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Whipple's disease is a chronic, curable, systemic bacterial infection caused by Tropheryma whipplei. The classic form usually begins with recurrent arthritis, followed several years later by weight loss and diarrhoea, associated with other diverse clinical signs.
The recent development of new tools has provided promising new possibilities for the understanding and management of this severe, and sometimes fatal, disease. New techniques for detection by gene amplification and isolation of T whipplei and DNA sequencing have extended our knowledge of this pathogen, which is now recognised as a ubiquitous commensal bacterium with healthy carriers. The advent of new techniques has also extended our knowledge of the spectrum of signs associated with T whipplei beyond the classic form. Children may present an acute primary infection, but only a small number of people subsequently develop authentic Whipple's disease. T whipplei may also cause localised chronic infections, including arthritis, without histologically detectable intestinal involvement.
This review discusses the recent scientific advances in infections linked to T whipplei, the latest methods for diagnosis of a classic Whipple's disease and of localised chronic infection, and empirical treatment.
The causal bacterium
Almost a century after its first description the bacterium responsible for Whipple's disease was eventually isolated.1 PCR amplification of the universal 16S ribosomal ribonucleic acid gene led to the detection of the causative actinomycete.2 ,3 The isolation of T whipplei triggered studies determining its susceptibility to antibiotics and the development of new indirect (serological) and direct (immunolabelling) methods for its detection. Sequencing showed that T whipplei had a small genome and a low metabolic capacity, consistent with its host-restricted lifestyle.4 ,5 More than 100 different genotypes, unrelated to clinical presentations, have been reported.
Until recently, T whipplei was considered to be a rare bacterium. Recent studies have shown that it is a ubiquitous commensal bacterium. The prevalence of healthy carriers (positively detected and identified by PCR of the bacterium in stools) has been estimated at between 1.5% and 7% in the general population.6–8 This prevalence is 12–25% in sewage treatment workers.7 ,9 T whipplei is also found in 0.2–1.5% of saliva samples from healthy subjects.7 ,8
In addition to chronic infections, T whipplei has been identified as a likely causal agent, either alone or with other pathogens, of acute paediatric infections and even, possibly, of pneumonia in adults.10–14 It is possible that primary infection in young children results in acute diarrhoea, with only a small number of individuals subsequently developing authentic Whipple's disease. This would account for the high seroprevalence reported in healthy adults (52%).1 ,15
In Senegal, T whipplei has been detected in the stools of 31.2% healthy subjects.14 It has been detected by PCR in the blood of 6.4% of patients with transitory fever, particularly in children.11 The overall seroprevalence is 72.8%, suggesting that more than two-thirds of subjects have come into contact with T whipplei.
As T whipplei may be detected in waste water and, sometimes, in stools, it is possible that the disease is contracted following environmental contamination, with the digestive system serving as an entry portal. The isolation of the bacterium from the stools of patients is consistent with fecal–oral transmission. The isolation of the bacterium from saliva suggests that transmission between subjects via the oro-oral route may also be possible.16
Whipple's disease is rare, with an incidence of about 0.5–1 case per million of the population. Infection seems to be more common among farmers and other workers in similar jobs. The disease mostly affects men (86% of patients are male) of Caucasian origin (97% of the patients).17 It occurs mostly in middle-aged men, with joint symptoms first occurring at a mean age of 40.3 years.18
A genetic component is suggested by the strong male predominance and association with the presence of HLA-B27 antigen.19 Subsequent studies did not confirm this association but rather a weak association with DRB1*13 and DQB1*06 alleles. A few familial cases have been reported. The discrepancy between the apparently frequent exposure to T whipplei and the tiny number of people developing Whipple's disease suggests the role of immunogenetic host factors. The frequency of asymptomatic T whipplei carriage in the relatives of patients with Whipple's disease is high.15 Finally, the demonstration of recurrence after reinfection with another strain of T whipplei provides additional evidence for immunogenetic susceptibility to the disease.20 This susceptibility factor is specific to the immune response to T whipplei because patients do not develop other infections, with the possible exception of giardiasis.
T whipplei is an intracellular bacterium with trophism for monocytes and macrophages, but it is also found in a metabolically active form in the extracellular medium. Its persistence within cells may account for late recurrences. The possibility of a cellular immunity defect has been raised on a number of occasions. Impairment of phagocytosis and of the intracellular degradation of T whipplei has been suggested.17 A defect of the TH1 immune response likely to lead to abnormal interactions between macrophages and T cells has been proposed.21 Impaired production of interleukin 12, a mediator inducing the production of interferon γ by TH1 cells, has been demonstrated in vitro.21 ,22 Consistent with this, an analysis of the gene expression profile of macrophages showed overexpression of the genes encoding CCL18 and interleukin 10 in intestinal lesions, associated with a predominance of TH2 cells during the immune response.23 The replication of T whipplei in macrophages is accompanied by induction of host cell apoptosis, leading to dissemination of the bacterium. In a macrophage/monocyte model, the interleukin 16 produced in vitro by the macrophages in response to infection promotes T whipplei replication and is likely to be required for this replication.24 ,25 In vitro treatment with interleukin 16 allows the bacterium to replicate in monocytes, whereas interleukin 16 blockade facilitates bacterial clearance.24 Interleukin 16 inhibits the fusion of phagosomes containing T whipplei with lysosomes.25 It modulates macrophage activation via the interferon γ and NF-κB pathway.25 The replication of T whipplei in late phagolysosomes is repressed in vitro by the inhibition of interleukin 16 production by interferon γ.25 Serum concentrations of interleukin 16 and apoptotic markers correlate with disease activity.24 ,26 In addition to a particular phenotype of infected macrophages potentially leading to the establishment of a permissive state,23 T whipplei induces a robust type I interferon response that is associated with intracellular bacterial replication and required for macrophage apoptosis.27
The paradoxical absence or low titre of antibodies in the serum of patients with Whipple's disease may be due to the glycosylation of bacterial antigenic structures. This glycosylation may be catalysed by the enzymatic apparatus of infected macrophages.28 The masking of its antigens may enable T whipplei to escape phagocytosis by macrophages and also the humoral immune response.
Whipple's disease is often diagnosed at an advanced stage owing to its rarity, its broad spectrum of clinical presentations and the existence of forms with no clinical symptoms or histologically detectable involvement of the intestinal tract.29 This diagnosis should therefore be considered in patients with diverse clinical signs, even in the absence of the cardinal manifestations of the infection (box 1).
Clinical situations in which Whipple's disease should be considered
Unexplained, recurrent, intermittent arthritis
Rheumatoid factor-negative chronic polyarthritis not affecting small joints
Unexplained prolonged fever
Unexplained neurological signs
Blood culture-negative endocarditis
Detection of a non-caseous epithelial-giant cell granuloma
Occurrence of extra-articular signs (digestive, cardiac, neurological signs or fever) during polyarthritis treated with biological agents
In most cases, intermittent arthritis or arthralgia precede the occurrence of other clinical signs of the disease by several years. At the time of diagnosis, the classic form of the disease is generally characterised by a combination of diverse manifestations, including chronic diarrhoea, bouts of fever, weight loss, adenopathies, joint problems and, in some cases, neurological, cardiac and ocular signs. The principal manifestations in historical series are indicated in table 1. The development of new diagnostic methods has made it possible to identify less advanced forms of the disease and isolated forms have also been described.
Most patients present intermittent, recurrent and migratory joint problems. Arthritis is more common (46–61% of cases) than arthralgia (26–54% of cases).18 The large joints are affected. The most common sites of involvement, in order of decreasing frequency, are the knees, wrists and ankles but hips, elbows and shoulders may also be affected.18 Small joints are much less often affected. A diagnosis of Whipple's disease should be considered in men presenting with intermittent episodes of unexplained seronegative polyarthritis or oligoarthritis of the large joints, even in the absence of intestinal symptoms (box 1).18 However, Whipple's disease is rarely diagnosed in patients with such symptoms because T whipplei does not often seem to be involved in undifferentiated arthritis or seronegative polyarthritis in men.34 Histological signs of intestinal involvement or bacterial gene amplification are reported in the vast majority of cases, but PCR tests for the presence of T whipplei in the intestinal tract may be negative in some cases.35
Bilateral, symmetric and chronic seronegative polyarthritis may also be seen.18 After acute, intermittent arthritis, the affected joints may begin to cause pain and stiffness almost daily.18 ,35 Subcutaneous nodules may occur. Some patients with long disease duration but no treatment develop radiological destruction, such as carpal or radiocarpal joint narrowing or global narrowing of the iliofemoral joint space with subchondral cyst formation18 but that does not affect the small joints. Progression to ankylosis occurs late in the disease. It is often mistaken for rheumatoid polyarthritis, but it does not affect the small joints and no rheumatoid factor is detected. The destruction has been associated with septic arthritis and it has been possible to isolate T whipplei from cultures of joint specimens.29 If the disease has not already been diagnosed, the subsequent appearance of gastrointestinal signs and sometimes favoured by biological treatment, generally leads to diagnosis (box 1).29
Axial involvement is less common and often accompanied by peripheral arthritis. Its prevalence has been estimated as between 6% and 40% of cases. Syndesmophytes, sacroiliac ankylosis and ankylosis of the posterior interapophyseal joints have been reported.18
Hypertrophic osteoarthropathy is a rare presentation. T whipplei has also been implicated in infections of joint prostheses and in spondylodiscitis.
The cardinal signs of the classic infection include weight loss and chronic diarrhoea.17 ,31–33 In most cases, the abdominal signs lead to diagnosis. Endoscopic results may be normal for the upper digestive tract. Multiple biopsies are required because the lesions may be localised. Specimens should ideally be frozen to increase the diagnostic sensitivity of molecular biology studies.
Central nervous system damage is the most severe complication of the disease. It is the symptom revealing the disease in <5% of cases,17 ,31 ,33 but it may occur during the course of the disease in 10–20% of patients.17 ,33 In cases of neurological manifestations, 80% of patients present systemic signs.36 ,37
The neurological signs observed are diverse (table 2) and combinations of these signs often occur in a given patient.36 ,37 Cognitive problems are the most common. Oculomasticatory myorhythmia is rare but pathognomonic.36 By contrast, repeated strokes are suggestive of a diagnosis of endocarditis.
Most patients with neurological signs have histologically detectable involvement of the proximal small intestine, making diagnosis possible.
For patients with clinical neurological abnormalities, PCR on cerebrospinal fluid (CSF) gives a positive result in 71% of cases.38 CT and MRI scans are non-specific. Focal abnormalities may sometimes be seen as a T2 hypersignal on MRI.
The prognosis remains poor for patients with central nervous system damage. Four-year death rates exceed 25% and a quarter of patients present serious sequelae.39 Recent therapeutic advances are likely to have improved this outcome.
Isolated neurological presentation without digestive symptoms has been reported: about 30 such cases have been described, with negative results for digestive tract histology, accompanied in most cases by negative results for PCR on intestinal specimens.6
More than half of the patients have pericarditis, but this condition is rarely shown to be present while the patient is alive.32 Myocarditis is rarer. With the advent of molecular biology, T whipplei has been shown to be responsible for blood culture-negative endocarditis.40 ,41 Patients have no fever but often a longlasting history of arthralgia. Valve replacement surgery is necessary in some cases.
About 20 cases have been described in which intestinal histology results were negative, with negative results also obtained by PCR for the digestive mucosa in most of these cases.6 ,41 ,42 These localised forms can be diagnosed only by PCR with samples from the affected valves.
Ocular signs occur in 4–27% of cases of classic Whipple's disease.17 ,31 Such signs are generally seen in patients with joint, intestinal or neurological symptoms. Uveitis, vitreous humour involvement and retinitis are the most commonly observed ocular signs. Retinal bleeding, choroiditis, papillary oedema, optic atrophy, keratitis, optic neuritis, intraocular crystals or crystalline-like deposits, or an ocular pseudotumour may also be found.
Uveitis may reveal the disease. Uveitis is generally chronic, bilateral and may be anterior or posterior. It may be isolated, with no intestinal symptoms, or accompanied by non-contributive duodenal histological features or, exceptionally, negative PCR findings for the digestive tract. Diagnosis in such cases is only possible by PCR with samples of the aqueous humour.
Pulmonary symptoms occur in 30–40% of cases of classic Whipple's disease.17 In rare cases, the disease may be revealed by these manifestations.43 Pleural effusion and granulomatous mediastinal adenopathies are the most common pulmonary manifestations. Pulmonary nodules and interstitial lung diseases are much rarer.43
A diagnosis of Whipple's disease should also be considered in cases of non-caseous epithelial-giant cell granuloma (box 1); such granulomas are seen in 9% of patients with classic Whipple's disease.17 Lymph node granulomas are the most common (figure 1), but granulomas have also been described in many other tissues. The diagnosis can be established by PCR testing of granulomatous and duodenal tissue.
Erythrocyte sedimentation rate and C-reactive protein are often high before treatment. No rheumatoid factor or antinuclear antibodies are detected. Anaemia, leucocytosis and eosinophilia may be found, together with biological abnormalities indicative of malabsorption.6
In classic Whipple's disease, duodenojejunal biopsies provide evidence of infiltration of the mucosa by foamy macrophages stained with periodic acid-Schiff (figure 2). The amplification of a T whipplei-specific gene by PCR from digestive tract specimens confirms the diagnosis.44
Patients with arthritis, central nervous system involvement, uveitis, endocarditis or spondylodiscitis may have no digestive symptoms and histological analyses of specimens from the proximal intestine may also be negative. In the vast majority of these patients, digestive tract specimens are PCR-positive for T whipplei.41 ,45 However, a negative PCR result for the proximal intestine mucosa does not exclude the diagnosis of a localised form.6 ,8 ,42 Bacterial nucleic acid may be detected in many different tissue or fluid specimens selected according to the clinical presentation (figure 3).
PCR tests for T whipplei on saliva and stool samples are now included among the initial diagnostic tests. In cases of arthritis, PCR with samples of joint fluid, saliva and stools has become the preferred examination for diagnosis. A proposed algorithm for the diagnosis of Whipple's arthritis is shown in figure 3. In almost all cases in which a positive PCR result is obtained with saliva, a positive result is also obtained with the stools. In patients with classic Whipple's disease, PCR results are positive for saliva in 65% of cases and for stools in 92% of cases.8 By contrast, PCR is much less sensitive for the detection of localised forms: 36% for saliva and 64% for stools.8 One problem is to differentiate patients with Whipple disease from chronic carriers who may also have positive T whipplei detection by PCR in stool and/or saliva specimens. The utility of PCR on a healthy skin biopsy specimen should be confirmed; in a short series such tests gave positive results for 84.6% of the patients.46 In atypical cases, specific PCR with specimens from different sites, with primers corresponding to two different genes, or real-time PCR is recommended.6
Electron microscopy can be used to detect T whipplei, which has a distinctive, easily recognisable three-layered wall. This method of detection is useful for diagnosis, but remains the preserve of a few specialist laboratories.
Immunohistochemical labelling can also be used for diagnosis. This approach makes use of antibodies directed against the bacterium and can reveal T whipplei in mononuclear cells from tissue fragments, blood or the aqueous humor. T whipplei has also been detected by autoimmunohistochemical staining, using serum antibodies against Tropheryma from the patient.
Specimens are cultured only in extremely specialised laboratories.
The paradoxical absence or low titre of antibodies in the serum of patients accounts for the absence of serological tests from current diagnostic strategies. In a patient with a positive PCR test for T whipplei in stools, the demonstration of a strong immune reaction on western blots provides evidence for chronic carriage rather than for classic Whipple's disease.47 Whether western blot might also discriminate between chronic carriage and localised infection due to T whipplei remains to be determined.
Treatment and outcome
Principles of treatment
Before the advent of antibiotics, Whipple's disease was inevitably fatal. The intracellular concentration of antibiotics must be sufficiently high and ideally the drugs used must be effective microbiologically. A PCR analysis of the CSF before treatment is recommended to ensure that neurological involvement is not underestimated. In cases of clinical neurological involvement or the positive detection of the bacterium in the CSF by PCR, the drug used must be able to cross the blood–brain barrier. Finally, it should be administered for a prolonged period.
Corticosteroid treatment may aggravate the infection or be useful for forms in which the central nervous system is severely damaged or an immune reconstitution syndrome occurs. Immunosuppressant drugs and tumour necrosis factor inhibitors are harmful and their use should be formally prohibited.36 ,48 ,49 The risk of aggravation by biological treatment should be known, particularly as it may be life-threatening.42 ,48 ,50 Such aggravation occurs a mean of 26 months after the start of treatment.50 In patients with symptoms consistent with T whipplei infection, the appearance of visceral manifestations on biotherapy (intestinal, cardiac, neurological signs or fever) should lead to a search for the bacterium (box 1).
Treatment recommendations are not evidence-based and do not rely on clinical trials. The treatment typically recommended was oral trimethoprim-sulfamethoxazole twice daily for 1–2 years. This treatment may be preceded by a parenteral administration for 2 weeks.51
The acquisition of resistance has been described during treatment with trimethoprim-sulfamethoxazole.36 ,39 ,52 T whipplei has no dihydrofolate reductase gene, the target of trimethoprim, and is therefore intrinsically resistant to trimethoprim. Resistance may be due to mutations of the gene encoding the synthetase targeted by sulfamethoxazole.53 Given the inefficacy of trimethoprim and the reports of resistance to sulfamethoxazole, some authors recommend that use of trimethoprim-sulfamethoxazole treatment for this indication should be abandoned.53–55
Treatment recommendations in the absence of neurological involvement
The combination of hydroxychloroquine, which renders the phagosome vacuole more alkaline, and doxycycline, is the only known bactericidal combination. This combination should be given as a first-line treatment to patients with no clinical neurological manifestations and negative PCR results for the CSF.6 ,53 However, this treatment based on microbiological data requires evaluation. Recurrences have been reported.20
Treatment recommendations for patients with neurological involvement
The trimethoprim-sulfamethoxazole combination should be replaced by sulfadiazine. Sulfadiazine is as effective as sulfamethoxazole in vitro, it reaches higher concentrations in the CSF and plasma and has a longer half-life.54 In patients with neurological manifestations or positive PCR results for the CSF, a combination of hydroxychloroquine, doxycycline and sulfadiazine can be used,6 ,53 ,55 but further evaluation of this combination is also required.
Clinical and biological improvement is rapid with antibiotic treatment, except for neurological manifestations.
PCR may be useful for following the response to treatment.44 ,52 ,55 When the disease persists or PCR-positive assays reappear, dosage of antibiotics and hydroxychloroquine may be used to verify drug compliance and to discuss therapeutic adaptations. The persistence of positive PCR results for the CSF should lead to the continuation or intensification of antibiotic treatment.38 Recommendations are to continue treatment for at least 2 years or lifelong antibiotic prophylaxis to prevent relapses.20
Immune reconstitution syndrome
After improvement over a few days or weeks with antibiotic treatment, the occurrence of inflammatory signs, lasting more than 1 week, including fever and arthralgia, may reflect an immune reconstitution syndrome.56 Such a syndrome occurs in 2–10% of patients, particularly in those previously treated with immunosuppressant drugs.56 ,57 PCR tests for T whipplei are negative. After the exclusion of all other infectious causes, rapid initiation of corticosteroid treatment may be beneficial.56 Thalidomide was shown to be effective in one case of treatment failure.57
Recurrences may occur. It is not possible to compare recurrence rates between the retrospective studies published owing to methodological weaknesses. In patients receiving trimethoprim-sulfamethoxazole treatment, the frequency of recurrence reported in older series was <5%,31 ,33 ,58 whereas the true frequency is probably between 9% and 15%.53 ,59 The mean interval between diagnosis and recurrence is 4.2 years.58 Recurrences preferentially affect the central nervous system and, more rarely, the heart. In cases of neurological recurrence in patients receiving trimethoprim-sulfamethoxazole treatment, cefixime has been shown to be effective,39 but reservations remain about prognosis. Interferon γ had some short-term therapeutic efficacy in a single patient with a severe recurrent form after several courses of antibiotic treatment.60
The detection by PCR of the bacterium responsible for Whipple's disease has proved a useful diagnostic tool, facilitating early diagnosis. It has extended the spectrum of clinical manifestations linked to T whipplei. The isolation of T whipplei and its sequencing have opened up new perspectives. In the future, the diagnosis of infection will probably be facilitated by the detection of specific antibodies and the generalisation of antigen detection by immunohistochemistry. The aim is to diagnose the disease earlier, thereby decreasing the morbidity and perhaps also the mortality of this disease, which is curable but still often fatal owing to late diagnosis and the occurrence of extensive systemic forms.
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