Whipple’s Disease

Whipple’s disease is a rare malabsorption syndrome with systemic manifestations (neurologic, cardiac, and musculoskeletal) caused by the bacterium Tropheryma whipplei. Patients often present with weight loss, diarrhea/steatorrhea, and arthralgias, as well as neurologic and cardiac manifestations. Whipple’s disease is diagnosed with biopsy after the visualization of periodic acid–Schiff (PAS)-positive foamy macrophages in the involved tissues or with PCR for the bacterial DNA. It is managed with antibiotics, namely ceftriaxone or penicillin G and sulfamethoxazole.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Whipple’s disease is a malabsorption syndrome with systemic manifestations that is caused by infection with Tropheryma whipplei.

Epidemiology

  • Rare disorder with worldwide distribution
  • Overall incidence: 1–3 in 1 million individuals 
  • Increased prevalence in farmers (since T. whipplei is soil-dwelling) and sewage workers
  • Possibly associated with HLA-B27 haplotype
  • Most common in White males (male:female ratio = 8:1)
  • Mean age at symptom onset: 49 years

Etiology

Causative agent is T. whipplei:

  • Rod-shaped, nonmotile, gram-positive bacillus
  • Related to Actinomycetes
  • Acid-fast smear–negative
  • Periodic acid–Schiff (PAS)-positive
  • Enveloped in a trilamellar plasma membrane and covered by a cell wall
  • Soil- and sewage-dwelling bacterium
  • Colonizes intestinal tract, lymphoreticular system, and CNS

Host immunodeficiency has been implicated in symptomatic infections.

Pathophysiology

  • Pathogenesis has not been entirely delineated.
  • Characterized by a general lack of host inflammatory response to T. whipplei
  • Specific immunologic derangements include:
    • Low activity of type 1 T-helper cells and increased type 2 T-helper cells
    • Low CD4:CD8 T-cell ratio
    • Deficient expression of complement receptor type 3 on host mononuclear cells
    • Diminished antigen presentation by major histocompatibility complex (MHC) class 2 apparatus on intestinal epithelial cells
  • There are no pronounced cytotoxic effects on host cells, so the organism can accumulate in tissues in large numbers.
  • The organism is ingested and incorporated into tissue macrophages.
  • T. whipplei invades a variety of tissues and organs:
    • Intestinal epithelium
    • Macrophages
    • Capillary and lymphatic endothelium
    • Liver
    • Brain
    • Kidneys
    • Bone marrow
    • Synovium
    • Skin
  • Infiltration of the lamina propria of the intestines disrupts villous function and causes malabsorption.
  • Infiltration of other organs causes organ-specific symptoms (e.g., arthralgia with synovial infiltration).

Clinical Presentation

Classic Whipple’s disease

  • Arthralgia: 
    • Frequently the first presenting symptom
    • Involves large joints
    • Migratory and nondestructive
  • Weight loss
  • Diarrhea:
    • Watery or steatorrheic
    • Occult or gross gastrointestinal bleeding can also occur.
  • Abdominal pain (intermittent, colicky)

Other manifestations

  • Cardiac:
    • Endocarditis (valve involvement; most common)
    • Myocarditis, pericarditis
    • Congestive heart failure
  • Neurologic:
    • Confusion
    • Seizures
    • Delirium
    • Cognitive impairment 
    • Hypersomnia
    • Extrapyramidal symptoms 
    • Ataxia and clonus
    • Pathognomonic findings:
      • Oculomasticatory myorhythmia (continuous eye convergence movements with concurrent masticatory muscle contractions)
      • Oculo-facial-skeletal myorhythmia
      • Vertical gaze palsy
  • Systemic:
    • Fever
    • Weight loss
    • Mesenteric or mediastinal lymphadenopathy (50% of cases)
    • Peripheral edema (due to hypoproteinemia secondary to poor nutrition and protein-losing enteropathy)

Diagnosis

History

  • Middle-aged White males
  • Occupational exposure: farmers, sewage workers
  • Chronic/long-standing diarrhea with no identifiable cause
  • Abdominal pain
  • Arthralgias
  • Weight loss

Physical exam

  • Nonspecific
  • Emaciated, malnourished appearance, with generalized edema
  • Neurologic/psychiatric findings may be present with nervous system involvement.

Laboratory studies

  • Anemia due to chronic disease and iron, folate, or vitamin B12 deficiency
  • Mild lymphopenia
  • Hypoalbuminemia with normal globulin levels
  • Prolonged prothrombin time 
  • Stool culture to rule out other infectious causes of diarrhea
  • Serologic tests to rule out autoimmune/rheumatic diseases (i.e., rheumatoid factor, antinuclear antibody)

Biopsy

  • Definitive
  • 1st test is usually upper endoscopy, with small bowel biopsy showing PAS-positive foamy macrophages:
    • Mucosa may or may not show gross abnormalities.
    • A false negative result is common if a patient begins receiving antibiotics before undergoing diagnostic testing.
  • Biopsy of other tissues (cardiac, synovial, cerebrospinal fluid) should be performed if:
    • The only presenting symptoms are extraintestinal.
    • Intestinal biopsy is negative, but suspicion remains high.
  • If PAS stain is negative, a diagnosis can be made with the following tests:
    • T. whipplei identification via PCR or 16s rRNA detection
    • T. whipplei antibody–positive immunohistochemical stain

Endoscopic view of the jejunal mucosa in Whipple’s disease:
white lesions compatible with diffuse intestinal lymphangiectasia

Image: “Endoscopy” by Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. License: CC BY 4.0

Management and Prognosis

Management

The mainstay of treatment is antibiotics:

  • Because there is a risk of CNS involvement, an antibiotic that can penetrate the blood–brain barrier is needed.
  • 1st-line regimen:
    • Intravenous ceftriaxone or penicillin G for 2 weeks (4 weeks for endocarditis)
    • Oral trimethoprim–sulfamethoxazole for 12 months 
  • Alternative regimens for patients with penicillin and/or sulfa allergies:
    • Intravenous meropenem for 2 or 4 weeks
    • Oral doxycycline + hydroxychloroquine for 12 months

Prognosis

  • Most patients with adequate treatment do very well.
  • Dramatic improvement can be seen within 7–21 days.
  • Neurologic damage can sometimes be irreversible.
  • Complications:
    • Immune reconstitution inflammatory syndrome (IRIS):
      • Can develop within the first few weeks of starting antibiotic regimen
      • High fever and symptoms mimicking relapse
    • Relapse:
      • Failure of clinical response to antibiotics
      • PCR-positive on repeat biopsy

Differential Diagnosis

  • HIV infection: HIV belongs to the family Retroviridae. Symptoms of the primary infection are flu-like, with low grade fever, myalgias, and lymphadenopathy. After decades of latent infection and weakening of host immunity, AIDS develops, which is characterized by opportunistic infections and cancers. Diagnosis is established by blood PCR testing, and treatment is with antiretroviral drugs.
  • Tuberculosis: infectious disease caused by Mycobacterium tuberculosis, acid-fast bacteria that can survive in macrophages, allowing for decades-long, latent, asymptomatic infections: Symptoms include fever, cough, anorexia, weight loss, malaise, and extrapulmonary manifestations, including pericarditis. The diagnosis is established with a tuberculin skin test, sputum culture, and lung imaging, and the mainstay of management is antimycobacterial drugs.
  • Connective tissue disease: Connective tissue disease comprises a number of conditions: (1) systemic lupus erythematosus (SLE), (2) antiphospholipid syndrome, (3) scleroderma, (4) myositis, and (5) Sjögren’s syndrome. These autoimmune diseases are characterized by autoantibody production and present with symptoms of immune dysfunction. Patients present with dermatologic, arthropathic, and systemic symptoms. Each disease has its own serologic markers and pathogenesis. Treatment frequently includes steroids and immunomodulating drugs.
  • Hyperthyroidism: a state of excess thyroid hormone synthesis and secretion: Hyperthyroidism is most often caused by Graves’ disease or a toxic multinodular goiter. Patients report palpitations, disrupted sleep, anxiety, weight loss, diarrhea, sweating, and heat intolerance. Physical exam shows tachycardia, weight loss, and tremors of the extremities. Diagnosis is established by measuring blood thyroid hormone levels, and treatment involves antithyroid drugs and beta-blockers.
  • Inflammatory bowel disease (IBD) with arthropathy:  
    • Crohn’s disease: a chronic, recurrent condition that causes patchy transmural inflammation that can involve any part of the gastrointestinal tract: Crohn’s disease typically presents with intermittent, nonbloody diarrhea and crampy abdominal pain. Arthropathy is an extraintestinal manifestation for both types of IBD. Diagnosis is confirmed by intestinal biopsy, and treatment includes immunosuppressive regimens.
    • Ulcerative colitis: an idiopathic inflammatory condition that involves the mucosal surface of the colon: The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative colitis typically presents with intermittent, nonbloody diarrhea and crampy abdominal pain. Arthropathy is an extraintestinal manifestation for both types of IBD. Diagnosis is confirmed by intestinal biopsy, and treatment includes immunosuppressive regimens.

References

  1. Antunes C., Singhal M. Whipple Disease. (2020). In: StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK441937/
  2. Apstein M. D., Schneider T. (2020). Whipple’s Disease. Retrieved February 21, 2021, from https://www.uptodate.com/contents/whipples-disease
  3. Bally J. F., Méneret A., Roze E., Anderson M., Grabli D., Lang A. E. (2018). Systematic review of movement disorders and oculomotor abnormalities in Whipple’s disease. Mov Disord. 33(11):1700-1711.
  4. Hujoel I. A., Johnson D. H., Lebwohl B., Leffler D., Kupfer S., Wu T. T., Murray J.A., Rubio-Tapia A. (2019). Tropheryma whipplei Infection (Whipple Disease) in the USA. Dig Dis Sci. 64:213-223. 
  5. Dolmans, R. A. V., Boel, C. H. E., Lacle, M. M., Kusters, J. G. (2017). Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections. Clin Microbiol Rev. 30:529-555.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details