Search

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.

Background:Whipple disease (WD) is a rare systemic infection with possible involvement of the central nervous system (CNS). The neurological manifestations of the disease are various and can mimic any neurologic condition.Objectives:To describe the severe neurological complications occurred in a patient with WD misdiagnosed as a chronic inflammatory immune-mediated disorder.Methods:Case reportResults:A 46-year-old woman developed acute right-sided hemiparesis and dysarthria. She had a 10-year history of ill-defined rheumatic condition (defined as seronegative rheumatoid arthritis, spondyloarthritis, and adult onset Still’s disease) presenting with polyarthritis, episodic fever > 38°C and rash of unclear etiology poorly responsive to different immunotherapies including methotrexate, anti-IL6 and anti-IL1 inhibitors. Brain MRI demonstrated multiple anterior circulation infarctions and stenosis of the bilateral M1 segments of the middle cerebral artery on MR angiography. Black blood sequences revealed contrast enhancement of the vessel walls consistent with vasculitis (Figure 1). Cerebrospinal fluid (CSF) analysis was unrevealing, including PCR for viruses and bacteria. A working diagnosis of primary CNS vasculitis and progressive neurologic deterioration with abnormal behavior and altered mental status prompted the initiation of intravenous (IV) methylprednisolone followed by cyclophosphamide without significant improvement. Re-evaluation of the long-standing history of joint symptoms unresponsive to immunotherapy, along with recurrent fevers and chronic diarrhea raised the suspicion of unrecognized Whipple’s disease. PCR for Tropheryma Whippleii was positive in stool, urine, blood and CSF, and duodenal mucosal biopsies confirmed the diagnosis. A combination of ceftriaxone, doxycycline, and hydroxychloroquine was initiated. Three days later the patient developed periocular burning pain and cutaneous vesicles consistent with shingles. Varicella-zoster virus DNA was detected in CSF and IV acyclovir was started. At 3 months follow-up neurologic examination was unremarkable except for a slightly fatuous behavior.Conclusion:Recognition of rare manifestations of WD is important to avoid diagnostic delay and inappropriate, potentially harmful treatments.Disclosure of Interests:Alessandro Giollo: None declared, Cecilia Zivelonghi: None declared, Davide Cardellini: None declared, Gian Marco Schiavi: None declared, Gaetano Vattemi: None declared, Ombretta Viapiana: None declared, Maurizio Rossini Speakers bureau: AbbVie, Abiogen, Amgen, BMS, Eli-Lilly, Novartis, Pfizer, Sanofi, Sandoz and UCB

Whipple’s disease is a rare and difficult-to-diagnose infectious disease, related to infection by gram-positive bacillum Tropheryma whipplei. Clinical manifestations are very variable, but the classic form usually begins with recurring arthritis, followed several years later by non-specific abdominal symptoms, leading to late diagnosis. We present the case of a 52-year-old man who was admitted in the emergency department with an insidious clinical picture characterised by weight loss, abdominal pain, diarrhoea and arthralgias. An abdominal ultrasound was performed, showing findings suggestive of Whipple’s disease, which, in conjunction with the clinical and laboratory findings, allowed the diagnosis to be correctly addressed. Upper endoscopy with duodenal biopsy revealed findings compatible with Whipple’s disease, and the diagnosis was also confirmed through PCR techniques of blood. The patient was given antibiotic therapy, with rapid and substantial clinical improvement.

Whipple's disease of the brain is one of the most challenging neurological diagnoses. "Is it Whipple's disease?" is a frequent question, but rarely is the answer yes. The neurological manifestations do not help to distinguish primary from secondary Whipple's disease of the brain, and although MR brain scanning with gadolinium is mandatory, it can be normal and any abnormalities are non-specific. There must be a comprehensive search for multisystem involvement such as raised inflammatory markers, lymphadenopathy or malabsorption; biopsy of lymph node or duodenum may be necessary. PCR and DNA sequencing for Tropheryma whipplei on lymphocytes from blood and cerebrospinal fluid is essential. Treatment is as difficult as the diagnosis-there are no randomised controlled trials.

A 54-year-old female patient presented to her local district general hospital with a painful, swollen left arm. Imaging revealed an ulnar artery aneurysm. The aetiology was embolic, with an echocardiogram revealing vegetations on the aortic valve. The patient was treated empirically for 6 weeks with amoxicillin and gentamicin for endocarditis. Eight months later, she had an elective aortic valve replacement for symptomatic aortic regurgitation. The valve was culture negative but analysis by 16S rDNA PCR was positive for Tropheryma whipplei. In retrospect, the ulnar artery aneurysm and a history of arthralgia were attributed to an underlying diagnosis of Whipple’s endocarditis. She continues on antibiotic treatment with resolution of her arthralgia and no clinical signs of infection. Once thought to be rare entity, molecular assays have revolutionised the diagnosis of Whipple’s endocarditis, but this case highlights the difficulties and pitfalls in diagnosis.

Whipple's disease has traditionally been considered to be a rare multisystem disorder dominated by malabsorption. The recent identification of the Whipple's disease bacillus has, using polymerase chain reaction based assays, fuelled advances in the investigation, diagnosis, and management of this disease. This leader reviews the aetiology, clinical manifestations, investigation, and treatment of Whipple's disease in the light of this new information.

In 1907, George Hoyt Whipple, then an instructor in pathology at Johns Hopkins University, published a case report of a 36 year old physician who had been domiciled in Constantinople.1 He developed recurring arthropathy, weight loss, and steatorrhoea, became worse, and died. At necropsy the intestine and mesenteric lymph glands were infiltrated by mononuclear and polynuclear giant cells and deposits of fat and fatty acids. Whipple described the large “foamy” mononuclear cells in the intestinal mucosa which were later shown to contain periodic acid Schiff (PAS) positive material. The aetiology of the condition was not established and he wrote “Gland tissue treated by the Levaditi method shows great numbers of a peculiar rod-shaped organism (?) which does not stain by the aniline dyes . . .” Whether this is the aetiological factor in this disease cannot be determined from this case”. A prescient observation. He suggested intestinal lipodystrophy as a name for the disease. Whipple's disease is rare—since its first description less than 1000 cases have been reported in the literature which is certainly an underestimate of all cases. Men are affected much more often than women (over 80%) and the mean age of onset approaches 50 although the age range extends from childhood to senility. Cases which have been reported have originated from Europe and North America in the main. Whether this is a true reflection of its aetiology or relates to technical difficulties in reaching a diagnosis is not clear. The natural habitat of the organism is not known, nor are the mechanisms by which infection takes place. The number of cases described in reports is too low to determine whether there is a racial susceptibility. The most common clinical presentation is a malabsorption syndrome with diarrhoea, abdominal pain, weight loss, generalised wasting, variable fever, and lymphadenopathy. …

Background Whipple9s disease is a chronic, systemic, curable bacterial infection, caused by Tropheryma whipplei and often mistaken for rheumatoid arthritis. Indeed, the classical form usually begins with intermittent joint involvement several years before the development of weight loss and diarrhea, associated with other diverse clinical manifestations. Objectives To know the main clinical presentations of Whipple9s disease and Tropheryma whipplei localized infections. To consider a diagnosis of Whipple9s disease in a middle-aged man presenting with isolated intermittent arthritis before the development of chronic persistent polyarthritis and of digestive signs and symptoms. To be able to diagnose Whipple9s disease by performing Tropheryma whipplei polymerase chain reaction from stools, saliva and synovial fluid. To know how to interpret polymerase chain reaction tests and pathological examination results. To know the therapeutic options in Whipple9s disease according to central nervous system involvement. Methods This presentation describes a patient with a 28-year history of isolated chronic severe bilateral destructive polyarthritis. Blood tests showed elevated acute phase reactants, persistent leukocytosis, but rheumatoid factor and antinuclear antibody tests were negative. He was treated for a presumed seronegative rheumatoid arthritis. He then presented with fever, weight loss, diarrhea and adenopathy. Results Tropheryma whipplei polymerase chain reaction was positive from synovial fluid, synovial tissue, and lymph node specimens. Duodenal biopsy confirmed periodic acid-Schiff-positive macrophages. Whipple9s disease was diagnosed. Tropheryma whipplei was successfully cultivated from the synovial fluid. Antibiotic treatment was instituted in the patient, after which his symptoms remitted. Conclusions Particular attention to a diagnosis of Tropheryma whipplei infection is warranted in a middle-aged man presenting with unexplained isolated intermittent arthritis. Tropheryma whipplei polymerase chain reaction from stools and saliva should be performed. Antibiotic therapy usually ensures the full resolution of all manifestations, which can otherwise be fatal, in case of late diagnosis of extended systemic forms. References Meunier M, Puechal X, Hoppe E,et al. Rheumatic and musculoskeletal features of Whipple disease: a report of 29 cases. J Rheumatol 2013;40:2061–6. Puechal X. Whipple9s disease. Ann Rheum Dis 2013;72:797–803. Disclosure of Interest None declared

A patient with isolated cerebral Whipple's disease presented with signs of raised intracranial pressure and multiple ring enhancing intracerebral mass lesions evident on CT and MRI imaging. Characteristic intracellular bacilliform inclusions were identified in a brain biopsy. Clinical improvement followed treatment with parenteral antibiotics for two weeks and long term sulphamethoxazole-trimethoprim. As CNS relapse of Whipple's disease may occur after several years, long term treatment should include antibiotics that are able to cross the blood-brain barrier.

A 45-year-old man presented with follicular exanthema in his lower limbs, alternating bowel habits and significant weight loss. His medical history included seronegative arthritis, bipolar disease and an inconclusive diagnostic laparoscopy. Diagnostic work up revealed microcytic anaemia and multivitamin deficiency. Skin biopsy of the exanthema suggested scurvy. Owing to these signs of malabsorption, upper endoscopy with duodenal biopsies was performed, exhibiting villous atrophy and extensive periodic acid-Schiff-positive material in the lamina propria, therefore diagnosing Whipple's disease (WD). After starting treatment with ceftriaxone and co-trimoxazole, an impressive recovery was noted, as the wide spectrum of malabsorption signs quickly disappeared. After a year of antibiotics, articular and cutaneous manifestations improved, allowing the patient to stop taking corticosteroids and antidepressants. This truly unusual presentation reflects the multisystemic nature of WD, often leading to misdiagnosis of other entities. Scurvy is a rare finding in developed countries, but its presence should raise suspicion for small bowel disease.

Whipple's disease is a rare disease caused by infection with the newly identified organism Tropheryma whippelii. Relapses of the disease most commonly occur in the central nervous system and are often resistant to antibiotics. We present the case of a man with recurring ophthalmoplegia, myoclonus, and hypothalamic symptoms while on treatment with cotrimoxazole for a previous relapse of Whipple's disease in the central nervous system. The patient had the clinical and electromyographic features of spinal myoclonus, a movement disorder not previously described in isolation in Whipple's disease. We then discuss the clinical features and pharmacological treatment of cerebral Whipple's disease. A 28 year old right handed man was admitted to the neurology ward of his local hospital for further investigations. The patient was Italian and worked as a bank clerk in Pisa. He gave an 18 month history of gradually worsening involuntary movements of both arms and the upper trunk. He also had impaired eye movements and a six month history of ejaculatory and erectile difficulties, weight gain, somnolence, and depression. He also complained of poor memory and difficulty with concentration. His medical history was that in 1986 he had presented with nausea, anorexia, abdominal pain, and weight loss. Endoscopy was performed, and duodenal mucosal biopsies showed macrophages that yielded a positive result when stained with the periodic acid Schiff reagent. Intestinal Whipple's disease was diagnosed, and he was treated for six months with oral amoxycillin. In 1992 he had presented with increased skin pigmentation, lethargy, weight gain, and decreased libido. He had paralysed vertical ocular movements. Staining with periodic acid Schiff reagent did not yield a positive result in duodenal biopsies but did in 15 mononuclear cells from the cerebrospinal fluid. Magnetic resonance imaging of the brain showed multiple focal lesions in the hypothalamus, striatum, and midbrain (fig 1 …

A 36 year old white man was diagnosed as having Whipple's disease after a prolonged illness of lethargy, night sweats, and weight loss associated with lymphadenopathy and splenomegaly. Biopsy specimen of an inguinal lymph node confirmed the presence of periodic acid Schiff positive macrophages and culture gave a pure growth of Corynebacterium jeikeium. Twelve hours after the introduction of oral co-trimoxazole and streptomycin the patient's condition deteriorated. He became confused, feverish, and developed florid retinal vasculitis with associated visual impairment. Both the systemic symptoms and the retinal vasculitis responded to treatment with corticosteroids and his vision returned to normal. We think this was a Jarisch-Herxheimer reaction not previously described in Whipple's disease and advise inspection of the fundi of such patients before starting treatment.

We report an unusual case of Whipple's disease, which remained undiagnosed for several years in a patient being treated with immunosuppressive therapy for many years. The patient presented with a purpuric rash, neurological symptoms, lymphadenopathy and gastrointestinal symptoms. The diagnosis was made by endoscopic biopsy of the duodenum with periodic acid Schiff staining, as well as PCR testing on blood and cerebrospinal fluid. The patient was successfully treated with intravenous ceftriaxone, followed by oral co-trimoxazole for 1 year.

Many authors emphasise the diagnostic difficulties and point out the multifaceted nature of Whipple's disease.1,2 Joint symptoms are present in 90% of all cases and may precede other disease manifestations by decades.3 We report here a case with fever of unknown origin accompanied by seronegative spondyloarthropathy with no typical gastrointestinal symptoms and initially negative upper panendoscopy. To confirm the diagnosis, the bacterial 16S ribosomal RNA sequence of Tropheryma whippelii was determined by polymerase chain reaction (PCR). A 58 year old white man had a 12 year history of intermittent arthralgias and seronegative polyarthritis. In 1993, monolateral stage II sacroiliitis was disclosed with no definite cause. Low dose methylprednisolone treatment was started, but there was no clinical improvement. In 1998 the patient became febrile, lost 10 kg of weight but had no gastrointestinal symptoms. He underwent an extensive examination, including radiological examinations of the chest and paranasal sinuses, abdominal sonography, echocardiography, abdominal computed tomography, upper panendoscopy, bone marrow biopsies, whole body gallium-67 citrate scan, multiple blood, stool, and urine cultures, as well as serological investigations for known …

Aortic valve endocarditis might be the first manifestation of Whipple’s disease without further multiorgan involvement. A case is reported of aortic valve endocarditis with severe aortic regurgitation without clinical evidence of gastrointestinal disease in a 47 year old man who was admitted …

Whipple's disease confined to the nervous system occurred in a 36-year old woman who presented with grand mal seizures and dementia. There was no evidence of extracerebral involvement and the jejunal biopsy was negative before treatment. Multiple enhancing lesions on CT scan progressed despite therapy with minocycline and prednisone, but resolved on treatment with tetracycline. The dementia did not progress while she was on antibiotic therapy. Whipple's disease should be considered as a treatable cause of progressive dementia even in the absence of an abnormal jejunal biopsy.

A patient who died of Whipple's disease had moderate mitral stenosis with large firm yellow vegetations on the contact area of the mitral leaflets. Light microsocopy showed PAS positive macrophages within the thickened cusps and overlying vegetations. Negative images of rod-shaped bodies were visible in the cytoplasm of the histiocytes. No Aschoff bodies were seen, and there was no history of rheumatic fever. The findings in this patient lend support to the concept that chronic rheumatic type valvar deformity may result from a persistent intrinsic infectious agent.

We report a patient with Whipple's disease who developed a myopathy that improved during antibiotic therapy. The muscle biopsy showed mild type 2 fibre atrophy, type 1 fibre preponderance, variability in fibre size, and changes in the myofibrillar pattern of affected fibres. Interfascicular macrophages contained PAS-positive material. With the electron microscope these macrophages contained membranous inclusions and bacillary bodies, similar to those seen in the jejunal biopsy.

Intestinal biopsies from 146 patients with adult coeliac disease and 13 patients with intestinal villous atrophy of different aetiology were assessed for the presence of subepithelial collagen and compared with a group of 20 control subjects. Subepithelial collagen was a common and non-specific finding observed in intestinal biopsies from patients suffering from adult coeliac disease (36%) and tropical sprue. In adult coeliac disease the described subepithelial changes usually regress following treatment, though marked subepithelial collagen deposition may indicate a poor prognosis. The study showed that the presence of marked subepithelial collagen in a flat jejunal biopsy does not define a separate clinical entity.

An uncharacteristic case of Whipple's disease is reported, in which, although overt intestinal involvement was absent, and there was only a patchy histological lesion, the diagnosis was confirmed by electron-microscopic examination of peroral intestinal biopsies.

Two patients with Whipple's disease are described in whom the diagnosis was established by peroral small intestinal biopsy. Scurvy occurred in one patient.

A cell wall deficient form of an alpha-haemolytic streptococcus was grown from a prolonged monolayer cell culture of a lymph node taken from a patient with Whipple's disease. Serological cross reactivity was shown between the organism and the material within Whipple's disease macrophages positive for diastase-resistant periodic acid-Schiff (D./P.A.S.). In vitro studies characterized the organism as a facultative intracellular parasite which caused the accumulation within cells of D./P.A.S.-positive material. These results suggest that a pathogenic bacterium is the essential aetiological agent and that the culture of Whipple's disease tissues in hypertonic media may have practical value.