Non-convulsive status epilepticus associated with Whipple's disease.

A 69-year-old woman developed non-convulsive status epilepticus during inpatient investigation for abdominal pain. Initial detailed investigations did not identify the cause of seizures, but a jejunal biopsy and PCR testing in various fluids led to the diagnosis of Whipple's disease with neurological involvement. The seizures were controlled but she subsequently had moderate cognitive impairment. Whipple's disease is an important diagnosis, being treatable with antibiotics. Testing for Whipple's disease is not part of the recommended workup in for status epilepticus, but this case highlights the importance of considering this condition.

Contribution of PCR to Differential Diagnosis between Patients with Whipple Disease and Tropheryma whipplei Carriers.

Differentiation between Whipple disease (WD) patients and patients carrying Tropheryma whipplei but suffering from disease other than WD ("carriers") remains complex. We aimed to evaluate T. whipplei PCR among patients with WD and carriers in a large cohort at our referral clinical microbiology laboratory. This is an observational retrospective cohort study, including all patients between 2008 and 2020 with at least one positive result for T. whipplei using the real-time PCR RealCycler TRWH-UX kit. A total of 233 patients were included: 197 were considered carriers, and 36 had WD. Among the WD patients, 32 underwent biopsies, of which 18 (56%) had a positive periodic acid-Schiff (PAS) staining. Among the 27 duodenal biopsy specimens, 13 (48%) were PAS positive. PCR results before antibiotic treatment were positive in both feces and saliva in 16/21 WD (76%) patients and 68/197 (35%) carriers (P < 0.001). Duodenal biopsy specimens yielded positive PCR in 20/22 (91%) WD patients and 27/72 (38%) carriers (P < 0.001). The cycle threshold (CT) value detected in duodenal biopsy specimens from WD patients was significantly lower than that of carriers (P < 0.001), regardless of the PAS staining results. For a diagnosis of WD, duodenal PCR sensitivity and specificity at a CT value below 30 were 52.4% and >99.9%, respectively. The high specificity of duodenal PCR with low CT values may help confirming the diagnosis of WD, especially in patients with negative PAS results in digestive biopsy specimens, who represent half of all patients. A low PCR CT value from a duodenal biopsy specimen provides valuable guidance, especially in patients with PAS-negative results.

A Case of Whipple Disease With Cutaneous Manifestations.

ABSTRACT: Whipple disease (WD) is a rare bacterial infectious disease that is classically characterized by years of arthralgia, followed by malabsorption, diarrhea, and weight loss. However, WD may manifest in virtually any organ system, and patients with WD rarely develop subcutaneous erythema nodosum-like lesions. We report a case of a 51-year-old man diagnosed with WD who subsequently developed widely distributed erythematous subcutaneous nodules after 5 months of antibiotic therapy.

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.

Clinical pitfalls of leishmaniasis and Whipple's disease hidden behind systemic lupus erythematosus: A case series.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that can affect major organs possibly leading to life-threatening complications and appears with heterogeneous clinical picture. SLE could present with broad spectrum of clinical and laboratory features that can resemble those of other diseases, such as hemopoietic malignancies, infections, or immune-mediated disorders. Its complexity and protean features overlap with many other diseases, hindering the differential diagnosis. Rarely, true overlap with other diseases may occur. Herein, we report a case series of two patients affected by infectious diseases, namely visceral leishmaniasis and Whipple's disease (WD), intertwined with clinical or serological features of SLE. In both cases, several confounding factors have led to a delay in the diagnosis. Moreover, we first describe the persistent elevation of autoantibodies and a monoclonal gammopathy in a patient with WD. Awareness of unusual presentations of infections or other rare disorders, which may be encountered in clinical practice when taking care of SLE patients, is essential for timely diagnosis and treatment of potentially lethal diseases.

Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections.

Whipple's disease is a rare infectious disease that can be fatal if left untreated. The disease is caused by infection with Tropheryma whipplei, a bacterium that may be more common than was initially assumed. Most patients present with nonspecific symptoms, and as routine cultivation of the bacterium is not feasible, it is difficult to diagnose this infection. On the other hand, due to the generic symptoms, infection with this bacterium is actually quite often in the differential diagnosis. The gold standard for diagnosis used to be periodic acid-Schiff (PAS) staining of duodenal biopsy specimens, but PAS staining has a poor specificity and sensitivity. The development of molecular techniques has resulted in more convenient methods for detecting T. whipplei infections, and this has greatly improved the diagnosis of this often missed infection. In addition, the molecular detection of T. whipplei has resulted in an increase in knowledge about its pathogenicity, and this review gives an overview of the new insights in epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Tropheryma whipplei infections.

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

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.

PCR analysis is superior to histology for diagnosis of Whipple's disease mimicking seronegative rheumatic diseases.

OBJECTIVES: The diagnosis of Whipple's disease (WD) is commonly confirmed by histology demonstrating Periodic Acid Schiff (PAS)-positive macrophages in the duodenal mucosa. Analysis of intestinal tissue or other specimens using polymerase chain reaction (PCR) is a more sensitive method. However, the relevance of positive PCR findings is still controversial. Therefore, we evaluated the relevance of histology and PCR findings to establishing the diagnosis of WD in a series of WD patients initially presenting with suspected rheumatic diseases. METHOD: Between 2006 and 2014, 20 patients with seronegative rheumatic diseases tested positive for Tropheryma whipplei (Tw) by PCR and/or histology and were enrolled in a retrospective analysis of the diagnostic value of both procedures. RESULTS: Seven of the 20 cases (35%) were diagnosed with 'classic' WD as indicated by PAS-positive macrophages. In the remaining 13 patients, the presence of Tw was detected by intestinal (n = 10) or synovial PCR analysis (n = 3). Two of the 20 patients (10%) with evidence of Tw did not respond to antibiotic therapy. They were not considered to suffer from WD. Therefore, relying only on histological findings of intestinal biopsies would have missed 11 (61%) of the 18 patients with WD in our cohort. In comparison, PCR of intestinal biopsies detected Tw-DNA in 14 (93%) of the 15 WD patients evaluated. Patients with a positive histology did not differ from PCR-positive patients with regard to sex, age, or duration of disease, but more often presented with gastrointestinal symptoms. CONCLUSIONS: A substantial number of WD patients present without typical intestinal histology findings. Additional PCR analysis of intestinal tissue or synovial fluid increased the sensitivity of the diagnostic evaluation and should be considered particularly in patients presenting with atypical seronegative rheumatic diseases and a high-risk profile for WD.

Erythema Nodosum Leprosum-Like Lesions Are a Histopathologic Pattern in Whipple's Disease and a Sign of the Immune Reconstitution Inflammatory Syndrome: A Case Series and Review of the Literature.

Inflammatory and subcutaneous nodules can arise in treated and untreated cases of Whipple disease (WD). The inflammatory immune reconstitution syndrome describes paradoxical clinical inflammatory worsening of a preexisting condition because of a return of immune function. Clinicopathologic examination of 4 patients with WD who presented with erythema nodosum leprosum (ENL)-like lesions and the findings of a systematic review of this phenomenon revealed that ENL-like lesions occurred in predominantly middle-aged male patients who suffered from WD, mostly on the legs. Patients showed a nonvasculitic, mostly septal panniculits with neutrophils, macrophages, and lymphocytes. Numerous bacteria-laden periodic acid-Schiff + macrophages and free bacilli were detected in the dermis, as well as subcutaneous septae and adipose lobules. These lesions occurred in both untreated and treated patients as part of inflammatory immune reconstitution syndrome. In conclusion, ENL-like lesions represent a characteristic histopathologic pattern associated with WD, which can occur in different contexts whenever there is a change in the immunological status of the patient. This change can be triggered by antimicrobial treatment, immunomodulatory and immunosuppressant therapy, or occur spontaneously, rarely.

Whipple's disease diagnosed using electron microscopy and polymerase chain reaction.

A 50-year-old man presented with bloody diarrhea and 25-kg weight loss over 3 months. Upper and lower endoscopy showed diffuse shaggy white villi in the duodenum and terminal ileum. In addition, capsule endoscopy and double-balloon enteroscopy revealed shaggy white villi in the entire small intestine. Histological examination of biopsy specimens found the lamina propria of the duodenal and intestinal mucosa to be densely infiltrated by rich foamy macrophages that were periodic acid-Schiff-positive. Electron microscopy showed numerous bacilli in the lamina propria. Tropheryma whipplei DNA was detected in the specimens by polymerase chain reaction. Based on these findings, the patient was diagnosed with Whipple's disease. He was treated with a 2-week course of ceftriaxone followed by trimethoprim-sulfamethoxazole. At the 2-month follow up, diffuse white shaggy villi improved dramatically.

Immunopathology of immune reconstitution inflammatory syndrome in Whipple's disease.

During antimicrobial treatment of classic Whipple's disease (CWD), the chronic systemic infection with Tropheryma whipplei, immune reconstitution inflammatory syndrome (IRIS), is a serious complication. The aim of our study was to characterize the immunological processes underlying IRIS in CWD. Following the definition of IRIS, we describe histological features of IRIS and immunological parameters of 24 CWD IRIS patients, 189 CWD patients without IRIS, and 89 healthy individuals. T cell reconstitution, Th1 reactivity, and the phenotype of T cells were described in the peripheral blood, and infiltration of CD4(+) T cells and regulatory T cells in the duodenal mucosa was determined. During IRIS, tissues were heavily infiltrated by CD3(+), predominantly CD45RO(+)CD4(+) T cells. In the periphery, initial reduction of CD4(+) cell counts and their reconstitution on treatment was more pronounced in CWD patients with IRIS than in those without IRIS. The ratio of activated and regulatory CD4(+) T cells, nonspecific Th1 reactivity, and the proportion of naive among CD4(+) T cells was high, whereas serum IL-10 was low during IRIS. T. whipplei-specific Th1 reactivity remained suppressed before and after emergence of IRIS. The findings that IRIS in CWD mainly are mediated by nonspecific activation of CD4(+) T cells and that it is not sufficiently counterbalanced by regulatory T cells indicate that flare-up of pathogen-specific immunoreactivity is not instrumental in the pathogenesis of IRIS in CWD.

Neurocognitive impairment in Whipple disease with central nervous system involvement.

Young-onset dementias pose a major challenge to both clinicians and researchers. Cognitive decline may be accompanied by systemic features, leading to a diagnosis of "dementia plus" syndromes. Whipple disease is a rare systemic illness characterized by arthralgias, chronic diarrhea, weight loss, fever, and abdominal pain. Central nervous system involvement, including severe cognitive deterioration, may precede systemic manifestations, appear during the course of the disease, or even be the only symptom. We report a previously highly functional 48-year-old man whom we first suspected of having early-onset neurodegenerative dementia but then diagnosed with Whipple disease based on a detailed clinical and laboratory evaluation. Initial neuropsychological evaluation revealed marked impairment in the patient's fluid intelligence and severe cognitive deficits in his information processing speed, complex attention, memory, visuomotor and construction dexterities, problem solving, and executive functions. At neuropsychological follow-up 21 months later, his information processing speed had improved only slightly and deficits persisted in his other cognitive functions. Repeat brain magnetic resonance imaging at that time showed that he had responded to antibiotic treatment. Because Whipple disease can cause young-onset "dementia plus" syndromes that may leave patients with neurocognitive deficits even after apparently successful treatment, we recommend comprehensive neuropsychological assessment for early detection of residual and reversible cognitive processes and evaluation of treatment response.

Specific cutaneous involvement in Whipple disease.

Cutaneous lesions in Whipple disease (WD) are infrequent, and the histological findings are usually nonspecific. Specific cutaneous lesions have rarely been described and usually involve the subcutaneous fat. We report a patient diagnosed with WD, who developed multiple small subcutaneous nodules after antibiotic treatment was administered. In addition to septal panniculitis, the cutaneous biopsy showed a mild granulomatous dermal reaction with PAS-positive macrophages characteristic of WD. A positive polymerase chain reaction in the cutaneous sample confirmed the presence of Tropheryma whipplei in the skin. Dermatopathologists should be aware that not only subcutaneous lesions but also dermal lesions may exhibit specific findings of WD.

[Tropheryma whipplei endocarditis]. / Tropheryma-whipplei-Endokarditis.

Whipple's disease is a rare infectious disease caused by the bacterium Tropheryma whipplei. Usually the course of the disease is characterized by fever, diarrhea, weight loss and polyarthritis. We report on a case with a 10-year course of the disease with endocarditis, myocarditis and involvement of the bone marrow but with negative histological results of the small intestine.

[Whipple's Disease: retrospective analysis of twelve cases and review of the literature]. / Doença de Whipple: análisis retrospectivo de doce casos e revisión de la literature.

BACKGROUND: Whipple's disease is a rare and chronic bacterial disease with multiorganic involvement. Although there is no valid estimate of its actual prevalence, only about 1,000 cases have been reported. OBJECTIVE: To describe the demographic, clinical, laboratory, endoscopic and pathologic features, type of treatment used, its duration and response. METHODS: Based on the duodenal histology, we identified twelve cases of Whipple's disease in the Hospital Centre of Vila Nova de Gaia, between 1997 and 2010. RESULTS. Nine patients (75%) were male and the mean age at diagnosis was 58 years. All patients experienced at least one gastrointestinal and general symptom. Arthralgia were reported in four patients (33%) and occurred on average six years before the onset of gastrointestinal and general symptoms. In 10 patients the initial treatment was trimethoprim-sulfamethoxazole. The initial treatment duration was one year in 8 cases (80%). Seven patients (70%) had a symptomatic resolution between the third and sixth months of antibiotic therapy, as well as an endoscopic and histological improvement. Even in these patients, there was maintenance of periodic acid-Schiff positive macrophages, although in small number and with a more diffuse distribution. Gastrointestinal symptoms predominated in cases of clinical relapse. CONCLUSIONS: The gastrointestinal and general symptoms as well as the arthralgia were the predominant manifestations. The majority of patients showed clinical and endoscopic improvement in response to treatment with trimethoprim-sulfamethoxazole. However, in these cases periodic acid-Schiff positive macrophages can remain for years. Thus, in the absence of clinical deterioration, the presence of these structures is not indicative ofactive disease.

Whipple's disease: A rare disease that can be spotted by many doctors.

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.

A rare case of Whipple disease presenting as a hydrosalpinx and granulomatous peritonitis.

INTRODUCTION: Whipple disease is a rare infectious disease caused by the bacterium Tropheryma whipplei. The classic form affects gastrointestinal and musculoskeletal systems; but other forms may damage the heart, brain, or lungs. Due to non-specific and diverse clinical symptoms, diagnosis of Whipple disease is challenging and often late. Adequate and timely antibiotic treatment is essential for favorable outcome. CASE PRESENTATION: Here we present a case of a young woman admitted to the gynecological clinic for diagnostic laparoscopy for suspected haemato-/hydro- salpinx and peritoneal endometriosis. Macroscopic findings during laparoscopy revealed miliary whitish lesions in the pelvis and histopathology reported granulomatous salpingitis and peritonitis. She was complaining of intermittent abdominal pain, bloating and weight loss. Subsequently, the laparoscopy symptoms worsened and her general condition deteriorated. Differential diagnosis included infective agents such as Mycobacterium tuberculosis; in addition to sarcoidosis, granulomatosis with polyangiitis, and malignancies; all of which were excluded. Finally, Tropheryma whipplei was suspected, and after esophagogastroduodenoscopy with duodenal biopsy, long-term antibiotic treatment was initiated and the patient fully recovered. CONCLUSIONS: Although Whipple disease is rare, it is important to have a high level of awareness for Tropheryma whipplei infection. The localization and course of Whipple's disease may be unpredictable, but a favorable outcome is expected with adequate antibiotic treatment.

Evaluation of arginine metabolism for the analysis of M1/M2 macrophage activation in human clinical specimens.

BACKGROUND: Macrophage heterogeneity reflects their plasticity in response to environmental stimuli. Usually human macrophages are characterized by analysis of surface molecules or cytokine expression while functional assays are established in the mouse system but lacking for various human specimens. METHODS: To evaluate the value of analysis of arginine metabolism for characterization of human macrophage differentiation, we analyzed nitrite production and arginase activity in plasma, duodenal biopsies, and in vitro differentiated macrophages of patients with classical Whipple's disease. RESULTS: We demonstrate that it is feasible to determine the content of urea in supernatants of stimulated duodenal biopsies, arginase activity in fresh duodenal biopsies and plasma samples, and arginase activity and nitrite production in lysates and supernatants of in vitro differentiated macrophages. However, only selected tests are appropriate to define macrophage polarization in human specimens. CONCLUSION: Analysis of arginine metabolism is not suitable for the characterization of in vitro differentiated human macrophages. Besides the measurement of nitrite in duodenal biopsy supernatants, the determination of arginase activity in human plasma seems to be a reasonable functional test to detect enhanced M2 macrophage activation and, thus, is of great value for the analysis of macrophage activity with a minimum of material and costs.