Whipple's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Whipple’s disease is a rare, systemic infectious disease caused by the bacterium Tropheryma whipplei. Tropheryma whipplei is usually transmitted through oral route to human hosts. Impaired macrophage function and cellular immunity are the main factors in replication of the bacteria and disease expansion to every tissue. Following contamination, based on immunologic response, patient might present with different manifestations including acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection. Individuals with positive HLA-B27 and defective cellular immunity including AIDS are at risk for Whipple’s disease. Whipple’s disease primarily causes malabsorption but may affect any part of the body including the heart, lungs, brain, joints, and eyes. Diagnostic findings of Whipple’s disease include PAS positive inclusions in macrophages of lamina propria. Endoscopy and small bowel biopsy may be helpful in the diagnosis of Whipple’s disease. Antimicrobial therapy is the mainstay of therapy for Whipple’s disease.

Whipple described the disease for the first time in 1907 as a gastrointestinal disorder and named it as “intestinal lipodystrophy.” Light and electron microscopy on small bowel biopsy were used to detect bacilli inside the intestinal mucosa. In 1952, systemic antibiotics were used to treat the disease which confirmed the infective nature of the disease. It took almost 100 years for investigators to cultivate the bacterium and sequenced the genome.

Whipple’s disease may be classified into two groups of acute and chronic infection. It might be classified as systemic or localized based on the organ involvement. It has four different clinical manifestations: Acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection.

Whipple’s disease is a rare systemic disease. Therefore, some aspects of pathogenesis have remained unclear. Tropheryma whipplei is usually transmitted through oral route to human hosts. There is no known causative genetic factor for Whipple’s disease. However, genetic and immunologic factors play important roles in clinical manifestation of Tropheryma whipplei infection. Individuals with positive HLA-B27 and defective cellular immunity including AIDS are at risk for Whipple’s disease. Impaired macrophage function and cellular immunity are the main factors in replication of the bacteria and disease expansion to every tissue. There is a decreased activity of the T helper cells type 1 and increased activity of the T helper cells type 2. Defective phagocytic system is responsible for replication of bacteria in macrophages and spread of bacteria to other tissues. Characteristic of Whipple’s disease is presence of foamy macrophages in the lamina propria that is periodic acid-Schiff stain positive.

Tropheryma whipplei is a bacterium and the causative organism of Whipple’s disease. While Tropheryma whipplei is categorized with the gram-positive Actinobacteria, the organism is commonly found to be gram-negative or gram-indeterminate when stained in the laboratory. Whipple himself probably observed the organisms as rod-shaped structures with silver stain in his original case, but no name was given to the organism until 1991 when the name Tropheryma whippelii was proposed after sections of the bacterial genome were sequenced. The name was changed to Tropheryma whipplei in 2001 (correcting the spelling of Whipple’s name) after deposition in bacterial collections.

Whipple’s disease must be differentiated from other diseases that cause malabsorption, chronic diarrhea, abdominal pain, multisystem involvement, such as celiac disease, cystic fibrosis, inflammatory bowel disease and systemic infections.

Whipple’s disease is a systemic disease among middle-aged white males in North America and western Europe. It affects males 8 times more than females. Few studies were done to evaluate the demographics of Whipple’s disease due to the sparsity of the disease. The incidence of Whipple’s disease is approximately 0.1 per 100,000 individuals and the prevalence is approximately 0.3 per 100,000 individuals in north-western Italy. Although the prevalence of carrier state is higher in Asian and African countries, the prevalence of the classic Whipple’s disease is less than American and western European countries. The case-fatality rate of Whipple’s disease is approximately 100%, if left untreated. The case-fatality rate of treated Whipple’s disease is unknown.

Common risk factors in the development of Whipple’s disease may be environmental, genetic, and immunologic. The most important risk factor in the development of Whipple’s disease is poor sanitation including living in homeless shelters and absence of toilets. Defective cellular immunity is the less common risk factor.

There is insufficient evidence to recommend routine screening for Whipple’s disease.

Tropheryma whipplei infection has different clinical manifestations. It could cause acute infection, localized infection and the classic Whipple’s disease. Acute infection might present with gastroenteritis, pneumonia or bacteremia. Acute infection might resolve without treatment but usually progress to systemic infection or carrier state. Classic Whipple’s disease has 3 clinical phases that starts with nonspecific symptoms and joint pain. It progresses to gastrointestinal symptoms such as diarrhea, steatorrhea, malabsorption, and weight loss. in the late phase, all the other organs including CNS, joints, eyes, heart, lung, liver and skin might be involved. The risk of relapse is approximately 40%, if treatment is not completed. Relapse of Whipple’s disease might occur up to 30 years after treatment and it is commonly responsible for morbidity and mortality.

Common complications of Whipple’s disease include malnutrition, cardiopulmonary, neurologic and osteoarticular involvement. Malabsorption mostly presents with fat-soluble vitamin deficiency, fatigue, and weight loss. Valvular heart disease and dementia are the most common cardiac and neurologic complication, respectively.

The prognosis of Whipple’s disease is good if diagnosed properly and long-term treatment with antibiotics started early. Without treatment, whipple’s disease is fatal.

There are no established criteria for the diagnosis of Whipple’s disease.

Patients with Whipple’s disease have various presentations. Most common symptoms of the classic Whipple’s disease include joint pain, weight loss, diarrhea, and abdominal pain. Other organ systems can be involved in Whipple’s disease including central nervous system, cardiac system, renal system, skeletal, muscles and pulmonary system.

Patients with Whipple’s disease usually appear weak. Physical examination of patients with Whipple’s disease is usually remarkable for weight loss and signs of vitamin deficiency. Further physical findings depend on the systems involved in the disease. Abnormal eye movements including oculomasticatory myorhythmia, or oculofacial-skeletal myorhythmia are pathognomonic for the Whipple’s disease.

Some patients with Whipple’s disease may have abnormal hematological findings and elevated acute phase reactants, which is suggestive of the infection. Laboratory evidence of malabsorption including hypoalbuminemia, hypokalemia, hypocalcemia, hypomagnesemia may be seen.

The imaging findings associated with Whipple’s disease depend on the system involved. These findings are not diagnostic. In patients with pulmonary involvement, chest imaging including x-ray or CT scan may demonstrate pulmonary infiltrates, pleural effusion, nodular pattern, small lung volumes, or mediastinal lymphadenopathy.

Abdominal CT scan may show thickening of small bowel folds and enlarged abdominal lymph nodes.

Head CT scan may show generalized cerebral atrophy or focal lesions including small granulomas in the gray matter of the cerebral and cerebellar cortex or microinfarctions.

Endoscopy and small bowel biopsy may be helpful in the diagnosis of Whipple’s disease. Diagnostic findings of Whipple’s disease include, PAS positive inclusions in macrophages of lamina propria. Other diagnostic studies for Whipple’s disease include electron microscopy which demonstrate bacteria, immunofluorescent assay to detect antibodies against Tropheryma whipplei and PCR, which demonstrates 16S rRNA gene of Tropheryma whipplei.

Antimicrobial therapy is the mainstay of therapy for Whipple’s disease. Intravenous ceftriaxone or penicillin G is indicated in the acute phase of Whipple’s therapy. For maintenance therapy, patients are typically treated with sulfamethoxazole-trimethoprim for at least 1 year. Patients who experience either Whipple’s disease or allergy to sulfamethoxazole-trimethoprim require a combination of doxycycline and hydroxychloroquine. Dietary supplements including vitamins, iron, folic acid, calcium and magnesium is needed. Following antibiotic therapy, immune reconstitution inflammatory syndrome (IRIS) might occur that requires oral corticosteroid. Lifelong follow-up is needed to detect relapse.

The mainstay of treatment for Whipple’s disease is medical therapy. Surgery is usually reserved for patients with cardiac complications and heart valves involvement.

There are no established measures for the primary prevention of Whipple’s disease. However, general measurement including proper sanitation decreases the risk of infection with Tropheryma whipplei.

There are no established measures for the secondary prevention of Whipple’s disease.

​ Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Whipple described the disease for the first time in 1907 as a gastrointestinal disorder and named it as “intestinal lipodystrophy.” Light and electron microscopy on small bowel biopsy were used to detect bacilli inside the intestinal mucosa. In 1952, systemic antibiotics were used to treat the disease which confirmed the infective nature of the disease. It took almost 100 years for investigators to cultivate the bacterium and sequenced the genome.

• In 1907, George Hoyt Whipple described a case who died after a course of gastrointestinal, malabsorption, pulmonary, neurologic and constitutional symptoms. Pathology showed rod-like bacilli in the lamina propria and fat deposition in intestinal and mesenteric lymph nodes. He named this disease as “intestinal lipodystrophy.”^[1]

• In 1947, Oliver-Pascual reported a case of “intestinal lipodystrophy” before the death of a patient.^[2]

• In 1949, Black-Schaffer used periodic acid-Schiff for staining the bacilli. Also, “Intestinal lipodystrophy” was renamed to “Whipple’s disease.”^[3]

• In 1952, Pauley treated a patient successfully by using systemic antibiotics, prolonged period of chloramphenicol.^[4]

• In 1958, Bolt reported the use of the small bowel biopsy to differentiate malabsorption diseases and confirm the Whipple’s disease.^[5]

• In 1961, Chears and Ashworth used electron microscopy and cytochemical study to detect the bacilli inside the intestinal macrophages.^[6] In that year, another team, Yardley and Hendrix demonstrated the rod-shaped structures in the intestinal mucosa by combined electron and light microscopy.^[7]

• In 1991, Wilson was able to partially sequence a 16S rRNA of a new bacterium. They classified this bacterium within the Actinomycetes clade.^[8]

• In 1992, Relman confirmed the previous result and extended the 16S rRNA sequence by using PCR. They used the term of “Tropheryma whippleii” for the first time for this bacterium.^[9]

• In 2000, Raoult reported isolation and cultivation of the bacterium responsible for the Whipple’s disease. They obtained the tissue from the mitral valve of a patient with a culture negative endocarditis.^[10]

• In 2001, La Scola isolated Whipple’s disease bacillus from the cardiac valve of a patient with endocarditis and characterized it phenotypically. They slightly changed the name to “Tropheryma whipplei.”^[11]

• In 2003, Bentley and Raoult analyzed and sequenced the genome of two different strains of Tropheryma whipplei.^[12][13]

Year	Investigator	Landmark event
1907	George Hoyt Whipple	Described the Whipple’s disease for the first time and named it as “intestinal lipodystrophy“.
1947	Oliver-Pascual	Reported a case of “intestinal lipodystrophy” before the death of a patient.
1949	Black-Schaffer	Strained the bacilli with periodic acid-Schiff stain; renamed to “Whipple’s disease.”
1952	Pauley	Successfully used systemic antibiotics for treatment of the “Whipple’s disease.”
1958	Bolt	Used small bowel biopsy to differentiate malabsorption diseases and confirm the Whipple’s disease.
1961	Chears and Ashworth	Used electron microscopy and cytochemical study to detect the bacilli inside the intestinal macrophages.
1961	Yardley and Hendrix	Used combined electron and light microscopy to detect the rod-shaped structures in the intestinal mucosa.
1991	Wilson	Sequenced a 16S rRNA of a new bacterium partially and classified it within the Actinomycetes clade.
1992	Relman	Confirmed the previous result and extended the 16S rRNA sequence by using PCR; named the bacterium “Tropheryma whippleii” for the first time.
2000	Raoult	Reported isolation and cultivation of “Tropheryma whippleii” for the first time.
2001	La Scola	Characterized the bacterium phenotypically; slightly renamed it to “Tropheryma whipplei.”
2003	Bentley Raoult	Analyzed and sequenced the genome of two different strains of Tropheryma whipplei.

• In 1952, Pauley treated a Whipple’s disease successfully by using systemic antibiotics, prolonged period of chloramphenicol.^[4]

​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Whipple’s disease may be classified into two groups of acute and chronic infection. It might be classified as systemic or localized based on the organ involvement. It has four different clinical manifestations: Acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection.

• Whipple’s disease may be classified to two groups of acute and chronic based on the duration.^[1][2]

Whipple’s disease classification based on the duration:

Whipple’s disease classification                                                                                                                           Acute               Chronic                                                                                                                           Gastroenteritis   Pneumonia   Bacteremia   Asymptomatic carrier state     Classic Whipple’s disease                                                                                                     Chronic localized infection

• Whipple’s disease may be classified to two groups of systemic and localized infection based on organ involvement.^[3]

Whipple’s disease classification based on organ involvement:

Whipple’s disease classification                                                                                                                                                                 Systemic involvement                           Localized involvement                                                                                                                                                                               Heart   CNS   Eye   Lung   Bone   Serosa   Skin                                                                                             • Blood culture negative endocarditis • Adhesive pericarditis • Myocardial fibrosis   • Encephalitis • Progressive dementia • Cerebellar ataxia • Personality changes • Hemiparesis • Seizure • Wernicke’s encephalopathy • Hypothalamic involvement • Supranuclear ophthalmoplegia   • Uveitis • Vitritis • Retinitis • Retrobulbar neuritis • Papilledema   • Chronic cough • Dyspnea   • Arthritis • Spondylodiscitis   • Pleuritic chest pain   • Hyperpigmentation

• Tropheryma whipplei infection may be classified to four groups based on the clinical manifestation:^[1][4][5][6]
  • Acute infections such as:
    • Gastroenteritis
    • Bacteremia
    • Pneumonia
  • Asymptomatic carrier state
  • The classic Whipple’s disease
  • Localized involvement of different organs including:
    • Heart:
      • Blood-culture negative endocarditis
      • Adhesive pericarditis
      • Myocardial fibrosis
    • CNS:
      • Encephalitis
      • Progressive dementia
      • Cerebellar ataxia
      • Personality changes
      • Hemiparesis
      • Seizure
      • Wernicke’s encephalopathy
      • Hypothalamic involvement
      • Supranuclear ophthalmoplegia
    • Eyes:
      • Uveitis
      • Vitritis
      • Retinitis
      • Retrobulbar neuritis
      • Papilledema
    • Lung:
      • Chronic cough
      • Dyspnea
    • Bone:
      • Arthritis
      • Spondylodiscitis
    • Serosa:
      • Pleuritic chest pain
    • Skin:
      • Hyperpigmentation

​ Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Whipple’s disease is a rare systemic disease. Therefore, some aspects of pathogenesis have remained unclear. Tropheryma whipplei is usually transmitted through oral route to human hosts. There is no known causative genetic factor for Whipple’s disease. However, genetic and immunologic factors play important roles in clinical manifestation of Tropheryma whipplei infection. Individuals with positive HLA-B27 and defective cellular immunity including AIDS are at risk for Whipple’s disease. Impaired macrophage function and cellular immunity are the main factors in replication of the bacteria and disease expansion to every tissue. There is a decreased activity of the T helper cells type 1 and increased activity of the T helper cells type 2. Defective phagocytic system is responsible for replication of bacteria in macrophages and spread of bacteria to other tissues. Characteristic of Whipple’s disease is presence of foamy macrophages in the lamina propria that is periodic acid-Schiff stain positive.

• Whipple’s disease is a rare bacterial systemic infection caused by Tropheryma whipplei.^[1]

• Tropheryma whipplei is a periodic acid-Schiff stain positive, gram-positive bacillus of Actinomycetes family.^[2]

• The bacterium lives in soil and wastewater. Farmers and everyone who has any contact with contaminated soil and water are at high risk of the infection.^[3]

• It is transmitted through oro-oral and feco-oral routes. The poor sanitation is associated with Tropheryma whipplei infection.^[4]

• It is believed that human being is the only host for this bacterium.^[5]

• Tropheryma whipplei invades intestines primarily and then every other organ including the heart, CNS, joints, lymph nodes, lungs, eyes, kidneys, bone marrow, and skin. Tissues are infected by macrophage infiltration contaminated by Tropheryma whipplei. Tropheryma whipplei multiplies in macrophages and monocytes.^[6] Although there is a massive infiltration of the intestinal mucosa with the bacteria, the immunologic response is not adequate to limit the infection. Bacterium-infected macrophages express less CD11b which leads to inappropriate antigen presentation. These macrophages are unable to turn into mature phagosomes and lower the thioredoxin expression. The impairment in T-helper 1 cells differentiation leads to the inability of the immune system to kill the bacteria.^[7][8]

• Tropheryma whipplei infection causes four different clinical manifestations: acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection.^[9][10]

Contamination via oro-oral or feco-oral route

Acute infection

Antibody production

Strong immune response

Insufficient immune response

Complete eradication

Chronic carrier

Chronic infection

Classic Whipple’s disease

Localized infection

Cure

Relapse

Re-infection

Death

• It is believed that host immunologic response to Tropheryma whipplei plays an important role on the clinical manifestation of the disease.^[6]

• Several studies suggested that the defective cellular immunity and humoral immunity may lead to the proliferation of the bacteria and clinical manifestation of the Whipple’s disease.^[8]

Followings are some of the observations that indicate the immunologic nature of the Whipple’s disease:

• Reduced T cell proliferative response^[8]
• Decreased CD4/CD8 ratio^[11]
• Decreased T helper cells type 1 response and subsequently reduced production of interleukin 2 (IL-2)
• Enhanced expression of interleukin 4 (IL-4) and functional activity of T helper cells type 2 (Th2)^[12]
• Increased numbers of regulatory T cells^[13]
• Reduced peripheral T cell proliferation to phytohemagglutinin and concanavalin A^[8]
• Up-regulated Interleukin 16 (IL-16) in monocyte-derived macrophages that enhanced Tropheryma whipplei replication^[14]

• Reduced Interleukin 12 (IL-12) production by peripheral blood mononuclear cells that leads to decreased functional activity of T helper cells type 1 (Th1) and subsequently decreased Interferon gamma secretion by peripheral blood mononuclear cells^[15][16][12]
• Reduced expression of complement receptor 3 (CD11b)^[8]
• Normal phagocytosis but impaired degradation^[15]

• Increased Immunoglobulin M production in the lamina propria^[11]

• Reduced Serum Immunoglobulin G2, an Interferon gamma dependent immunoglobulin subclass, and serum TGF-beta levels^[15]

There is no known causative genetic factor for Whipple’s disease. However, there is an association between Whipple’s disease and some immunologic defects.

• Studies showed that individuals with specific HLA type (HLA alleles DRB1*13 and DQB1*06) have a higher risk of Whipple’s disease.^[9]

The most important conditions associated with Whipple’s disease include:

• HLA-B27 individuals
• Defective cellular immunity
• HIV infection

• On endoscopy, pale yellow mucosa with whitish spots, greenish brown and erythematous patches, and both engorged and flattened folds are characteristic findings of Whipple’s disease.^[17]

• On microscopic histopathological analysis, PAS-positive macrophages in the lamina propria containing non-acid-fast gram-positive bacilli are characteristic findings of Whipple’s disease.^[17][18]

Below images show the characteristic feature of Whipple’s disease: foamy macrophages are present in the lamina propria.^[19]

​ Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Tropheryma whipplei is a bacterium and the causative organism of Whipple’s disease. While Tropheryma whipplei is categorized with the gram-positive Actinobacteria, the organism is commonly found to be gram-negative or gram-indeterminate when stained in the laboratory. Whipple himself probably observed the organisms as rod-shaped structures with silver stain in his original case, but no name was given to the organism until 1991 when the name Tropheryma whippelii was proposed after sections of the bacterial genome were sequenced. The name was changed to Tropheryma whipplei in 2001 (correcting the spelling of Whipple’s name) after deposition in bacterial collections.

Tropheryma whipplei is a gram-positive rod-shaped bacterium. It was finally isolated in eukaryotic cells in the year 2000 and propagated in a culture at 37 degrees Celsius, but was believed to resist culturing for a long time. In fact, it still can only be cultured if part of its eukaryotic host is present. The isolation from human cells and the culturing has allowed more characterization, including sequencing its genome that has resulted in 808 predicted protein-coding gene sequences, even though it grows at a very slow rate of about 4 to 17 days.^[1][2]

It is mesophilic, meaning it grows best at moderate temperatures ranging between 25 and 40 degrees Celsius. Its optimal temperature is 37 degrees Celsius. However, Tropheryma whipplei has a special ability as even though it is not affected by heat shock, it can modify its transcriptome following cold shock at a temperature of 4 degrees Celsius; this proves that although it lacks a lot of typical regulatory elements, it still has a highly adaptive response to thermal stresses that would be typical with its potential environmental origin being that of something probably at lower temperatures (something still being studied), thereby allowing it to live and adapt in cold conditions.^[1][2]

Tropheryma whipplei has a 0.92 Mb genome, placing it in a high-GC-content gram-positive bacterial group.^[2] It is the only known human pathogen with a reduced genome sequence within the class of Actinobacteria. This means that this pathogen is the smallest known within its class. It is a reduced genomic species and it does not have many genes regulating transcription. It has a circular genome of 927,303 base pairs. Tropheryma whipplei has a low GC content at 46%. Yet, it was originally considered high because 552/808 identified open reading frames have their closest homologs within other Actinobacteria class genomes. An open reading frames (ORF) is important to determine once a gene has been sequenced, as it deals with where the encoded proteins are first transcribed into messenger RNA and then translated into a protein. A particular nucleotide will start and another will stop (known as a stop codon) translation; this is an ORF. Due to its small genomic size, much has yet to be discovered.^[3][4]

The most interesting thing about Tropheryma whipplei is the fact that it has such a tiny genome. “Dr Stephen Bentley, who led the team at The Wellcome Trust Sanger Institute, said, ‘This really is a wolf in sheep’s clothing. Within this amazingly small genome, it has packed a sophisticated array of tools to escape our defense mechanisms. It’s an incredibly adept operator which can tell us a great deal about bacteria and their evolution'”. It is the “master of disguise”, as even though it has only caused a few cases of disease and, once again, has such a small genome, it really molds itself to its environment in a noteworthy way. Just to put into perspective how small it is, most bacterial genomes are three to four times larger, code for about 3,000 genes as opposed to around 800, and have hardly any repetitive DNA.^[2] Tropheryma whipplei has about five percent of its DNA sequences repeated which also aides in its ability to deviate itself over and over again. It “carries a set of DNA sequences unlike anything previously seen in bacterial genomes.” This is the case because it, as far as research has come to discover, selects new regions that it then incorporates into the genes that encode its single outer coating; this is the reason why Dr. Stephen is quoted saying it is like a wolf in sheep’s clothing, because it never gives its host a chance to realize what it is, as it is constantly morphing and changing into something repeatedly different. Not only does it disguise itself in this manner, but it also takes the membranes from the host cells to “hide” in as well. Hence, with these two forms of camouflage, the body doesn’t or has a hard time detecting the presence of Tropheryma whipplei, as it hides in the lining of the human gut, where it gains its energy.^[2] Even though it is so small, it still is well equipped for its metabolic activities. However, there are deficiencies of ten amino acids in the biosynthetic pathways. For example, there is a lack of thioredoxin and thioredoxin reductase gene homologues. Thioredoxin is usually in its reduced state in an NADPH-dependent reaction, acting as an electron donor. Tropheryma whipplei also has a mutation in the DNA gyrase, which relates to the fact that it is resistant to quinolone antibiotic. Because of its metabolic deficiencies, like the major energy producing system, which is the Krebs or TCA it must get the nutrients it needs from the environment, in this case, the stomach lining. It also has to rely on its host for the synthesis of essential amino acids like arginine and histidine, as it cannot produce these for itself either.^[5][6]

Tropheryma whipplei is suspected to have an environmental origin because its closest known relatives originated from the soil. However, Tropheryma whipplei is solely dependent on humans. Tropheryma whipplei inside its host is constantly reshaping itself and invade other organs. The fact that it is also very difficult to cultivate without human cells, makes understanding this pathogen harder.^[7]

See Whipple’s disease

​

• NCBI Tropheryma whipplei Taxonomy Browser
• Tropheryma whipplei Microbe Wiki Page

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Whipple’s disease must be differentiated from other diseases that cause malabsorption, chronic diarrhea, multisystem involvement, such as celiac disease, cystic fibrosis, inflammatory bowel disease and systemic infections.

Whipple’s disease must be differentiated from other diseases that cause malabsorption, chronic diarrhea, abdominal pain and multisystem involvement.^{[1][2][3][4][5][6][7][8][9][10][11]}

The table below summarizes the diseases that cause malabsorption, diarrhea and abdominal pain.

Abbreviations: WBC: White blood cells; Plt: Platelets, Hgb: Hemoglobin, IgE: Immunoglobulin E, IgA: Immunoglobulin A

Cause	Peak age of onset	History					Physical exam	Lab findings				Additional findings	Cause/Pathogenesis	Gold standard diagnosis
		Fever	Abdominal pain	Diarrhea		Weight loss
				Watery	Fatty			WBC	Hgb	Plt	Other lab findings
Whipple’s disease	40-60	±	+	+	+	+	Abnormal extraocular movement Lymphadenopathy Hyperpigmentation Decreased breathing sound	↓	↓	↓/↑	Hypoalbuminemia	Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Ascites Pleural effusion	Tropheryma whipplei HLA-B27	Small intestine biopsy for Tropheryma whipplei testing PCR testing
Celiac disease	Childhood Adult	–	+	+/-	+/-	+	Abdominal distention Tetany Mouth ulcers	–	↓	–	IgA endomysial antibody Anti-tissue transglutaminase antibody Anti-gliadin antibody	Signs of the fat-soluble vitamins A, D, E, and K deficiency Dementia Hepatosplenomegaly Ascites Dermatitis herpetiformis Must follow Gluten-free diet	HLA-DQ2 HLA-DQ8 Innate responses to wheat proteins	IgA endomysial antibody IgA tissue transglutaminase antibody
Cystic fibrosis	Childhood Adult	±	+	–	+	+	Digital clubbing Abnormal breathing sounds Cyanosis	–	↓	–	Positive DNA analysis for CFTR Evaluated nasal transepithelial potential difference (NPD)	Diabetes Recurrent upper and lower respiratory tract infections Infertility	Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein	Elevated sweat chloride ≥60 mmol/L
Crohns disease	Young adults (20th)	+	+	+	+	+	Abdominal tenderness Tachycardia Hypotension	↑	↓	↑	Iron deficiency Vitamin B12 deficiency Elevated ESR Elevated CRP	Blood seen on rectal exam	Abnormal immune response to self antigens	Colonoscopy with biopsy
Irritable bowel syndrome	30-50	–	±	±	±	–	Abdominal tenderness Flatulence Hard stool in the rectal vault	–	–	–				Diagnosis of exclusion
VIPoma	30-50	–	+	+	+	+	Tachycardia Rash Facial flushing Abdominal distention Abdominal RUQ tenderness	–	–	–	Elevated VIP level Hypokalemia Hypochlorhydria or achlorhydria Low osmotic gap (<50 mOsm/kg)	Dehydration Lethargy Muscle weakness Nausea Vomiting	Primary secretory tumor	Elevated VIP levels Followed by imaging
Zollinger-Ellison syndrome	20-50	–	+	+	+	+	Abdominal tenderness	–	↓	–	Positive secretin stimulation test Elevated serum chromogranin A	Heartburn	Gastrin producing tumor mainly in duodenum	Elevated basal or stimulated serum gastrin> 120 pg/mL
Lactose intolerance	Any age	–	+	+	–	–	Abdominal tenderness Hypotension Tachycardia Nausea and vomiting	–	–	–	Hydrogen breath test	Bloating Flatulence Symptoms begin mainly after ingestion of lactose	Reduction of lactase enzyme activity or inability to produce persistent lactase Congenital lactase deficiency	Lactase activity assay
Eosinophilic gastroenteritis	30th	–	+	+	+	+	Abdominal distention	↑	–	–	Elevated serum IgE levels Eosinophilia Elevated ESR Hypoalbuminemia	Other allergic disorders Associated with an identifiable dietary antigen	Autoimmune allergic response to food antigens	Eosinophilic infiltration of the gastrointestinal tract on biopsy
Primary bile acid malabsorption	Childhood Adult	–	+	+	+	+		–	↓	–	Low vitamins A, D, E, and K		Genetic defects in SLC10A2 (solute carrier family 10 member 2 gene)	Elevated total and specific bile acids in stool Positive SeHCAT
Abetalipoproteinemia	Infancy Adult	–	+	+	+	+	Abdominal distension Visual field defect Dysarthria	–	–	–	Low triglyceride Low total cholesterol levels  Acanthocytes Low vitamin E levels	Visual impairment Ataxia	Autosomal recessive disorder caused by mutations encoding the microsomal triglyceride transfer protein (MTP)	Clinical findings and low triglyceride and cholesterol level
Microscopic colitis	50-70	–	+	+	–	+	Abdominal tenderness	–	↓	–	Elevated autoantibodies include: RF ANA AMA ANCA	Fecal urgency Fecal incontinence Arthralgia Arthritis Uveitis	Mucosal immune responses to luminal factors in a genetically predisposed individual	Colonoscopy with mucosal biopsy with mononuclear infiltrates: Collagenous colitis is characterized by a colonic subepithelial collagen band >10 micrometers in diameter Lymphocytic colitis is characterized by ≥20 intraepithelial lymphocytes (IEL) per 100 surface epithelial cells
Hyperthyroidism	Any age	±	+	+	–	+	Lump in the neck Proptosis Tremor Increased DTR	–	–	–	Elevated T4 Elevated T3 Decreased TSH	Lid lag Sweating Hyperpigmentation	Graves’ disease Hashimoto’s thyroiditis Toxic adenoma	TSH
Grain allergy	Childhood	–	+	+	–	+	Vomiting Abdominal distension	–	–	–	Elevated IgE	Atopic dermatitis Dysphagia	Abnormal immune response to wheat antigens	Measurement of grain-specific immunoglobulin E (IgE)
Chronic giardiasis	Childhood	–	+	+	+	+	Abdominal distension Mild epigastric tenderness Signs of malnutrition in chronic cases	↔	↓	↔	↓ Iron, folate, or B12 from malabsorption Hypoproteinemia	Flatulence Foul-smelling stools May mimic IBS or other malabsorptive disorders	Caused by Giardia lamblia, a flagellated protozoan Transmitted via fecal-oral route Adheres to small intestinal mucosa, causing mucosal injury, enzyme dysfunction, and malabsorption without invasion	Stool antigen test (ELISA or immunoassay) or PCR Stool ova and parasite exam Duodenal biopsy or aspirate (if stool tests negative and high index for suspicion)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Whipple’s disease is a systemic disease among middle-aged white males in North America and western Europe. It affects males 8 times more than females. Few studies were done to evaluate the demographics of Whipple’s disease due to the sparsity of the disease. The incidence of Whipple’s disease is approximately 0.1 per 100,000 individuals and the prevalence is approximately 0.3 per 100,000 individuals in north-western Italy. Although the prevalence of carrier state is higher in Asian and African countries, the prevalence of the classic Whipple’s disease is less than American and western European countries. The case-fatality rate of Whipple’s disease is approximately 100%, if left untreated. The case-fatality rate of treated Whipple’s disease is unknown.

• The incidence of Whipple’s disease is approximately 0.1 per 100,000 individuals in north-western Italy.^[1]
• The incidence of Whipple’s disease is approximately 12 annually worldwide.^[2]
• Between 1907 and 1987, the incidence of Whipple’s disease was estimated to be 696 cases worldwide.^[2]

• The prevalence of Whipple’s disease is approximately 0.3 per 100,000 individuals in north-western Italy.^[1]

• In Europe, the prevalence of chronic carrier of Tropheryma whipplei is 1,000-11,000 per 100,000 of general adult population.^[3][4]
• In Senegal, the prevalence of chronic carrier of Tropheryma whipplei is 75,000 per 100,000 of children under 4 years of age.^[5]
• In Laos, the prevalence of chronic carrier of Tropheryma whipplei is 48,000 per 100,000 individuals by using quantitative real-time PCR (qPCR) of the feces of children.^[6]
• In Ghana, the prevalence of chronic carrier of Tropheryma whipplei is 27,500 per 100,000 individuals by using quantitative real-time PCR (qPCR) of the feces of children.^[7]

• The case-fatality rate of Whipple’s disease is approximately 100%, if left untreated.^[8]
• The case-fatality rate of treated Whipple’s disease is unknown.^[9]

• Whipple’s disease commonly affects individuals between 40 to 60 years of age; the median age at diagnosis is 50 years.^[10]

• Whipple’s disease usually affects individuals of the caucasian race. Africans and Asians are less likely to develop Whipple’s disease.^[11]

• Males are more commonly affected by Whipple’s disease than females. The male to female ratio is approximately 8 to 1.^[10]

• The majority of Whipple’s disease cases are reported in North America and western Europe.^[12]

• In Europe, the prevalence of chronic carrier of Tropheryma whipplei is 1,000-11,000 per 100,000 of general adult population.^[3][4]

• In Senegal, the prevalence of chronic carrier of Tropheryma whipplei is 75,000 per 100,000 of children under 4 years of age.^[5]
• In Laos, the prevalence of chronic carrier of Tropheryma whipplei is 48,000 per 100,000 individuals by using quantitative real-time PCR (qPCR) of the feces of children.^[6]
• In Ghana, the prevalence of chronic carrier of Tropheryma whipplei is 27,500 per 100,000 individuals by using quantitative real-time PCR (qPCR) of the feces of children.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Common risk factors in the development of Whipple’s disease may be environmental, genetic, and immunologic. The most important risk factor in the development of Whipple’s disease is poor sanitation including living in homeless shelters and absence of toilets. Defective cellular immunity is the less common risk factor.

• Risk factors in the development of Whipple’s disease may be environmental, genetic, and immunologic.^{[1][2][3][4][5][6][7][8][9][10]}

• The most potent risk factor in the development of Whipple’s disease is poor sanitation including living in homeless shelters and absence of toilets.

• Common risk factors in the development of Whipple’s disease include:
  • Poor sanitation
  • Living in homeless shelters
  • Absence of toilets
  • Sewage influxed plants
  • Close contact with patients or chronic carriers

• Less common risk factors in the development of Whipple’s disease include:
  • Genetic predisposition including HLA DRB1*13 and HLA DQB1*06 positive
  • HIV infection
  • Immunosuppressed patients

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

There is insufficient evidence to recommend routine screening for Whipple’s disease.

There is insufficient evidence to recommend routine screening for Whipple’s disease.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Tropheryma whipplei infection has different clinical manifestations. It could cause acute infection, localized infection and the classic Whipple’s disease. Acute infection might present with gastroenteritis, pneumonia or bacteremia. Acute infection might resolve without treatment but usually progress to systemic infection or carrier state. Classic Whipple’s disease has 3 clinical phases that starts with nonspecific symptoms and joint pain. It progresses to gastrointestinal symptoms such as diarrhea, steatorrhea, malabsorption, and weight loss. in the late phase, all the other organs including CNS, joints, eyes, heart, lung, liver and skin might be involved. The risk of relapse is approximately 40%, if treatment is not completed. Relapse of Whipple’s disease might occur up to 30 years after treatment and it is commonly responsible for morbidity and mortality. Common complications of Whipple’s disease include malnutrition, cardiopulmonary, neurologic and osteoarticular involvement. Malabsorption mostly presents with fat-soluble vitamin deficiency, fatigue, and weight loss. Valvular heart disease and dementia are the most common cardiac and neurologic complication, respectively. The prognosis of Whipple’s disease is good if diagnosed properly and long-term treatment started early. Without treatment, Whipple’s disease is fatal.

Tropheryma whipplei infection has different clinical manifestations. It could cause acute infection, localized infection and the classic Whipple’s disease. Each of them has its own progression and natural history. Acute infection might resolve without treatment but usually progress to systemic infection or carrier state. The risk of relapse is approximately 40%, if treatment is not completed. Relapse of Whipple’s disease might occur up to 30 years after treatment and it is commonly responsible for morbidity and mortality.^[1]

• Tropheryma whipplei causes acute infections, including:
  • Gastroenteritis: Patients have watery diarrhea, steatorrhea, and colicky abdominal pain.^[2]
  • Pneumonia: Tropheryma whipplei causes pneumonia in HIV patients.^[3]
  • Bacteremia: Tropheryma whipplei infection could cause self-limiting bacteremia.^[4]

Patients who developed the classic Whipple’s disease usually have 3 clinical phases:

• In the early phase, patients have nonspecific symptoms including fever and arthralgia that could last for years.^[5]
• In the middle phase, patients develop gastrointestinal symptoms including diarrhea, abdominal pain and weight loss.^[6]
• In the late phase, other organs might be involved. Neurologic symptoms including progressive dementia, personality changes and seizures might happen. Eyes, heart, lung, liver, and skin can be involved in this phase.^[7]

Patients might present with localized infection instead of systemic involvement after being infected by Tropheryma whipplei.

• Endocarditis: Patients might develop blood culture-negative endocarditis.^[8]

• Encephalitis: Ataxia and dementia are common. Empirical antibiotic therapy might be considered for rapid resolution.^[9]

• Pulmonary involvement: Patients might present with interstitial lung disease, dry cough and shortness of breath.^[10]

• Osteoarticular involvement: Isolated arthritis and spondylodiscitis are happened without systemic manifestations.^[11]

• Eyes involvement: Patients might present with isolated uveitis. PCR of aqueous humor is used to establish the diagnosis.^[12]

Common complications of Whipple’s disease include:^{[13][14][15][1][16]}

• Malnutrition
  • Vitamin deficiency
    • Vitamin A deficiency that presents with night blindness.
    • Vitamin D deficiency that presents with nonspecific symptoms including fatigue, muscle pain and osteomalacia.
    • Vitamin E deficiency that presents with neuromuscular problems and immunity impairment. 
    • Vitamin K deficiency that presents with bleeding.
  • Weight loss
• Cardiac complications
  • Adhesive pericarditis
  • Myocardial fibrosis
  • Congestive heart failure
  • Valvular heart disease
  • Acute ischemic stroke
  • Embolic events

• Neurologic complications
  • Progressive dementia
  • Cerebellar ataxia
  • Personality changes
  • Hemiparesis
  • Seizure
  • Wernicke’s encephalopathy
  • Hypothalamic involvement
  • Supranuclear ophthalmoplegia

• Pulmonary complications
  • Pulmonary hypertension

• Osteoarticular complications
  • Destructive arthritis
  • Joint deformity

• The prognosis of Whipple’s disease is good if diagnosed properly and long-term treatment started early.^[14]
• The prognosis of Whipple’s disease is generally very poor if left untreated.^[13]
• The presence of neurologic symptoms is associated with a particularly poor prognosis among patients with Whipple’s disease.^[15]

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