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Whipple disease caused by Tropheryma whipplei a gram-positive bacterium is a systemic disorder that impacts not only the gastrointestinal tract but also the vascular system, joints, central nervous system, and cardiovascular system. Due to the lack of an approved vaccine, this study aimed to utilize immunoinformatic approaches to design multiepitope -based vaccine by utilizing the proteomes of five representative T. whipplei strains. The genomes initially comprised a total of 4,844 proteins ranging from 956 to 1012 proteins per strain. We collected 829 nonredundant lists of core proteins, that were shared among all the strains. Following subtractive proteomics, one extracellular protein, WP_033800108.1, a WhiB family transcriptional regulator, was selected for the chimeric-based multiepitope vaccine. Five immunodominant epitopes were retrieved from the WhiB family transcriptional regulator protein, indicating MHC-I and MHC-II with a global population coverage of 70.61%. The strong binding affinity, high solubility, nontoxicity, nonallergenic properties and high antigenicity scores make the selected epitopes more appropriate. Integration of the epitopes into a chimeric vaccine was carried out by applying appropriate adjuvant molecules and linkers, leading to the vaccine construct having enhanced immunogenicity and successfully eliciting both innate and adaptive immune responses. Moreover, the abilityof the vaccine to bind TLR4, a core innate immune receptor, was confirmed. Molecular dynamics simulations have also revealed the promising potential stability of the designed vaccine at 400 ns. In summary, we have designed a potential vaccine construct that has the ability not only to induce targeted immunogenicity for one strain but also for global T. whipplei strains. This study proposes a potential universal vaccine, reducing Whipple's disease risk and laying the groundwork for future research on multi-strain pathogens., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction. Tropheryma whipplei is responsible for the classical Whipple's disease. Recently, a new Tropheryma species was described in a Belgian immunocompromised patient with pleuritis. Gap Statement. There is currently no specific molecular diagnostic test detecting other Tropheryma species than Tropheryma whipplei . Aim. To develop and validate two broad-range pan- Tropheryma genus PCRs detecting both T. whipplei and new Tropheryma species. Methodology. From shotgun sequencing data of the lung tissue biopsy of the Belgian subject, we designed two PCRs targeting the 23S rRNA and rnpB genes. Prospectively, requests for T. whipplei PCR were tested with T. whipplei -specific PCRs and the two Tropheryma broad-range PCRs from January 2019 to November 2022. Results. In total, 2605 samples were tested using both the pan- Tropheryma 23S rRNA PCR and the T. whipplei -specific PCR. In addition, 833 of the 2605 samples were also tested using the pan- Tropheryma rnpB PCRs. Sensitivity was 78.8% and 79.7% for 23S rRNA and rnpB PCRs, as compared with the species-specific T. whipplei PCR. Specificity was 99.9% and 99.7% for the 23S rRNA and the rnpB PCRs, respectively. We identified a patient whose bronchoalveolar lavage tested positive with the two broad-range PCRs with >10 5 copies ml -1 . Specific T. whipplei PCRs were negative. Known for panuveitis, this 49-year-old male presented with an eye inflammation recurrence, and a CT scan showed multiple mediastino-hilar necrotic adenopathies. Doxycyclin (1 year), hydroxychloroquin (1 year) and co-trimoxazol (1 month) treatments led to a favourable outcome. Conclusion. Specific T. whipplei PCR exhibited better sensitivity than the pan- Tropheryma PCRs. However, both broad-range pan- Tropheryma PCRs demonstrated excellent specificity and were pivotal to identifying a new probable case of Tropheryma infection due to another species-level lineage.

Tropheryma whipplei is the causative agent of Whipple's disease, which is a rare multiorgan systemic disease. We report two cases of Tropheryma whipplei infection, all routine tests were negative and it was finally detected by mNGS. This may help clinicians increase awareness of the diagnosis and treatment of acute severe pneumonia and interstitial pneumonia caused by Tropheryma whipplei., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Whipple disease is a rare systemic illness associated with weight loss, diarrhea, and arthralgia. Asymptomatic carriage is common, but the disease can be complicated by cardiac involvement and may result in culture-negative endocarditis. Cardiac manifestations of the disease can lead to death. This report presents the case of a 66-year-old man with Whipple disease and biventricular heart failure with cardiogenic shock. Medical therapy followed by successful replacement of the aortic and mitral valves resulted in substantial improvement., (© 2024 The Authors. Published by The Texas Heart Institute®.)

Whipple's disease is a chronic systemic infectious disease that mainly affects the gastrointestinal tract. In some cases, Tropheryma whipplei can cause infection at the implant site or even throughout the body. In this study, we collected alveolar lavage fluid samples from patients with Tropheryma whipplei from 2020 to 2022, and retrospectively analyzed the clinical data of Tropheryma whipplei positive patients. Patient's past history, clinical manifestations, laboratory examinations, chest CT findings, treatment, and prognosis were recorded. 16 BALFs (70/1725, 4.0 %) from 16 patients were positive for Tropheryma whipplei. 8 patients were male with an average age of 50 years. The main clinical symptoms of patients included fever (9/16), cough (7/16), dyspnea (7/16), and expectoration (5/16), but neurological symptoms and arthralgia were rare. Cardiovascular and cerebrovascular diseases were the most common comorbidity (n=8). The main laboratory characteristics of the patient are red blood cell count, hemoglobin, total protein and albumin below normal levels (11/16), and/or creatinine above normal levels(14/16). Most chest computed tomography mainly show focal or patchy heterogeneous infection (n=5) and pleural effusion (n=8). Among the 6 samples, Tropheryma whipplei was the sole agent, and Klebsiella pneumoniae was the most common detected other pathogens. Metagenomic next-generation sequencing technology has improved the detection rate and attention of Tropheryma whipplei. Further research is needed to distinguish whether Tropheryma whipplei present in respiratory samples is a pathogen or an innocent bystander., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Whipple disease (WD) is a rare infection in genetically susceptible people caused by the bacterium Tropheryma whipplei. An indirect immunofluorescence serological assay (IFA), detecting patient antibodies to the bacterium, was developed using T. whipplei as antigen. We hypothesised that this assay could be used to rule out WD in patients in whom the diagnosis was being considered, based on high immunoglobulin (Ig) G titres to T. whipplei. In this study, 16 confirmed WD patients and 156 age-matched controls from across Australia were compared serologically. WD patients mostly underproduced IgG antibody to T. whipplei, with titres of ≤1:32 being common. While at an antibody titre of <1:64 the assay sensitivity for WD was only 69% [95% confidence interval (CI) 41-89%], its specificity for excluding WD was 91% (95% CI 85-95%). This specificity increased to 95% (95% CI 90-98%) at an antibody titre of <1:16. Patients with antibody titres of >1:64 were unlikely to have WD. At this titre, the seroprevalence of T. whipplei IgG antibody was 92% (223/242) in Australian blood donors. Unlike other serological assays, which are used to confirm a specific infection, this novel assay is designed to rule out WD infection with a specificity in Australia of 91%. Further validation of this assay, by trialling in other countries, should now be undertaken, as its usefulness is dependent on there being a high background seropositivity to T. whipplei in the general population at the location in which the assay is being used., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Abstract: Whipple disease is a rare disorder caused by infection with the gram-positive bacterium Tropheryma whipplei . It can invade various organs and systems of the whole body. This case report describes a patient with invasion of multiple lymph nodes throughout the body misdiagnosed as lymphoma by PET/CT., Competing Interests: Conflicts of interest and sources of funding: This work was supported by grants from the NSFC Incubation Program of GDPH (KY012021162) and the Guangdong Provincial Medical Science and Technology Research Fund Project (B2023004)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of interests TW received honoraria for lectures from Bayer, GlaxoSmithKline and Novartis, and from Retrophin, USA for advisory board activities. PFZ received consulting fees from Eleva and Novartis, and honoraria from Alexion and Bayer. JK holds shares from MoKi Analytics. AM received speaker honoraria from, Chiesi and Biomerieux and holds shares in Moter Diagnostics and MoKi Analytics. EH received fees from Morphosys, Planegg, Germany and Novartis, Basel, Switzerland for advisory board activities. RAKS received fees from Morphosys, Planegg, Germany for advisory board activities. DS received honoraria for lectures and advisory board activities from Alexion, GlaxoSmithKline, Travere Therapeutics, and Astellas. All other authors declare no competing interests.

Whipple's disease is a chronic and systemic disease caused by the Gram-positive bacterium Tropheryma whipplei that primarily affects the gastrointestinal tract. Data from the last two decades have substantially increased our knowledge of the spectrum and our understanding of T whipplei infections. Although T whipplei seems ubiquitously present in the environment, Whipple's disease itself is very rare. Remarkably, primary infections can be symptomatic, but most cases result in bacterial clearance and seroconversion. However, some individuals are unable to clear the bacterium leading to persistence and asymptomatic carriage. In very rare cases, which might be associated with a subtle immune defect, T whipplei replication is uncontrolled and manifests as classical Whipple's disease or T whipplei localised infections. In this review, we provide a comprehensive outline of T whipplei infection, including the epidemiology, clinical manifestations, diagnosis, and treatment. We also provide an up-to-date overview of our understanding of the host immune response and pathophysiology and discuss future research avenues to resolve the lacking pieces of the puzzle of T whipplei infections., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2021. Published by Elsevier Ltd.)

Tropheryma whipplei , is an actinobacterium that causes different infections in humans, including Whipple's disease. The bacterium infects and replicates in macrophages, leading to a Th2-biased immune response. Previous studies have shown that T. whipplei harbors complex surface glycoproteins with evidence of sialylation. However, the exact contribution of these glycoproteins for infection and survival remains obscure. To address this, we characterized the bacterial glycoprofile and evaluated the involvement of human β-galactoside-binding lectins, Galectin-1 (Gal-1) and Galectin-3 (Gal-3) which are highly expressed by macrophages as receptors for bacterial glycans. Tropheryma whipplei glycoproteins harbor different sugars including glucose, mannose, fucose, β-galactose and sialic acid. Mass spectrometry identification revealed that these glycoproteins were membrane- and virulence-associated glycoproteins. Most of these glycoproteins are highly sialylated and N-glycosylated while some of them are rich in poly-N-acetyllactosamine (Poly-LAcNAc) and bind Gal-1 and Gal-3. In vitro, T. whipplei modulates the expression and cellular distribution of Gal-1 and Gal-3. Although both galectins promote T. whipplei infection by enhancing bacterial cell entry, only Gal-3 is required for optimal bacterial uptake. Finally, we found that serum levels of Gal-1 and Gal-3 were altered in patients with T. whipplei infections as compared to healthy individuals, suggesting that galectins are also involved in vivo . Among T. whipplei membrane-associated proteins, poly-LacNAc rich-glycoproteins promote infection through interaction with galectins. T. whipplei modulates the expression of Gal-1 and Gal-3 both in vitro and in vivo . Drugs interfering with galectin-glycan interactions may provide new avenues for the treatment and diagnosis of T. whipplei infections.

Significance: Whipple disease is a rare chronic, systemic bacterial infection that predominantly affects the small intestine but also other organs of the body. When left untreated, it can be not only vision threatening but also life threatening because of its central nervous system involvement. Therefore, early detection and treatment are important., Purpose: We report a rare case of unilateral optic disc edema as a critical identifying sign of Whipple disease., Case Report: An asymptomatic 49-year-old African American man presented for an eye examination and was found to have optic nerve edema of the right eye. His best-corrected visual acuity was 20/20 in the right and left eye. He denied symptoms of diplopia, amaurosis fugax, or eye pain. His medical history was significant for HIV with no recent detectable viral load at the time of his eye examination. The patient denied any other infectious risk factors or changes in medical status. Extensive ophthalmic, neuroimaging, and laboratory investigations were completed as a comprehensive approach to rule out more common etiologies for unilateral optic disc edema. This initial workup yielded no identifying etiology, and the patient was monitored closely with frequent examinations with a retina specialist. Soon after his diagnosis of optic nerve edema, the patient developed new symptoms of chronic diarrhea, weight loss, and fatigue requiring hospitalization. Evaluations by internal medicine and gastroenterology, including serological testing, stool analysis, histological and microbiological analysis, esophagogastroduodenoscopy, and gastrointestinal biopsy, confirmed a diagnosis of Whipple disease that was successfully treated with oral antibiotics., Conclusions: Whipple disease is a rare cause of infectious optic nerve edema that may present with other rheumatoid and gastrointestinal symptoms. A comprehensive medical approach for investigating unilateral optic nerve edema is paramount in diagnosing and treating Whipple disease.

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.

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.

Background: 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., Case Report: 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., Conclusion: 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.

Introduction: 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.

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., Competing Interests: The authors have declared that no competing interests exist.

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 (C t ) 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 C t 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., (© 2018 John Wiley & Sons Ltd.)

Background: Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA., Aims: To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection., Methods: Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids., Results: Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11-75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%)., Conclusions: TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.

Purpose of Review: 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., Recent Findings: 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., Summary: 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.

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., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: 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., Objective: Our objective was to evaluate additional diagnostic possibilities for WD., Methods: 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., Results: 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., Conclusion: 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.

Objectives: To determine when Tropheryma whipplei polymerase chain reaction (PCR) is appropriate in patients evaluated for rheumatological symptoms., Methods: In a retrospective observational study done in rheumatology units of five hospitals, we assessed the clinical and radiological signs that prompted T. whipplei PCR testing between 2010 and 2014, the proportion of patients diagnosed with Whipple's disease, the number of tests performed and the number of diagnoses according to the number of tests, the patterns of Whipple's disease, and the treatments used. Diagnostic ascertainment was based on 1- Presence of at least one suggestive clinical finding; 2- at least one positive PCR test, and 3- a response to antibiotic therapy described by the physician as dramatic, including normalization of C Reactive Protein., Results: At least one PCR test was performed in each of 267 patients. Rheumatic signs were peripheral arthralgia (n = 239, 89%), peripheral arthritis (n = 173, 65%), and inflammatory back pain (n = 85, 32%). Whipple's disease was diagnosed in 13 patients (4.9%). The more frequently positive tests were saliva and stool. In the centres with no diagnoses of Whipple's disease, arthritis was less common and constitutional symptoms more common. The group with Whipple's disease had a higher proportion of males, older age, and greater frequency of arthritis. The annual incidence ranged across centres from 0 to 3.6/100000 inhabitants., Conclusion: Males aged 40-75 years with unexplained intermittent seronegative peripheral polyarthritis, including those without constitutional symptoms, should have T. whipplei PCR tests on saliva, stool and, if possible, joint fluid., Competing Interests: The authors have declared that no competing interests exist.

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance., Competing Interests: AG, GK, NM, JM, FF, NW, SB, DA, CM, SB, MB, VB, ED, CO, TL, LW, TN, EP, CD, RM, SB, XA, SE, SB, VR, BB, GV, FG, LQ, DC, ST, DR, LA, JB, JC No competing interests declared, (Copyright © 2018, Guérin et al.)

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., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Whipple's disease is considered an infection of middle-aged white men of European ancestry. Cases are rare and disproportionately associated with occupational exposure to soil or animals. We report the case of a man aged 22 years with no risk factors, erroneously diagnosed with, and treated for, toxoplasmosis on the basis of consistent lymph node histology. The correct diagnosis was delayed by the dramatic symptomatic improvement resulting from this therapy. Whipple's disease should be considered in cases of granulomatous lymphadenopathy of unknown cause, even if the age of the patient does not fit the classic presentation of the disease., (2017 BMJ Publishing Group Ltd.)

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.

In recent years, it has become apparent that Tropheryma whipplei not only causes a chronic multisystemic infection which is often preceded by arthropathies for many years, well known as 'classical' Whipple's disease, but also clinically becomes manifest with localized organ affections and acute (transient) infections in children. T. whipplei is found ubiquitously in the environment and colonizes in some healthy carriers. In this review, we highlight new aspects of this enigmatic infectious disorder.

Whipple's disease (WD) is a rare infection caused by the bacterium Tropheryma whipplei that can affect multiple organs and most commonly occurs in the immunocompetent host. Only 3 cases of WD have been reported in the setting of immunosuppression for organ transplantation. Here, we report the first case of WD, to our knowledge, in a patient after liver transplantation with comorbid graft-versus-host-disease. We discuss the diagnostic challenges in this setting and the value of electron microscopy and in situ hybridization methods for confirming the infection. WD may be under-diagnosed in immunosuppressed transplant patients because the disease can present with atypical clinical and histological features that suggest other conditions., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The bacterium Tropheryma whipplei, which causes Whipple disease in humans, is commonly detected in the feces of persons in Africa. It is also associated with acute infections. We investigated the role of T. whipplei in febrile patients from 2 rural villages in Senegal. During June 2010-March 2012, we collected whole-blood finger-prick samples from 786 febrile and 385 healthy villagers. T. whipplei was detected in blood specimens from 36 (4.6%) of the 786 febrile patients and in 1 (0.25%) of the 385 apparently healthy persons. Of the 37 T. whipplei cases, 26 (70.2%) were detected in August 2010. Familial cases and a potential new genotype were observed. The patients' symptoms were mainly headache (68.9%) and cough (36.1%). Our findings suggest that T. whipplei is a cause of epidemic fever in Senegal.

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

Whipple's disease is a rare infection caused by Tropheryma whipplei, a Gram-negative Bacillus usually found in macrophages of the lamina propria of the small intestine. The typical clinical manifestations of classic Whipple's disease are diarrhea, weight loss, malabsorption, abdominal pain, and arthralgia. The disease's laboratory diagnosis is currently based on duodenal biopsy. Treatment generally includes primary therapy for 2 weeks with intravenous antibiotics capable of reaching high levels in the cerebrospinal fluid, such as ceftriaxone, usually followed by treatment with oral cotrimoxazole for 1 year. Early diagnosis should enable appropriate treatment and improves the prognosis, and prolonged antibiotic treatment often leads to complete remission. Our case report focuses on a 72-year-old man who had been passing watery stools for 1-2 months, accompanied by low-grade fever. He reported profound asthenia, a weight loss of about 3 kg, and loss of appetite. Thirty years earlier (in 1984), he had been working as a horse keeper at a University Department of Agricultural and Veterinary Studies, where he had contracted Whipple's disease. Laboratory tests and microbiological studies led to a diagnosis of recurrent Whipple's disease. Esophagogastroduodenoscopy was performed under deep sedation. Biopsy samples obtained from the stomach and duodenum were stained with hematoxylin and eosin, Giemsa, and periodic acid-Schiff to identify any accumulation of typical periodic acid-Schiff-positive macrophages in the lamina propria. A specific quantitative real-time PCR assay using specific oligonucleotide probes for targeting repeated sequences of Tropheryma whipplei was also performed to detect its DNA in the duodenum samples.

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tropheryma whipplei has been hypothesized to be able to cause diarrhoea, but data from young children are scarce. In this hospital-based case-control study 534 stool samples of children aged between 2 months and 15 years from rural Ghana were analysed for the presence of T. whipplei. Overall stool prevalence of T. whipplei was high (27.5%). Although there was no difference in T. whipplei carriage overall between cases and controls, cases aged between 0 and 12 months carried T. whipplei in their stool twice as often as controls without diarrhoea. The results from this study may support the hypothesis that T. whipplei can cause diarrhoea in first-time infection., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)