Novel Patterns in High-Resolution Computed Tomography in Whipple Pneumonia.

With the use of metagenomic next-generation sequencing, patients diagnosed with Whipple pneumonia are being increasingly correctly diagnosed. We report a series of 3 cases in China that showed a novel pattern of movable infiltrates and upper lung micronodules. After treatment, the 3 patients recovered, and lung infiltrates resolved.

Whipple's disease: Rare case of malabsorption with hyperpigmentation in a female.

Whipple's disease is a multisystem disorder and responds well to antibiotic therapy if treated timely. It is seen in the fourth to fifth decades of life with a male to female ratio of 10:1. It mainly affects the intestine, the central nervous system, and joints. To the best of our knowledge, we present the first case of duodenal Whipple's disease in an Indian female, who presented with hyperpigmentation and chronic diarrhea with malabsorption. Whipple's disease was diagnosed based on specific upper GI endoscopic and histopathology findings.

Whipple disease: a 15-year retrospective study on 36 patients with positive polymerase chain reaction for Tropheryma whipplei.

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.

Case Report: Tropheryma whipplei Infection Presenting with Optic Disc Edema.

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.

Unintentional weight loss as presenting form of Whipple's disease. Role of PET-CT scanning and review of the literature

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Another Whipple's triad? Pericardial, myocardial and valvular disease in an unusual case presentation from a Canadian perspective.

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.

Comparison of screening tests without a gold standard-A pragmatic approach with virtual reference testing.

Well-defined diagnostic gold standards are rarely available for the diagnosis of rare diseases such as some tropical infections. Algorithms for reliable test evaluation without gold standard are therefore desirable. On the basis of previous work of Gart and Buck (1966); Rogan and Gladen (1978), and Hui and Walter (1980), a modeling approach for the comparison of diagnostic tests without a gold standard - and thus without reliably characterized reference sample material - is established especially for situations not fulfilling the requirement of conditional independence of the diagnostic tests evaluated. In the approach introduced, each test is conducted within two populations with different values of prevalence and the test results are used to define two virtual reference tests. The model is useful for the comparison of tests for rare tropical diseases where no gold standard can be provided.

[Whipple's disease: very rare, fatal without treatment but easily cured]. / Whipples sjukdom: sällsynt, dödlig utan behandling, men lätt botad.

Whipple's disease is a chronic infectious disease that primarily affects the small intestine, but several organs can be involved simultaneously. The disease is caused by a gram-positive bacterium called Tropheryma whipplei. The disease is difficult to suspect because it is rare, and produces unspecific and long-term symptoms. Whipple's disease can lead to death if not treated. We here present a case of a man who presented with gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy and who was finally diagnosed with Whipple's disease 4 years after the occurrence of manifestations from the joints. The diagnosis was made both with 16S rRNA against Tropheryma whipplei and histopathologically from biopsy taken from the duodenum and distal ileum. The purpose of this case report is to raise awareness of a very rare disease that presented with a combination of symptoms similar to other and significantly more common diseases.

Enfermedad de Whipple: cuando la diarrea está ausente / Whipple's disease: when diarrhea is absent

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Tropheryma whipplei intestinal colonization in Italian and migrant population: a retrospective observational study.

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.

Whipple's disease in a man of North African descent : case report and brief review of the literature.

A 62-year-old man of North African descent presented with weight loss in the past year and diarrhea for three weeks. His medical history included erosive rheumatoid arthritis, treated with methotrexate and adalimumab. Histological examination of a duodenal biopsy showed foamy macrophages in the lamina propria, with PAS-positive cytoplasmatic inclusions. These findings are compatible with Whipple's disease, a rare chronic infectious disease caused by Tropheryma whipplei, an opportunistic bacterium. It is typically seen in middle-aged Caucasian men and the immunocompromised host. The classical presentation of Whipple's disease consists of intermittent migratory arthralgia, followed by intestinal symptoms which typically occur six to seven years later. The clinical image can be very variable, and this complicates the diagnostic process. PAS-staining and PCR are the diagnostic cornerstones. In our case, treatment consisted of a prolonged cure of antibiotics: intravenous ceftriaxone for two weeks, followed by an oral maintenance therapy of doxycycline and hydroxychloroquine for at least one year. A therapeutic dilemma arose as continued anti-TNF blockade was necessary to maintain remission of the rheumatoid arthritis. Lifelong follow-up is necessary because relapse is possible.

Fluorescent in situ hybridization can be used as a complementary assay for the diagnosis of Tropheryma whipplei infection.

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.

Potential Role for Urine Polymerase Chain Reaction in the Diagnosis of Whipple's Disease.

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

Tropheryma whipplei Infection (Whipple Disease) in the USA.

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.

Limbic encephalitis as a relapse of Whipple's disease with digestive involvement and spondylodiscitis.

INTRODUCTION: Many clinical manifestations can be related to Tropheryma whipplei infection. CASE REPORT: We report a Tropheryma whipplei limbic encephalitis developed as a relapse of classical Whipple's disease. DISCUSSION: This case is to the best of our knowledge the first proof of the effective brain-blood barrier crossing of both doxycycline and hydroxychloroquine as demonstrated by direct concentration monitoring on brain biopsy.

Whipple's disease: case report and review of the literature.

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.

Novel Tropheryma species in a lung biopsy sample from a kidney transplant recipient.

OBJECTIVES: A kidney transplant recipient with recurrent pleuritis underwent an open lung biopsy, the results of which revealed multiple nodular infiltrates. Grocott and periodic acid-Schiff staining were positive. Fungal and Tropheryma whipplei PCR were, however, negative. Further identification was needed. METHODS: Formalin-fixed, paraffin-embedded (FFPE) extraction was performed using an FFPE extraction kit. T. whipplei was searched for using a real-time PCR targeting the noncoding repeat specific for T. whipplei. Identification of the bacteria in the extract was done using 16S rDNA and 23S rDNA sequencing and BLAST analysis. Internal transcribed spacer PCR was used for fungal DNA identification. RESULTS: The FFPE extract was negative for fungi and T. whipplei. 16S rDNA sequence analysis of a 1375 bp fragment gave T. whipplei as the best match with 26 mismatches, resulting in only 98% agreement. Sequence analysis of the 23S rDNA gene again gave T. whipplei as the best match, but with only 91% agreement. A pan-Tropheryma 16S rDNA real-time PCR was developed, and both the biopsy sample and a respiratory sample of the patient were strongly positive. The patient received antimicrobial treatment targeting T. whipplei with good clinical outcome. CONCLUSIONS: 16S and 23S rDNA sequencing gave T. whipplei as the best hit, although with limited agreement. These findings suggest that a novel Tropheryma species that lacks the noncoding repeat, most frequently used for molecular detection of Whipple disease, might be the cause of the pulmonary disease. Adaptation of current PCR protocols is warranted in order to detect all Tropheryma species.