Diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease: Data from the French Tw-IRD registry.

OBJECTIVES: Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease. METHODS: We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease. RESULTS: Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases. CONCLUSIONS: Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation.

Uptake of Tropheryma whipplei by Intestinal Epithelia.

BACKGROUND: Tropheryma whipplei (TW) can cause different pathologies, e.g., Whipple's disease and transient gastroenteritis. The mechanism by which the bacteria pass the intestinal epithelial barrier, and the mechanism of TW-induced gastroenteritis are currently unknown. METHODS: Using ex vivo disease models comprising human duodenal mucosa exposed to TW in Ussing chambers, various intestinal epithelial cell (IEC) cultures exposed to TW and a macrophage/IEC coculture model served to characterize endocytic uptake mechanisms and barrier function. RESULTS: TW exposed ex vivo to human small intestinal mucosae is capable of autonomously entering IECs, thereby invading the mucosa. Using dominant-negative mutants, TW uptake was shown to be dynamin- and caveolin-dependent but independent of clathrin-mediated endocytosis. Complementary inhibitor experiments suggested a role for the activation of the Ras/Rac1 pathway and actin polymerization. TW-invaded IECs underwent apoptosis, thereby causing an epithelial barrier defect, and were subsequently subject to phagocytosis by macrophages. CONCLUSIONS: TW enters epithelia via an actin-, dynamin-, caveolin-, and Ras-Rac1-dependent endocytosis mechanism and consecutively causes IEC apoptosis primarily in IECs invaded by multiple TW bacteria. This results in a barrier leak. Moreover, we propose that TW-packed IECs can be subject to phagocytic uptake by macrophages, thereby opening a potential entry point of TW into intestinal macrophages.

Whipple's disease and Tropheryma whipplei infections: from bench to bedside.

Whipple's disease is a chronic and systemic disease caused by the Gram-positive bacterium Tropheryma whipplei that primarily affects the gastrointestinal tract. Data from the last two decades have substantially increased our knowledge of the spectrum and our understanding of T whipplei infections. Although T whipplei seems ubiquitously present in the environment, Whipple's disease itself is very rare. Remarkably, primary infections can be symptomatic, but most cases result in bacterial clearance and seroconversion. However, some individuals are unable to clear the bacterium leading to persistence and asymptomatic carriage. In very rare cases, which might be associated with a subtle immune defect, T whipplei replication is uncontrolled and manifests as classical Whipple's disease or T whipplei localised infections. In this review, we provide a comprehensive outline of T whipplei infection, including the epidemiology, clinical manifestations, diagnosis, and treatment. We also provide an up-to-date overview of our understanding of the host immune response and pathophysiology and discuss future research avenues to resolve the lacking pieces of the puzzle of T whipplei infections.

Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience.

OBJECTIVES: Tropheryma whipplei has been detected in 3.5% of the blood culture-negative cases of endocarditis in Spain. Experience in the management of T. whipplei endocarditis is limited. Here we report the long-term outcome of the treatment of previously reported patients who were diagnosed with infective endocarditis (IE) caused by T. whipplei from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES) and discuss potential options for antimicrobial therapy for IE caused by T. whipplei. PATIENTS AND METHODS: Seventeen patients with T. whipplei endocarditis were recruited between 2008 and 2014 in 25 Spanish hospitals. Patients were classified according to the therapeutic regimen: ceftriaxone and trimethoprim/sulfamethoxazole, doxycycline + hydroxychloroquine and other treatment options. RESULTS: Follow-up data were obtained from 14 patients. The median follow-up was 46.5 months. All patients completed the antibiotic treatment prescribed, with a median duration of 13 months. Six patients were treated with ceftriaxone and trimethoprim/sulfamethoxazole (median duration 13 months), four with doxycycline + hydroxychloroquine (median duration 13.8 months) and four with other treatment options (median duration 22.3 months). The follow-up after the end of the treatments was between 5 and 84 months (median 24 months). CONCLUSIONS: All treatment lines were effective and well tolerated. Therapeutic failures were not detected during the treatment. None of the patients died or experienced a relapse during the follow-up. Only six patients received antibiotic treatment in accordance with guidelines. These data suggest that shorter antimicrobial treatments could be effective.

Acute infections caused by Tropheryma whipplei.

Tropheryma whipplei is the causative bacterium of Whipple's disease. Its first culture has led to an enlargement of the field of the caused infections. Here, we comprehensively review acute T. whipplei infections. In a cohort study featuring 4000 children, T. whipplei was significantly more common in patients with diarrhea (4%) than in those without (1.7%). A case-controlled study highlighted 58 patients suffering from pneumonia with the detection of T. whipplei in their bronchoalveolar fluids. Finally, a recent study detected T. whipplei in the blood of 36 febrile patients experiencing pulmonary symptoms in a rural area of Senegal. T. whipplei is definitively an agent of acute gastroenteritis, a cause of nonmalarial fever in Africa, and probably a cause of pulmonary infections.

Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections.

Whipple's disease is a rare infectious disease that can be fatal if left untreated. The disease is caused by infection with Tropheryma whipplei, a bacterium that may be more common than was initially assumed. Most patients present with nonspecific symptoms, and as routine cultivation of the bacterium is not feasible, it is difficult to diagnose this infection. On the other hand, due to the generic symptoms, infection with this bacterium is actually quite often in the differential diagnosis. The gold standard for diagnosis used to be periodic acid-Schiff (PAS) staining of duodenal biopsy specimens, but PAS staining has a poor specificity and sensitivity. The development of molecular techniques has resulted in more convenient methods for detecting T. whipplei infections, and this has greatly improved the diagnosis of this often missed infection. In addition, the molecular detection of T. whipplei has resulted in an increase in knowledge about its pathogenicity, and this review gives an overview of the new insights in epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Tropheryma whipplei infections.

Deglycosylation of Tropheryma whipplei biofilm and discrepancies between diagnostic results during Whipple's disease progression.

Whipple's disease is a systemic infectious disease associated with the bacterium Tropheryma whipplei. Numerous reports have presented puzzling discrepancies between diagnosis methods. We addressed this confusion using fluorescent in situ hybridization and immunofluorescence assays to evaluate 34 duodenal biopsies and 1 lymph node biopsy from Whipple's patients. We showed the presence of bacteria in both CK20(+) epithelial cells and CD68(+) macrophages. Bacteria are found embedded in a biofilm hindering the detection of T. whipplei. Only after treatment of biopsies by glycosidases, co-localization of T. whipplei RNA/DNA with bacterial proteins was restored. Moreover, using 13 bronchoalveolar lavages and 7 duodenal biopsies, we found that hydrolysis of the biofilm weakened the bacteria, facilitated bacterial DNA extraction and improved the sensitivity of qPCR detection by up to 1000x opening new perspectives for diagnostic and scientific approaches.

Tropheryma whipplei , Immunosuppression and Whipple's Disease: From a Low-Pathogenic, Environmental Infectious Organism to a Rare, Multifaceted Inflammatory Complex.

BACKGROUND: The actinobacterium Tropheryma whipplei was detected 20 years ago by molecular techniques, and following its culture has been characterized as the cause of a systemic infection known as Whipple's disease (WD). T. whipplei occurs in the environment, is prevalent only in humans, is believed to be transmitted via oral routes and to be host dependent. KEY MESSAGES: The classical form of T. whipplei infection, i.e. classical WD (CWD), is rare. It is well defined as slowly progressing chronic infection with arthralgia, diarrhea and weight loss, mostly in middle-aged men. However, current research revealed a much broader spectrum of clinical features associated with T. whipplei infection. Thus, T. whipplei may cause acute and transient infections (observed primarily in children) and the bacterium, which is found in soil and water, occurs in asymptomatic carriers as well as in CWD patients in clinical remission. In addition, T. whipplei affects isolated and localized body compartments such as heart valves or the central nervous system. Subtle immune defects and HLA associations have been described. New findings indicate that the progression of asymptomatic T. whipplei infection to clinical WD may be associated with medical immunosuppression and with immunomodulatory conditions. This explains that there is a discrepancy between the widespread occurrence of T. whipplei and the rareness of WD, and that T. whipplei infection triggered by immunosuppression presents with protean clinical manifestations. CONCLUSIONS: This review highlights recent findings and the clinical spectrum of infection with T. whipplei and WD, focusing specifically on the role of host immunity and immunosuppression. Current concepts of the pathogenesis, diagnosis and therapy are discussed.

Positron emission tomography in the diagnosis of Whipple's endocarditis: a case report.

BACKGROUND: Whipple's disease is a systemic infection that sometimes is associated with cardiac manifestations. The diagnosis of Tropheryma whipplei endocarditis is still the result of chance because there are no diagnostic criteria and clinical signs are often those of cardiac disease rather than infection. CASE PRESENTATION: Culture-negative endocarditis was suspected in a non-febrile 77-year-old French woman from North France with a history of a graft replacement 4 years prior. Positron emission tomography revealed intense fluorodeoxyglucose uptake around the metal ring of the aortic graft. The valve was replaced, and T. whipplei was detected in a valve sample by molecular assays. Immunohistochemical staining of the valve for T. whipplei was also positive. CONCLUSION: The localization of infectious foci by positron emission tomography and systematically testing valve specimens for T. whipplei are promising for diagnosing Whipple's disease.

[Weight loss, dementia and ataxia susceptible to doxycycline: a likely new case report caused by T. whipplei]. / Prise de poids, démence et syndrome cérébelleux sensible à la doxycycline : un probable nouveau cas lié à T. whipplei.

INTRODUCTION: Whipple's disease is a rare infectious disease due to Tropheryma whipplei, a bacterium rarely causing severe localized neurological infection (only 25 cases reported in the literature), which are more often diagnosed by a positive T. whipplei PCR performed on cerebrospinal fluid. CASE REPORT: We report the third case of progressive dementia associated with obesity and ataxia in a 52-year-old man. Classic laboratory results performed to identify the etiology of the clinical features were non-contributive: only a saliva T. whipplei PCR was strongly positive and the Western blot serology has detected an asymptomatic carriage profile. The (18)FDG-PET highlighted a frontal area hypometabolism. An antibiotic treatment by doxycycline allowed a partial regression of the neurological manifestations, a weight loss and a significant improvement of the (18)FDG frontal hypometabolism. CONCLUSION: Progressive dementia associated with ataxia and obesity is a new clinical syndrome caused by T. whipplei. Antibiotic test by doxycycline can help to the diagnosis and (18)-FDG could facilitate the follow-up.

Tropheryma whipplei as a commensal bacterium.

Tropheryma whipplei is the bacterial agent of the well-known and rare Whipple's disease, mainly observed among Caucasians. This bacterium has recently been involved in other chronic and acute infections. For a long time, the only known source of the bacterium was patients with Whipple's disease; however, thanks to the advent of molecular biology, T. whipplei has now been detected in specimens from healthy individuals, mainly in stool and saliva samples. The prevalence of carriage depends on several factors, such as age, exposure and geographical area, reaching 75% in stool specimens from children less than 4 years old in rural Africa. T. whipplei is a commensal bacterium that only causes Whipple's disease in a subset of individuals, probably those with a still-uncharacterized specific immunological defect.

Tropheryma whipplei, the Whipple's disease bacillus, induces macrophage apoptosis through the extrinsic pathway.

Tropheryma whipplei, the etiological agent of Whipple's disease, is an intracellular bacterium that infects macrophages. We previously showed that infection of macrophages results in M2 polarization associated with induction of apoptosis and interleukin (IL)-16 secretion. In patients with Whipple's disease, circulating levels of apoptotic markers and IL-16 are increased and correlate with the activity of the disease. To gain insight into the understanding of the pathophysiology of this rare disease, we examined the molecular pathways involved in T. whipplei-induced apoptosis of human macrophages. Our data showed that apoptosis induction depended on bacterial viability and inhibition of bacterial protein synthesis reduced the apoptotic program elicited by T. whipplei. Induction of apoptosis was also associated with a massive degradation of both pro- and anti-apoptotic mediators. Caspase-specific inhibition experiments revealed that initiator caspases 8 and 10 were required for apoptosis, in contrast to caspases 2 and 9, in spite of cytochrome-c release from mitochondria. Finally, the effector caspases 3 and 6 were mandatory for apoptosis induction. Collectively, these data suggest that T. whipplei induces apoptosis through the extrinsic pathway and that, beside M2 polarization of macrophages, apoptosis induction contributes to bacterial replication and represents a virulence trait of this intracellular pathogen.

Isolated Whipple disease of the brain resembling a tumour.

INTRODUCTION: Isolated Whipple disease of the central nervous system is a rare occurrence. Migratory arthralgias and gastrointestinal problems, including malabsorption, abdominal pain, diarrhea, and weight loss, are common presenting symptoms. DISCUSSION: For those patients with systemic signs and symptoms of Whipple disease, 6% to 43% will have clinically manifested CNS involvement that may include alterations in personality, ataxia, and dementia. We report our experience with a patient, who was successfully treated for Whipple disease 12 years prior to presentation and had a magnetic resonance image of the brain that revealed two solitary lesions resembling a tumor upon presentation.