We searched PubMed and Cochrane databases with the following keywords in all combinations and without date restriction: “Whipple”, “Whipple disease”, “Whipple's”, “Whipple's disease”, “intestinal lipodystrophy”, “Tropheryma”, “Tropheryma whipplei”, “Tropheryma whippelii”, “PAS”, “PCR”, “CNS”, “immunology”, “therapy”, “biological therapy”, and “immunosuppression”. We searched for English language publications, but major Italian or German publications were also taken into account.
ReviewTropheryma whipplei infection and Whipple's disease
Introduction
Whipple's disease is a rare, systemic illness often characterised by weight loss, diarrhoea, and arthralgia. George H Whipple suspected an infectious disease at his first description of the disorder in 1907.1 Further findings suggested a bacterial cause: macrophages with cytoplasmic periodic acid-Schiff (PAS) inclusions were described in 1949,2 and bacteria were observed by electron microscopy in 1960.3, 4, 5 The disease was fatal until the first successful antibiotic treatment was introduced in 1952.6 The causative organism was finally identified in the 1990s by sequencing of its 16S ribosomal RNA genes.7, 8 The first cultivation of the bacterium in macrophages was described in 1997,9 and, in 2000, stable cultures were established10 enabling sequencing of Tropheryma whipplei's whole genome 3 years later.11, 12 The aim of this Review is to summarise the pathogenesis, diagnosis, and treatment of Whipple's disease. For example, immunosuppressive treatment (under the misdiagnosis of a rheumatic disorder) was recognised to influence the course of Whipple's disease. In addition, we aim to enhance the awareness of life threatening complications during treatment like immune reconstitution inflammatory syndrome (IRIS) that occurs particularly in patients following immunosupressive treatment.
Section snippets
Microbiology of T whipplei
T whipplei, the causative bacterium of Whipple's disease, is a rod-shaped organism that can be visualised by electron microscopy (figure 1).2, 3, 4 The bacterium has a trilaminar plasma membrane that is surrounded by a homogeneous cell wall.1, 2, 3, 4 Genomic amplification by PCR was used to detect bacterial 16S RNA gene from duodenal lesions of patients with Whipple's disease.7, 8 The analysis enabled the phylogenetic characterisation of the new genus Tropheryma.8
The organism was first
Natural habitat, prevalence, and transmission of T whipplei
Exposure to contaminated soil (eg, by farmers) has been postulated to be a possible route of infection.1 Actinobacteria are environmental microorganisms found in soil, freshwater, or seawater sediments; therefore, it is not surprising that T whipplei has been found in 37–66% of influxes to sewage plants.15, 23, 24, 25
T whipplei is frequently detected in stool and saliva samples from patients with Whipple's disease and, to a small degree, in asymptomatic carriers (roughly 2–4%).16, 24, 26 T
Pathogenesis of Whipple's disease
Chronic systemic infection with T whipplei seems to occur only in predisposed patients who show a lifetime susceptibility to T whipplei infection;35 on the one hand Whipple's disease is very rare and usually develops over the course of many years or even decades (insidious replication), while on the other hand asymptomatic carriage of T whipplei is frequent.26, 27, 28, 36, 37, 38 A specific genetic predisposition involves HLA associations (HLA alleles DRB1*13 and DQB1*06) that interfere with
Clinical features of T whipplei infection and Whipple's disease
In recent years, the clinical spectrum of T whipplei infection has broadened substantially,36, 61, 62 and now encompasses several distinct disease characteristics: the classic form, predominantly involving the intestinal tract with diarrhoea and weight loss as the main features; localised forms in extra-intestinal organs without involvement of the alimentary tract; acute, self-limiting infections such as acute gastroenteritis or acute pneumonia; and asymptomatic, healthy carriers.
Classic
Histopathology and immunohistochemistry
The diagnosis of Whipple's disease can be made from duodenal biopsies in most cases.61, 87, 88, 89, 90 However, some patients will need a more elaborate diagnostic algorithm to confirm the diagnosis (figure 3). Despite a massive infiltration of the duodenal mucosa with T whipplei, most cases show an unsuspicious appearance of the duodenum at upper endoscopy.61, 87 A pale yellow mucosal surface with clumsy and dilated villi and ectasia of lymph vessels might be present, but is not specific for
Standard antibiotic treatment
After antibiotic treatment of classic Whipple's disease, rapid improvement and clinical remission is usually reported. Diarrhoea and fever often disappear within days to weeks, and arthropathy and other symptoms improve after several weeks.1, 15, 36, 65
A non-randomised retrospective study of 30 patients101 and a retrospective analysis of 52 patients66 showed that treatment with co-trimoxazole was superior to treatment with tetracycline and was more effective for CNS disease. In 2010, a
Prognosis, relapse, and follow-up
Untreated Whipple's disease has a fatal course.1, 6 The mortality rate of treated Whipple's disease is unknown.1, 15, 87 In two prospective trials comprising 80 individuals, 5% of patients had a probable Whipple's disease-related fatal outcome during an observation period of 85 months.70, 94
Relapses are largely responsible for morbidity and mortality—ie, for prognosis of Whipple's disease. By contrast with the historically reported relapse rates of about 30%,1, 15, 65, 107, 108 two more recent
Future directions
Although much knowledge on Whipple's disease has been gained within the past few years, a deeper knowledge of this model rare disease is needed. Not much is known about the reservoir of T whipplei and the host factors enabling classic Whipple's disease. For some infections with T whipplei, such as isolated endocarditis, development of a non-invasive test would be useful. Patients with immunosuppressive therapy for suspected autoimmune or rheumatic disorders should be followed up closely and, in
Search strategy and selection criteria
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