is not available, use alcohol-based hand sanitizer over the entire surface of your hands until dry.
• Clean cuts and scrapes right away with warm, soapy water. Apply antibacterial cream or ointment and cover the cut or scrape with a fresh bandage at least daily. Tell your doctor if any redness or drainage develops.
• Brush your teeth after meals, and floss at least daily. Have a dental exam every six months. Tooth decay and gum disease are types of infection.
• There are vaccines available for some common viruses (like the flu) and bacteria (like certain types of pneumonia) that you may want to consider. Getting vaccinated may lessen the severity of symptoms or prevent these infections altogether. Talk to your doctor about whether you should get a flu, pneumonia or other vaccine.

If you notice any of the following, you may have an infection:

• Fever
• Chills
• Nasal congestion or discharge
• Cough
• Diarrhea
• Vomiting
• Tenderness or pain
• Unusual discharge
• Swelling or redness on the skin
• If you suspect you have an infection of any kind, call your doctor right away.

Healthy Diet

A healthy diet boosts the immune system’s ability to fight infection. Actions you can take to help strengthen the immune system include:

• Maintain a healthy weight.
• Eat a variety of foods daily, including grains, fruits, vegetables, lean meats and dairy products.
• Take a multivitamin supplement containing 100 percent of the Recommended Daily Allowance (RDA). RDAs are the minimum amounts of nutrients that a healthy person requires each day.
• Your doctor or registered dietitian can help recommend a healthy diet for you.

Enough Rest

Adequate sleep and rest give your body and your immune system time to maintain and repair themselves. Quiet activities like reading or crafts are helpful during times of rest or illness.

Regular Exercise

Regular exercise impacts your overall fitness by improving heart and muscle function. Most people who exercise regularly also feel an increased sense of well-being. Walking, swimming and biking are only some of the activities people with immune deficiencies can do. Children should be encouraged to participate in safe, age-appropriate activities. Talk with your doctor about recommending an exercise program for you.

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