Diagnosis Of Whipple's Disease Research Articles

Whipple's disease diagnosis following the use of TNF- blockade

A 46-year-old man with inflammatory back pain and large and small joint arthritis was diagnosed with AS 10 years following symptom onset. Physical examination showed decreased vertebral range of motion. Laboratories revealed ESR of 40 mm/h, RF negative, ANA negative with positive HLA-B27. Plain radiographs demonstrated sacroiliac pseudo-widening. Anti-inflammatories, MTX (25 mg s.c. weekly) and prednisone (7.5–10 mg daily) were initiated. Five months later, infliximab (5 mg/kg increased to 10 mg/kg every 6 weeks) was added for inflammatory back pain with improvement. After 2 years of infliximab, the patient developed fevers and migratory arthritis precipitating hospitalization. Abnormal laboratories included white blood cell (WBC) count 36 k/mm3, haemoglobin (Hgb) 11.6 g/dl and ESR 58 mm/h. Evaluation including WBC scan, histoplasma antigen, brucella serology, routine and lysis centrifugation blood cultures, hepatitis and HIV serology, and bone marrow biopsy were negative. Symptoms resolved with cessation of infliximab and MTX. Three months later, re-challenge with adalimumab and MTX for recurrent inflammatory symptoms resulted in fevers, migratory arthritis and new weight loss with diarrhoea. Endoscopy with duodenal biopsy showed altered architecture and intracellular bacilli on periodic acid-Schiff stain (Fig. 1). Trophyrema whipplei was detected from blood and duodenal tissue by PCR. Intravenous ceftriaxone (2 g daily for 2 weeks) was commenced followed by trimethoprim-sulphamethoxazole with improved symptoms. Fig. 1 Detection of Whipple's disease. (A) Duodenal mucosa showing loss of normal villous architecture with foamy macrophages filling and expanding the lamina propria (haematoxylin and eosin stain, objective magnification 10×). (B) Intense periodic acid–schiff ... Trophyrema whipplei is a ubiquitous organism, rarely associated with multisystemic and relapsing disease. The organism may be detectable by PAS staining of involved organ tissue or with 16S rRNA gene identification [1]. Arthropathies associated with T. whipplei may precede diagnosis and exhibit axial and peripheral involvement, with symptom exacerbation following TNF-α inhibitors [1, 2]. Our case illustrates the consideration of alternative aetiologies in patients with articular symptoms, most importantly following clinical deterioration on immunomodulatory agents like TNF-α inhibitors. Disclosure statement: The authors have declared no conflicts of interest.

Isolated inctracranial Whipple's disease—Report of a rare case and review of the literature

Whipple's disease (WD) is a rare multisystemic infectious disease that can involve a variety of organs namely the gastrointestinal tract, lymphatic system, heart and nervous system. Myorhythmia is a hallmark of WD. Isolated CNS involvement is very rare. We present a 50 year-old African-American woman with rapid cognitive decline, visual hallucinations, insomnia, dysarthria, and gait unsteadiness. She subsequently developed pendular nystagmus and gaze paresis. Serial brain MRI scans showed T2 hyperintense lesions in the left striatum and right parahippocampal gyrus. FDG-PET scan showed marked increase of glucose uptake in the left putamen. Serum and CSF PCR for Tropheryma whipplei was negative. Stereotactic biopsy of the lesion and tissue PCR was consistent with WD. A systematic review identified 24 cases of isolated intracranial presentation of WD since 1975. Cases with systemic and extracranial manifestations were excluded. In patients with rapidly progressive cognitive decline with negative workup for common etiologies, there should be a high index of suspicion for WD. Diagnosis of WD remains a challenge as traditional methods commonly fail to culture T. whipplei. PET scans can help in identifying areas of inflammation that can be biopsied. Our case proves that a negative serum and CSF PCR should not exclude CNS WD and a brain biopsy of the lesion with PCR assay should be performed when possible.

Hearing loss, uveomeningitis, and stroke in a 55‐year‐old man

Hearing loss, uveomeningitis, and stroke in a 55‐year‐old man

Tropheryma whippleiin Patients with Pneumonia

Tropheryma whipplei is the etiologic pathogenic agent of Whipple disease (WD), characterized by various clinical signs, such as diarrhea, weight loss, lymphadenopathy, and polyarthritis. PCR-based methods for diagnosis of WD have been developed. T. whipplei has been identified in saliva and stool samples from patients with WD and from healthy persons. T. whipplei DNA has also been found in bronchoalveolar lavage (BAL) samples of a child with pneumonia. We detected DNA of T. whipplei in 6 (3%) of 210 BAL samples collected in intensive care units by using 16S rDNA and specific quantitative PCR. We identified 4 novel genotypes of T. whipplei. In 1 case, T. whipplei was the only bacterium; in 4 others, it was associated with buccal flora. We suggest that T. whipplei should be investigated as an etiologic agent of pneumonia.

Resistance to trimethoprim/sulfamethoxazole and Tropheryma whipplei

Whipple's disease (WD) is a chronic infection caused by Tropheryma whipplei. A 1-year treatment of oral trimethoprim/sulfamethoxazole (SXT) is commonly used. Advances in the culture of T. whipplei have allowed for full genome sequencing and antibiotic susceptibility testing, which has demonstrated resistance of T. whipplei to trimethoprim. Several mutations in the folP gene that encodes dihydropteroate synthase, the target of sulphonamides, has been reported for one patient with clinically acquired resistance to SXT. Here we report three new patients who experienced clinically acquired resistance to SXT during treatment and one patient with biological failure. Sixty-two folP sequences from DNA samples of 59 WD patients were also obtained. Among the detected amino acid changes, two positions (N4S and S234F) significantly predicted secondary sulfamethoxazole failure (four of five). We suggest that these mutations should be detected at the time of WD diagnosis by sequencing folP in order to avoid sulfamethoxazole monotherapy.

Value ofTropheryma whippleiQuantitative Polymerase Chain Reaction Assay for the Diagnosis of Whipple Disease: Usefulness of Saliva and Stool Specimens for First‐Line Screening

Whipple disease (WD) is a chronic infectious disease caused by Tropheryma whipplei. WD DNA has been found in stool and saliva specimens from patients and asymptomatic carriers. A total of 4418 samples that were sent to our center for determination of WD were tested by a T. whipplei-specific quantitative polymerase chain reaction (PCR) based on repetitive sequences. Definite WD was diagnosed in 71 patients, including 55 patients with classic WD (defined by positive results of periodic acid-Schiff staining and/or specific immunohistochemistry of small-bowel biopsy specimens) and 16 patients with localized WD (including patients with endocarditis, neurologic infection, and uveitis). Of the persons without WD, 2.3% had stool specimens positive for T. whipplei by PCR and 0.2% had saliva specimens positive for T. whipplei by PCR. Diagnosis of WD was likely in patients with positive results of both PCR of saliva specimens and PCR of stool specimens (positive predictive value, 95.2%). When the bacterial load was >10(4) colony-forming units per g of stool, the positive predictive value was 100%. A negative result of PCR of a saliva or stool specimen had a negative predictive value of 99.2% for classic WD. For localized WD, positive results of both PCR of saliva specimens and PCR of stool specimens had a sensitivity of 58% (compared with 94% for classic WD). The positive predictive value of testing of blood, cerebrospinal fluid, and urine specimens was 100% for each, and the positive predictive value for testing of duodenal biopsy specimens was 97.5%. T. whipplei-specific quantitative PCR of saliva and stool specimens should be performed as first-line noninvasive screening for WD. When the results for both types of specimens are positive, diagnosis of classic WD should be highly suspected, especially if a high bacterial load is detected. Because PCR of saliva and stool specimens lacks sensitivity for determination of localized WD, invasive samples should be tested on the basis of clinical manifestations.

Tropheryma whipplei et maladie de Whipple : résultats de la recherche par polymerase chain reaction (PCR) dans les échantillons à visée diagnostique

Background PCR can be used to detect T. whipplei (Tw) in samples from variable tissue types and body fluids. We report clinical, evolutive characteristics and final diagnosis in patients with positive Tw PCR assay. Methods Retrospective study of Tw PCR realized since 10 years in a microbiology laboratory. Results Twenty-five Tw PCR assays were positive among 200 realized. Diagnosis was not confirmed in six cases. One patient was missing for follow up. Eighteen patients presented with Whipple's disease. Among these 18 patients, 14 had a classic Whipple's disease, three patients presented an endocarditis and one patient isolated neurological manifestations. Ten patients presented fever, seven a weight loss and 12 joint involvement. Four patients presented cutaneous manifestations, only six had gastrointestinal symptoms. Neurological involvement was reported in five cases, pulmonary symptoms in four cases, cardiac involvement in six cases and ocular signs in two cases. Anemia was reported in four patients and elevated levels of acute-phase reactants in 14 cases. Positive predictive value of Tw PCR for Whipple's disease diagnosis was 75%. Thirteen patients had a good evolution with antibiotics. Three patients presented recurrence and two cases with cardiovascular involvement died. Conclusion Whipple's disease is rare but often mentioned in internist experience. The diagnosis should be every time confirmed. Tw PCR assay is an important diagnostic tool but is not sufficient to establish the diagnosis and must be interpreted with histopathology and immunohistochemical testing results.

An immunoproteomic approach for identification of clinical biomarkers of Whipple's disease

Whipple's disease (WD) is a chronic multisystemic infection, caused by the bacterium Tropheryma whipplei. The main clinical presentations are classic WD (CWD) with histologic lesions in the gastrointestinal tract, endocarditis, and isolated neurologic infection. The current strategy for diagnosis remains invasive.The present study aimed to select the protein candidates for serological diagnosis of WD. The first step was to identify candidate proteins by an immunoproteomic approach combining 2-DE using a total extract of a T. whipplei, immunoblotting, and MS. The second step was to validate the discovered biomarkers using a recombinant protein-based ELISA. Serum samples from 18 patients with WD and from 54 control individuals were tested. Asugar ABC transporter, TWT328 (sensitivity (Se) 61%, specificity (Sp) 87%, positive predictive value (PPV) 61%, negative predictive value (NPV) 87%, and positive likelihood ratio (PLR) 4.69) was the best marker for development of serodiagnosis for CWD. We also obtained a reproducible immunoreactive protein pattern for patients with isolated neurological infection due to T. whipplei (Se 100%, Sp 93%, PPV 55.5%, NPV 100%, and PLR 13.51) as an encouraging step towards noninvasive diagnosis of this particular manifestation. Nine recombinant candidates have been successfully screened with serum samples. Results from these ELISA assays skewed with those obtained with immunoblots.

Advances in Tropheryma Whipplei Research: The Rush to Find Biomarkers for Whipple‘s Disease

Whipple's disease (WD) is a systemic chronic infection, caused by the Gram-positive bacterium Tropheryma whipplei. There are several clinical traits linked to WD: histological lesions in the GI tract in association with diverse clinical manifestations (classic WD), endocarditis with negative blood cultures, and isolated neurological infection. WD is rare, predominantly affects middle-aged men and is fatal without treatment. The most recent strategy for diagnosing WD uses the results of diastase-resistant periodic acid Schiff staining and PCR in parallel, both performed on involved organ/tissue biopsy (small intestine, cardiac valve and cerebrospinal fluid). The generation of rabbit polyclonal antibodies has enabled the detection of the bacterium in tissues by immunohistochemical staining. However, the diagnosis of WD remains an invasive procedure. The recent achievement of stable bacterial culture and sequencing of the T. whipplei genome has opened a framework for the development of a biomarker platform. Several studies in different fields have been performed, for example, transcriptomics, immunoproteomics and comparative proteomics. Biomarker candidates have been proposed for the development of less invasive procedures for diagnosing WD.

Four Different Presentations of a Rare Disease – Whippleʼs Disease

Whipple's disease (WD) is a rare chronic infectious multisystem disease caused by bacterium Tropheryma whipplei. Only about 1000 cases have been reported to date. We describe our experience with 4 cases diagnosed with WD between 2002 and 2007: first 3 cases from Brooklyn, New York and case #4 from Western Massachusetts. Case #1: A 72 year-old (yo) Caucasian male from Spain, living in Brooklyn since 1975, presented with 30 lbs weight loss, pulmonary nodules and retroperitoneal lymphadenopathy. Lymph node biopsy revealed foamy macrophages (FM) containing periodic acid-Schiff (PAS) positive (+) material and negative Ziehl-Neelsen stain (ZN). Retrospectively, he had arthralgia for 10 years and developed intermittent diarrhea, epigastric pain and progressive cognitive decline for the last 6 months. Laboratory data were significant for anemia and evidence of malabsorbtion. On upper endoscopy (EGD) duodenal mucosa had small lymphangiectasia and biopsy was consistent with WD with PAS + FM in lamina propria (LP). Case # 2: A 61 yo Caucasian male from Russia, living in Brooklyn for the last 7 years, with long history of arthralgia was evaluated for iron deficiency anemia. Colonoscopy was unrevealing and EGD showed normal appearing duodenal mucosa with distended villi by FM PAS + and negative ZN on biopsies, consistent with WD. Case #3: A 25 yo African American male presented with diarrhea for 1 year. Colonoscopy with ileoscopy revealed erythema of the terminal ileum mucosa with PAS + FM on biopsies. EGD confirmed the diagnosis of WD with similar findings on duodenal biopsy. Case #4: A 41 yo Caucasian male of Irish descend, with history of seronegative polyarthritis on treatment with high doses of aspirin and intermittent steroids presented with an episode of diarrhea for 4 weeks with negative work-up including colonoscopy. The episode resolved, but subsequently the patient had recurrence of diarrhea and weight loss. On EGD duodenal mucosa appeared flat, pale and biopsies showed PAS + FM in LP suggestive of WD. The diagnosis was confirmed by a PCR assay. All patients were treated with Ceftriaxone for 2 weeks followed by Trimethoprim -sulfamethoxazole for 1 year. Diarrhea and anemia resolved and arthralgia was significant improved in all patients. Patient in case #1 had weight gain and improvement in adenopathy and cognitive function. Discussion: WD has a variety of clinical manifestations and should be considered in patients who present with migratory arthralgias of the large joints, weight loss, diarrhea, and abdominal pain.

Whipple disease revealed by musculocutaneous symptoms, with muscle biopsy cultures positive for Tropheryma whipplei

A patient experienced sudden onset of musculocutaneous symptoms 3 years after being diagnosed with polyarthritis. Biopsies from the duodenum, skin, and muscle established the diagnosis of Whipple disease. Cultures of muscle biopsy specimens grew Tropheryma whipplei. Adequate antibiotic therapy ensured a favorable outcome. To our knowledge, this is the first case in which T. whipplei was recovered from muscle biopsy specimens, confirming the infectious nature of muscle involvement in Whipple disease.

Ultrastructural Evidence of Tropheryma whippelii in Pas-negative Granulomatous Lymph Nodes

The presence of Tropheryma whippelii was demonstrated in the PAS-negative mesenteric granulomatous lymph nodes of a patient affected by Whipple disease. Ultrastructurally a few bacteria, enclosed by a membrane characteristic of Tropheryma whippelii, were found in the extracellular spaces and remnants of bacteria were found in the phagocytic vacuoles of macrophages. The scarce number of bacilli, probably due to the fact that the disease was at an initial phase, could explain the absence of PAS positivity. This case confirms the role of the electron microscopy in the diagnosis of Whipple disease, especially for extra-intestinal lesions and at the initial phase of the disease, when the characteristic PAS-positive macrophages can be absent.

Hypersomnia in Whipple disease: case report

Whipple disease (WD) is a rare systemic infection caused by Tropheryma whippelii. Neurological involvement has been recognised in 40% of patients, either as initial manifestations or during the course of the disease. We report on a 45 years-old man with WD with initial, persistent and irresistible episodes of daytime somnolence. The patient was HLA-DQB1*0602 positive (genetic marker for narcolepsy). WD diagnosis was suspected on clinical and MRI basis and confirmed by histological and immunohistochemical study of duodenal biopsy. Forty months later all clinical features improved, narcoleptic-like episodes disappeared and cerebral MRI and CSF normalised. Longitudinal neurophysiological studies revealed persistent sleep pattern abnormalities with sleep fragmentation, paucity of slow wave and of REM sleep. The disruption of the hypocretin circuitry in the hypothalamic - diencephalic region triggered by the infection was the probable cause of the hypersomnia and narcopleptic symptoms. WD should be added to the list of causes of secondary hypersomnia.

Primary Whipple's disease of the brain: characterization of the clinical syndrome and molecular diagnosis

Whipple's disease (WD) of the brain without evidence of systemic involvement is a rare illness that is difficult to recognize and potentially life-threatening. To elucidate the clinical features and diagnosis of primary WD of the brain. A single case study, with review of published data. We linked the information about our patient with 956 citations to published WD material. We were able to identify 19 other patients with primary WD of the brain. Our patient was a 48-year-old woman who presented 2 years ago with generalized tonic/clonic seizures. WD of the brain was diagnosed after a life-threatening subacute deterioration leading to reduced consciousness and eye movement abnormalities. She had atrophy and gliosis of the right hippocampal formation, and nodular enhanc-ing lesions. She developed the syndrome of inappropriate ADH secretion, blepharospasm with a complete paralysis of vertical gaze, a severe amnesic syndrome, obstructive sleep apnoea, altered sleep physiology and CSF oligoclonal bands. Primary WD of the brain was diagnosed after PCR confirmed Tropheryma whipplei DNA in CSF and blood. She recovered after intravenous methylprednisolone, meropenem and cotrimoxazole. She has now survived for 24 months, lives independently and drives. Comparing our patient with the 19 others, two clinical syndromes were apparent, in both adults and children: (i) multifarious neurological symptoms and signs with a CT or MRI showing multiple nodular enhancing lesions; (ii) focal neurology secondary to solitary mass lesions. Primary WD of the brain may be diagnosed by recognition of these two clinical syndromes, and confirmed by the application of molecular biological techniques such as PCR.

Identification of candidate antigen in Whipple's disease using a serological proteomic approach

Whipple's disease (WD) is a chronic multisystemic infection, caused by Tropheryma whipplei, a Gram-positive rod. Recently, a reliable method has been developed for cultivating T. whipplei in vitro. This together with the availability of complete genome sequence of T. whipplei prompted us to initiate proteome analysis of T. whipplei. The objective of the present study was to identify candidate proteins for serological diagnosis of WD. Immunoreactivities of sera collected from 18 patients with WD were compared with those of 24 control subjects who did not have WD. For this, we used 2-DE, immunoblotting, and MS. In total, we identified 23 candidate antigenic proteins. These included a subset of six proteins, each of which was found significantly more frequently in cases as compared to their controls. The remaining 17 proteins were found exclusively in cases. The methods we used in the current study enabled us to identify candidate antigens that, in our view, might be useful for serological diagnosis of WD.

Whipple’s disease

Whipple's disease (WD) is a chronic debilitating disease caused by the bacillus Tropheryma whippleii. WD classically presents with the main clinical symptoms of polyarthralgias, chronic diarrhea, weight loss, and abdominal pain. Given its systemic involvement, it is common for WD to present with a multitude of other clinical scenarios--sometimes with predominant neurologic, cardiac, and dermatologic manifestations. WD can occur at any age, but it generally occurs during the fifth decade and predominantly in men. The diagnosis of WD is established by demonstrating the organism on biopsies from the involved system, by histology, electron microscopy, polymerase chain reaction, and more recently, by culture of bacteria. The histologic features include a coarse granular cytoplasm and foamy macrophages that stain strongly with the period-acid Schiff reagent. Current therapy includes an initial 2-week course of intravenous cephalosporins followed by 1-year oral trimethoprim-sulfamethoxazole.

Whipple disease and central nervous system

Whipple disease (WD) is a rare systemic infection caused by the bacteria Tropheryma whipplei. Slowly progressive dementia, supranuclear ophthalmoplegia, headache, myoclonus, hypothalamic dysfunction, oculomasticatory-skeletal myorythmia are characteristic manifestations when WD involves the central nervous system (CNS). Treatment of cerebral WD should be performed with antibiotics that reach the CNS for at the least one-year. We alert for the early diagnosis of WD in patients with exclusively neurological clinical pictures, sometimes with atypical or non-definitive diagnosis, because it is a potential treatable disease.

PCR analysis in the pathological diagnosis of Whipple's disease: emphasis on extraintestinal involvement or atypical morphological features.

PCR analysis of species-specific bacterial 16S rRNA gene of Tropheryma whippelii was performed in biopsies from 10 cases of Whipple's disease (WD). In seven patients showing the typical clinical picture of WD, PCR was performed on the diagnostic intestinal biopsy. In the remaining three cases (an autopsy case of disseminated WD and two patients showing lymphadenopathy as the initial clinical presentation), PCR was done on lymph node specimens. In one of the lymph node biopsies, an unusual sarcoidlike granulomatous reaction had led to the diagnosis of sarcoidosis. The specific bacterial DNA was detected in all cases, both in intestinal biopsies and in lymph node specimens. Follow-up biopsies after antibiotic therapy were evaluated in two patients. The two follow-up biopsies were negative, although in both of them scattered nests of PAS-positive macrophages remained. The results of this study suggest that PCR analysis of species-specific sequences of the 16S rRNA of Tropheryma whippelii is a very useful tool for the pathological diagnosis of WD. It confirms the diagnosis of WD in intestinal biopsies as well as in extraintestinal sites, even when the morphological appearance is not typical. It is also the most precise technique for monitoring therapeutic effects.

PCR analysis in the pathological diagnosis of Whipple's disease: emphasis on extraintestinal involvement or atypical morphological features

PCR analysis in the pathological diagnosis of Whipple's disease: emphasis on extraintestinal involvement or atypical morphological features

Whipple disease presenting as posterior uveitis without prominent gastrointestinal symptoms

Purpose: To describe the clinical presentation and course of Whipple disease in an adult. Methods: A 34-year-old man with phthisis bulbi in the right eye secondary to uveitis-induced neovascular glaucoma presented with severe acute posterior uveitis in the left eye. He underwent esophagogastroduodenoscopy and jejunal biopsy for evaluation of anemia. The posterior uveitis was treated with a subtenon injection of triamcinolone. Result: The diagnosis of Whipple disease was confirmed by polymerase chain reaction analysis of the jejunal biopsy that demonstrated Tropheryma whippelii rDNA. Conclusion: Although Whipple disease is typically evident with malabsorption, it can also present as uveitis without prominent gastrointestinal symptoms.