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We present the case of a 70-year-old woman with a history of seronegative arthritis, recurrent pleural effusion and weight loss. A prior lung biopsy had revealed non-caseating epithelioid cell granulomas without evidence for microbial organisms on special stains. Intestinal biopsy findings where suspicious for Whipple’s disease, which was confirmed by PCR testing, both on the intestinal and retrospectively on the lung tissue. Treatment with ceftriaxone resulted in clinical deterioration with fever, arthritis and recurrent pleuritis consistent with immune reconstitution inflammatory syndrome. Dose increase of glucocorticoids and therapy rotation to doxycycline and hydroxychloroquine resulted in rapid clinical improvement.

Whipple’s disease is a rare and systemic infectious disease that classically presents with gastrointestinal symptoms. The epidemiology of cardiac involvement is unknown. However, with the advent of improved molecular techniques, it is increasingly recognized as a cause of culture-negative endocarditis. Monotherapy treatment with trimethoprim-sulfamethoxazole is associated with relapses, sometimes in organs different than those previously affected. We present the case of a man diagnosed with classic Whipple disease, initially treated with trimethoprim-sulfamethoxazole. Twenty-two years later, he is diagnosed with endocarditis by the same agent. Whipple’s disease, particularly Whipple’s endocarditis is an extremely difficult entity to diagnose and to treat. Indications for treatment remain controversial and are still based on clinical experience and case series. This particular patient, with a recurrence two decades after the initial episode, highlights the ineffectiveness of trimethoprim/sulfametoxazole for the treatment of Tropheryma whipplei infection, even when used for long periods. Furthermore, this case illustrates the diagnostic difficulty so often associated with endocarditis and the importance of interdisciplinarity when addressing this infection.

Whipple disease is a systemic chronic infection caused by Tropheryma whipplei. Although chronic diarrhea is a common gastrointestinal symptom, diagnosis is often difficult because there are no specific endoscopic findings, and the pathogen is not detectable by stool culture. We present a female patient with Whipple disease who developed chronic bloody diarrhea and growth retardation at the age of 4 years. Colonoscopy showed a mildly edematous terminal ileum and marked erythema without vascular patterns throughout the sigmoid colon and rectum. Subsequently, a primary diagnosis of ulcerative colitis was made. Histopathological analysis of the terminal ileum showed the presence of foamy macrophages filled with periodic acidSchiff-positive particles. Polymerase chain reaction using DNA from a terminal ileum biopsy sample amplified a fragment of 16S rRNA from T. whipplei. Antibiotic treatment relieved the patient’s symptoms. There was no evidence of immunodeficiency in the present case. Since Whipple disease worsens after anti-tumor necrosis factor inhibitor therapy, considering this infection in the differential diagnosis may be important in patients with inflammatory bowel disease, especially before initiation of immunotherapy.

Background Whipple’s disease (WD) is a rare, chronic, infection caused by gram-positive filamentous aerobic actinobacterium Tropheryma whipplei occurs classically in the gastrointestinal tract and shows histopathologically foamy macrophages with typical numerous PAS-positive, non-acid fast particles. Ocular WD in the form of uveitis may occur in the absence of systemic disease but has not been reported to present with scleral manifestation. We describe for the first time to the best of our knowledge 2 cases of scleral nodules with typical histopathological morphology of WD and without systemic involvement. Case presentation The first was a 53-year old diabetic male farmer who presented with 2 nontender right eye scleral nodules for 3 months, had a negative systemic workup, and surgical excision showed Periodic acid Schiff (PAS)-positive eosinophilic structures inside macrophages. Grocott’s methenamine silver (GMS) stain and acid-fast bacilli (AFB) stain of the tissue itself were negative. The second case was a 60-year old male who presented with an asymptomatic superior scleral nodule for 4 months, which showed similar appearance and negative GMS and AFB stains. Conclusion WD should be included in the differential diagnosis of scleral nodules even in the absence of systemic symptoms. Surgical excision without systemic treatment resulted in successful outcome without recurrence.

Whipple's disease is caused by Tropheryma whipplei and is known to have protean clinical presentation which could be influenced by patient's immunologic and genetic features. In contemporary literature abundant amount of data could be found on extensive prevalence of infectious endocarditis caused by Tropheryma whipplei . This article presents history of a patient who was observed because of ischemic heart disease, angina pectoris, myocardial infarction, possible ischemic cardiomyopathy and in whom infectious endocarditis complicated by severe aortic regurgitation needing aortic valve replacement surgery was eventually diagnosed. Our patient did not meet Duke criteria, which is a sign of infectious endocarditis caused by Tropheryma whipplei , but a thorough analysis of the disease course, clinical features, heart ultrasound and clinical improvement on specific therapy against Tropheryma whipple i aroused our suspicion, and morphological and bacteriological analysis of the involved (excised) valve, confirmed the diagnosis of Whipple disease. The article presents differential diagnostic criteria of aortic insufficiency and possible causes of coronary insufficiency in the absence of marked coronary atherosclerosis.

BACKGROUND Whipple's disease is a very rare disease needing a long-term treatment. The most frequent symptoms are recurrent arthralgia or arthritis, chronic diarrhea, abdominal pain, and weight loss. OBJECTIVES In this article, we have highlighted the main clinical features and diagnostic procedures that lead to the diagnosis and comment on the clinical response, treatment, and the factors of relapse. METHODS Subjects were recruited from the Internal Medicine and Rheumatologic Departments of an University Hospital from November 1997 to January 2016. Overall, 12 subjects were finally diagnosed. RESULTS Mean age was 54.3 years (age range: 30-81), with more male patients (58.3%). Almost all patients had articular symptoms and impaired general condition (91.7%); and a majority had digestive symptoms (75%). Regardless of the symptoms, the most efficient diagnostic tools were the PCR screening on the gastrointestinal biopsies and saliva (83.3 and 72.7% positive results, respectively). More than half of the patients relapsed (55.6%). The relapsing patients were older [63.2 (44-81)] and mostly male with a majority (60%) of digestive symptoms and a delayed diagnosis. CONCLUSIONS In current practice, it is highly difficult to diagnose Whipple's disease. In order to decrease the delay between the first symptoms and the diagnosis, effective tools such as saliva and stools PCR should be used because higher delays of diagnosis lead to a higher number of relapses.

Introduction Whipple's disease (WD) is a rare multi-systemic disorder caused by actinomycetes, Tropheryma Whipplei (T. Whipplei). It presents with weight loss, arthralgia and diarrhea and may involve the heart, lung or central nervous system. The use of immunosuppressive medications or underlying immunodeficiency states are associated risk factors. Six cases in transplant recipients have so far been reported worldwide. We describe our experience of Whipple's disease in renal transplant recipients. Methods All renal transplant recipients who presented with diarrhea and were diagnosed with Whipple's disease on duodenal biopsy from 2016 till 2019 were included. Their data regarding duration since transplantation, immunosuppressive therapy, symptoms, treatment response and outcome was analyzed. Results Seven cases were diagnosed as Whipple's disease based on duodenal biopsy, with histological findings of Periodic acid Schiff positive granules in macrophages. All were male. The most common symptoms were chronic diarrhea and weight loss. Average time since transplantation was 4.8 years. All patients were on azathioprine and everolimus. Clinical relapse or adverse effects was seen in 5 of 7 patients treated with doxycycline and hydroxychloroquine which was discontinued. Trimethoprim/sulphamethoxazole for one year, with initial intravenous ceftriaxone in 2 patients, resulted in complete remission in all patients at a follow-up period averaging 1.5 years. Conclusion Whipple's diseases in renal transplant recipients most commonly presents as an intestinal disorder. Treatment of one year with Trimethoprim/sulphamethoxazole has good response with complete remission at 1.5 years of follow up. This article is protected by copyright. All rights reserved.

Background Whipple’s disease is a clinically relevant multi-system disorder that is often undiagnosed given its elusive nature. We present an atypical case of Whipple’s disease involving pan-valvular endocarditis and constrictive pericarditis, requiring cardiac intervention. A literature review was also performed assessing the prevalence of atypical cases of Whipple’s disease. Case presentation A previously healthy 56-year-old male presented with a four-year history of congestive heart failure with weight loss and fatigue. Notably, he had absent gastrointestinal symptoms. He went on to develop pan-valvular endocarditis and constrictive pericarditis requiring urgent cardiac surgery. A clinical diagnosis of Whipple’s disease was suspected, prompting duodenal biopsy sampling which was unremarkable, Subsequently, Tropheryma whipplei was identified by 16S rDNA PCR on the cardiac valvular tissue. He underwent prolonged antibiotic therapy with recovery of symptoms. Conclusions Our study reports the first known case of Whipple’s disease involving pan-valvular endocarditis and constrictive pericarditis. A literature review also highlights this presentation of atypical Whipple’s with limited gastrointestinal manifestations. Duodenal involvement was limited and the gold standard of biopsy was not contributory. We also highlight the Canadian epidemiology of the disease from 2012 to 2016 with an approximate 4% prevalence rate amongst submitted samples. Routine investigations for Whipple’s disease, including duodenal biopsy, in this case may have missed the diagnosis. A high degree of suspicion was critical for diagnosis of unusual manifestations of Whipple’s disease.

Background Whipple’s disease is caused by Tropheryma whipplei and causes a self-limiting gastrointestinal infection. The majority of the population is an asymptomatic carrier, however, in some patients, it causes an invasive infection with for example arthritis, endocarditis, or involvement of the eyes. Case summary This case describes a man with long-lasting complaints of progressive dyspnoea caused by heart failure due to total destruction of the aortic and mitral valve as a result of T. whipplei endocarditis, diagnosed with serum polymerase chain reaction. The patient was treated with ceftriaxone and prolonged co-trimoxazole therapy and surgical replacement of the aortic and mitral valve. He was discharged to a rehabilitation centre. Discussion Tropheryma whipplei is one of the possible microorganisms classified as causing blood culture-negative endocarditis, with predominantly afebrile patients that do not fulfil the Dukes criteria, which makes it difficult to diagnose. Polymerase chain reaction is the cornerstone of the diagnosis. It requires long-term antibiotic treatment up to 12 months. It is recommended by the European Society of Cardiology to discuss treatment in an Endocarditis Team because Whipple’s endocarditis has only rarely been described in the literature previously. Whipple’s endocarditis has high mortality and relapse rates.

We report 2 cases of Whipple disease (WD), previously diagnosed as seronegative polyarthritis and treated for several years with immunosuppressive agents, accordingly. Both cases had been treated over years with cDMARDs and bDMARDs. The first patient was a 48-year-old male, who developed a life-threatening disease characterized by fever, significant weight loss, and bloody diarrhoea, supported with RBC transfusions. The second patient was a 55-year-old man, presenting with arthritis, fever, serositis, lymphadenopathy, thoracic rash, and systemic inflammation; at the beginning he was diagnosed as adult onset Still’s disease. He was treated with steroids and antitumour necrosis factor agents, but showed no improvement. Both patients were eventually treated with antimicrobial therapy for WD with dramatic improvement and no clinical relapse in 6 months. This paper reviews the literature on WD mimicking chronic inflammatory arthritis. WD may lead to chronic seronegative arthritis that might often be misrecognized. Importantly, patients treated with bDMARDs and glucocorticoids might develop a life-threatening disease. Therefore, WD should be suspected and excluded in patients showing resistance or frequent recurrence of chronic arthritis, if seronegative, under treatment with bDMARDs, especially in the presence of new, unexpected sign and/or symptoms.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that can affect major organs possibly leading to life-threatening complications and appears with heterogeneous clinical picture. SLE could present with broad spectrum of clinical and laboratory features that can resemble those of other diseases, such as hemopoietic malignancies, infections, or immune-mediated disorders. Its complexity and protean features overlap with many other diseases, hindering the differential diagnosis. Rarely, true overlap with other diseases may occur. Herein, we report a case series of two patients affected by infectious diseases, namely visceral leishmaniasis and Whipple’s disease (WD), intertwined with clinical or serological features of SLE. In both cases, several confounding factors have led to a delay in the diagnosis. Moreover, we first describe the persistent elevation of autoantibodies and a monoclonal gammopathy in a patient with WD. Awareness of unusual presentations of infections or other rare disorders, which may be encountered in clinical practice when taking care of SLE patients, is essential for timely diagnosis and treatment of potentially lethal diseases.

Whipple's disease is a rare, multisystem infection caused by the Gram-positive Tropheryma whippelii organism. In addition to neurological and rheumatological manifestations, this disease can result in significant gastrointestinal symptoms such as malabsorption, diarrhea, and weight loss. Given the diagnostic challenge and rare occurrence, a high index of suspicion is critical to prevent morbidity and mortality from this otherwise highly infectious disease transmitted via the fecal-oral route. We present a very rare but near-fatal case of hypovolemic shock secondary to protein-losing enteropathy and gastrointestinal bleeding from small bowel T. whippelii infection. Furthermore, the epidemiology, clinical presentation, diagnosis, and management of Whipple's disease is reviewed.

Histiocytic proliferations are heterogeneous lesions with distinct pathogenic and clinical-pathological features. While many of these conditions are nonspecific immune responses to variable causes, a minority of them is associated with specific etiological factors and unique clinical-pathological pictures. By presenting a rare case of Whipple adenopathy, we address the peculiar histological features of this condition and the differential diagnosis of nodal histiocytosis in general.

Background/Aims A 45-year-old male patient presented in 2015 with a six-month history of relapsing and remitting polyarthralgia. Hand X-rays appeared normal. Serology showed mildly elevated inflammatory markers. Autoimmune profile including anti-CCP antibody, rheumatoid factor and ANA was negative. His initial diagnosis was palindromic rheumatism. He was under watchful waiting in rheumatology clinic having declined a trial of hydroxychloroquine, when in 2018 he developed severe epigastric pain. Over the subsequent 18 months he was noted to have dramatic weight loss, fatigue and drenching night sweats. Methods Investigations showed microcytic anaemia with elevated inflammatory markers (Hb 98 g/L, CRP 161 mg/L, ESR 68 mm/hr). Serum ACE, bone profile, thyroid function and urate levels were normal. Chest X-ray was unremarkable. HIV and hepatitis screening was negative. Endoscopy with jejunal biopsy was performed, with mild gastritis only on histopathology and normal D2 biopsies. He was found to be H pylori positive, and notably felt his B-symptoms much improved with triple antibiotic and PPI eradication therapy. CT abdomen demonstrated widespread mesenteric lymphadenopathy. Para-aortic lymph node biopsy showed non-necrotising granulomata suggestive of either sarcoidosis or an infective etiology such as tuberculosis (TB). Given the clinical picture, the patient was commenced on high dose oral prednisolone and methotrexate for suspected sarcoidosis. Results The patient made some clinical improvement, particularly with regards to arthralgia, however his B-symptoms returned with any reduction in steroid dose. Serology showed worsening anaemia with iron and folate deficiency, and increasing inflammatory markers. We therefore decided to perform a PET CT and refer to Haematology for consideration of a lymphoproliferative disease. PET CT demonstrated lymphadenopathy without avid uptake. A second lymph node biopsy was performed which showed florid histiocytic infiltration within which there were numerous PAS positive particles consistent with Whipple's disease. This was confirmed as tropheryma whipplei on PCR. Whipple's disease is a rare systemic infectious disease causing arthralgia, diarrhoea, abdominal pain and weight loss. Treatment consists of antibiotic therapy. On further questioning, the patient had grown up on a farm. There is a known association with Whipple's disease in the agricultural community as it is a soil-borne organism. Conclusion Our patient has made an excellent recovery. He remains under the care of our rheumatology team and the London School of Tropical Medicine and Hygiene. Treatment plan is 12 months of combined therapy with doxycycline and hydroxychloroquine. He underwent a lumbar puncture to rule out meningeal Whipple disease. We have also commenced sulfasalazine for persistent arthritis, which we feel could be a reactive phenomenon. Our key learning points from this case were to use a stepwise approach to diagnosis, involve relevant specialty teams and that it in complex cases it is useful to go back to the history. Disclosure F. Baldeweg: None. A. Nuttall: None. D. Arul: None. A. Childerhouse: None.

Whipple disease (WD) is a rare bacterial infectious disease that is classically characterized by years of arthralgia, followed by malabsorption, diarrhea, and weight loss. However, WD may manifest in virtually any organ system, and patients with WD rarely develop subcutaneous erythema nodosum-like lesions. We report a case of a 51-year-old man diagnosed with WD who subsequently developed widely distributed erythematous subcutaneous nodules after 5 months of antibiotic therapy.

To describe posterior ocular involvement features of Whipple's disease (WD) in a patient with no gastrointestinal symptoms.Retrospective case report.A 53-year-old man with a 2-year history of seronegative arthritis presented with bilateral intraocular inflammation, optic disc edema, and cystoid macular edema (CME) in the left eye. A diagnosis of noninfectious uveitis was made and oral prednisolone was started. Despite initial improvement, after 6 weeks, CME was found in both eyes. Because of the initial response, the anti-tumor necrosis factor agent Adalimumab was started. Twelve weeks after initiation of adalimumab, fundus examination revealed widespread dot-blot retinal hemorrhages and multifocal chorioretinal lesions at the posterior pole and mid-periphery. The chorioretinal lesions appeared as hyperreflective drusen-like deposits located in the sub-retinal pigment epithelium (RPE) space on the tomographic scan. WD was considered and confirmed by polymerase chain reaction test and duodenal biopsy.Posterior ocular involvement in WD may present with a wide clinical spectrum including intraocular inflammation and unique features of sub-RPE deposits, widespread retinal hemorrhages, and optic disc edema.

Background Whipple’s disease is a chronic infectious disease caused by the Gram-positive bacterium Tropheryma whipplei (TW), which not only affects the gastrointestinal tract and causes malabsorption of nutrients, but several other systems, such as the cardiovascular system, central nervous system, the joints, and the vascular system, can also be simultaneously involved. The aim of this report was to be able to alert the clinician to severe pneumonia caused by TW combined with Candida sp. Case presentation The case study was conducted on patients in September and November 2019. After routine examination and treatment, the results were not satisfactory. A bronchoalveolar lavage (BAL) using metagenomics next-generation sequencing was conducted on two adults who presented with fever, cough, and progressive dyspnea and who had no history of gastrointestinal symptoms, immunodeficiency diseases, or use of immunosuppressive agents. TW and Candida sp. were detected in in BAL. Conclusions This is a report of life-threatening pneumonia caused by TW combined with Candida sp. in a Chinese population.

Tropheryma whipplei is a bacterium that causes a rare infection called Whipple's disease and can cause devastating effects if left untreated. It is important to recognize that patients with this infection may present with atypical symptoms and are often apyrexial with normal inflammatory markers. Moreover, routine blood cultures often do not isolate these bacteria in conventional growth media. Therefore, it requires a high level of clinical suspicion to make this diagnosis. Here, we present two cases of Tropheryma whipplei aortic valve endocarditis, with atypical presentation and similar unusual but striking echocardiographic images.

Background Whipple's disease is a chronic infectious disease that primarily affects the small intestine, but several organs can simultaneously be involved. The disease is caused by a gram-positive bacterium called Tropheryma whipplei. The disease is difficult to suspect because it is rare with unspecific and long-term symptoms; it can be lethal if not properly treated. Case presentation We here present three patients who presented with a plethora of symptoms, mainly long-standing seronegative arthritis and gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy. They were after extensive investigations diagnosed with Whipple's disease, in two of them as long as 8 years after the first occurrence of joint manifestations. The diagnosis was made by PCR targeting the T. whipplei 16S rRNA gene from small bowel specimen in all three patients, and, besides from histopathologic findings from the duodenum and distal ileum in one and mesenteric lymph nodes in another patient. Conclusions This report aims to raise awareness of a very rare disease that presents with a combination of symptoms mimicking other and significantly more common diseases.

Whipple disease (WD) is a rare infectious systemic disease. Rheumatologists are at the frontline of WD diagnosis due to the early rheumatological manifestations. An early diagnosis is crucial, as usual anti-rheumatic drugs, especially TNF inhibitors, may worsen the disease course. We conducted a retrospective multicentre national study from January 2010 to April 2020 to better characterize the rheumatological features of WD. Classic WD (CWD) was defined by positive periodic acid-Schiff (PAS) staining of a small-bowel biopsy sample, and non-CWD (NCWD) was defined by negative PAS staining of a small-bowel biopsy sample but at least one positive Tropheryma whipplei (TW) polymerase chain reaction (PCR) for a digestive or extradigestive specimen. Sixty-eight patients were enrolled, including 11 CWD patients. Twenty patients (30%) received TNF inhibitors during the WD course, with inefficacy or symptom worsening. More digestive symptoms and systemic biological features were observed in CWD patients than in NCWD patients, but both patient groups had similar outcomes, especially concerning the response to antibiotics and relapse rate. Stool and saliva TW PCR sensitivity were both 100% for CWD and 75% for NCWD and 89% and 60% for small-bowel biopsy sample PCR, respectively. WD encountered in rheumatology units has many presentations, which might result from different pathophysiologies that are dependent on host immunity. Given the heterogeneous presentations and the presence of chronic carriage, multiple TW PCR tests on samples from specific rheumatological sites when possible should be performed, but samples from nonspecific digestive and extradigestive sites also have great value.

Whipple’s Disease (WD) was first described by George H. Whipple in 1907. Classic Whipple disease (CWD) is a systemic chronic infection by Tropheryma whipplei (T. whipplei) that can involve various organ systems such as gastrointestinal tract, joints, and central nervous system (CNS). Central nervous system Whipple’s disease (CNS- WD) can be a part of the classical WD, a recurrent phenomenon or an isolated disease. It encompasses a wide array of clinical manifestations depending on the anatomic region affected by the pathological process. Diagnosis is made by polymerase chain reaction testing. It is vital to implement an aggressive mode of treatment to reduce the chances of complications like cognitive impairment, or disease recurrence, even many years later.

Vasculitis can also present with GI or solid organ involvement. IgA and ANCA associated vasculitis are more likely to have GI involvement. A 56-year-old female was admitted to the ER due to nausea, vomiting, epigastric pain and fever. The patient had a medical history of acromegaly and chronic kidney disease of an undetermined etiology, elevated C-reactive protein and renal dysfunction. Abdominal-CT revealed duodenal parietal thickening and pancreatic head edema. On esophagogastroduodenoscopy (EGD), duodenal mucosa had a diffusely nodular aspect with ulcerated areas. The following differential diagnosis were made, infectious enteritis, Whipple disease, infiltrative disorder and GI vasculitis. After discussion between a multidisciplinary team of Gastroenterology and Nephrology, they decided to initiate oral glucocorticoids due to worsening of the renal function, which lead to the resolution of digestive symptoms and renal function stabilization. Myeloperoxidase antineutrophilic-cytoplasmic antibodies (MPO-ANCA) were subsequently positive and histology confirmed duodenal involvement by vasculitis. The patient was asymptomatic after 4-weeks, with endoscopic healing and renal function stabilization. GI involvement limited to the duodenum in the setting of ANCA-MPO vasculitis is a rare condition. Moreover, histopathologic confirmation of vasculitis in endoscopic biopsy samples is exceptional.

A 51-year-old man presented with watery diarrhea and 7-kg weight loss for six months. As computed tomography scans showed multiple mesenteric and retroperitoneal lymphadenopathy, 18F-fluoro-deoxyglucose positron emission tomography was performed, showing marked accumulation in the jejunum. Enteroscopy disclosed diffuse yellow-white swollen villi in the jejunum and biopsies revealed clubbed villi with marked periodic acid-Schiff-positive foamy macrophages. The electron microscopic examination showed numerous extracellular bacilli and bacillary forms of degradation in the macrophages. 16S rRNA PCR revealed Tropheryma whipplei in the mucosal specimens, making the diagnosis of Whipple’s disease. Therapy with ceftriaxone followed by long-term trimethoprim-sulfamethoxazole was effective. Whipple's disease is briefly discussed.

A 59-year-old female patient was diagnosed with Whipple's disease (WD) after several months of constitutional complaints and adenopathies that were initially misinterpreted as sarcoidosis. Initial treatment included doxycycline, hydroxychloroquine and prednisolone, which was suspended due to long-term clinical stability. Four months after prednisolone suspension, the patient presented with right periorbital oedema and erythema. Ophthalmological examination revealed restricted eye movements. A computed tomography (CT) scan demonstrated signs of myositis. The patient was treated with anti-inflammatory and antibiotic drugs, that induced remission of the orbitopathy. During the following two years, she presented three relapses, affecting both the right or the left eyes. The last episode was also associated with systemic corticosteroid tapering. Orbitopathy is a rare form of WD presentation and the diagnosis of this condition may be challenging. As the clinical spectrum may range from an incidentaloma to a severe compressive neuropathy, proper recognition and management of WD orbitopathy is essential.

Background: Little is known about long-term morbidity and mortality in Whipple’s disease (WD). Aim: To describe morbidity and mortality in patients with WD on a long-term follow-up. Materials & methods: Comorbidities, mortality and causes of death were retrospectively registered. Results: A total of 35 patients with WD (9F, 54 ± 11 years) were followed-up for a median of 104 months. Nine patients developed ten complications; three patients died. A total of 31 severe comorbidities apparently unrelated to WD were found in 20 patients: preneoplastic/neoplastic disorders in seven, thromboembolic and cardiovascular events in seven, pneumonia in four, candidiasis in ten patients. Conclusion: WD is frequently complicated by potentially life-threatening infectious, neoplastic and thromboembolic disorders, thus highlighting the need for a life-long multidisciplinary follow-up.

The alimentary tract serves as host to a large number of diseases. In the non-neoplastic group of disorders, conventional histochemistry continues to play an important diagnostic role. It is particularly important in recognizing specific infectious diseases, such as Helicobacter gastritis, Whipple disease, intestinal tuberculosis and other forms of mycobacteriosis, malakoplakia, intestinal spirochetosis, fungal enteritides, amebiasis, cryptosporidiosis, isosporiasis, and microsporidiosis. Those conditions and their histochemical properties are discussed in this review, along with the use of histochemistry in the characterization of structural gastrointestinal disorders. The latter include mucosal metaplasias, amyloidosis, glycogenic acanthosis of the esophagus, lymphocytic-collagenous colitis, gastric neuroendocrine hyperplasia, and pill gastritis.

Background Whipple’s disease (WD) is a rare infection with Tropheryma whipplei that is fatal if untreated. Diagnosis is challenging and currently based on invasive sampling. In a case of WD diagnosed from a kidney biopsy, we observed morphologically-intact bacteria within the glomerular capsular space and tubular lumens. This raised the questions of whether renal filtration of bacteria is common in WD and whether polymerase chain reaction (PCR) testing of urine might serve as a diagnostic test for WD. Methods We prospectively investigated urine samples of 12 newly-diagnosed and 31 treated WD patients by PCR. As controls, we investigated samples from 110 healthy volunteers and patients with excluded WD or acute gastroenteritis. Results Out of 12 urine samples from independent, therapy-naive WD patients, 9 were positive for T. whipplei PCR. In 3 patients, fluorescence in situ hybridization visualized T. whipplei in urine. All control samples were negative, including those of 11 healthy carriers with T. whipplei–positive stool samples. In our study, the detection of T. whipplei in the urine of untreated patients correlated in all cases with WD. Conclusions T. whipplei is detectable by PCR in the urine of the majority of therapy-naive WD patients. With a low prevalence but far-reaching consequences upon diagnosis, invasive sampling for WD is mandatory and must be based on a strong suspicion. Urine testing could prevent patients from being undiagnosed for years. Urine may serve as a novel, easy-to-obtain specimen for guiding the initial diagnosis of WD, in particular in patients with extra-intestinal WD., We found that in the majority of therapy-naive Whipple’s disease patients, Tropheryma whipplei is detectable in urine samples by polymerase chain reaction; therefore, urine may serve as a novel, easy-to-obtain diagnostic specimen for the initial diagnosis of Whipple’s disease.

Purpose: To emphasize the different manifestations of ocular involvement in Whipple disease with challenge in establishing the diagnosis as clinical, laboratory, and histological features c...

Tropheryma whipplei is a bacterial pathogen responsible for a wide range of infections in humans, covering asymptomatic carriage, acute infections, chronic isolated infections and classic Whipple's disease. Although the bacterium is commonly found in the environment, it very rarely causes disease. Genetic comparison of clinical isolates has revealed that main variations were found in region encoding T. whipplei surface glycoproteins called WiSP. However, no association has been made between the genetic diversity and the clinical manifestations of the infection. In this study we evaluated the phenotypic diversity of 26 clinical isolates from different origins and taken from patient with different infection outcomes. MRC5 and macrophages cells were infected, and bacterial uptake, survival and the pro-and anti-inflammatory potential of the different clinical isolates was assessed. No significant difference of phagocytosis was found between the different isolates; however, we found that bacterial replication was increased for bacteria expressing high molecular weight WiSP. In addition, we found that the expression of the genes coding for IL-1β and TGF-β was significantly higher when MRC5 cells were stimulated with isolates from chronic infections compared to isolates from localized infections while no significant differences were observed in macrophages. Overall, our study revealed that, as previously observed at the genetic level, phenotypic diversity of T. whipplei isolates is associated with the expression of different WiSP, which may result in subtle differences in host responses. Other host factors or genetic predisposition may explain the range of clinical manifestations of T. whipplei infections.

A 61-year-old woman received a diagnosis of undifferentiated non-erosive arthritis in 2010 and assumed methotrexate and steroids in 2014. After 1 year, she experienced watery diarrhea, vomiting, fever, weight loss, and severe hypoalbuminemia, thus being admitted into our Unit. Esophagogastroduodenoscopy showed duodenal lymphangiectasia and duodenal biopsy samples several foamy PAS-positive macrophages and villous subtotal atrophy. Transmission electron microscope demonstrated several extracellular and intracellular rod-shaped bacteria (Tropheryma whipplei). Therefore, we diagnosed Whipple's disease. Our patient assumed doxycycline/hydroxychloroquine with prompt remission of gastrointestinal symptoms. At 1 year of follow-up, she was symptom-free, histological reassessment showed almost complete mucosal healing and transmission electron microscope demonstrated bacteria breaking/disappearance. The present report demonstrates that: (i) rheumatological manifestations are common onset symptoms of Whipple's disease; (ii) immunosuppressive therapy may delay the diagnosis and worsen clinical presentation; (iii) transmission electron microscopy for specific bacteria detection/disappearance is an helpful diagnostic tool, when available.

Classical Whipple's disease (CWD) affects the gastrointestinal tract and rather elicits regulatory than inflammatory immune reactions. Mechanisms of malabsorption, diarrhea, and systemic immune activation are unknown. We here analyzed mucosal architecture, barrier function, and immune activation as potential diarrheal trigger in specimens from 52 CWD patients. Our data demonstrate villus atrophy and crypt hyperplasia associated with epithelial apoptosis and reduced alkaline phosphatase expression in the duodenum of CWD patients. Electrophysiological and flux experiments revealed increased duodenal permeability to small solutes and macromolecules. Duodenal architecture and permeability ameliorated upon antibiotic treatment. Structural correlates for these alterations were concordant changes of membranous claudin-1, claudin-2, claudin-3, and tricellulin expression. Tumor necrosis factor-α and interleukin-13 were identified as probable mediators of epithelial apoptosis, and altered tight junction expression. Increased serum markers of microbial translocation and their decline following treatment corroborated the biological significance of the mucosal barrier defect. Hence, mucosal immune responses in CWD elicit barrier dysfunction. Diarrhea is caused by loss of absorptive capacity and leak flux of ions and water. Downregulation of tricellulin causes increased permeability to macromolecules and subsequent microbial translocation contributes to systemic inflammation. Thus, therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist symptomatic control of CWD.

Tropheryma whipplei, the agent of Whipple disease, causes a rare bacterial disease that may be fatal if not treated. The classical form of the disease includes diarrhoea, weight loss, arthritis, endocarditis and neurological manifestations. Genotyping studies done in Europe, Africa and Asia showed high genetic diversity with no correlation between genotypes and clinical features, but contributed to a better understanding of the epidemiology of the disease. More than 70 genotypes have been described. No similar assessment of T. whipplei in the USA and the Caribbean has been performed. In this study, we describe genetic analysis of DNA from histopathological samples obtained from 30 patients from the Americas with Whipple disease and compare the genotypes with those previously identified. Complete genotypes were obtained from 18 patients (60%). Only 4 genotypes were previously described, and 14 were newly reported, confirming the diversity of T. whipplei strains.

Diffuse leptomeningeal glioneuronal tumor is a new entity under the neuronal and mixed neuronal-glial tumors in the WHO 2016 updated classification and commonly found in children and adolescents. The initial diagnosis is challenging because of its non-specific radiologic feature and negative CSF cytology analysis. A 17 years male was presented with intractable headache subsequently followed by back pain and joint pain. MRI showed enhancement of arachnoid membrane at basal cistern, bilateral sylvian fissure and cerebral cistern with slight enlargement of ventricles. There were no evidences of infection in CSF and blood samples. Based on the duodenal biopsy and prodromal symptom of joint pain, the patient was suspected of having Whipple's disease. Eleven months after the onset, a small mass lesion was observed at the anterior horn of right lateral ventricle. The histology was remarkable for anaplastic oligodendroglioma. Immunostainings revealed positivity for GFAP, Olig2, synaptophysin and negativity for IDH1 mutation, H3K27M. MIB1 labeling index was 40% and 1p19q FISH analysis showed only 1p deletion. Therefore, a final diagnosis of DLGNT was made.DLGNT should be included as a differential diagnosis of patients with leptomeningeal-enhanced and high CSF protein level with normal white blood cell count.

International audience; 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.

Background Whipple’s disease (WD) is a rare multisystem infectious disorder that is caused by the actinomycete Tropheryma whipplei. It presents with joint pain followed by abdominal pain, diarrhea, malabsorption and finally failure to thrive. Diagnosis requires tissue sampling and histology with periodic acid-Schiff [PAS] staining. Thrombocytopenia associated with endocarditis associated with WD has been reported twice. Case presentation A 56 year old Caucasian male presented with years of steroid treated joint pain and recent onset diarrhea, weight loss and abdominal pain. Ultimately he was found to have a platelet count of 4000 with concomitant endocarditis and embolic stroke. Small bowel biopsy confirmed the diagnosis of WD approximately 1 year after his first visit. His platelets improved with antibiotic treatment but he eventually expired 16 months after his initial consult and 5 months after his definitive diagnosis. Conclusion WD can remain undiagnosed and untreated until late in the course of the illness. A high index of suspicion is recognized as necessary for early diagnosis to begin treatment. Critical thrombocytopenia associated with endocarditis is a rare and potentially poor prognostic sign in late stage Whipple’s disease.

International audience; Joint complaints, most commonly intermittent arthritis, are the initial manifestation in about three-fourths of Whipple's disease cases. We herein report on two cases wherein Whipple's disease manifested itself as chronic bursitis and tenosynovitis at several sites. A 42 year-old man had bilateral olecranon bursitis, a right patellar bursitis and an extensor tenosynovitis on the left wrist and a 54 year-old man had extensor tenosynovitis at both wrists and a bilateral tenosynovitis of the extensors at both ankle. Methotrexate in both patients and etanercept in one of them were not effective. Polymerase chain reaction testing revealed Tropheryma whipplei on feces, bursitis and articular fluid samples. Duodenal biopsy proved to be normal. Doxycycline and hydroxychloroquine were rapidly effective. Chronic bursitis and tenosynovitis must be added to the list of rheumatologic manifestations that may evoke the diagnosis of Whipple disease.

Whipple’s Disease, a rare diagnosis caused by the slow-growing bacterium Tropheryma whipplei, most often presents with the classically described signs of malabsorption due to gastrointestinal colonization. However, it can also have signs and symptoms that clinically overlap with rheumatic diseases, potentially resulting in misdiagnosis. Furthermore, treatment with modern potent biologic immunosuppressive agents and classic disease modifying anti-rheumatic drugs (DMARDs) can lead to serious exacerbation of undiagnosed infections. We present the case of a middle-aged woman with long term complaints of arthalgias, who was diagnosed with seronegative rheumatoid arthritis and subsequently treated for almost 7 years with such immunosuppressive therapies. The patient’s disease course included chronic diarrhea that abruptly intensified and culminated in fatal hypovolemic shock/sepsis. A diagnosis of WD was made by autopsy examination, wherein several organ systems were found to be heavily involved by Tropheryma whipplei organisms, and their identification was confirmed with histochemical and molecular evaluation. Notably, most bacterial organisms were located deeply in the submucosa/muscularis of affected organs, a practical reminder to practicing pathologists that challenges the classic histopathologic description of Whipple disease as an infiltration of predominantly lamina propria, and the potential for sampling bias in typically superficial endoscopic biopsies during routine procedures.

International audience

A 49-year-old man developed cold intolerance as an isolated symptom 2 years prior to presentation. At age 48, he developed jerks in the trunk and lower limbs during the day and tapping movements in the arms during sleep. After 6 months, sleep disturbance worsened with talking and gesticulations, culminating in sleeping 1–3 hours per night with associated daytime somnolence. He developed mild slurred speech, hypersalivation, and dysphagia. He reported poor memory but was able to continue driving and working. He had been diagnosed with obstructive sleep apnea 4 years prior.

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 17 janvier 2020