Tropheryma whipplei (TW) pneumonia is a rare disease caused by Tropheryma whipplei infection. Due to the difficulty in obtaining pathogenetic evidence, the misdiagnosis rate is high, posing significant challenges for early diagnosis and treatment. Targeted sequencing technology based on nanopore sequencing technology (tNGS) allows for detecting rare pathogens that are difficult to identify using traditional methods, leading to improved detection rates for TW. This paper reports a case of pneumonia diagnosed as a TW infection through the use of tNGS on bronchoalveolar lavage fluid (BALF), with the patient showing improvement after treatment with sequential administration of meropenem followed by compounded sulfamethoxazole.

To analyse the joint manifestations of Whipple's disease and compare clinical isolated joint involvement (CIJI) with systemic joint involvement (SJI).

A cohort study included patients diagnosed with Whipple's disease and joint involvement at two expert centres. Patients were divided according to their clinical presentation at diagnosis: those with CIJI and those with SJI.

Of the 60 patients, 17 (28 %) exhibited CIJI. Both groups were predominantly middle-aged men (75 %) with a median time to diagnosis of six (2-11) years. Joint involvement was similar, with initial episodic migratory arthritis (91 %) predominantly affecting large joints and lasting 2-7 days. Saliva and stool PCR tests were positive in 59 % and 75 % of CIJI patients, respectively, compared to 91 % and 88 % in the SJI group (P = 0 02 and P = 0 24, respectively). In CIJI patients, duodenal PCR was negative in 65 % of cases and PAS staining consistently negative. Synovial fluid PCR was positive in 100 % of CIJI and 89 % of SJI patients. Treatment with doxycycline and hydroxychloroquine, initiated in 52 (88 %) patients, resulted in resolution of joint symptoms within ten (7-15) days in all but one patient, who had destructive arthritis.

Whipple's disease can present with isolated articular forms. Joint involvement is usually inaugural and stereotypical, with little difference between the CIJI and SJI groups. The diagnosis should be considered in cases with the typical pattern of recurrent intermittent large joint arthritis with elevated acute phase reactants, particularly in middle-aged men. Synovial fluid PCR is a valuable diagnostic tool. Doxycycline and hydroxychloroquine resulted in dramatic improvement.

Whipple's disease (WD), triggered by Tropheryma whipplei ( T. whipplei ), is a rare, chronic, inflammatory, systemic infectious disease that typically manifests in adults. The most frequent initial manifestations include arthritis, followed by diarrhea, abdominal pain, and weight loss. Half the world's population is exposed to T. whipplei , but only one in a million develop WD. This suggests that acquired or inborn errors of immunity (IEI) may underlie WD. Anti-TNF treatment is a well established risk factor for flare-ups of WD.

We have also reported two rare IEI in patients with WD. Six WD patients from two unrelated kindreds were found to have autosomal dominant IRF4 deficiency acting via a mechanism of haploinsufficiency. These patients were otherwise healthy. In addition, a single patient with a history of WD and other infections was found to have autosomal recessive CD4 deficiency.

Rare IEI can underlie WD. Human genetic studies of patients with WD are warranted for the development of precision medicine for affected kindreds and to improve our understanding of the pathogenesis of this rare infectious disease.

Previous studies have shown that intravenous ceftriaxone or meropenem for 14 days, followed by oral trimethoprim-sulfamethoxazole for 1 year, cures 98% of people with Whipple's disease. However, intravenous therapy requires hospitalisation and carries risks for treatment-associated complications. The aim of this study was to investigate whether oral-only treatment for Whipple's disease is non-inferior to intravenous therapy.

This phase 2/3, prospective, open-label, randomised, controlled, non-inferiority trial enrolled individuals aged 18 years or older with confirmed Whipple's disease from across Germany who had received treatment for less than 1 month at Charité-Universitätsmedizin Berlin. Participants were randomly assigned (1:1) with block randomisation to receive either intravenous ceftriaxone (2 g once per day) for 14 days, followed by oral trimethoprim-sulfamethoxazole (960 mg twice per day) for 12 months, or oral doxycycline (100 mg twice per day) plus hydroxychloroquine (200 mg twice per day) for 12 months. Ten participants who had already received intravenous ceftriaxone were non-randomly assigned to the intravenous treatment group. Participants in the oral-only treatment group were PCR-positive for Tropheryma whipplei in cerebrospinal fluid received trimethoprim-sulfamethoxazole (960 mg five times per day) until clearance. The primary outcome was complete clinical remission without recurrence during the observation period of 24 months, assessed in the intention-to-treat (ITT) population. The prespecified non-inferiority margin was -18%. Safety was a secondary endpoint, assessed in the ITT population. The study was registered with the EU Clinical Trials Register, EudraCT 2008-003951-54, and is completed.

Between May 26, 2010, and Oct 30, 2018, we screened 310 individuals and enrolled 64 participants in the study. After exclusion of four individuals whose diagnosis was not confirmed, 31 participants were assigned to the intravenous treatment group and 29 to the oral-only treatment group. By ITT, 25 (81%) of 31 participants in the intravenous treatment group and 28 (97%) of 29 participants in the oral-only treatment group had complete clinical remission without recurrence. The risk difference was 15·9 percentage points (95% CI -1·2 to 33·1), with the lower bound of the 95% CI above our non-inferiority margin of -18%. A post-hoc per-protocol analysis confirmed the non-inferiority of oral-only treatment. No participant relapsed, but two participants in the intravenous treatment group died from nosocomial infections. Serious adverse events occurred in 13 (42%) of 31 participants in the intravenous treatment group and eight (28%) of 29 participants in the oral-only treatment group, but this difference was not statistically significant (p=0·244).

Oral-only treatment of Whipple's disease was safe and non-inferior to sequential intravenous-oral treatment. Oral treatment facilitates patient management and might reduce hospital-acquired treatment complications and costs.

German Research Foundation and the Robert Koch Institute.

For the German translation of the abstract see Supplementary Materials section.

Tropheryma whipplei (T. whipplei) infection can be difficult to diagnose due to its variable clinical manifestations and the limitations of standard diagnostic tests. This case describes a 78-year-old male with blurry vision and floaters in his right eye five months after cataract surgery, along with new onset weight loss and arthralgias. Ophthalmologic examination revealed inflammation and posterior vitritis, and vitreous biopsy identified T. whipplei via broad-range bacterial PCR, despite negative vitreous cultures and unremarkable flow cytometry. Gastrointestinal endoscopic and cerebrospinal fluid studies revealed no pathological or molecular evidence of the disease, complicating the diagnosis. Treatment with intravenous ceftriaxone followed by oral trimethoprim-sulfamethoxazole for 12 months resulted in resolution of symptoms and inflammation, with normalization of laboratory markers. This case underscores the diagnostic utility of broad-range bacterial PCR in atypical infections and highlights Whipple infection as a differential diagnosis in ocular presentations. Comprehensive interdisciplinary evaluation was critical for effective management.

Whipple's disease, an extremely rare, chronic infection caused by Tropheryma whipplei, an actinobacterium ubiquitously present in the environment, is a multisystemic condition that can affect several organs. Therefore, Whipple's disease should always be considered by physicians working across various branches of medicine, including internal medicine, rheumatology, infectious diseases, gastroenterology, haematology, and neurology. Initially, Whipple's disease is challenging to diagnose due to both its rarity and non-specific clinical features, almost indistinguishable from rheumatological conditions. A few years later, the onset of gastrointestinal symptoms increases the specificity of its clinical picture and helps in reaching the correct diagnosis. Diagnosis is typically made by finding PAS-positive macrophages in the lamina propria at duodenal biopsy. PCR for Tropheryma whipplei is nowadays also increasingly available, and represents an undeniable help in diagnosing this condition. However, it may also be misleading as false positives can occur. If not promptly recognized and treated, central nervous system involvement may develop, which can be fatal. The therapeutic gold standard has not yet been fully established, particularly in cases of recurrent disease, neurological involvement, and an immune reconstitution inflammatory syndrome that may arise following the initiation of antibiotic therapy.

Whipple's disease caused by Tropheryma whipplei is difficult to diagnose because of a broad spectrum of manifestations and non-specific clinical signs. In the current global era, the incidence of duodenal infection/inflammation caused by T. whipplei in Korea may has been underestimated. Here we estimated the prevalence of T. whipplei in duodenal biopsy tissues of Koreans using real-time PCRs (RT-PCRs). A total of 252 duodenal biopsy tissues were collected from Korean patients who underwent esophagogastroduodenoscopy and duodenal biopsy. DNA extracted from the duodenal biopsy tissues was analyzed using three RT-PCRs targeting T. whipplei-specific regions of the 16S-23S rRNA intergenic spacer, hsp65, and Dig15 in parallel. In the samples positive in RT-PCRs, direct sequencing was performed for each RT-PCR target. The prevalence of T. whipplei was estimated based on the RT-PCR and sequencing results. Among the analyzed samples, T. whipplei was not detected. The prevalence of T. whipplei in duodenal biopsy tissues of Koreans was estimated to be less than 0.4%. This is the first study to attempt to detect T. whipplei in duodenal biopsy tissues of Koreans and estimate its prevalence. Our findings infer that while T. whipplei carriers exist in Korea, the incidence of duodenal infection/inflammation caused by T. whipplei is extremely rare.

Kidney transplantation is the standard treatment for end-stage renal disease. Particularly, rare and specific pathogenic infections which are asymptomatic are often difficult to diagnose, causing delayed and ineffective treatment and thus seriously affecting prognosis. Tropheryma whipplei (T. whipplei) is a Gram-positive actinomycete widely found in soil, sewage, and other external environments and is present in the population as an asymptomatic pathogen. There is relatively little documented research on T. whipplei in renal transplant patients, and there are no uniform criteria for treating this group of post-transplant patients. This article describes the treatment of a 42-year-old individual with post-transplant T. whipplei infection following kidney transplantation.

To analyze clinical features of Whipple's disease and summarize its diagnosis and treatment effects after renal transplantation. Clinical data of a Whipple's disease patient treated in the affiliated hospital of Guizhou Medical University were collected and assessed retrospectively. The treatment outcomes and clinical experience were then summarized via literature review. The patient was admitted to the hospital due to recurrent diarrhea for 1 mo, shortness of breath, and 1 wk of fever, after 3 years of renal transplantation. The symptoms of the digestive and respiratory systems were not significantly improved after adjusting immunosuppressive regimen and anti-diarrheal, empirical antibiotic treatments. Bronchoscopic alveolar fluid was collected for meta-genomic next-generation sequencing (mNGS). The deoxyribonucleic acid sequence of Tropheryma whipplei was detected, and Whipple's disease was diagnosed. Meropenem, ceftriaxone, and other symptomatic treatments were given, and water-electrolyte balance was maintained. Symptoms resolved quickly, and the patient was discharged after 20 d of hospitalization. The compound sulfamethoxazole tablet was continued for 3 mo after discharge. No diarrhea, fever, and other symptoms occurred during the 6-month follow-up.

Whipple's disease is rare, with no specific symptoms, which makes diagnosis difficult. Polymerase chain reaction or mNGS should be immediately performed when the disease is suspected to confirm the diagnosis.