Whipple's disease overview: Difference between revisions
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==Overview== | ==Overview== | ||
Whipple's disease is a rare, [[systemic]] [[infectious]] disease caused by the bacterium [[Tropheryma whipplei|''Tropheryma whipplei'']]. [[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 (biology)|tissue]]. Following contamination, based on [[Immunological|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 stain|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. | |||
==Historical Perspective== | ==Historical Perspective== | ||
[[George Whipple|Whipple]] described the disease for the first time in 1907 as a [[gastrointestinal]] disorder and named it as "[[intestinal lipodystrophy]]." Light and [[Electron microscope|electron microscopy]] on [[Small intestine|small bowel]] [[biopsy]] were used | [[George Whipple|Whipple]] described the disease for the first time in 1907 as a [[gastrointestinal]] disorder and named it as "[[intestinal lipodystrophy]]." Light and [[Electron microscope|electron microscopy]] on [[Small intestine|small bowel]] [[biopsy]] were used to detect [[bacilli]] inside the [[intestinal]] [[mucosa]]. In 1952, systemic [[Antibiotic|antibiotics]] were used to treat the disease which confirmed the [[Infection|infective]] nature of the disease. It took almost 100 years for investigators to cultivate the [[bacterium]] and sequenced the [[genome]]. | ||
==Classification== | ==Classification== | ||
Whipple’s disease may be classified into | 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 (biology)|organ]] involvement. It has four different [[clinical]] manifestations: [[Acute]] [[infection]], [[asymptomatic carrier]] state, the classic Whipple’s disease, and localized [[chronic]] [[infection]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
Whipple’s disease is a | Whipple’s disease is a rare systemic disease. Therefore, some aspects of [[pathogenesis]] have remained unclear. [[Tropheryma whipplei|''Tropheryma whipplei'']] is usually transmitted through [[oral route]] to human [[Host (biology)|hosts]]. There is no known causative [[genetic]] factor for Whipple's disease. However, [[genetic]] and [[Immunological|immunologic]] factors play important roles in [[clinical]] manifestation of [[Tropheryma whipplei|''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 [[Macrophage|macrophages]] in the [[lamina propria]] that is [[periodic acid-Schiff stain]] positive. | ||
==Causes== | ==Causes== | ||
Tropheryma whipplei is a [[Bacteria|bacterium]] and the causative organism of [[Whipple's disease]]. While ''Tropheryma whipplei'' is categorized with the [[ | '''''Tropheryma whipplei''''' is a [[Bacteria|bacterium]] and the causative organism of [[Whipple's disease]]. While ''Tropheryma whipplei'' is categorized with the [[gram-positive]] [[Actinobacteria|''Actinobacteria'']], the organism is commonly found to be [[gram-negative]] or gram-indeterminate when stained in the laboratory. [[George Hoyt Whipple|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== | ==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 [[ | 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== | ==Epidemiology and Demographics== | ||
Whipple's disease is | 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. | ||
==Risk Factors== | ==Risk Factors== | ||
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==Natural History, Complications, and Prognosis== | ==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]]. 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. | ===Natural History=== | ||
[[Tropheryma whipplei|''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 & Mortality|morbidity and mortality]]. | |||
===Complications=== | |||
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. | |||
===Prognosis=== | |||
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]]. | |||
==Diagnosis== | ==Diagnosis== | ||
===Diagnostic Criteria=== | ===Diagnostic Criteria=== | ||
There are no established criteria for the | There are no established criteria for the diagnosis of Whipple's disease. | ||
===History and Symptoms=== | ===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 [[ | 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. | ||
===Physical Examination=== | ===Physical Examination=== | ||
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===Laboratory Findings=== | ===Laboratory Findings=== | ||
Some patients with Whipple's disease may have abnormal [[hematological]] findings and elevated [[Acute phase reactant|acute phase reactants]], which is suggestive of the infection | Some patients with Whipple's disease may have abnormal [[hematological]] findings and elevated [[Acute phase reactant|acute phase reactants]], which is suggestive of the infection. Laboratory evidence of [[malabsorption]] including [[hypoalbuminemia]], [[hypokalemia]], [[hypocalcemia]], [[hypomagnesemia]] may be seen. | ||
===Imaging Findings=== | ===Imaging Findings=== | ||
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 | 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. | [[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. | |||
===Other Diagnostic Studies=== | ===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 stain|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]]. | [[Endoscopy]] and [[Small intestine|small bowel]] [[biopsy]] may be helpful in the diagnosis of Whipple's disease. Diagnostic findings of Whipple's disease include, [[PAS stain|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|''Tropheryma whipplei'']] and [[PCR]], which demonstrates 16S [[rRNA]] gene of [[Tropheryma whipplei|''Tropheryma whipplei'']]. | ||
==Treatment== | ==Treatment== | ||
===Medical Therapy=== | ===Medical Therapy=== | ||
[[Antimicrobial]] therapy is the mainstay of [[therapy]] for Whipple's disease | [[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|sulfamethoxazole-trimethoprim]] for at least 1 year. Patients who experience either Whipple's disease or [[allergy]] to [[Sulfamethoxazole-Trimethoprim|sulfamethoxazole-trimethoprim]] require a combination of [[doxycycline]] and [[hydroxychloroquine]]. [[Dietary supplement|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]]. | ||
===Surgery=== | ===Surgery=== | ||
The mainstay of [[treatment]] for Whipple's disease is [[medical]] therapy. [[Surgery]] is usually reserved for patients with [[cardiac]] complications and [[heart valves]] involvement. | |||
===Primary Prevention=== | ===Primary Prevention=== | ||
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|''Tropheryma whipplei'']]. | |||
===Secondary Prevention=== | ===Secondary Prevention=== | ||
There are no established measures for the secondary prevention of Whipple's disease. | |||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
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{{WH}} | {{WH}} | ||
{{WS}} | {{WS}} | ||
[[Category:Medicine]] | |||
[[Category:Gastroenterology]] | |||
[[Category:Infectious disease]] | |||
[[Category:Up-To-Date]] | |||
Latest revision as of 00:44, 30 July 2020
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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]
Overview
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.
Historical Perspective
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.
Classification
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.
Pathophysiology
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.
Causes
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.
Risk Factors
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.
Screening
There is insufficient evidence to recommend routine screening for Whipple's disease.
Natural History, Complications, and Prognosis
Natural History
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.
Complications
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.
Prognosis
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.
Diagnosis
Diagnostic Criteria
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.
Physical Examination
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.
Laboratory Findings
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.
Imaging Findings
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.
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.
Treatment
Medical Therapy
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.
Surgery
The mainstay of treatment for Whipple's disease is medical therapy. Surgery is usually reserved for patients with cardiac complications and heart valves involvement.
Primary Prevention
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.
Secondary Prevention
There are no established measures for the secondary prevention of Whipple's disease.