Tropheryma whipplei

Background

Microbiology

• Fastidious Gram-positive bacillus

Epidemiology

• Ubiquitous environmental organism, but rarely causes disease with only about 12 new cases diagnosed annually worldwide
  • Can be found in saliva of one third of healthy people
• Disease is more common in white European (98%) males (85%)
• Mean age at diagnosis is 40 to 60 years
• Farming or occupational soil/animal/sewage exposures are common

Pathophysiology

• Lack of host immune response

Clinical Manifestations

Classic Whipple Disease

• Cardinal features include: arthralgias (80%), followed by weight loss (90%), diarrhea (75%), and abdominal pain (60%)
• Arthralgias are typically migratory in the larger peripheral joints, including knees, ankles, and wrists, but can have essentially any presentation
  • May be present for up to 6 years before development of other symptoms
  • May be polyarticular or oligoarticular
  • Rarely destructive
• The diarrhea is intermittent, with colicky abdominal pain
  • Diarrhea can be watery or have steatorrhea
  • Occasional GI bleeding (25%)
  • Malabsorption may lead to hypoalbuminemia, peripheral edema, and ascites
• Also common are fevers (45%), myalgias (25%), lymphadenopathy (45%) (mainly mesenteric or mediastinal with non-caseating granulomas)
• Bloodwork shows anemia (81%), leukocytosis 948%), thrombocytosis (56%), and elevated CRP (69%)

Transient Whipple Disease

• Transient, acute presentation of fever and diarrhea
• Occurs mainly in children in Africa

Asymptomatic Whipple Disease

• Asymptomatic carriage of the bacterium, more common in sewage workers

Localised Whipple Disease

• Causes localised culture-negative endocarditis or CNS infection without systemic systems
• Very difficult to diagnose

Other Symptoms

• Fever in 25 to 40%
• Lymphadenopathy, mostly of mesenteric and mediastinal nodes
• CNS disease
  • Dementia, supranuclear ophthalmoplegia, nystagmus, and myoclonus
  • Oculomasticatory myorhythmia and oculo-facial-skeletal myorhythmia with a supranuclear vertical gaze palsy
  • Cerebellar ataxia
  • Symptoms can occur with disease or as a post-treatment relapse
• Cardiac disease
  • Culture-negative endocarditis, pericarditis, and myocarditis
  • Endocarditis may occur on its own without other features of disease
• Skin hyperpigmentation in 40%
• Pleural effusion, chronic cough, interstitial lung disease, pulmonary hypertension
• Anemia in 80%, leukocytosis in 50%, thrombocytosis in 50%
• Elevated C-reactive protein in 70%

Immunosuppression

• Likely related to reactivation of latent infection, often in the context of HIV and IRIS
• Can present with any of the above syndromes

Diagnosis

• Samples should be taken from involved sites, with a strong preference for small bowel biopsy if there are GI symptoms
  • At least 5, and ideally up to 7 to 10, biopsies from small bowel
  • Other possible sites include synovial fluid or joint tissue biopsy, lymph node biopsy, CSF or brain biopsy, aqueous humour, cardiac valves, intervertebral disk biopsy, or PCR of blood
• Diagnosis is based on the presence of any of the following:
  • Presence of oculomasticatory or oculo-facial-skeletal myorhythmia
  • Periodic acid-Schiff-positive (PAS-positive) bacilli in macrophages on small bowel biopsy
  • Two different positive tests (PAS, PCR, or IHC) on a single sample
  • One positive test (PAS, PCR, or IHC) on two different samples

Management

• All patients should have lumbar puncture to send CSF for PCR
• Consider echo to rule out valve involvement
• Generally treat with parenteral ceftriaxone 2 g IV daily or penicillin 2 MU IV q4h for 2 weeks (classic) or 4 weeks (endocarditis or CNS disease), followed by TMP-SMX DS PO bid for at least 1 year
  • Treatment can precipitate a Jarisch-Herxheimer reaction
  • May also see immune reconstitution inflammatory syndrome in early treatment
  • Other options include meropenem, doxycycline, macrolides, ketolides, aminoglycosides, rifampin, teicoplanin, and chloramphenicol
• Consider repeating small bowel biopsies annually for a few years

Syndrome	Induction	Maintenance
Initial
General	ceftriaxone 2 g IV daily for 2 weeks	TMP-SMX DS 1 tablet bid for 1 year
Endocarditis	ceftriaxone 2 g IV daily for 4 weeks
CNS disease
β-lactam allergy	meropenem 1 g IV q8h for 2 to 4 weeks
Sulfa allergy		doxycycline 100 mg p.o. bid plus hydroxychloroquine 200 mg p.o. tid for 1 year
Relapse
All	ceftriaxone 2 g IV q12h for 4 weeks	TMP-SMX DS 2 tablets bid for 1 year
Sulfa allergy		doxycycline 100 mg p.o. bid plus hydroxychloroquine 200 mg p.o. tid for 1 year

Prognosis

• Clinical improvement takes 1 to 3 weeks of treatment
• Neurologic sequelae may be permanent
• Relapses after treatment, including of CNS disease, can happen in up to a third of patients