What is Whipple disease

Whipple disease also known as Whipple’s disease or lipodystrophy intestinalis, is a rare multi-system infectious bacterial disease that interferes with your body’s ability to metabolize fats. Whipple disease is caused by the gram-positive bacterium Tropheryma whipplei, which is transferred through facal–oral transmission ¹, ². Whipple disease affects your body’s ability to absorb nutrients, such as fats and carbohydrates. Whipple disease is characterized by arthritis followed by diarrhea and steatorrhea (oily, smelly stools, which often float) with severe weight loss but can also be associated with anemia, fever, polyarthritis (a term used when five or more joints are affected with arthritis or joint pain), spondyloarthropathy (a type of arthritis that attacks the spine and, in some people, the joints of the arms and legs), and involvement of the central nervous system ³, ⁴, ⁵. Recent assessments also suggested isolated acute and chronic manifestations of Tropheryma whipplei comprising pneumonia, diarrhea, endocarditis, arthritis, uveitis and central nervous system involvement ⁶, ⁷, ⁸, ⁹. Whipple’s disease can be fatal if left untreated, although exact numbers on the mortality rate are unknown ¹⁰, ¹¹, ¹².

Tropheryma whipplei bacterium initially affects the mucosal lining of your small intestine, forming small lesions within the intestinal wall. The Tropheryma whipplei bacterium also damages the fine, hair-like projections (villi) that line the small intestine. With time, the infection can spread to other parts of your body.

Dr. George Hoyt Whipple initially described this condition in 1907 ¹³. Dr. Whipple described a case of a 36-year-old male who presented with malabsorption associated with mesenteric lymphadenopathy, arthralgias, and skin pigmentation ². The condition named by him “Intestinal Lipodystrophy,” and his article was published in the Bulletin of Johns Hopkins Hospital. Dr. Whipple hypothesized that an infectious agent was responsible, but the bacteria Tropheryma whipplei was only fully identified in 1992 ¹⁴, ¹⁵, ¹⁶.

Not much is known about the Tropheryma whipplei bacterium. Although it seems readily present in the environment, scientists don’t really know where it comes from or how it’s transmitted to humans. Not everyone who carries the Tropheryma whipplei bacterium develops Whipple disease. Some researchers believe that people with Whipple’s disease may have a genetic defect in their immune system response that makes them more susceptible to becoming ill when exposed to the bacterium.

Whipple disease is extremely uncommon, affecting fewer than one in 1 million people.

The infection may spread to any organ in the body; however, it more commonly affects the:

• joints
• central nervous system, which includes the brain, the spinal cord, and nerves located throughout the body
• heart
• eyes
• lungs

Left untreated, Whipple disease gets worse and is usually life threatening and fatal.

Neurological symptoms occur in up to 40 percent of individuals and may include dementia, abnormalities of eye and facial muscle movements, headaches, seizures, loss of muscle control, memory loss, weakness, and vision problems. Gastrointestinal symptoms may include diarrhea, weight loss, fatigue, weakness, and abdominal bleeding and pain. Fever, cough, anemia, heart and lung damage, darkening of the skin, and joint soreness may also be present. The disease is more common in men and neurological symptoms are more common in individuals who have severe abdominal disease, Rarely, neurological symptoms may appear without gastrointestinal symptoms and can mimic symptoms of almost any neurologic disease.

Whipple disease is NOT to be confused with Whipple surgery, which is a surgical procedure in which the head of the pancreas, the gallbladder, part of the stomach, part of the small intestine, and the bile duct are removed ¹⁷. In Whipple surgery enough of the pancreas is left to produce digestive juices and insulin.

Figure 1. Tropheryma whipplei bacterium

Footnote: Tropheryma whipplei is rod shaped, a gram-postive bacterium. False-color image of Tropheryma whipplei in which the genome is represented by the yellow-colored regions.

Figure 2. Tropheryma whipplei bacteria in human macrophages

Footnote: Illustrative image of periodic acid-Schiff (PAS)-positive Tropheryma whipplei bacteria in human macrophages

[Source ¹⁸ ]

The small intestine

The small intestine is part of the upper gastrointestinal (GI) tract and is a tube-shaped organ between the stomach and large intestine. The upper GI tract also includes the mouth, esophagus, stomach, and duodenum, or the first part of the small intestine.

The small intestine is the longest part of the alimentary canal and it begins at the pyloric sphincter of the stomach, coils through the central and inferior part of the abdominal cavity, and eventually opens into the large intestine.

The term small intestine refers not to its length but to its diameter—about 2.5 cm (1 in.).

The small intestine is approximately 6 to 7 m long (range 3–7 m) with a narrowing diameter from beginning to end.

The small intestine consists of the duodenum, the jejunum, and the ileum.

The small intestine receives chyme from the stomach and secretions from the pancreas, liver, and gallbladder. It completes digestion of the nutrients in chyme, absorbs the products of digestion, and transports the residue to the large intestine.

Most food digestion and nutrient absorption take place in the small intestine. The small intestine the site of most enzymatic digestion and about 90 percent of all nutrients absorption and most of the rest occurs in the proximal portion of the large intestine. Its length alone provides a large surface area for digestion and absorption, and that area is further increased by circular folds, villi, and microvilli. Villi—tiny, fingerlike protrusions—line the inside of the small intestine. Villi normally let nutrients from food be absorbed through the walls of the small intestine into the bloodstream. Most digestive enzymes that operate within the small intestine are secreted not by the intestine, but by the pancreas. During digestion, the small intestine undergoes active segmentation movements, shuffling the chyme back and forth and thereby maximizing its contact with the nutrient-absorbing mucosa.

Peristalsis propels chyme through the small intestine in about 3–6 hours.

Figure 3. Small intestine

Whipple disease causes

Bacteria called Tropheryma whipplei (T. whipplei) cause Whipple disease. Tropheryma whipplei infection can cause internal sores, also called lesions, and thickening of tissues in the small intestine. The villi take on an abnormal, clublike appearance and the damaged intestinal lining does not properly absorb nutrients, causing diarrhea and malnutrition. Diarrhea is frequent, loose, and watery bowel movements. Malnutrition is a condition that develops when the body does not get the right amount of vitamins, minerals, and other nutrients it needs to maintain healthy tissues and organ function. Over time, the infection spreads to other parts of the person’s body and will damage other organs.

Who is more likely to develop Whipple disease?

Anyone can get Whipple disease. However, it is more common in Caucasian men between 40 and 60 years old ¹⁹. Whipple disease is rare, and fewer than one in 1 million people get this disease each year ²⁰. The condition appears to be more common in farmers and other people who work outdoors and have frequent contact with soil and sewage wastewater ²¹.

Experts are not sure how Tropheryma whipplei infects people; however, scientists have noted:

• the bacteria are found in soil and sewage wastewater
• the bacteria are also found in people who are carriers of the disease—healthy individuals who have the bacteria, yet do not get sick
• Whipple disease is not transmitted from person to person

Some people may be more likely to develop Whipple disease because of genetic factors—related to genes, or traits passed from parent to child—that influence the body’s immune system. The immune system normally protects people from infection by identifying and destroying bacteria, viruses, and other potentially harmful foreign substances.

Human-to-human transmission

While the incidence of classic Whipple’s disease is low, Tropheryma whipplei is now recognized as a widespread bacterium, as in the general populations of Europe and Senegal, respectively, 48% and 72% carried antibodies against the bacterium ²², ²³. Recent data suggest that the presence of Tropheryma whipplei in fecal samples from asymptomatic individuals varies between 1.5 to 4% ²⁴, ²⁵, ²⁶ in the general population of Europe but that it can be up to 12 to 25% in specific populations like sewage workers, HIV-infected, and the homeless ²⁵, ²⁷. Also, patients with cirrhosis were found to have a high carriage rate of 12.5% ²⁸. A small proportion of the classic Whipple’s disease patients with positive stool samples have positive saliva carriage as well, and viable bacteria have been found in saliva samples from carriers ²⁹. Salival carriage was found to be 0.2% to 2.2% in sewage workers and 3.7% in the homeless. Interestingly, when saliva samples are positive, stool samples are generally positive as well ³⁰. This suggests that the bacterial load in stools is higher than in saliva samples and that the gut is the preferred niche of this bacterium. The amount of bacteria in fecal samples is also significantly higher in symptomatic patients than it is in carriers ³¹, ³², indicating that a high load is associated with symptoms of Tropheryma whipplei infections.

Relatives of chronic Whipple’s disease patients have a higher chance of carrying the bacterium ³⁰. It is unclear whether these family members have a higher rate of carriage because of human-to-human transmission or because they are infected by the same environmental source ³⁰. Saliva and stool samples of these relatives have been found to be 8% and 31% positive, respectively ³⁰. Eighty percent of relatives of carriers had positive stool samples, and 20% of relatives had positive saliva samples ³⁰. This suggests that oral-oral and fecal-oral transmission with this bacterium occurs ²⁹. In a study on gastroenteritis in 2- to 4-year-olds, a clonal outbreak of Tropheryma whipplei was found, which indicates that it is circulating in the population or their direct environment ³³. Also, in a study in Senegal, only three different epidemic genotypes were found ³¹. Finally, outbreaks of two different genotypes in homeless shelters in France have been reported ³⁴. These three studies all suggest that clonal outbreaks of Tropheryma whipplei do occur.

It is assumed that the Tropheryma whipplei bacterium is acquired during childhood ³⁵, ³⁶. In Senegal, up to 75% of children of <4 years of age were found to carry the bacterium ³⁵. By using quantitative real-time PCR (qPCR), a study in Laos showed a prevalence of 48% in the feces of children ³⁶. In Ghana, PCR-based prevalence in stool samples of 534 children (aged 2 months to 15 years) was 27.5% using multiple qPCRs ³⁷. Sewage and surface water have been shown to contain Tropheryma whipplei-specific DNA and are thus a possible environmental source of infection ²⁸. It has been postulated that based on the results of analysis of the genome sequences, Tropheryma whipplei might form spores ³⁸. Although these spores have never been observed, they may explain the long-term survival in the environment. Finally, in addition to the oral route of transmission, there is some evidence for a respiratory route, as Tropheryma whipplei was shown to be present in bronchoalveolar lavage (BAL) fluid samples of patients with pneumonia ³⁹.

Nonhuman sources of Tropheryma whipplei

Animals may be carriers of Tropheryma whipplei, although there is little experimental proof for this ³⁵. Granulomatous colitis of dogs showing microscopic similarity to Whipple’s disease has been found, but no specific microbiologic diagnosis was made ⁴⁰. Tropheryma whipplei was not found in the stools of 127 monkeys or apes ²⁵. Intestinal biopsy specimens from a small collection of domestic animals (24 pigs, 20 cattle, 19 chickens, 15 sheep, 14 cats, 13 dogs, and 10 horses) were also investigated and showed no positive results after analysis by PCR ⁴¹. Furthermore, in Senegal where the bacterium is highly prevalent, only 4 of the 1,002 environmental specimens (including domestic and synanthropic animals) tested positive for Tropheryma whipplei ⁴². Although it is commonly believed that there is no significant nonhuman reservoir, this cannot be definitely excluded without proper studies on this subject.

Risk factors for Whipple disease

Because so little is known about the bacterium that causes Whipple disease, risk factors for the disease haven’t been clearly identified. Based on available reports, it appears more likely to affect:

• Men
• People ages 40 to 60
• Whites in North America and Europe
• Farmers and other people who work outdoors and have frequent contact with sewage and wastewater.

Whipple disease prevention

Experts have not yet found a way to prevent Whipple disease.

Whipple disease prognosis

Generally, long-term antibiotic treatment to destroy the bacteria can relieve symptoms and cure the disease. If left untreated, the disease is progressive and fatal. Individuals with involvement of the central nervous system generally have a worse prognosis and may be left with permanent neurologic disability. Deficits may persist and relapses may still occur in individuals who receive appropriate treatment in a timely fashion. Prognosis may improve with earlier recognition, diagnosis, and treatment of the disorder.

Whipple disease complications

People with Whipple disease may have complications caused by malnutrition, which is due to damaged villi in the small intestine. As a result of delayed diagnosis or treatment, people may experience the following complications in other areas of the body:

• long-lasting nutritional deficiencies
• heart and heart valve damage
• brain damage

A person with Whipple disease may experience a relapse—a return of symptoms. Relapse can happen years after treatment and requires repeat treatments.

Whipple disease is a progressive and potentially fatal disease. Although the infection is rare, associated deaths continue to be reported, due in large part to late diagnoses and delayed treatment. Death often is caused by the spread of the infection to the central nervous system, which can cause irreversible damage.

Whipple disease signs and symptoms

Signs and symptoms of Whipple disease can vary widely from person to person ¹. There are four commonly recognized signs and symptoms of infections with Tropheryma whipplei bacteria (Table 1) ³³, ³⁰, ⁴³, ³⁹:

1. Classic Whipple’s disease;
2. Localized chronic infections, predominantly endocarditis;
3. Acute infections, e.g., pneumonia, bacteremia, and gastroenteritis; and
4. Carriage.

The most common symptoms of Whipple disease are:

• diarrhea
• weight loss caused by malabsorption

A person may not have diarrhea. Instead, other signs and symptoms of Whipple disease may appear, such as:

• abnormal yellow and white patches on the lining of the small intestine
• joint pain, with or without inflammation, that may appear off and on for years before other symptoms
• fatty or bloody stools
• abdominal cramps or bloating felt between the chest and groin
• enlarged lymph nodes—the small glands that make infection-fighting white blood cells
• loss of appetite
• fever
• fatigue, or feeling tired
• weakness
• anemia
• darkening of the skin

People with a more advanced stage of Whipple disease may have neurologic symptoms—those related to the central nervous system—such as:

• vision problems.
• memory problems or personality changes.
• facial numbness.
• headaches.
• muscle weakness or twitching.
• difficulty walking.
• hearing loss or ringing in the ears.
• dementia—the name for a group of symptoms caused by disorders that affect the brain. People with dementia may not be able to think well enough to do normal activities such as getting dressed or eating.

Less common symptoms of Whipple disease may include:

• chronic cough.
• chest pain.
• pericarditis—inflammation of the membrane surrounding the heart.
• heart failure—a long-lasting condition in which the heart cannot pump enough blood to meet the body’s needs. Heart failure does not mean the heart suddenly stops working.

Table 1. Whipple disease signs and symptoms

Classic Whipple’s disease (% incidence)	Chronic localized infections	Acute infections
Weight loss (79–99)	Endocarditis	Gastroenteritis
Gastroenteritis (63–85)	Encephalitis	Pneumonia
Abdominal pain (23–60)		Bacteremia
Arthritis (20–83)
Neurological symptoms (6–63)

[Source ¹ ]

Classic Whipple’s disease

The typical patient with classic Whipple’s disease is a Caucasian male (73 to 87% of patients with the disease were male) 48 to 54 years old who has had initial intermittent arthralgia (73 to 80% of patients) or chronic digestive troubles with diarrhea (72 to 81%) and/or is suffering from weight loss (79 to 93% of patients) ⁴⁴. However, before patients display these characteristic signs, they often go through a long period (6 to 8 years) where they have only some nonspecific symptoms (Table 2) ⁴⁵.

Among the most common symptoms of patients with classic Whipple’s disease are arthralgia, diarrhea, steatorrhea, weight loss, lymphadenopathy, abdominal pain, hypoalbuminemia, and anemia ¹², ¹⁰. These symptoms tend to develop in three phases, the early, middle, and late phases. Patients in the early phase of the disease can have symptoms of infection, fever, arthritis, and arthralgia. Patients in the middle phase have symptoms like diarrhea and weight loss (Table 2). Most patients with Whipple’s disease had arthritis, arthralgia, or other joint problems years before they were diagnosed with the disease⁴⁶. Every organ system can be involved in the late phase, but mostly the eyes, heart, and central nervous system are infected ⁴⁷.

Arthalgia, arthritis, and/or spondylodiscitis

The first prodromal sign of classic Whipple’s disease in 80 to 90% of the cases is seronegative arthritis and/or arthralgia, frequently accompanied by fever and elevated acute-phase reactants ¹⁰. This is why patients are often misdiagnosed with palindromic rheumatism (inflammatory arthritis) ⁴⁸. In any middle-aged male with joint arthritis and/or arthralgia where there is no effect of immunosuppressive treatment, Whipple’s disease should be considered, even if there are no other typical symptoms ¹². Other associated clinical manifestations like anemia and weight loss increase the likelihood of Whipple’s disease, as they are not characteristic for palindromic rheumatism (inflammatory arthritis) ⁴⁸. It is important that clinicians are aware of this, because up to 50% of the patients with classic Whipple’s disease were initially misdiagnosed and given antirheumatic agents like disease-modifying antirheumatic drugs (DMARDs), anti-necrosis factor alpha, glucocorticoids, or drugs that can enhance the spread of the infection and thus may have fatal consequences ¹⁰. In retrospect, physicians should consider occult Tropheryma whipplei infections in patients treated for unrelated bacterial infections showing a surprising decrease in their previously unexplained arthralgia ⁴⁹.

Table 2. Most common disease course of classic Whipple’s disease

Symptom (%) for early phase (<6 yrs)	Symptom (%) for middle phase (6 to 8 yrs)	Symptom (%) for late phase (>8 yrs)
Intermittent arthralgia (73–80%) Fever (19–54%)	Chronic obstructive troubles with diarrhea (72–81%)	Neurological symptoms (6–63%)
	Weight loss (79–93%)
	Abdominal pain (23–60%)
	Lymphadenopathy (35–66%)

[Source ¹ ]

Gastrointestinal symptoms

Gastrointestinal manifestations are the most prominent symptoms of Whipple’s disease ¹. The duodenum, jejunum, and ileum are affected in most patients with classic Whipple’s disease. The liver, esophagus, and stomach can also be affected, but this is less common ⁵⁰. Most diagnoses are based on at least one symptom related to these organ systems (64). Diarrhea, abdominal pain, and steatorrhea are among the most frequent symptoms in classic Whipple’s disease. Apart from these symptoms, hepatosplenomegaly, anorexia, nutritional deficiencies, cachexia, hematochezia, and malabsorption are also common ⁴⁷. These manifestations can progress to a severe wasting syndrome (with significant weight loss, fatigue, weakness, muscle atrophy, and loss of appetite) and abdominal lymphadenopathy ⁴⁷. Although gastrointestinal involvement is common, it is not necessarily present, as endocarditis and neurological symptoms without gastrointestinal symptoms have been reported ⁵¹, ⁵².

Neurological symptoms

Symptoms of the central nervous system (brain and spinal cord) are the third most frequent manifestation of Whipple’s disease ⁵³ and range from 6 to 63% ¹⁰. Depending on the location of the lesions, symptoms can be both central or peripheral and either isolated or multifocal. Symptoms associated with Whipple’s disease range from abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia), hypersomnia, coma, ophthalmoplegia, cognitive impairment, frontal lobe syndrome, cerebellar ataxia, or upper motor neuron and extrapyramidal symptoms ⁵⁴. It has even been suggested that there is a relation between T. whipplei infection and the development of Parkinson’s disease ⁵⁵, but it is unlikely that there is a causative relation. Although most Whipple’s disease patients do not present any obvious neurological symptoms, postmortem investigation showed that 90% of brain and spinal cord specimens from both patients and presumed carriers revealed lesions of the central nervous system, meaning that central nervous system involvement is more common than expected from the clinical manifestations ⁵⁶. Another indication for frequent neurological involvement is the presence of T. whipplei DNA in the cerebrospinal fluid (CSF) of patients with classic Whipple’s disease even in the absence of evident neurological manifestations ⁵⁷. The prognosis for patients with symptomatic central nervous system involvement remains poor, as major complications are seen in 25% of patients and 4-year survival rates are <75% ⁵⁸. Early diagnosis and treatment are thus essential in these patients ⁵³.

Whipple endocarditis

Endocarditis can also occur in the classic form of Whipple’s disease and is usually present only in the late phase ⁵⁹. This manifestation is often preceded by arthralgia or arthritis without gastrointestinal signs ⁶⁰. A case of predominant pleuropericarditis caused by T. whipplei with developing dense pleural fibrosis requiring decortication has recently been reported ⁶¹. Pleuropericardial involvement is a frequent pathological finding in patients with Whipple’s disease, although it rarely results in clinical symptoms ⁶¹.

Less common symptoms

Especially in the early phase of Whipple’s disease, several less common symptoms of Whipple’s disease can be manifested. Dermatologists should be aware that both cutaneous ⁶² and subcutaneous ⁶³ lesions may be a manifestation of Whipple’s disease, as cutaneous biopsy specimens containing PAS-positive macrophages characteristic of Whipple’s disease have been reported ⁶⁴. If lymphadenopathy, anemia, and pancytopenia are present, apart from lymphoma of other nonspecific granulomatous reticuloendothelial disorders, Whipple’s disease has to be considered as well ⁶⁵, ⁶⁶. Retroperitoneal  Whipple’s disease tumor formation was found in a patient with loss of appetite, weight loss, malnutrition, malaise, abdominal pain, diarrhea, vomiting, and intermittent fever ⁶⁷. After negative diagnostic results for malignancy, Whipple’s disease was confirmed as a diagnosis, and the patient was treated with ceftriaxone, resulting in clinical improvement and weight gain ⁶⁷. There is an association between thrombocytopenia and T. whipplei infection, which probably results from peripheral platelet sequestration. This thrombocytopenia rapidly resolves upon treatment ⁶⁸. Finally, ocular manifestations have been described ⁶⁹ and crystalline keratopathy has been reported as a typical characteristic of ocular Whipple’s disease ⁷⁰.

Acute Whipple infections

Tropheryma whipplei has also been associated with acute infections, including gastroenteritis, pneumonia, and bacteremia ³³, ⁷¹. As only limited data exist on these clinical manifestations, further research is required to determine the exact involvement of the bacterium in these acute infections ¹.

Gastroenteritis

A 3-year study on the correlation between Tropheryma whipplei carriers and gastroenteritis was performed by Raoult et al. ³³. PCRs on feces and Western blotting on sera for Tropheryma whipplei were performed for a cohort of children between 2 and 4 years of age with diarrhea in Marseille, France ³³. The presence of Tropheryma whipplei was established in 36 (15%) of 241 children with gastroenteritis, and in 23 (64%) of these 36 positive samples, no other diarrheal pathogens were found ³³. In addition, a study of 534 stool samples from children aged between 0 and 12 years from rural Ghana, it was found that children with diarrhea carried Tropheryma whipplei in their stool twice as often as controls without diarrhea ⁷². Tropheryma whipplei-infected patients usually have watery diarrhea, and periodically, they have colicky abdominal pain ⁷³. In another study, Tropheryma whipplei was associated with adult traveler’s diarrhea in two of nine pilgrims, as Tropheryma whipplei DNA was found in rectal swabs of travelers suffering from diarrhea ⁷⁴. These studies indicate that Tropheryma whipplei infections can cause diarrhea.

Pneumonia

Tropheryma whipplei was shown to be an etiological pathogen in pneumonia ⁷⁵. Tropheryma whipplei was found to be an etiological pathogen in pneumonia in a study where 210 BAL fluid samples obtained from patients in intensive care units were tested using both a generic 16S rRNA gene PCR and a specific quantitative PCR ⁷¹. A total of six (3%) of these samples contained Tropheryma whipplei, and in one of these samples, Tropheryma whipplei was in fact the only bacterium found ⁷¹. In a recent study, Tropheryma whipplei was shown to be the only bacterium present in bronchoalveolar (BAL) fluid samples from a patient with severe pneumonia ³⁹. In addition, an unexpectedly large number of HIV patients carried high loads of Tropheryma whipplei in bronchoalveolar (BAL) fluid samples ⁷⁶. This provides further support that Tropheryma whipplei might be a causative agent in lung disease. Macrophages are the main target cell for Tropheryma whipplei infection, and as macrophages are abundant in the alveolar tissue, they might provide a suitable niche for Tropheryma whipplei.

Bacteremia

A study in Senegal where blood samples from patients with fever were tested using PCR showed a 6.4% presence of Tropheryma whipplei ⁷⁷. Interestingly, cough and sleep disorders were significantly more present in patients with Tropheryma whipplei than those without Tropheryma whipplei. There was no correlation between the occurrence of the bacterium in saliva and stool samples and bacteremia ⁷⁷. This suggests that Tropheryma whipplei infections can result in acute, self-limiting bacteremia ⁷⁷.

Localized chronic Whipple infections

Tropheryma whipplei can also cause localized infections which do not develop into the classic form of Whipple’s disease. In these cases, there is no systemic involvement of Tropheryma whipplei, and the stool and saliva samples tested by PCR and/or PAS-stained duodenal biopsy specimens may often be negative ⁷⁸.

Endocarditis

This form of endocarditis is an intracellular infection rather than a biofilm-like superficial cardiovalvular colonization with the bacterium. In most patients, there are no other manifestations of classic Whipple’s disease ⁵⁹, and clinical signs are similar to those of cardiac disease with negative blood cultures ⁵⁹. In spite of the negative blood cultures, 80% of these patients displayed an increased C-reactive protein level, indicative of an infection and vegetations in 79% of cases ⁵⁹. The first reported localized Tropheryma whipplei endocarditis case was diagnosed by broad-range bacterial PCR analysis ⁷⁹. As there are no evident diagnostic criteria, clinicians should be especially alert for a potential Tropheryma whipplei endocarditis when dealing with white men who are around 50 years of age with cardiac symptoms like heart failure, large vegetations, and destruction of the heart valve, acute ischemic stroke, and embolic events ⁸⁰. Of all patients with blood culture-negative endocarditis, PCR revealed the presence of a Tropheryma whipplei infection in 1.9 to 6.3% of patients ⁸⁰. These patients include 1,135 endocarditis patients who underwent cardiac surgery in two German university hospitals. In 255/1,135 (22%) of the cases, a bacterial cause could be established by a combination of molecular methods and culture. Surprisingly, 16/255 (6.3%) of the patients with a proven bacterial infection (1.5% of the total population) carried Tropheryma whipplei, making it the fourth most frequent pathogen identified from these proven infectious cases ⁸⁰. Follow-up of these patients revealed that most of these Tropheryma whipplei-positive patients displayed no symptoms of classic Whipple’s disease and had thus neither been diagnosed nor treated properly for their potentially lethal Tropheryma whipplei infection.

In a study from 2004 ⁸¹, the cardiac valves from five patients with Tropheryma whipplei endocarditis were histologically evaluated and compared to those of patients with endocarditis but without Whipple’s disease. The histologic findings were significantly more fibrosis, a lack of calcification, slightly less vegetations, and reduced inflammation and vascularization compared to a control group with endocarditis ⁸¹.

Encephalitis

Several studies by a French group ⁵⁴, ⁸² reported the clinical implications of isolated encephalitis caused by Tropheryma whipplei. The most common neurological symptoms are cognitive impairment, ataxia, and supranuclear ophthalmoplegia ⁸³. A study from 2011 showed that ataxia and dementia were more severe in patients with encephalitis than in patients with classic Whipple’s disease, making early recognition clinically important ⁸³. Recently, a paradoxical association between Tropheryma whipplei encephalitis (as was documented by brain biopsy specimen) and obesity has been found in several cases ⁸³. These patients suffered from unexplained progressive dementia that was in most cases associated with ataxia and recent obesity. These patients rapidly recovered from their neurological manifestations after antibiotic treatment, and surprisingly, the obesity also rapidly reversed. The combination of cerebellar syndromes, dementia, and obesity should therefore trigger physicians to consider a Tropheryma whipplei infection. Definite diagnosis is complicated, as it would involve obtaining brain biopsy specimens, but since empirical treatment was reported to rapidly resolve the clinical symptoms, one might consider starting treatment even in the absence of a final diagnosis ⁸³.

Infections in other locations

Tropheryma whipplei has also been linked to interstitial lung disease, pulmonary hypertension, and other pulmonary manifestations ³⁹. Two recent studies of BAL fluid samples from hospitalized patients provided the best evidence that Tropheryma whipplei is a probable etiologic agent of pneumonia, as they found a total of 10 patients where Tropheryma whipplei was the only bacterium found ⁸⁴. While it was postulated that these infections resulted from aspiration ⁸⁴, an infectious route resulting from translocation through the circulation system or direct de novo infection from the environment cannot be excluded at this time. Clinical respiratory symptoms include dry cough, chest pains, and shortness of breath ⁸⁵. These symptoms often present without gastrointestinal symptoms ⁸⁵.

Finally, osteoarticular involvement ¹⁰, uveitis ⁸⁶ and lymphadenopathy ¹⁰ have also been reported to result from Tropheryma whipplei infection.

Whipple disease diagnosis

A health care provider may use several tests and exams to diagnose Whipple disease, including the following:

• medical and family history
• physical exam
• blood tests
• upper gastrointestinal (GI) endoscopy and enteroscopy

A patient may be referred to a gastroenterologist—a doctor who specializes in digestive diseases.

A health care provider may first try to rule out more common conditions with similar symptoms, including:

• Inflammatory rheumatic disease—characterized by inflammation and loss of function in one or more connecting or supporting structures of the body.
• Celiac disease—a digestive disease that damages the small intestine and interferes with the absorption of nutrients from food. People who have celiac disease cannot tolerate gluten, a protein in wheat, rye, and barley.
• Neurologic diseases—disorders of the central nervous system.
• Intra-abdominal lymphoma—abdominal cancer in part of the immune system called the lymphatic system.
• Mycobacterium avium complex—an infection that affects people with AIDS.

Whipple’s disease is frequently diagnosed at a late stage, because it is rare and has a broad spectrum of nonspecific clinical presentations, which makes it hard for clinicians to diagnose ¹². In the early stage, often some of the typical manifestations may be not be present. The presence of the Tropheryma whipplei bacterium can be established diagnostically in various tissues and body fluids by several routine methods ⁵⁷. The different laboratory methods to diagnose Tropheryma whipplei infections will be discussed below.

Figure 4. Whipple’s disease diagnostic algorithm

Footnote: (A) Diagnostic strategy for classic Whipple’s disease. (B) Diagnostic strategy for chronic localized Tropheryma whipplei infection.

[Source ¹ ]

Medical and Family History

Taking a family and medical history can help a health care provider diagnose Whipple disease.

Physical Exam

A physical exam may help diagnose Whipple disease. During a physical exam, a health care provider usually:

• examines a patient’s body
• uses a stethoscope to listen to sounds related to the abdomen
• taps on specific areas of the patient’s body checking for pain or tenderness

Blood Tests

A technician or nurse draws a blood sample during an office visit or at a commercial facility and sends the sample to a lab for analysis. The health care provider may use blood tests to check for:

• Malabsorption. When the damaged villi do not absorb certain nutrients from food, the body has a shortage of protein, calories, and vitamins. Blood tests can show shortages of protein, calories, and vitamins in the body.
• Abnormal levels of electrolytes. Electrolytes—chemicals in body fluids, including sodium, potassium, magnesium, and chloride—regulate a person’s nerve and muscle function. A patient who has malabsorption or a lot of diarrhea may lose fluids and electrolytes, causing an imbalance in the body.
• Anemia. Anemia is a condition in which the body has fewer red blood cells than normal. A patient with Whipple disease does not absorb the proper nutrients to make enough red blood cells in the body, leading to anemia.
• Tropheryma whipplei DNA. Although not yet approved, rapid polymerase chain reaction diagnostic tests have been developed to detect T. whipplei DNA and may be useful in diagnosis.

Immunohistochemistry

The presence of Tropheryma whipplei can be detected by using immunohistochemistry ⁸⁷. With this method, antibodies are used to specifically detect Tropheryma whipplei in fixed specimens ⁸⁸. In vitro cultivation of Tropheryma whipplei has allowed generation of these highly specific antibodies in rabbits ⁸⁹, enabling clinicians to detect Tropheryma whipplei in formalin-fixed, paraffin-embedded biopsy specimens.

In a study performed in 2003 by Lepidi and colleagues ⁸⁹, the diagnostic value of Tropheryma whipplei-specific immunohistochemistry on duodenal biopsy samples was evaluated. Immunohistochemistry was highly specific and also more sensitive than PAS staining, as some of the PAS-negative duodenal biopsy samples were positive by immunohistochemistry ⁸⁹. These patients later relapsed. After treatment (varying from 6 to 160 months), immunodetection signals of the bacterium were lower compared to PAS stains ⁸⁹. The reason for this might be that dead bacteria are no longer well detected by immunohistochemistry, whereas PAS can still detect them ⁸⁹. In another study, Lepidi and colleagues successfully used immunohistochemistry to detect Tropheryma whipplei in the lymph nodes of two Whipple’s disease patients suffering from lymphadenopathy, without gastrointestinal signs ⁹⁰.

Serology

After the development of a reliable culture method for Tropheryma whipplei, several serological methods to diagnose classic Whipple’s disease could be developed ⁹¹. The development of serology is difficult, because of the paradoxically higher specific immunoglobulin M (IgM) titers in carriers compared to patients with Whipple’s disease ⁹². The initial antigens were used for the specific detection of IgM class antibodies but had a low specificity ⁹¹. As with immunohistochemistry, this technique is employed by only a few specialized laboratories due to the lack of a readily available (commercial) source of antigen and/or antibodies. When there are only saliva or stool samples with positive PCR results for patients, Western blot serology could be used to differentiate between carriers and patients based on the higher antibody titers in carriers compared to patients in these studies ⁹³. It is unclear whether this finding also applies to a larger population and thus has any practical application for routine diagnostic use.

Fluorescence in situ hybridization (FISH)

The fluorescence in situ hybridization (FISH) technique is useful to detect and confirm the presence of T. whipplei in extraintestinal tissues and in PAS-positive small bowel biopsy specimens ⁸⁰. The target for these probes is the ribosomes, which degrade more rapidly in dead bacteria, in contrast to the target of PAS staining that stays positive for a longer period under treatment ⁹⁴.

Upper Gastrointestinal Endoscopy and Enteroscopy

Classic Whipple’s disease is typically accompanied by histological lesions in the duodenum or other parts of the small bowel. An upper gastrointestinal (GI) endoscopy and enteroscopy are procedures that use an endoscope—a small, flexible tube with a light—to see the upper gastrointestinal tract. A health care provider performs these tests at a hospital or an outpatient center. The health care provider carefully feeds the endoscope down the esophagus and into the stomach and duodenum.

Once the endoscope is in the duodenum, the health care provider will use smaller tools and a smaller scope to see more of the small intestine. These additional procedures may include:

• Push enteroscopy, which uses a long endoscope to examine the upper portion of the small intestine.
• Double-balloon enteroscopy, which uses balloons to help move the endoscope through the entire small intestine.
• Capsule enteroscopy, during which the patient swallows a capsule containing a tiny camera. As the capsule passes through the GI tract, the camera will transmit images to a video monitor. Using this procedure, the health care provider can examine the entire digestive tract.

A small camera mounted on the endoscope transmits a video image to a monitor, allowing close examination of the intestinal lining. A health care provider may give a patient a liquid anesthetic to gargle or may spray anesthetic on the back of the patient’s throat. A health care provider will place an intravenous (IV) needle in a vein in the arm or hand to administer sedation. Sedatives help patients stay relaxed and comfortable. The test can show changes in the lining of the small intestine that can occur with Whipple disease.

The health care provider can use tiny tools passed through the endoscope to perform biopsies. A biopsy is a procedure that involves taking a piece of tissue for examination with a microscope. A pathologist—a doctor who specializes in examining tissues to diagnose diseases—examines the tissue from the stomach lining in a lab. The pathologist applies a special stain to the tissue and examines it for T. whipplei-infected cells with a microscope. Once the pathologist completes the examination of the tissue, he or she sends a report to the gastroenterologist for review.

Duodenal biopsy

An important step in diagnosing Whipple disease is taking a tissue sample (biopsy), usually from the lining of the small intestine ⁷⁸. To do this, your doctor typically performs an upper endoscopy. The procedure uses a thin, flexible scope that passes through your mouth, throat, esophagus and stomach to your small intestine. The scope allows your doctor to view your digestive passages and obtain biopsies.

During the procedure, tissue samples are removed from several intestinal sites. This tissue is microscopically examined for the presence of disease-causing bacteria and their lesions, and specifically for Tropheryma whipplei bacteria. If biopsies of the small intestine don’t confirm the diagnosis, your doctor might biopsy an enlarged lymph node or perform other tests.

A DNA-based test known as polymerase chain reaction (PCR), which is available at some medical centers, can detect Tropheryma whipplei bacteria in biopsy specimens or spinal fluid samples.

Most patients with classic Whipple’s disease usually have large numbers of Tropheryma whipplei bacteria in their duodenal mucosa, but this seldom results in an inflamed appearance of the duodenum during endoscopy ⁷⁸. The mucosa of the duodenum frequently has dilated villi with ectatic lymph vessels and a pale yellow color ¹². As the bacterium is not evenly distributed over the duodenum, several samples of the duodenum should be obtained in order to avoid sampling bias in patients who do carry the bacterium in their duodenum. In addition, it is also advisable to obtain samples from the gastric antrum, jejunum, and/or ileum ¹².

Polymerase chain reaction (PCR)

Polymerase chain reaction (PCR) is becoming a popular technique for diagnosing Whipple’s disease, as it is thought to be more specific and sensitive than other methods ⁵⁷. Recently, a patient in Japan was presumptively diagnosed with Whipple’s disease based solely on clinical suspicion followed by a positive PCR result on duodenal biopsy specimens ⁹⁵. The corresponding small bowel biopsy samples from this patient were negative by PAS staining, and if PCR had not been performed, this patient would have been misdiagnosed ⁹⁵. The presumptive diagnosis was supported by clinical symptoms and fast remission of symptoms after the start of Tropheryma whipplei-specific antibiotic treatment, but it lacks confirmation on a second independent specimen ⁹⁵. An explanation for the discrepancy between histology and PCR may be an uneven distribution of the bacterium within the gut. Due to its higher sensitivity and larger sample size (that is homogenized during the DNA isolation step), PCR may not suffer as much from these sampling errors caused by a patchy distribution of the bacterium ¹¹.

In 2012, a retrospective study on the value of PCR for diagnosing Whipple’s disease was performed by Edouard and colleagues ⁵⁷ using histology as the gold standard. They concluded that quantitative real-time PCR (qPCR) on stool and saliva samples is a good initial screening method ⁵⁷. However, it is critical to validate the specificity of the PCR, as false-positive PCR results on saliva has been reported, especially when using 16S rRNA gene-based primers as the Tropheryma whipplei 16S rRNA genes are very similar to those of other bacteria that can be present in the oral cavity ⁹⁶. Whole-genome sequencing of Tropheryma whipplei identified more-specific PCR targets like the repetitive sequences, which when used in addition to other targets helped to rule out false-positive results ⁹⁷.

The main risk of PCR techniques is contamination, which can occur during several steps of the PCR process, including collection of the samples, isolation of DNA, and performing the PCR amplifications ¹¹. It is advisable that in atypical cases of Tropheryma whipplei, two different specific target genes are tested and that the results for both target genes should be positive in order to rule out potential false-positive results ⁹⁸. The occurrence of false-positive PCR results has been reported, e.g., in cerebrospinal fluid samples and duodenal biopsy specimens ⁹⁶. In order to minimize the chance of false-positive results caused by contamination or due to a nonspecific PCR, quantitative real-time PCR (qPCR) should preferably be performed on more than one sample and whenever possible also include invasive samples, for instance, blood or biopsy specimen ⁵⁷. In cases of arthralgia and arthritis, qPCR on joint fluids has become the preferred method of diagnosis ⁹⁹. In addition, it is good practice to test the cerebrospinal fluid by PCR, as even without clinical signs of neurological involvement in many patients, Tropheryma whipplei is present in the CNS ⁷⁸. If localized endocarditis is suspected in a patient, a blood sample should be taken. The positive predictive value of PCR of blood samples was found to be 100%. However, the sensitivity (and negative predictive value) on blood samples is low ⁵⁷.

Electron microscopy

Electron microscopy can be a useful method for diagnosis of T. whipplei infections ¹⁰⁰, but only a few laboratories have the means to perform electron microscopy. Due to sampling error, the negative predictive value of electron microscopy is low. Also, electron microscopy is rather laborious and therefore more suited for experimental studies on the pathology of T. whipplei ¹⁰¹.

Whipple disease differential diagnosis

The differential diagnoses of Whipple disease include ²:

• HIV
• Tuberculosis
• Inflammatory bowel disease with arthropathy
• Connective tissue disorder
• Hyperthyroidism.

Whipple disease treatment

The health care provider prescribes antibiotics to destroy the T. whipplei bacteria and treat Whipple disease. Health care providers choose antibiotics that treat the infection in the small intestine and cross the blood-brain barrier—a layer of tissue around the brain. Using antibiotics that cross the blood-brain barrier ensures destruction of any bacteria that may have entered the patient’s brain and central nervous system.

Antibiotics

The health care provider usually prescribes IV antibiotics for the first 2 weeks of treatment. Most patients feel relief from symptoms within the first week or two ¹⁰². A nurse or technician places an IV in the patient’s arm to give the antibiotics.

IV antibiotics used to treat Whipple disease may include:

• ceftriaxone (Rocephin)
• meropenem (Merrem I.V.)
• penicillin G (Pfizerpen)
• streptomycin (Streptomycin)

After a patient completes the IV antibiotics, the health care provider will prescribe long-term oral antibiotics. Patients receive long-term treatment—at least 1 to 2 years—to cure the infection anywhere in the body.

Oral antibiotics may include:

• trimethoprim with sulfamethoxazole (Septra, Bactrim)—a combination antibiotic
• doxycycline (Vibramycin)

Patients should finish the prescribed course of antibiotics to ensure the medication destroyed all T. whipplei bacteria in the body. Patients who feel better may still have the bacteria in the small intestine or other areas of the body for 1 to 2 years. A health care provider will monitor the patient closely, repeat the blood tests, and repeat the upper GI endoscopy with biopsy during and after treatment to determine whether T. whipplei is still present.

People may relapse during or after treatment. A health care provider will prescribe additional or new antibiotics if a relapse occurs. Some people will relapse years after treatment, so it is important for patients to schedule routine follow-ups with the health care provider. Most patients have good outcomes with an early diagnosis and complete treatment.

Relapsing neurologic Whipple’s disease (marked by bouts of worsening of symptoms) is sometimes treated with a combination of antibiotics and weekly injections of interfron gamma, a substance made by the body that activates the immune system.

Health care providers treat patients with neurologic symptoms at diagnosis or during relapse more aggressively. Treatment may include:

• a combination of antibiotics
• hydroxychloroquine (Plaquenil)—an antimalarial medication
• weekly injections of interferon gamma—a substance made by the body that activates the immune system
• corticosteroids—medications that decrease inflammation

The currently recommended treatment by UpToDate ¹⁰³ is based on a single randomized controlled trial where 40 patients were successfully treated with ceftriaxone (one dose of 2 g/day) or meropenem (three doses of 1 g/day) for 14 days followed by oral co-trimoxazole (the combination of trimethoprim and sulfanomides) for 12 months ¹⁰⁴. While clinically effective, there is solid in vitro evidence that the target for trimethoprim is missing in the bacterium. This regimen results in good antibiotic levels in the brain, which is important, as even without specific symptoms, Whipple’s disease often affects the CNS ¹⁰⁴. In patients who are intolerant to ceftriaxone, meropenem can be used as an alternative, and for patients intolerant to co-trimoxazole, doxycycline can be used ¹⁰⁵. Whole-genome sequence analysis and the successful culturing of Tropheryma whipplei enabled both sequence-based analysis and in vitro susceptibility testing of the bacterium ¹⁰⁶. This resulted in some serious discussion on the effectiveness of the first-choice regimen, as in vitro data suggest an intrinsic resistance of Tropheryma whipplei to trimethoprim ¹⁰⁷, which was confirmed by sequence analysis revealing that the target for trimethoprim (dihydrofolate reductase) is missing ¹⁰⁸. In addition, mutations in the gene encoding dihydropteroate synthase (folP), the target of sulfanomide, were reported to result in resistance to sulfamethoxazole and sulfadiazine ¹⁰⁹. This hypothetical resistance was confirmed by a recent retrospective analysis where all 14 patients who were first treated with co-trimoxazole failed treatment ¹⁰⁸. Also, co-trimoxazole is associated with significant toxicity, and it is thus remarkable that co-trimoxazole is currently still a component of the first-choice treatment ¹⁰³, and therefore, replacement of co-trimoxazole by an alternative antibiotic is probably more appropriate ¹.

A more rational alternative approach to ceftriaxone followed by co-trimoxazole is the combined use of hydroxychloroquine and doxycycline which is the only in vitro bactericidal treatment against cultured Tropheryma whipplei ¹⁰⁸. This treatment algorithm (Figure 4) for classic Whipple’s disease involves doxycycline (200 mg/day) and hydroxychloroquine (600 mg/day) for 12 months (104, 199, 207). For localized Tropheryma whipplei infection, treatment with doxycycline (200 mg/day) and hydroxychloroquine (600 mg/day) for 12 to 18 months, followed by a lifetime follow-up, has been proposed ¹⁰⁸. These antibiotics are effective against intracellular pathogens and are relatively safe when used for short-term treatment, for example, in Q-fever patients ¹⁰⁸. While in vitro susceptibility data support this regimen ¹⁰⁸, thus far, there is only limited in vivo evidence supporting the choice for this combination of antibiotics, as only a handful of prospective trials have been performed ¹⁰⁴, ¹⁰⁵.

Figure 4. Proposed therapeutic strategy to treat Whipple’s disease

[Source ¹ ]

Other treatment

Immune reconstitution inflammatory syndrome (IRIS) is a serious complication during antibiotic treatment observed in approximately 10% of patients with classic Whipple’s disease ¹¹⁰, ¹¹¹. A study done by Moos and colleagues ¹¹¹ concluded that Tropheryma whipplei must have an immunosuppressive effect on CD4+ T cells because of the frequent emergence of immune reconstitution inflammatory syndrome (IRIS) after antibiotic treatment of Whipple’s disease. Activated CD4+ cells escape the peripheral blood and home onto affected tissues, causing the clinical symptoms seen in IRIS patients (220). Increased peripheral and local CD4+ T cell counts are early prognostic markers for IRIS in these patients ¹¹¹. In patients in whom IRIS develops, adequate therapy is essential, as untreated IRIS can be fatal ¹¹⁰. Oral corticosteroids are the first-choice treatment, and patients usually respond rapidly. If the inflammation does not subside within 24 hour, additional or alternative immunosuppressive agents should be prescribed ¹¹². Thalomidine seems to be a good alternative treatment in cases of corticosteroid resistance ¹¹³.

Eating, Diet, and Nutrition

A person with Whipple disease and malabsorption may need:

• a diet high in calories and protein
• vitamins
• nutritional supplements

People with Whipple disease should discuss their nutritional needs with a dietitian or other health care professional and meet regularly with him or her to monitor changing nutritional needs.

Taking supplements

Because of the nutrient-absorption difficulties associated with Whipple disease, your doctor may recommend taking vitamin and mineral supplements to ensure adequate nutrition. Your body may require additional vitamin D, folic acid, calcium, iron and magnesium.

Treatment follow-up

It is generally advised to obtain duodenal biopsy specimens at 6-month intervals, and therapy needs to be continued as long as these biopsy specimens remain positive ¹. However, this advice might be outdated for the following reasons:

1. Obtaining biopsy samples is both costly and not without risk for complications.
2. The procedure can be stressful for the patient.
3. It is known that Whipple’s disease is associated with a lifetime susceptibility to Tropheryma whipplei infections ¹¹⁴.
4. Macrophages can remain in the lamina propria for years after successful treatment, and thus, the detection of PAS-positive foamy macrophages cannot be considered definitive evidence for incomplete bacterial remission ¹¹⁵.

There is an apparent discrepancy in the therapeutic monitoring between PCR and FISH on one side versus immunohistochemistry and microscopy on the other side ¹¹⁶. This could explain the relapses in patients with PCR-negative duodenal biopsy samples. Recent work showed that both PCR and FISH can give false-negative results due to a biofilm that prevents detection of a low bacterial load after antimicrobial treatment ¹¹⁶. While in general PCR is more sensitive, PAS staining and immunohistochemistry are not influenced by the masking effect of the biofilm and are therefore more suitable to detect Tropheryma whipplei after treatment. Enzymatic disruption of the biofilm during the isolation of DNA prior to PCR was shown to solve this problem. Therefore, new and noninvasive PCR-based diagnostic methods for Tropheryma whipplei infection are being improved and tested for their usefulness to monitor patients. If the sensitivity and specificity of PCR for Tropheryma whipplei detection in feces or saliva is proven to be high enough, and a better correlation with remission is achieved, they might eventually completely replace biopsy specimen-based monitoring.

There is evidence for a genetic predisposition of Whipple’s disease or increased risk of reinfection. This translates to an increased risk of developing relapses even after complete clinical remission ¹¹⁴. Relapse rates of Whipple’s disease were initially reported to be 30% ¹¹⁷ but have seriously declined over the past decades ¹⁰⁵. There is some discrepancy between the reported relapse rates when treating with beta-lactam and co-trimoxazole versus doxycycline and hydroxychloroquine ¹⁰⁵. Some of these differences can be explained by differences in the length of time of therapeutic monitoring, as relapses usually occur after several years, and thus, good estimates of these relapse rates can be reported only when long-term monitoring is performed. Late relapses can occur even after several years, and it is argued that patients should be monitored for life ¹¹⁸. Although there is evidence that relapses can be treated successfully using the same antibiotics that were used in the initial treatment ¹¹⁹, it may be prudent to change the antibiotic regimen when treating a patient with a relapse ¹.

These frequent relapses led to the recent proposal that the alternative therapy (doxycycline [200 mg/day] and hydroxychloroquine [600 mg/day] for 12 months) should be followed by a lifetime treatment with doxycycline to avoid reinfection ¹²⁰, ¹¹⁴, ¹⁰⁸. However, lifetime treatment with doxycycline may lead to development of resistance ¹²¹, and it is not clear whether this treatment is sufficient for every clinical manifestation of Tropheryma whipplei infection ¹¹⁴. Both doxycycline and hydroxychloroquine are known to have adverse effects when used for a longer period ¹²². For hydroxychloroquine, the main complication is retinal toxicity and to a lesser extent, cardiotoxicity and neuromyotoxicity ¹²². Long-term side effects of doxycycline use include mainly gastrointestinal and skin manifestations ¹²³. Although not scientifically proven, resistance to tetracyclines has been suggested to exist, as the use of this antibiotic is associated with frequent relapses ¹²¹.

Whipple disease prognosis

Generally, long-term antibiotic treatment to destroy the bacteria can relieve symptoms and cure the disease. If left untreated, Whipple’s disease is progressive and fatal. Individuals with involvement of the central nervous system generally have a worse prognosis and may be left with permanent neurologic disability. Deficits may persist and relapses may still occur in individuals who receive appropriate treatment in a timely fashion. Prognosis may improve with earlier recognition, diagnosis, and treatment of Whipple’s disease.

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