Whipple's disease overview
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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.
Differentiating Whipple's disease from other Diseases
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.
Epidemiology and Demographics
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.
Natural History, Complications, and Prognosis
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.
There are no established criteria for the diagnosis of Whipple's disease.
History and Symptoms
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.
Other Diagnostic Studies
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.
There are no established measures for the secondary prevention of Whipple's disease.