Whipple Disease

Whipple disease is a rare, chronic, multisystem infection caused by Tropheryma whipplei, a Gram positive actinomycete. Classically it causes malabsorption, weight loss, arthralgia and abdominal pain. It can involve virtually any organ system, including the central nervous system and heart. It is uniformly fatal if untreated, but outcomes are generally excellent when it is recognised and treated with prolonged antibiotic therapy.

Pathophysiology

• The organism is widely present in the environment and appears to be acquired by a substantial proportion of the population without producing clinical disease. Overt Whipple disease is believed to reflect a specific, incompletely understood host susceptibility, likely related to impaired macrophage mediated clearance of the organism rather than simple exposure alone.
• Infected macrophages accumulate within the lamina propria of the small intestine. They contain characteristic periodic acid Schiff positive inclusions of partially degraded bacterial material. This infiltration disrupts normal villous architecture and lymphatic drainage, producing the characteristic malabsorptive picture. Haematogenous and lymphatic spread accounts for the frequently observed multisystem involvement.

• Migratory, seronegative polyarthralgia or arthritis frequently precedes gastrointestinal symptoms by years, sometimes by a decade or more, an important and often retrospectively recognised diagnostic clue in patients diagnosed with the disease.
• Diarrhoea, steatorrhoea, abdominal pain and progressive weight loss reflecting small intestinal malabsorption represent the classical and most recognisable presentation once gastrointestinal involvement develops, often accompanied by lymphadenopathy and low grade fever.
• Neurological involvement, occurring in a meaningful proportion of cases either alongside or, less commonly, in isolation without prominent gastrointestinal disease, produces a wide range of manifestations. These include cognitive decline, supranuclear gaze palsy and, classically though not commonly observed, oculomasticatory myorhythmia (a virtually pathognomonic pendular convergent nystagmus with concurrent masticatory muscle contraction).
• Cardiac involvement, particularly culture negative endocarditis, represents an increasingly recognised manifestation, sometimes occurring without other classical systemic features of the disease, and should be considered in the differential diagnosis of culture negative endocarditis.
• Other manifestations include skin hyperpigmentation, ocular inflammation (uveitis), and, given the frequently prolonged diagnostic delay characteristic of this rare disease, significant cumulative nutritional deficiency by the time diagnosis is eventually established.

• Small intestinal biopsy, obtained at upper gastrointestinal endoscopy, remains a key diagnostic investigation, with histology showing characteristic periodic acid Schiff positive, diastase resistant macrophages within the lamina propria, together with blunting of intestinal villi.
• Polymerase chain reaction testing for Tropheryma whipplei deoxyribonucleic acid is performed on intestinal biopsy tissue, blood, cerebrospinal fluid, or synovial fluid according to the pattern of clinical involvement. It offers superior sensitivity and specificity compared with histology alone and is increasingly central to diagnosis.
• It is particularly valuable for confirming or excluding central nervous system involvement. This should be actively sought in every confirmed case, given the implications for treatment duration and choice of antibiotic with adequate central nervous system penetration.
• Cerebrospinal fluid analysis, including specific polymerase chain reaction testing, is recommended in every patient with confirmed Whipple disease regardless of the presence or absence of overt neurological symptoms. This reflects the risk of clinically silent central nervous system involvement and the serious consequences of undertreated neurological disease.
• Given the rarity and non specific nature of the presenting features, a high index of suspicion is required, particularly in a patient with the combination of chronic unexplained arthralgia, weight loss and malabsorptive symptoms, or in culture negative endocarditis, prompting the specific targeted investigation.

• Initial induction treatment comprises ceftriaxone 2 g intravenously once daily, or benzylpenicillin, for two to four weeks, chosen specifically to achieve adequate central nervous system penetration given the risk of occult neurological involvement and the serious consequences of inadequately treating this specific site.
• Following intravenous induction, maintenance treatment with oral trimethoprim with sulfamethoxazole (co trimoxazole) 960 mg twice daily is continued for a prolonged period, typically twelve months. This reflects the need for sustained treatment to achieve durable eradication and prevent the recognised risk of relapse with shorter treatment courses.
• Doxycycline 100 mg twice daily combined with hydroxychloroquine 200 mg three times daily is an alternative maintenance regimen used in some centres, chosen given evidence of activity against intracellular organisms within macrophages, with the combination approach reflecting the specific intracellular survival strategy of this organism.
• Nutritional support and correction of specific deficiencies (iron, folate, vitamin B12, fat soluble vitamins) is an essential component of management given the frequently significant malabsorptive nutritional depletion present at diagnosis, with gradual reintroduction of normal diet as intestinal function recovers over the course of treatment.
• Immune reconstitution inflammatory syndrome, a paradoxical clinical worsening that can occur, particularly in the early weeks of treatment as an inflammatory response develops against dying organisms, is a recognised complication requiring careful monitoring and, in significant cases, corticosteroid treatment.
• Regular clinical follow up, together with repeat small intestinal biopsy and polymerase chain reaction testing at intervals to confirm eradication, and long term monitoring given the recognised risk of relapse. Relapse sometimes presents many years after apparently successful initial treatment, particularly with neurological manifestations. This underpins full long term management of this chronic condition.