Diagnosis Of Whipple's Disease Research Articles

Clinical and laboratory predictors and prevalence of immune reconstitution inflammatory syndrome in patients with Whipple's disease.

Whipple's disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time. Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not. Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h, P < 0.01), platelet (PLT; 234 × 109 /L vs 363 × 109 /L, P < 0.01), and body mass index (22.0 ± 2.0 kg/m2 vs 19.8 ± 3.0 kg/m2 , P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72-1.00) and PLT ≤ 327 × 109 /L (AUROC 0.85, 95% CI 0.70-1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time. Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades.

Whipple's Disease - delay of diagnosis by immunosuppressive therapy; a case-series report.

Risk factors for the development of Whipple's disease (WD) are largely unknown. Case reports, case series, and reviews suggest immunosuppressive therapy as a potential triggering factor in WD. The low incidence of WD and non-specific symptoms at disease onset contribute to the frequent delay of diagnosis. We describe our centre´s experience on differences in the clinical presentation of patients with classic WD compared to patients with "masked" WD because of immunosuppressive therapy. In this retrospective case series, 8 patients were included. Diagnosis of WD was confirmed by histological staining of duodenal biopsies revealing T. whipplei within foamy macrophages or by PCR- based detection of specific T. whipplei DNA. Clinical manifestations, laboratory data, and medication have been recorded over a period of 19 years. Subgroup analyses for the two different variants of WD were performed. Seven of eight patients were initially diagnosed with rheumatic disease (polyarthritis, polymyalgia rheumatica). One patient was correctly diagnosed at the beginning without any medication. Three patients were on immunosuppressive therapy and being treated with disease-modifying drugs (DMARDs), three patients were receiving low-dose cortisone in combination with non-steroidal anti- inflammatory drugs (NSAIDs), and one patient was receiving NSAIDs only. All patients presented with increased parameters of inflammation and with clinical and/or laboratory signs of a malabsorption. From the onset of first symptoms, diagnosis of WD took a median of 36 months (range: 6-120 months). The time between onset of joint complaints and onset of gastrointestinal symptoms was 36 months (range: 0-117 months). WD patients receiving immunosuppressive therapy, compared to those not receiving it, had a longer duration of gastrointestinal symptoms (12 months versus 6 months) and reported a greater weight loss (20,3 kg versus 7,8 kg) up to diagnosis of WD. Immunosuppressive drugs may delay the diagnosis of WD and prolong the course of T. whipplei infection with deterioration of clinical symptoms. If a patient with rheumatic complaints develops gastrointestinal symptoms, diagnosis of WD should be considered and proper diagnostic investigation carried out.

Rheumatological features of Whipple disease

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.

POS-427 WHIPPLE DISEASE IN A PATIENT WITH MEMBRANOUS GLOMERULONEPHRITIS: FIRST CASE IN LITERATURE

The Whipple Disease (WD) is an extremely rare infective condition with an incidence of one individual in a million people1, mainly attributed to the Tropherima Whipplei (TW). It is described as a gram-positive belonging to the family of Actinomycetes.Along with other factors, the genetic plays its role through the immunological hyperactivity towards TW. Here we report an atypical presentation of this disease, in a patient admitted to our Department several times. Male patient, 46 years old, affected by essential epilepsy, treated with Carbamazepine, and a serum-negative rheumatoid arthritis treated with NSAID. The patient reported a right-sided hearing loss due to suspected viral infection and had a history of papillary thyroid carcinoma, treated with a total thyroidectomy and radiometabolic therapy. The patient was hospitalized to our Nephrology Unit for the onset of a nephrotic syndrome (24h-proteinuria 13640 mg/day) and US-guided renal biopsy was performed, where leading to a histological diagnosis of Membranous Nephropathy (MN) with high titre of serum PLA2R antibodies and normal kidney function (Tab.1). Because of his personal history of neoplasia, we could not follow KDIGO guidelines recommendations for MN, which indicate a first-line treatment with an alkylating agent alternated with cortisone for six months2.Therefore we opted for a treatment with mycophenolate of 2g/die. Due to the failed remission, we started a treatment with Rituximab.The patient has been hospitalized three more times for the onset of dyspepsia, anaemia, joint pain, weight loss, diarrhea and fever, which have been studied by the following examinations (Tab. 2). In particular, a diffuse lymphangiectasia was highlighted at the second esophagogastroduodenoscopy (EGD) performed (Fig. 1). The last EGD revealed a flocculating appearance of the second duodenal portion mucosa, resembling grain of millet. The histological examination noted the presence of massive macrophage infiltration and a slight shortening of the villi. The pictures were perfectly compatible with the diagnosis of WD (Fig 2.). The patient undertook antibiotic therapy with doxycycline 200 mg/day in combination with hydroxychloroquine 600 mg/day with a maintenance dosage of prednisone 5 mg/day. After two months, he reached the complete remission of joint and gastrointestinal manifestations with improvement of renal parameters: albuminemia raised of 13% (2.75 mg/dl), and 24h-proteinuria reduced of 60% (3596 mg). The WD diagnosis and the response to the therapy clarified the pathogenesis of other symptoms previously attributed to other idiopathic different diseases. Therefore, we assume that these manifestations may be caused by the overlapping action of the autoimmune renal pathology and WD.

Multifocal secondary amyloidosis and Whipple disease: a case report

Background: Whipple disease (WD) is an exceedingly rare disease. Despite its rarity, there has been a longstanding allure with this disease. The classic form manifests with arthralgia, weight loss, abdominal pain, and diarrhea. However, the infection may involve other organs causing a great diversity of symptoms. Case Presentation: We report a case of a patient presenting to the emergency room with weight loss, abdominal pain and diarrhea. Duodenal biopsies revealed periodic acid Schiff-positive macrophages and Tropheryma whipplei was detected on a cervical lymph node. Diagnosis of WD was established. The patient also had multifocal secondary amyloidosis. We started the patient on a standardized antibiotic regimen for 1 year. Clinical improvement was seen early during the treatment. Conclusion: This case is an example of the protean nature of WD. To the authors’ knowledge, this is the first case report on WD with multifocal secondary amyloidosis affecting several digestive organs.

710. Non-invasive Diagnosis of Whipple Endocarditis Using Next-Generation Sequencing for Microbial Cell-free DNA in Plasma

Background Tropheryma whipplei is a gram-positive bacillus that causes Whipple’s disease, a protean multisystemic syndrome classically characterized by arthralgias, chronic diarrhea, malabsorption, and weight loss. T. whipplei infection has a wide spectrum of clinical manifestations including pleuropulmonary disease, skin hyperpigmentation and cardiac infection. Endocarditis has been diagnosed in a small number of patients and may represent an atypical presentation of T. whipplei infection. Diagnosis can be challenging and has typically been accomplished with histopathology on resected valvular tissue or GI tract biopsy. Next-generation sequencing (NGS) of microbial cell-free DNA (mcfDNA) in plasma offers a rapid, non-invasive means of diagnosis of this rare cause of culture-negative endocarditis and challenging clinical entity.MethodsMcfDNA analysis was performed in a patient with culture negative endocarditis. McDNA was extracted from plasma and NGS was performed by Karius, Inc. (Redwood City, California). Human sequences were removed and remaining sequences were aligned to a curated database of over 1,400 pathogens. Organisms present above a predefined statistical significance threshold were reported and quantified in DNA molecules per microliter (MPM). Chart review was performed for clinical correlation.ResultsA 64 year-old male with history of valve replacement presented with significant deterioration of the mitral valve. An exhaustive infectious workup including blood cultures was negative. Karius testing detected T. whipplei at 766 MPM within two days of sample receipt. The normal range for T. whipplei is 0 MPM based on a cohort of 684 healthy individuals. Blood PCR for T. whipplei was confirmatory.Table 1: Clinical Parameters of Case ConclusionNGS for mcfDNA in plasma offers a rapid, non-invasive method for identifying T. whipplei and, to our knowledge, the first diagnosis of Whipple disease using NGS of plasma mcfDNA.DisclosuresChristiaan R. de Vries, MD, PhD, Karius (Consultant, Independent Contractor)Stanford University (Employee) Ann Macintyre, DO, Karius (Employee)

A Case of Whipple's Disease Related Infectious Endocarditis

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.

Peripheral-blood b-cell subset disturbances in inflammatory joint diseases induced by Tropheryma whipplei.

ObjectiveTo look for abnormalities in circulating B-cell subsets in patients with rheumatic symptoms of Whipple’s disease (WD).MethodConsecutive patients seen between 2010 and 2016 for suspected inflammatory joint disease were identified retrospectively. Results of standardized immunological and serological tests and of peripheral-blood B-cell and T-cell subset analysis by flow cytometry were collected. Patients with criteria suggesting WD underwent PCR testing for Tropheryma whipplei, and those with diagnosis of WD (cases) were compared to those without diagnosis (controls). We used ROC curve analysis to evaluate the diagnostic value of flow cytometry findings for WD.ResultsAmong 2917 patients seen for suspected inflammatory joint disease, 121 had suspected WD, including 9 (9/121, 7.4%) confirmed WD. Proportions of T cells and NK cells were similar between suspected and confirmed WD, whereas cases had a lower proportion of circulating memory B cells (IgD-CD38low, 18.0%±9.7% vs. 26.0%±14.2%, P = 0.041) and higher ratio of activated B cells over memory B cells (4.4±2.0 vs. 2.9±2.2, P = 0.023). Among peripheral-blood B-cells, the proportion of IgD+CD27- naive B cells was higher (66.2%±18.2% vs. 54.6%±18.4%, P = 0.047) and that of IgD-CD27+ switched memory B cells lower (13.3%±5.7% vs. 21.4%±11.9%, P = 0.023), in cases vs. controls. The criterion with the best diagnostic performance was a proportion of IgD+CD27- naive B cells above 70.5%, which had 73% sensitivity and 80% specificity.ConclusionOur study provides data on peripheral-blood B-cell disturbances that may have implications for the diagnosis and pathogenetic understanding of WD.

Whipple's disease and Tropheryma whipplei infections: when to suspect them and how to diagnose and treat them.

The delay between first clinical signs and diagnosis of Whipple's disease and Tropheryma whipplei infections is more than 6 years, and relapses are frequently observed, resulting in a need for clinicians to be aware of this infection. 18 FDG-PET is useful in the diagnosis and the follow-up of patients (particularly in case of neurological involvement). Histological involvement remains the goldstandard for classic Whipple's disease diagnosis. PCR performed on biopsies of fluid is the main tool for the diagnosis of localized chronic infections. PCR performed on urine samples should become an important role of noninvasive diagnostic strategies, while T. whipplei PCR performed on saliva and stool lack specificity. Because of lifetime susceptibility to T. whipplei and in-vitro susceptibility data, a 1-year course of doxycycline and hydroxychloroquine followed by a lifelong treatment by doxycycline is recommended for Whipple's disease, localized endocarditis and encephalitis. Clinical involvement of the different T. whipplei infections is well described, as well as the treatment of Whipple's disease, endocarditis and encephalitis. The place of PCR performed on urine remains to be clarified for diagnosis of localized T. whipplei infections and acute infections as well as the optimal treatment for arthritis and acute infections.

Whipple's Disease: Diagnostic Value of rpoB Gene PCR from Peripheral Blood Mononuclear Cells.

Chronic infection with Tropheryma whipplei, known as Whipple's disease (WD), classically affects the gastrointestinal tract, but any organ system may be affected, and isolated manifestations occur. Reliable diagnosis based on a combination of periodic acid-Schiff (PAS) staining, T. whipplei-specific immunohistochemistry (IHC), and polymerase chain reaction (PCR) from duodenal biopsies may be challenging in cases without classical gastrointestinal infection, so the need for additional diagnostic materials is urgent. Our objective was to evaluate additional diagnostic possibilities for WD. We analyzed samples from 20 patients with WD and 18 control subjects in a prospective observational pilot study. In addition to WD diagnosis by PAS staining, T. whipplei-specific IHC and PCR of duodenal or extra intestinal tissues, whole EDTA blood, peripheral blood mononuclear cells (PBMCs) and PBMC fractions enriched with or depleted of cluster of differentiation (CD)-14+ cells were examined using T. whipplei rpoB gene PCR. Tropheryma whipplei DNA was detected in 35 of 60 (58.3%) preparations from 16 of 20 patients with WD, most of whom lacked gastrointestinal signs and characteristic PAS-positive duodenal macrophages. This study provides evidence for the potential suitability of blood, particularly PBMCs, as material to assist in the diagnosis of WD via rpoB gene real-time PCR. Thus, PCR from blood preparations can be helpful for diagnostic decision making in atypical cases of WD.

Fluorescence In Situ Hybridization for Diagnosis of Whipple's Disease in Formalin-Fixed Paraffin-Embedded Tissue.

Whipple’s disease (WD) is a rare chronic systemic infection with a wide range of clinical symptoms, routinely diagnosed in biopsies from the small intestine and other tissues by periodic acid–Schiff (PAS) diastase staining and immunohistological analysis with specific antibodies. The aim of our study was to improve the pathological diagnosis of WD. Therefore, we analyzed the potential of fluorescence in situ hybridization (FISH) for diagnosing WD, using a Tropheryma (T.) whipplei-specific probe. 19 formalin-fixed paraffin-embedded (FFPE) duodenal biopsy specimens of 12 patients with treated (6/12) and untreated (6/12) WD were retrospectively examined using PAS diastase staining, immunohistochemistry, and FISH. 20 biopsy specimens with normal intestinal mucosa, Helicobacter pylori, or mycobacterial infection, respectively, served as controls. We successfully detected T. whipplei in tissue biopsies with a sensitivity of 83% in untreated (5/6) and 40% in treated (4/10) cases of WD. In our study, we show that FISH-based diagnosis of individual vital T. whipplei in FFPE specimens is feasible and can be considered as ancillary diagnostic tool for the diagnosis of WD in FFPE material. We show that FISH not only detect active WD but also be helpful as an indicator for the efficiency of antibiotic treatment and for detection of recurrence of disease when the signal of PAS diastase and immunohistochemistry lags behind the recurrence of disease, especially if the clinical course of the patient and antimicrobial treatment is considered.

Diagnostic Approach and Testing of Whippleʼs Disease

Introduction: Whipple's disease (WD) is a rare systemic infection caused by Tropheryma whipplei that remains a diagnostic challenge due to its non-specific symptoms and variable presentation. The diagnostic role of T. whipplei polymerase chain reaction (PCR) is unclear as small bowel biopsy with periodic acid-Schiff (PAS) staining remains diagnostic gold standard. Individualized diagnostic approaches based on disease clinical phenotype have not yet been evaluated. We retrospectively investigated the methodology employed at our institution to diagnose WD. Methods: We retrospectively collected all cases of WD diagnosed at our institution since the development of PCR in 1992. Microbiology laboratory and anatomic pathology databases were queried for all positive results of PCR and PAS, respectively, for all specimen sources. The cohort of positive results was cross-checked against query of WD cases in our medical record. Each case with at least one positive laboratory result was reviewed and confirmed with clinical correlation of WD symptoms and WD treatment response. Two cases with a single PCR without WD symptoms or treatment for WD were excluded. Case characteristics and disease clinical phenotype (classical (CWD), localized arthralgia predominant without GI involvement (LWD), and CNS predominant) were reported. Results were analyzed using descriptive statistics and likelihood ratio analysis to compare diagnostic test yield. Results: Thirty-three cases of WD were diagnosed from 1992 to present (18 CWD, 8 LWD, 7 CNS predominant WD). Patients were 85% male with a mean (SD) age of 52 (13) years. Symptoms preceded diagnosis on average of 61 months, furthermore 43% of patients had been misdiagnosed with immunosuppressive therapy initiated. Table 1 shows symptom proportions. Diagnostic approach and test yield differed by disease clinical phenotype (Table 2). PAS stain/PCR of small bowel biopsy were overwhelmingly positive (86%/92%) in CWD, yet seldom positive (0%/42%) in LWD (p < 0.001). Affected joint synovial fluid PCR was positive frequently in both CWD and LWD.Table 1: Proportion of Symptoms and Laboratory Findings differ by Whipple's Disease Clinical Phenotype.Table 2: Diagnostic Approach and Test Yield differ by Whipple's Disease Clinical Phenotype.Conclusion: These results support the role of small bowel biopsy PAS stain and PCR in the diagnosis of CWD. However, the diagnostic yield of small bowel biopsy PAS stain and PCR significantly decreased in WD without GI symptoms. PCR of other sources such as synovial fluid or cerebrospinal fluid was helpful in diagnosis of WD without GI symptoms.

Malabsorption Syndrome Due to Tropheryma Whipplei Severe Infection in a Patient Thirteen Years after Kidney Transplantation

Whipple's disease (WD) is a rare chronic and multi-systemic infectious illness. The exposing factor to WD is an underlying genetic predisposition that leads to colonization of T. whipplei throughout the intestinal tract. Here, we report the first case of WD, to our knowledge, with typical systemic and gastrointestinal manifestations, malabsorption syndrome and serious alteration leading to death in a kidney transplant recipient. We intend to describe its clinical presentation, the methods for its diagnosis, and the outcome of treatment. It's a 27-year-old man without history of arthritis or diarrheal illness. He received a cadaveric graft in 23/12/1999 at the age of fifteen. His HLA analysis was A1 A33 B14 B35 BRB1*01 DRB1*11. The recipient lived in an urban environment without well water or animals. Five years after transplantation, he complained of diarrhoea and fever with a negative infectious work up. These gastrointestinal symptoms were resolved after empiric antibiotics. The recipient was hospitalized in 2012, thirteen years after transplantation, to explore a second episode of chronic afebrile diarrhoea with loss of weight and worsening of the graft function. Labs showed malabsorption syndrome, anaemia and leukopenia but no inflammatory signs. Anti-gliadine and anti-transglutaminase antibodies were negative. Bacteriological and parasitological stools tests as well as blood cultures were negative. Cytomegalovirus antigenemia and tumor markers were also negative. The patient has not been treated with antibiotics for WD and MMF toxicity was more likely to be responsible of the malabsorption syndrome. The mycophenolate mofetil was switched to Azathioprine. In October 2015, he was hospitalized for fever, diarrhoea and arthralgia without arthritis, hypokalemia, dehydration, important loss of weight and worsening of the graft function. The endoscopic exploration showed erythematous antral mucosa, severe gastritis and duodenal lymphangiectasia. Biopsies showed atrophied villi, abraded epithelium and filled villi axis with foamy macrophages strongly stained in PAS coloration. This histologic aspect is typically suggestive of T. whipplei intestinal infection. Sixteen years after transplantation, the patient was dead after two days in the intensive care unit. The diagnosis of WD was certain based on clinical and histopathological proofs.

Systematic review: Whipple's disease (Tropheryma whipplei infection) and its unmasking by tumour necrosis factor inhibitors.

The classical form of Whipple's disease (WD), clinically characterised by arthropathy, diarrhoea and weight loss, is rare. Recently, other more frequent forms of Tropheryma whipplei infection have been recognised. The clinical spectrum includes an acute, self-limiting disease in children, localised forms affecting cardiac valves or the central nervous system without intestinal symptoms, and asymptomatic carriage of T. whipplei which is found in around 4% of Europeans. Genomic analysis has shown that T. whipplei represents a host-dependent or opportunistic bacterium. It has been reported that the clinical course of T.whipplei infection may be influenced by medical immunosuppression. To identify associations between immunomodulatory treatment and the clinical course of T. whipplei infection. A PubMed literature search was performed and 19 studies reporting on immunosuppression, particularly therapy with tumour necrosis factor inhibitors (TNFI) prior to the diagnosis in 41 patients with Whipple?s disease, were evaluated. As arthritis may precede the diagnosis of WD by many years, a relevant percentage (up to 50% in some reports) of patients are treated with immunomodulatory drugs or with TNFI. Many publications report on a complicated Whipple?s disease course or T. whipplei endocarditis following medical immunosuppression, particularly after TNFI. Standard diagnostic tests such as periodic acid-Schiff stain used to diagnose Whipple?s disease often fail in patients who are pre-treated by TNFI. In cases of doubt, Whipple?s disease should be excluded before therapy with TNFI. The fact that immunosuppressive therapy contributes to the progression of T. whipplei infection expands our pathogenetic view of this clinical entity.

Complicated Whipple's disease and endocarditis following tumor necrosis factor inhibitors.

To test whether treatment with tumor necrosis factor inhibitors (TNFI) is associated with complications of Tropheryma whipplei (T. whipplei) infection. Because unexplained arthritis is often the first Whipple's disease (WD) symptom, patients may undergo treatment with TNFI before diagnosis. This may influence the course of infection with T. whipplei, which causes WD, because host immune defects contribute to the pathogenesis of WD. A literature search and cross referencing identified 19 reports of TNFI treatment prior to WD diagnosis. This case-control study compared clinical data in patients receiving TNFI therapy (group I, n = 41) with patients not receiving TNFI therapy (group II, n = 61). Patients from large reviews served as controls (group III, n = 1059). The rate of endocarditis in patient group I was significantly higher than in patient group II (12.2% in group I vs 1.6% in group II, P < 0.05), and group III (12.2% in group I vs 0.16% in group III, P < 0.01). Other, severe systemic or local WD complications such as pericarditis, fever or specific organ manifestations were increased also in group I as compared to the other patient groups. However, diarrhea and weight loss were somewhat less frequent in patient group I. WD is typically diagnosed with duodenal biopsy and periodic acid Schiff (PAS) staining. PAS-stain as standard diagnostic test had a very high percentage of false negative results (diagnostic failure in 63.6% of cases) in group I. Polymerase chain reaction (PCR) for T. whipplei was more accurate than PAS-stainings (diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01). TNFI trigger severe WD complications, particularly endocarditis, and lead to false-negative PAS-tests. In case of TNFI treatment failure, infection with T. whipplei should be considered.

A severe Whipple disease with an immune reconstitution inflammatory syndrome: An additional case of thalidomide efficiency

We report the case of a 38-year-old man who presented with severe diarrhea, weight loss of 10kg, ankles paresthesia and severe motor weakness in the left fibular nerve territory after introduction of azathioprine and corticosteroid for proteinuria. Coloscopy and gastroscopy revealed a typical aspect of Whipple disease (WD), associated with both positive PAS staining and specific immunohistochemistry. T. whipplei PCR results were positive in blood, faeces, saliva and duodenal biopsy specimens. Diagnosis of WD with systemic manifestations was retained and doxycycline plus hydroxychloroquine therapy were started. This treatment improved joint pain, and skin and intestinal symptoms. One month later, our patient presented with fever and an important inflammatory syndrome (CRP 150mg/dL and 16.8 109/L leukocytes), while no infection was found despite a thorough review. We concluded it was an immune reconstitution inflammatory syndrome (IRIS). Manifestations persisted despite increasing corticosteroids and thalidomide (200mg/day) was introduced with good efficacy on these symptoms. WD may be revealed by non-specific symptoms such as weight loss or arthralgia, but also by many other misleading signs. Our observation illustrates the highly polymorphic clinical presentation of WD, and the diagnostic difficulties that may arise. This is also a new report of thalidomide effectiveness in IRIS in WD.

Rheumatic and Musculoskeletal Features of Whipple Disease: A Report of 29 Cases

Whipple disease is a rare infection caused by Tropheryma whipplei. Although patients commonly complain of osteoarticular involvement, musculoskeletal manifestations have been poorly described. We report cases of Whipple disease with rheumatic symptoms and describe their clinical presentation, modes of diagnosis, and outcomes. This retrospective multicenter study included patients with Whipple disease diagnosed and referenced between 1977 and 2011 in 10 rheumatology centers in France and Italy. Twenty-nine patients were included. The median age was 55 years. The median time to diagnosis from first symptoms was 5 years. Polyarthritis was the most frequent presentation (20/29), and was most often chronic, intermittent (19/29), seronegative (22/23), and nonerosive (22/29). In all cases, the symptoms had led to incorrect diagnosis of inflammatory rheumatic disease and immunosuppressants, including biotherapy, were prescribed in most cases (24/29) without success. The diagnosis of Whipple disease was made by histological analysis, molecular biology tests, or both in 21%, 36%, and 43% of the cases, respectively. Duodenal biopsies were performed in most cases (86%). Synovial biopsies were performed in 18% of cases, but all contributed to diagnosis. The clinical outcomes after antibiotic therapy were good for all patients. Polyarthritis is the main feature observed in cases of Whipple disease; it is seronegative and associated with general and gastrointestinal symptoms. The molecular analysis of duodenal tissue and/or other tissues remains the method of choice to confirm the diagnosis. Reducing the time to diagnosis is important because severe late systemic and fatal forms of the disease may occur.

The Rise of Tropheryma whipplei: a 12-Year Retrospective Study of PCR Diagnoses in Our Reference Center

Tropheryma whipplei is the causative agent of classic Whipple's disease (WD) and other clinical entities, such as localized infection. Asymptomatic carriers have also been reported, mainly based on the testing of fecal samples. Our objective was to undertake a retrospective analysis of molecular biology usage for the diagnosis of WD over a 12-year period in our reference center. We tested 27,923 samples from 15,473 patients. The number of patients tested and the number of patients with a positive PCR result for T. whipplei have increased significantly over the last 12 years (P < 0.0001). Overall, T. whipplei was more frequently recovered from stools (43%), saliva (15%), duodenal biopsy samples (12.5%), blood (5%), and cerebrospinal fluid (CSF) (6%) and less commonly from cardiac valves (3%), urine (0.5%), skin biopsy samples (1%), lymph nodes (2.5%), aqueous humor (0.5%), and intra-articular fluid (1%). Among all the positive samples, we observed that stool samples and skin biopsy samples exhibited a higher prevalence of positivity by real-time quantitative PCR (qPCR) at 10.07% and 15.4%, respectively. The number of patients with a positive PCR result for T. whipplei has increased significantly over the last 12 years, although the positive ratio has not changed. Improvements in diagnostic tools have contributed greatly toward greater knowledge of WD and, consequently, the interest of physicians in this condition. In addition, we propose here an update of the diagnostic strategy for WD when qPCR is being used.

Whipple Disease Revealed by Lung Involvement: A Case Report and Literature Review

We report the case of a man with a history of intermittent fever and arthritis who presented with a dry cough and associated lung involvement, who was eventually given the diagnosis of Whipple disease. The pulmonary symptoms preceded the development of GI manifestations. Five years later, periodic acid-Schiff (PAS)-positive macrophages were identified in duodenal biopsy specimens and polymerase chain reaction for Tropheryma whipplei was positive in the duodenum, stools, saliva, and cerebrospinal fluid. Pulmonary T whipplei was retrospectively confirmed by positive PAS staining and immunoreactivity to specific antibodies in endobronchial biopsy specimens. Antibiotic treatment was followed by remission. A literature review identified eight other cases of Whipple disease presenting with lung parenchymal involvement, predominantly interstitial lung disease (ILD), and without initial GI symptoms. In the absence of GI symptoms, a diagnosis of Whipple disease should be considered in middle-aged men presenting with ILD or lung nodules, if the patient has a history of unexplained arthralgia and/or fever. The association of mediastinal adenopathy or pleural effusion offers additional concern. Whipple disease may be fatal in the absence of treatment, but prolonged antibiotic treatment often leads to complete remission.

A case of refractory rheumatoid pericarditis

A case of refractory rheumatoid pericarditis