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The skin can provide significant clues to screen, investigate, diagnose, and formulate management protocols with the help of gastroenterologists. These cutaneous manifestations are highly varied, diverse, and can include specific or nonspecific changes. Broadly these skin changes can be classified into four major categories: (1) Dermatological manifestations of disorders of the pharynx, esophagus, and stomach. Systemic sclerosis, Plummer-Vinson syndrome, and mechanobullous or immunobullous disorders that involve the upper gastrointestinal tract have distinct skin changes. Conditions such as acanthosis nigricans, acrokeratosis neoplastica (Bazex syndrome), seborrhoic keratosis (signs of Lese-Trelat), florid cutaneous papillomatosis (Schwartz-Burgess syndrome), Sister Mary Joseph nodule, and hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) give clues to underlying gastrointestinal malignancies. (2) Dermatological manifestations of disorders of intestinal involvement. Examples are dermatitis herpetiformis, Henoch-Schonlein purpura, inflammatory bowel disease (Crohn disease and ulcerative colitis), bowel-associated dermatitis arthritis syndrome (BADAS), Whipple disease, and hereditary intestinal polyposis have characteristic skin changes along with intestinal involvement. (3) Dermatological manifestations of liver and pancreas disorders. Lichen planus, Gianotti- Crosti syndrome, and cutaneous features of liver cell failure are examples of liver disorder due to various causes. Grey-Turner sign, migratory thrombophlebitis (Trousseau syndrome), and necrolytic migratory erythema may give clues to pancreatic disorders. (4) Dermatological manifestations of miscellaneous gastrointestinal disorders. These include, e.g., malabsorption, stomas, and drugs.

To study the results and safety of diagnostic vitrectomy in patients with unknown etiology panuveitis.A retrospective descriptive observational study was carried out in which a total of 29 patients (37 eyes) were included, who underwent a vitreous biopsy due to acute intraocular inflammatory processes. In all, demographic and clinical data were collected. We studied the specific samples extraction methods and their diagnosic processing.Of the 29 patients analyzed, 18 were men. Mean of age was 63.11 years old (standard deviation: 14.55). The most frequent initial symptom was visual acuity decrease, with mean initial visual acuity being 20/40, excluding 8 eyes that had vision lower than 20/200. 21 presented unilateral ocular involvement. Vitrectomy was performed in all of them obtaining a dry sample. Vitrectomy was performed in all of the patients obtaining a dry sample. Moreover, the following techniques were done: 5 retinal biopsies, obtaining 5 muestras diluidas, 1 subretinal abscess aspirate and 1 aqueous humor aspirate. The most frequent processing technique that was used was cytology in 25 eyes, followed by PCR (polymerase chain reaction) in 11 eyes and culture in 10 eyes. Diagnosis was achieved in 94.5% of patients. Main diagnosis found was lymphoma, followed by toxoplasmosis.Diagnostic vitrectomy is very important in ophthalmic inflammation identification. Different techniques for obtaining and processing can be used.

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Immunohistochemistry and Periodic acid–Schiff (PAS) staining have been routinely used for the diagnosis of Whipple’s disease (WD). However, these methods present limitations. As a result, the last years, Fluorescence in situ hybridization (FISH) has been increasingly used as a complementary tool for the diagnosis of WD from various tissue samples. In this study, we visualized, by FISH, Tropheryma whipplei within macrophages of a lymph node from a patient with WD. Moreover, we report in this study a patient with a pulmonary biopsy compatible with WD by PAS, immunostaining and FISH, although the specific molecular assays for T. whipplei were negative. Sequencing analysis of the 16S rDNA revealed a T. whipplei-related species with unknown classification. FISH can be a valuable method for the detection of Tropheryma species in formalin-fixed paraffin-embedded tissues. FISH cannot replace the other already approved diagnostic techniques for WD, it can be used as a complementary tool and can provide supplementary information in a relatively short time.

Malabsorptive bariatric techniques are associated with nutritional deficiencies. However, when patients do not respond to supplemental intensive treatments they should be closely followed because they can hide other pathological conditions. We present the case of a 47-year-old man with morbid obesity (body mass index [BMI]: 48 kg/m2) who underwent bariatric surgery. In 2016, he presented severe pneumonia and hospitalization at the Intensive Unit Care was required. After this episode, his nutritional state impaired, presenting 6-7 diarrhea/steatorrhea events per-day and requiring several hospitalizations due to the persistence of severe hypoproteinemia. He was given parenteral high-protein associated with low-fat oral diet. He presented a temporary biochemical improvement, but the hypoproteinemia recurred. Finally, tests revealed the presence of Tropheryma whipplei as protein-losing enteropathy. Whipple's disease (WD) is a rare cause of diarrhea and malnutrition, and these symptoms can be confused with the postoperative status of malabsorptive bariatric techniques. WD requires early diagnosis with prolonged antibiotic treatment to avoid severe complications.Las técnicas bariátricas malabsortivas suelen asociarse a deficiencias nutricionales. Sin embargo, cuando los pacientes no responden a tratamientos intensivos suplementarios, deben valorarse otras condiciones patológicas. Presentamos el caso de un hombre de 47 años, obeso mórbido (índice de masa corporal [IMC]: 48 kg/m2) sometido a cirugía bariátrica, que dos años más tarde presentó neumonía severa, por lo que requirió ingreso en la Unidad de Cuidados Intensivos. Posteriormente, el estado nutricional se deterioró, presentando 6-7 episodios de diarrea-esteatorrea/día y requiriendo varias hospitalizaciones por hipoproteinemia severa. Recibió infusión parenteral rica en proteínas asociada con una dieta baja en grasas y presentó mejoría analítica temporal. Finalmente, las pruebas revelaron la presencia de Tropheryma whipplei, una bacteria que genera enteropatía pierde-proteínas. La enfermedad de Whipple (EW) es una causa poco común de diarrea y malnutrición. Estos síntomas pueden confundirse con el posoperatorio de técnicas bariátricas malabsortivas. La EW requiere un diagnóstico precoz con un tratamiento antibiótico prolongado para evitar complicaciones graves.

Aim:To obtain the first molecular epidemiological survey of Tropheryma whipplei intestinal colonization in Italy. Materials & methods: Retrospective, observational study to assess the prevalence of T. whipplei, the causative agent of Whipple's disease, in stool samples (real-time PCR) of patients attending the Center for Tropical Diseases (Italy) and risk factors associated. Results:Overall prevalence was 6.9% (85/1240). The younger age group showed a significantly higher rate than older age group (12.7 vs 5.9%, p = 0.002). The prevalence was 4.9% for Italians and 9.3% for migrants (p = 0.003). Among the latter, children less than 10 years had higher prevalence than older ones (17.3 vs 7.3%, p = 0.003). The young age, male gender and Giardia duodenalis and Entamoeba histolytica coinfection were risk factors. Conclusion:Our study confirms an increased risk of acquiring T. whipplei infection during childhood, under poor sanitary conditions.

Objective To look for abnormalities in circulating B-cell subsets in patients with rheumatic symptoms of Whipple’s disease (WD). Method Consecutive 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. Results Among 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. Conclusion Our study provides data on peripheral-blood B-cell disturbances that may have implications for the diagnosis and pathogenetic understanding of WD.

Whipple's disease is a rare infectious disease, which can affect various organ systems. Arthritis is a common symptom and therefore the infection is often misdiagnosed as seronegative rheumatoid arthritis. In rare cases an infection with Tropheryma whipplei can also cause skin lesions, such as subcutaneous nodules, erythema nodosum or vasculitis. This article reports the case of a 77-year-old female patient with erosive joint changes, persistently elevated serological inflammation markers and recurrent ulcerative lesions of the lower extremities, which were initially misdiagnosed as rheumatoid vasculitis. In cases of a clinically suspected infection with Tropheryma whipplei an early biopsy of the affected organ system is essential for the diagnosis.

Our institution has performed microbiological diagnosis of Tropheryma whipplei since 2001, initially with a PCR targeting 16S rRNA before the development of a quantitative PCR in 2012. Here we report the clinical characteristics of a cohort of patients suffering from Whipple disease (WD) and evaluate the impact of these molecular techniques. Patients with a positive PCR for T. whipplei between 2001 and 2016 were retrospectively collected from microbiological databases. Two infectious diseases specialists reviewed their medical records and classified them as definite WD, probable WD or carriage of T. whipplei without disease. A total of 1153 samples were tested for T. whipplei; 76 samples taken from 36 patients were positive. Fifteen were considered as presenting a definite WD, seven as a probable WD and 14 as carriers. Median age was 56.4 years (extremes, 6.6–76.1). Median time from symptoms to diagnosis was 3 years (2.5 months to 13.3 years). About 60% were immunosuppressed. The most frequent clinical presentations were joint pain (16/22), weight loss (15/22) and/or digestive tract disorder (15/22); 41% had neurological manifestations, 32% pulmonary involvement and 32% lymphadenopathies. Bacterial load in faeces or saliva were 88 425 copies/mL (IQR 6175-292 725) in definite and probable WD and 311 copies/mL (IQR 253–2090) in carriers, respectively. We observed a 90% PPV above 32 200 copies/mL in faeces. WD is a chronic multisystemic disease with frequent pulmonary involvement. Underlying immunodeficiency is commonly observed leading to more complex clinical presentation. Positive T. whipplei PCR in both stool and saliva has a high positive predictive value. Moreover, patients with WD present higher bacterial load in faeces with a threshold of >32 200 copies/mL predicting ongoing infection.

Introduction: Wipple disease (WD) is a rare chronic disease caused by the bacillus Tropheryma whipplei. Constitutive, rheumatologic, gastrointestinal, cardiac, cerebral, lymphatic, cutaneous, and ophthalmological signs are possible systemic symptoms. However, thrombotic manifestations are rarely described as “stroke-like syndrome” or arterial thrombosis. Diagnosis is based on clinical manifestations and pathological examination. Laboratory findings may include anemia, leukocytosis, and thrombocytosis. Objective: We report a case of venous thrombosis as initial manifestation of WD. Case Report: We describe the case of a 53-year-old male with iliofemoral vein thrombosis followed by intermittent diarrhea, loss of appetite, abdominal distension, and bloating. A mild malnutrition state with a weight loss of 13 kg, pallor (+/4 +), presence of lower-limb edema (+/4 +), and hypertympanic distended abdomen occurred. Laboratory tests on admission revealed anemia, positive inflammatory activity tests, and normal coagulation. Endoscopic examination showed villous edema with white dotted infiltrates in the second duodenal portion and intestinal lymphangiectasia in the terminal ileum. Pathological examination revealed numerous macrophages with positive periodic acid-Schiff inclusions. Venous Doppler ultrasound showed extensive deep thrombosis on the left lower limb and recanalization of the femoral vein in the right lower limb. The patient was treated with ceftriaxone and enoxaparin sodium, which led to an improvement of gastrointestinal and thrombosis symptoms. Comments: Hypercoagulability, endothelial damage, vasculitis, and blood stasis are present in T. whipplei infection, which are associated with the activation of inflammatory mechanisms as well as procoagulant and thromboembolic events. WD should be part of the differential diagnosis of diseases that cause venous thrombosis of unknown origin.

Whipple disease is a rare, chronic multisystem infectious disease. The central nervous system (CNS) is secondarily involved in 43% of patients; 5% of patients have isolated or primary CNS involvement. The most frequent CNS symptoms are cognitive changes. Prosopagnosia is an inability to recognize familiar faces, in a person who does not have vision impairments or cognitive alterations. This relatively rare condition is usually related to vascular, traumatic, degenerative, or infectious lesions. We report a 54-year-old woman who presented subacutely with fever, headache, and seizures that led to a diagnosis of infectious meningoencephalitis. She improved temporarily on broad-spectrum antibiotics, but then developed a chronically evolving cognitive impairment with associative prosopagnosia as the major complaint. She had a history of sporadic abdominal pain and mild sacroiliac arthralgia. After a negative duodenal biopsy, we confirmed primary CNS Whipple disease by polymerase chain reaction and brain biopsy. We treated the patient with ceftriaxone for 15 days and then co-trimoxazole for 2 years. At 8-year follow-up, she had no further impairments, but continuing prosopagnosia. To our knowledge, this is the first description of isolated prosopagnosia in a patient with primary CNS Whipple disease. Because CNS Whipple disease can lead to serious, irreversible lesions if not promptly treated, clinicians must suspect the diagnosis, treat with long-term antibiotics, and follow patients carefully to prevent recurrence.

Summary Recent advances in medical microbiology, epidemiology, cellular biology, and the availability of an expanded set of diagnostic methods such as histopathology, immunohistochemistry, PCR, and bacterial culture have improved our understanding of the clinical range and natural course of Tropheryma whipplei infection and Whipple's disease. Interdisciplinary and transnational research activities have contributed to the clarification of the pathogenesis of the disorder and have enabled controlled trials of different treatment strategies. We summarise the current knowledge and new findings relating to T whipplei infection and Whipple's disease.

Whipple's disease (WD) is a rare infectious disease developed through fecal-oral transmission and caused by Tropheryma whipplei , a ubiquitous gram bacillus [1]. The pathogenesis remains unclear, and several host factors seem to be implicated, including male sex, comorbidities and genetic susceptibility [1]. WD is a multivisceral disorder with frequent gastro-intestinal, joint and neurological involvement, as well as pulmonary, cardiovascular, mucocutaneous, and ophthalmologic lesions [2]. The diagnosis is made via small bowel biopsy with Periodic Acid Schiff staining (PAS) positivity and by polymerase chain reaction (PCR) on different biological samples [1]. Classical treatment requires prolonged antibiotic therapy and allows rapid improvement. The association of doxycycline and hydroxychloroquine over 1 year followed by lifetime treatment with doxycycline has been shown to lead to good clinical responses and fewer relapses [3]. Others have recommended initial use of intravenous antibiotics, followed by trimethoprim-sulfamethoxazole for 1 year [4]. Among lung complications of WD, pulmonary hypertension (PH) is very rare and remains poorly understood [5–8]. Here, we report the first well-documented case of a man with concomitant diagnosis of severe precapillary PH and multivisceral WD who had total reversibility in hemodynamics and clinical state after treatment of WD and PH. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Yan reports grants from National Institutes of Health, during the conduct of the study;. Conflict of interest: Dr. Camboulive has nothing to disclose. Conflict of interest: Dr. Jutant has nothing to disclose. Conflict of interest: Dr. Savale has nothing to disclose. Conflict of interest: Dr. Jais has nothing to disclose. Conflict of interest: Dr. SITBON reports grants, personal fees and non-financial support from Actelion, personal fees from Acceleron, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from MSD, grants from GlaxoSmithKline, personal fees from Ferrer, personal fees from Gossamer Bio, outside the submitted work. Conflict of interest: Dr. Mussini has nothing to disclose. Conflict of interest: Dr. Benichou has nothing to disclose. Conflict of interest: Dr. Lagier has nothing to disclose. Conflict of interest: Dr. Humbert reports personal fees from Acceleron, grants and personal fees from Actelion, grants and personal fees from Bayer Heathcare, personal fees from GSK, personal fees from Merck, personal fees from Novartis, personal fees from Astrazeneca, personal fees from Sanofi, outside the submitted work. Conflict of interest: Dr. Montani has nothing to disclose.

Background:Whipple disease (WD) is a rare systemic infection with possible involvement of the central nervous system (CNS). The neurological manifestations of the disease are various and can mimic any neurologic condition.Objectives:To describe the severe neurological complications occurred in a patient with WD misdiagnosed as a chronic inflammatory immune-mediated disorder.Methods:Case reportResults:A 46-year-old woman developed acute right-sided hemiparesis and dysarthria. She had a 10-year history of ill-defined rheumatic condition (defined as seronegative rheumatoid arthritis, spondyloarthritis, and adult onset Still’s disease) presenting with polyarthritis, episodic fever > 38°C and rash of unclear etiology poorly responsive to different immunotherapies including methotrexate, anti-IL6 and anti-IL1 inhibitors. Brain MRI demonstrated multiple anterior circulation infarctions and stenosis of the bilateral M1 segments of the middle cerebral artery on MR angiography. Black blood sequences revealed contrast enhancement of the vessel walls consistent with vasculitis (Figure 1). Cerebrospinal fluid (CSF) analysis was unrevealing, including PCR for viruses and bacteria. A working diagnosis of primary CNS vasculitis and progressive neurologic deterioration with abnormal behavior and altered mental status prompted the initiation of intravenous (IV) methylprednisolone followed by cyclophosphamide without significant improvement. Re-evaluation of the long-standing history of joint symptoms unresponsive to immunotherapy, along with recurrent fevers and chronic diarrhea raised the suspicion of unrecognized Whipple’s disease. PCR for Tropheryma Whippleii was positive in stool, urine, blood and CSF, and duodenal mucosal biopsies confirmed the diagnosis. A combination of ceftriaxone, doxycycline, and hydroxychloroquine was initiated. Three days later the patient developed periocular burning pain and cutaneous vesicles consistent with shingles. Varicella-zoster virus DNA was detected in CSF and IV acyclovir was started. At 3 months follow-up neurologic examination was unremarkable except for a slightly fatuous behavior.Conclusion:Recognition of rare manifestations of WD is important to avoid diagnostic delay and inappropriate, potentially harmful treatments.Disclosure of Interests:Alessandro Giollo: None declared, Cecilia Zivelonghi: None declared, Davide Cardellini: None declared, Gian Marco Schiavi: None declared, Gaetano Vattemi: None declared, Ombretta Viapiana: None declared, Maurizio Rossini Speakers bureau: AbbVie, Abiogen, Amgen, BMS, Eli-Lilly, Novartis, Pfizer, Sanofi, Sandoz and UCB

Primary Whipple disease of the Central Nervous System is a rare entity whose outcome might be fatal if not promptly diagnosed and treated. Few cases are reported in the literature with heterogeneous clinical and radiological presentations which often make the diagnosis extremely challenging.We report a case of primary Whipple disease of the Central Nervous System presenting with rhombencephalitis in a female patient in immunosuppressive treatment for rheumatoid arthritis. We describe the management of our patient and discuss the features of this rare clinical entity. Keywords: Primary Whipple disease, Rhombencephalitis, Immunocompromised host

Malabsorptive bariatric techniques are associated with nutritional deficiencies. However, when patients do not respond to supplemental intensive treatments they should be closely followed because they can hide other pathological conditions. We present the case of a 47-year-old man with morbid obesity (body mass index [BMI]: 48 kg/m2) who underwent bariatric surgery. In 2016, he presented severe pneumonia and hospitalization at the Intensive Unit Care was required. After this episode, his nutritional state impaired, presenting 6-7 diarrhea/steatorrhea events per-day and requiring several hospitalizations due to the persistence of severe hypoproteinemia. He was given parenteral high-protein associated with low-fat oral diet. He presented a temporary biochemical improvement, but the hypoproteinemia recurred. Finally, tests revealed the presence of Tropheryma whipplei as protein-losing enteropathy. Whipple's disease (WD) is a rare cause of diarrhea and malnutrition, and these symptoms can be confused with the postoperative status of malabsorptive bariatric techniques. WD requires early diagnosis with prolonged antibiotic treatment to avoid severe complications.

Infectious agents causing infection of the small bowel include viruses, bacteria, fungi, and parasites. This chapter covers histopathology of small bowel infections of the duodenum and small intestine (jejunum and ileum). Infectious agents which cause disease that may result in a biopsy to obtain a diagnosis are covered in this chapter. Clinical features, histopathologic features, differential diagnosis, and treatment and prognosis are covered for each infectious entity. Parasites encompass the largest group of infectious agents leading to small intestinal disease. The nematodes Strongyloides, Anisakis, and Angiostrongylus are discussed, as is Giardia, the most common intestinal protozoan worldwide. Intestinal disease due to the coccidian parasites Cryptosporidium and Cyclospora is also described. A description of adenoviral disease and comparison of cytopathic effects of other viruses common to the intestine is provided. Whipple disease due to Tropheryma whipplei is also discussed, and a histologic differential diagnosis of this disease is provided. Finally, microsporidial small intestinal disease in immunocompromised hosts is discussed.

Whipple’s disease is a rare and difficult-to-diagnose infectious disease, related to infection by gram-positive bacillum Tropheryma whipplei. Clinical manifestations are very variable, but the classic form usually begins with recurring arthritis, followed several years later by non-specific abdominal symptoms, leading to late diagnosis. We present the case of a 52-year-old man who was admitted in the emergency department with an insidious clinical picture characterised by weight loss, abdominal pain, diarrhoea and arthralgias. An abdominal ultrasound was performed, showing findings suggestive of Whipple’s disease, which, in conjunction with the clinical and laboratory findings, allowed the diagnosis to be correctly addressed. Upper endoscopy with duodenal biopsy revealed findings compatible with Whipple’s disease, and the diagnosis was also confirmed through PCR techniques of blood. The patient was given antibiotic therapy, with rapid and substantial clinical improvement.

Whipple's disease (WD) is a rare, chronic multiorgan disease which can caused by Tropheryma whipplei, a ubiquitous gram positive bacterium. Detection of T. whipplei is mostly performed histologically using periodic acid-Schiff (PAS) staining in affected tissues to visualize characteristic PAS-positive macrophages and by the polymerase chain reaction (PCR). Clinically, WD is often characterized by gastrointestinal symptoms (diarrhea, colic-like abdominal pain and weight loss). Arthritis is a common presentation of WS, often leading to a misdiagnosis of seronegative rheumatoid arthritis and as a consequence to immunosuppressive therapy. The clinical presentation of WD is highly polymorphic affecting different organ systems (e. g. cardiac or neurological manifestation) and making an appropriate clinical diagnosis and even the diagnostic process itself difficult. This article reports on three cases presenting with completely different leading symptoms (initially misdiagnosed as seronegative rheumatoid arthritis, spondyloarthritis and adult onset of Still's disease, respectively) that illustrate the rich diversity of WD. The cases were chosen to draw attention to the fact that although WD is mainly associated with the field of gastroenterology and gastrointestinal (GI) involvement is common, it may appear without GI symptoms. In cases of a clinical suspicion of WD, diagnostic efforts should be made to detect the bacterium in the affected organ. The German S2k guidelines on GI infections and WD published in January 2015 summarized the current state of the art for WD. The currently recommended primary treatment is antibiotics that can infiltrate the cerebrospinal fluid, e. g. ceftriaxone, followed by cotrimoxazole, which should be maintained over several months.

OBJECTIVE: Prior studies on the epidemiology of Whipple’s disease are limited by small sample size and case series design. We sought to characterize the epidemiology of Whipple’s disease in the United States utilizing a large population-based database. METHODS: We queried a commercial database (Explorys Inc, Cleveland, OH), an aggregate of Electronic Health Record (EHR) data from 26 major integrated healthcare systems in the US. We identified a cohort of patients with a diagnosis of Whipple’s disease based on Systemized Nomenclature of Medical terminology (SNOMED-CT) codes. We calculated the overall and age, race, ethnicity, and gender based prevalence of Whipple’s disease and prevalence of associated diagnoses using univariate analysis. RESULTS: A total of 35,838,070 individuals were active in the database between November 2012 and November 2017. Of these, 350 individuals had a SNOMED-CT diagnosis of Whipple’s disease, with an overall prevalence of 9.8 cases per 1 million. There was no difference in prevalence based on sex. However, prevalence of Whipple’s disease was higher in Caucasians, non-Hispanics, and individuals >65 years old. Individuals with a diagnosis of Whipple’s disease were more likely to have associated diagnoses/findings of arthritis, CNS disease, endocarditis, diabetes, malignancy, dementia, vitamin D deficiency, iron deficiency, chemotherapy, weight loss, abdominal pain, and lymphadenopathy. CONCLUSIONS: To our knowledge, this is the largest study to date examining the epidemiology of Whipple’s disease. In this large population-based study, the overall prevalence of Whipple’s disease in the US is 9.8 cases per 1 million people. It affects men and women at similar rates and is more common in Caucasians, non-Hispanics, and people >65 years old.

Objective Tropheryma whipplei, the causative agent of Whipple's disease, can also be identified in stool samples of humans without systemic disease. It is much more frequently detected in human stool samples in tropical environments than in industrialized countries. PCR-screening has been applied for point prevalence studies and environmental assessments in tropical settings, but results depend on the applied assay. We compared one commercial qPCR kit with two well-described in-house assays for detection of T. whipplei from stool. Methods Residual materials from nucleic acid extractions of stool samples from two groups with presumably different prevalences and increased likelihood of being colonized or infected by T. whipplei were tested. One group comprised 300 samples from study participants from western Africa (group 1); the second group was of 300 returnees from tropical deployments (group 2). Each sample was assessed with all three qPCR assays. Cycle threshold (Ct ) values were descriptively compared. Results Based solely on mathematical modeling, the three PCR assays showed considerably different detection rates of T. whipplei DNA in stool samples (kappa 0.67 (95% confidence interval [0.60, 0.73])). Considering the calculated test characteristics, prevalence of 28.3% for group 1 and 5.0% for group 2 was estimated. Discordant test results were associated with later Ct values. The study did not validate the assays for the detection of T. whipplei in Whipple's disease and for diagnostic purposes since clinical specificity and sensitivity were not investigated. Conclusions In spite of the observed diagnostic uncertainty, PCR-based screening approaches can be used for epidemiological purposes and environmental samples to define the source and reservoir in resource-limited tropical settings if prevalence is calculated using diagnostic accuracy-adjusted methods.

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 (WD) is known as an infrequent, systemic, chronic infection caused by the actinomycete Tropherima whipplei (T. whipplei). The disease is frequently characterized by a long prodromal and protean extra-intestinal phase, which often causes misdiagnosis and inappropriate treatments. Herein, we describe the case a 62-year-old man with a histological diagnosis of WD established when oral steroid treatment was started due to rheumatic manifestations, triggering intestinal symptoms. Systematic review of the literature was performed to include studies where WD was eventually diagnosed on duodenal biopsies. Three patients’ subgroups were identified according to the clinical presentation.

Background & Aims Infection with Tropheryma whipplei has a range of effects—some patients can be chronic carriers without developing any symptoms, whereas others can develop systemic Whipple disease, characterized by a lack a protective inflammatory immune response. Alterations in HLA-G function have been associated with several diseases. We investigated the role of HLA-G during T whipplei infection. Methods Sera, total RNA, and genomic DNA were collected from peripheral blood from 22 patients with classic Whipple’s disease, 19 patients with localized T whipplei infections, and 21 asymptomatic carriers. Levels of soluble HLA-G in sera were measured by enzyme-linked immuosorbent assay, and expressions of HLA-G and its isoforms were monitored by real-time polymerase chain reaction. HLA-G alleles were identified and compared with a population of voluntary bone marrow donors. Additionally, monocytes from healthy subjects were stimulated with T whipplei, and HLA-G expression was monitored by real-time polymerase chain reaction and flow cytometry. Bacterial replication was assessed by polymerase chain reaction in the presence of HLA-G or inhibitor of tumor necrosis factor (TNF) (etanercept). Results HLA-G mRNAs and levels of soluble HLA-G were significantly increased in sera from patients with chronic T whipplei infection compared with sera from asymptomatic carriers and control individuals. No specific HLA-G haplotypes were associated with disease or T whipplei infection. However, T whipplei infection of monocytes induced expression of HLA-G, which was associated with reduced secretion of TNF compared with noninfected monocytes. A neutralizing antibody against HLA-G increased TNF secretion by monocytes in response to T whipplei, and a TNF inhibitor promoted bacteria replication. Conclusions Levels of HLA-G are increased in sera from patients with T whipplei tissue infections, associated with reduced production of TNF by monocytes. This might promote bacteria colonization in patients.

Background Whipple disease (WD) is a rare disease caused by the bacterium Tropheryma whipplei (TW), which manifestations may range from joint and GI-tract involvement to severe neurological complications. Objectives To present a clinical case of WD with non-erosive seronegative polyarthritis, sacroiliitis, abdominal and CNS involvement, and immune reconstitution inflammatory syndrome after antibiotic therapy. Methods Case report. Prospective follow-up of the patient E. with WD, who was diagnosed HLA-B27-negative nonerosive seronegative rheumatoid arthritis in 2013. The disease was partially responsive to glucocorticoids with temporary effect to different DMARDs (MTX, leflunomid, etanercept, abatacept, tocilizumab either as monotherapy or in combination). Results A 54 y.o. male patient E. was admitted to the Rheumatological department with complaints of joint swelling, low back pain, weight loss, diarrhoea, headache and low grade fever. Peripheral joint arthritis appeared about 4 years ago with progressive worsening of general condition and development of additional complaints during the past year. From 2013 to 2017 the patient received in-hospital and outpatient treatment because of active seronegative polyarthritis without sufficient effect. On admission: clinical examination and joint ultrasound (US) investigation revealed the signs of polyarthritis. Neurological evaluation showed organic psychiatric disorder with signs of pseudodementia, bradykinesia without focal neurological deficits. Because of both incomplete responsiveness to DMARD-therapy and suspicion of chronic infection or malignant neoplasm, abdominal US and transthoracic echocardiography, gastroscopy, colonoscopy, immunofixation, bone marrow biopsy, chest X-ray and bone scintigraphy, tests for viral hepatitis (B,C), HIV, Lues and QFT-Tb were performed, however without objective evidence of the cause. PET-CT was performed as well, but showed no signs of malignancy or infection. MRI revealed bifrontal brain atrophy, low-grade bilateral sacroiliitis and degenerative changes of the cervical spine. For differential diagnosis PCR stool investigation for TW was performed and was positive. Upon the suspicion of WD duodenoscopy with duodenal biopsy were done. Histological examination showed PAS-positive macrophages, typical for WD. Immunohistochemical analysis also supported the diagnosis. PCR investigation of liquor and synovial fluid from ankle joint for TWi were also positive. Antibiotic treatment using a 2 week course of parenteral Ceftriaxon 2 g/day was initiated. On the third day of the treatment the patient developed immune reconstitution inflammatory syndrome with febrile temperature and increased inflammatory markers. The symptoms regressed after additional prednisolon 20 mg/day prescription. Because of organic brain syndrome, administration of Co-trimoxazole was recommended. Under the antibacterial therapy the patient had rapid positive response. PCR stool test in October 2017 didn’t detect TW. Conclusions This presentation emphasises the importance of excluding a rare infection as a cause of atypical inflammatory arthropathy. In patients with seronegative rheumatoid arthritis or axial and peripheral spondyloarthritis, who don’t adequately response to immunosuppression, Whipple disease should be taken into account. Disclosure of Interest None declared

Although neurological features are commonly encountered in Whipple"s disease (WD), presentation with purely neurological patterns is uncommon. Exclusive confinement to the central nervous system (CNS) is extremely rare. In these cases, the development of an isolated cerebral mass is exceptional. In the present paper, the authors describe a case of a 68-year-old man who presented with partial seizures. The neurological examination was normal. The imaging showed a cystic lesion. This tumor-like lesion was removed by performing frontal craniotomy. A histopathological investigation revealed the presence of numerous perivascular foamy histiocytes infiltrating the brain parenchyma. The majority of these histiocytes showed Periodic acid-schiff (PAS)-positive intense staining, which is distinctive feature of cerebral WD. The diagnosis was confirmed by polymerase chain reaction (PCR) analysis of cerebrospinal fluid. There were no gastrointestinal symptoms and no PAS inclusions in intestinal mucosa. The patient received Ceftriaxone intravenously followed by oral trimethoprime-sulfamethoxazole (TMP-SMZ) for 12 months and recovered well. This case illustrates atypical WD, confined exclusively to the central nervous system.

Se presenta el primer caso de cirugía de Whipple realizada en el Hospital Regional de Tumbes para tratamiento de ampuloma con resultado exitoso. Reporte de caso de una paciente con diagnóstico de ampuloma en la que se realizó la primera cirugía de Whipple efectuada en el Hospital Regional de Tumbes en octubre del año 2014. La paciente con diagnóstico de síndrome ictérico obstructivo por ampuloma fue sometida a cirugía de Whipple, cursó el post operatorio con mejoría paulatina, no presentó patología respiratoria, ni cursó con fiebre, la paciente toleró la vía oral, la ictericia disminuyó y fue dada de alta hospitalaria a los 13 días. Cursó con fístula pancreática de gasto bajo (30 cc/día) la cual remitió a las 3 semanas. La paciente presentó mejoría clínica evidente y con resultados quirúrgicos satisfactorios hasta la fecha. La cirugía de Whipple es la técnica quirúrgica de elección en el tratamiento del ampuloma y es factible de realizarse, en casos que lo ameriten, en hospitales de frontera si se cuenta con el personal capacitado y la logística necesaria. To report the first case of Whipple surgery performed at the Regional Hospital of Tumbes for the treatment of ampullary adenocarcinoma with successful results. A case report of a patient with diagnosis of ampullary adenocarcinoma, in whom was performed the first Whipple surgery at the Regional Hospital of Tumbes, in October, 2014. The patient diagnosed with an obstructive jaundice syndrome due to ampullary adenocarcinoma underwent Whipple surgery. She performed the postoperative period with gradual improvement, she did not present with respiratory pathology, she not have fever, the patient tolerated the oral route, the jaundice decreased and she was discharged after 13 days. She presented low-output pancreatic fistula (30 cc/day), which remitted at 3 weeks. The patient presented evident clinical improvement and satisfactory surgical results to date. Whipple surgery is the surgical technique of choice in the treatment of the ampullary adenocarcinoma and it is feasible to perform, in cases that is indicated, in bounderies hospitals if you have the trained personnel and necessary logistics.

A mutation in a transcription factor makes people susceptible to Tropheryma whipplei, the bacterium that causes a rare condition called Whipple's disease.

Whipple’s disease is a chronic, rare, multisystemic, infectious entity, described for the first time in 1907. Its aetiological agent is the Gram-negative rod, Tropheryma whipplei, which was isolated for the first time in 2001 from a cardiac valve of a patient with endocarditis. We present the case of a 71-year-old man, who came into the emergency room complaining of anorexia, weakness, abdominal pain and diarrhoea with haematochezia and presented disseminated palpable purpuric lesions, predominantly in the lower limbs. The upper endoscopy showed a duodenal vasculitis and the biopsy of that location revealed aspects suggestive of Whipple’s disease. We started him on antibiotics according to the recent orientations with progressive clinical and analytical improvement, although he developed an immune reconstitution syndrome, which lasted for 2 weeks.

A 72-year-old man presented with anorexia and 15-kg weight loss over 3 years. Endoscopy revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum. Biopsy specimens showed massive infiltration of periodic acid-Schiff-positive macrophages in the lamina propria, consistent with Whipple's disease. The patient was treated with intravenous ceftriaxone for four weeks, followed by oral trimethoprim-sulfamethoxazole. His condition improved, and he gradually gained weight. Although the endoscopic findings improved with continuous trimethoprim-sulfamethoxazole administration, macrophage infiltration of the duodenal mucosa persisted. However, the patient has been symptom-free for eight years.

Although it is an orphan disease, isolated central nervous system Whipple's disease is one of the "must be known" conditions in neurology because it belongs to the list of "treatable disorders". Here, we present two cases which highlight the importance of early diagnosis. Additionally, we provide a discussion on up to date diagnostic approach to this life-threatening disorder.

Whipple's disease, a systemic, chronic infectious disease caused by Tropheryma whipplei, is extremely rare in Asian populations. A correct diagnosis is necessary due to its high mortality rate. Unfortunately, patients are apt to be misdiagnosed with connective tissue diseases since they typically present with arthritis or arthralgia. There are three diagnostic tools for Whipple's disease using intestinal tissues: 1) periodic acid-Schiff (PAS)-positive macrophages; 2) electron microscopic observation; and 3) polymerase chain reaction (PCR). It is challenging to diagnose this disease in the absence of histological findings, especially in Japan, where the clinical protocol currently used to make the diagnosis needs improvement, although symptomology and PCR results may be sufficient. Herein, we investigated a 24-year-old Japanese woman who had suffered from intermittent fever, migratory arthralgia, and watery diarrhea for several months. Her biopsied intestinal tissue was negative for foamy macrophages and PAS-positive cells, and electron microscopy did not provide diagnostic insight. PCR amplification of the specimens, however, successfully revealed T. whipplei. Whipple's disease was diagnosed based on a positive PCR result and strong clinical suspicion. The patient was treated parenterally with ceftriaxone (2 g daily) for two weeks, followed by oral treatment with 160 mg trimethoprim and 800 mg sulfamethoxazole twice per day. After one month of treatment, her symptoms disappeared and inflammatory markers returned to normal levels. This case illustrates the practicality and effectiveness of a PCR-based diagnostic test in combination with clinical suspicion to correctly diagnose Whipple's disease, especially in cases when a histological examination does not provide insight.

Department of Rheumatology, Tokyo Metropolitan TamaMedical Center, Fuchu City, Tokyo, Japan; Division of Infectious Diseases, Tokyo Metropolitan TamaMedical Center, FuchuCity, Tokyo, Japan; Division of Rheumatology, NagoyaMedical Center, Nagoya, Japan; University of California, San Francisco, San Francisco, CA, USA; Faculte de Medecine, Unite des Rickettsies, Marseille, France; Japan Community Healthcare Organization, Tokyo, Japan.