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Classical Whipple's disease (CWD) affects the gastrointestinal tract and causes chronic diarrhea, malabsorption, and barrier dysfunction with microbial translocation (MT). Immune reconstitution inflammatory syndrome (IRIS) is a serious complication during antimicrobial treatment of CWD. The pathomechanisms of IRIS have not been identified and mucosal barrier integrity has not been studied in patients with IRIS CWD.In 96 CWD patients (n = 23 IRIS, n = 73 non-IRIS) and 30 control subjects, we analysed duodenal morphology by histology, measured serum markers of MT, and proinflammatory cytokines in biopsy supernatants, and correlated microbial translocation with T cell reconstitution and activation.Before treatment, duodenal specimens from patients who later developed IRIS exhibited a more pronounced morphological transformation that suggested a disturbed barrier integrity when compared with the non-IRIS group. Villous atrophy was mediated by increased apoptosis of epithelial cells, which was insufficiently counterbalanced by regenerative proliferation of crypt cells. Pretreatment deficiencies in the mucosal secretion of proinflammatory cytokines and chemokines (e.g., IL-6, CCL2) in these patients markedly resolved after therapy induction. High serum levels of lipopolysaccharides (LPS), soluble CD14 (sCD14), and LPS-binding protein (LBP) combined with low endotoxin core antibody (EndoCAb) titres suggested systemic MT in CWD patients developing IRIS. CD4Prolonged MT across a dysfunctional intestinal mucosal barrier due to severe tissue damage favors dysbalanced immune reconstitution and systemic immune activation in IRIS CWD. Therefore, the monitoring of inflammatory and MT markers in CWD patients might be helpful in identifying patients who are at risk of developing IRIS. Therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist in the prevention of IRIS.

A 61-year-old woman received a diagnosis of undifferentiated non-erosive arthritis in 2010 and assumed methotrexate and steroids in 2014. After 1 year, she experienced watery diarrhea, vomiting, fever, weight loss, and severe hypoalbuminemia, thus being admitted into our Unit. Esophagogastroduodenoscopy showed duodenal lymphangiectasia and duodenal biopsy samples several foamy PAS-positive macrophages and villous subtotal atrophy. Transmission electron microscope demonstrated several extracellular and intracellular rod-shaped bacteria (Tropheryma whipplei). Therefore, we diagnosed Whipple's disease. Our patient assumed doxycycline/hydroxychloroquine with prompt remission of gastrointestinal symptoms. At 1 year of follow-up, she was symptom-free, histological reassessment showed almost complete mucosal healing and transmission electron microscope demonstrated bacteria breaking/disappearance. The present report demonstrates that: (i) rheumatological manifestations are common onset symptoms of Whipple's disease; (ii) immunosuppressive therapy may delay the diagnosis and worsen clinical presentation; (iii) transmission electron microscopy for specific bacteria detection/disappearance is an helpful diagnostic tool, when available.

Whipple disease (WD) is usually a systemic infectious disease that can have central nervous system (CNS) involvement. WD confined to the CNS is extremely rare and difficult to diagnose, but can be fatal if not treated in a timely fashion. We present the case of a 42-year-old man with a subacute dementia accompanied by a movement disorder consisting of progressive supranuclear gaze palsy, myoclonus, and ataxia. Our patient lacked the typical magnetic resonance imaging (MRI) findings reported with isolated CNS WD and had a false-positive cerebrospinal fluid (CSF) 14-3-3 protein. The patient expired, and definitive diagnosis of isolated CNS WD was made by autopsy with characteristic macrophage accumulations found in the brain but not in the gastrointestinal tract. We examine the literature on isolated CNS WD and discuss how these previously unreported findings make a rare diagnosis even more challenging. The reported patient is the first in the literature with tissue diagnosis of isolated CNS WD in the setting of normal brain MRI and positive CSF 14-3-3 protein. Isolated CNS WD should be added to the list of considerations for a false-positive CSF 14-3-3 protein. Even in the absence of typical MRI lesions, a patient with subacute progressive dementia, supranuclear gaze palsy, and other various neurologic abnormalities should have the diagnosis of isolated CNS WD considered.

In order to evaluate the specificity of the increased urinary excretion of conjugated histamine in myotonic dystrophy, patients with various gastrointestinal disorders have been studied. Occasionally the urinary excretion of conjugated histamine in urine was elevated in patients with idiopathic steatorrhoea, coeliac disease and gastritis/peptic ulcer. When determined, the histamine-like activity in the stools was augmented in cases with increased urinary output of conjugated histamine. A significantly increased urinary excretion of conjugated histamine was found in cases of chronic pancreatitis. The increased faecal histamine-like activity indicated an intestinal origin of the urinary conjugated fraction in this disorder.

The proteome of Tropheryma whipplei, the intracellular bacterium responsible for Whipple's disease (WD), was analyzed using two complementary approaches: 2-DE coupled with MALDI-TOF and SDS-PAGE with nanoLC-MS/MS. This strategy led to the identification of 206 proteins of 808 predicted ORFs, resolving some questions raised by the genomic sequence of this bacterium. We successfully identified antibiotic targets and proteins with predicted N-terminal signal sequences. Additionally, we identified a family of surface proteins (known as T. whipplei surface proteins (WiSPs)), which are encoded by a unique group of species-specific genes and serve as both coding regions and DNA repeats that promote genomic recombination. Comparison of the protein expression profiles of the intracellular facultative host-associated WD bacterium with other host-associated, intracellular obligate, and environmental bacteria revealed that T. whipplei shares a proteomic expression profile with other host-associated facultative intracellular bacteria. In summary, this study describes the global protein expression pattern of T. whipplei and reveals some specific features of the T. whipplei proteome.

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. A sugar 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.

Whipple's disease is a multisystem disorder with protean manifestations and with poorly understood aetiopathogenesis. It is unclear how the immune system reacts, whether it functions normally or not, whether it protects the organism or is defeated in one way or another by the 'Whipple bacillus'. The purpose of our study was to assess humoral and cellular immunity at the level of the intestinal mucosa. This histochemical, immunocytochemical and electronmicroscopic study, based on 16 cases, has shown that the changes in components of the mucosal immune system in Whipple's disease are quite different from normal. The phagocytic capacity of the macrophages, assessed microscopically, is abnormal, the number of intra-epithelial lymphocytes is increased, the CD 4/CD 8 cell ratio is decreased and the IgM positive cells in the lamina propria outnumber the IgA positive cells. These changes may be inter-dependent.

This report describes a patient who presented with fever, weight loss, diarrhea, and adenopathy. At the time of presentation he had a 28-year history of unusually severe destructive polyarthritis. Duodenal biopsy revealed periodic acid-Schiff-positive macrophages. Polymerase chain reaction studies showed positivity for Tropheryma whipplei in synovial fluid, synovial tissue, and lymph node specimens, and Whipple's disease was diagnosed. T whipplei was successfully cultivated from the synovial fluid by both cell culture and axenic culture. This strain (named ART1) was subcultured and subsequently established and genotyped. Antibiotic treatment was instituted in the patient, after which his symptoms remitted. These findings show for the first time that Whipple's arthritis may be, at least in some cases, a septic arthritis.

Intestinal malabsorption results from a wide variety of causes, which can most easily be organized into three groups. Maldigestion arises from problems with mixing or with digestive mediators, and includes post-gastrectomy patients and those with deficiencies of pancreatic or intestinal enzymes, or of bile salts. Mucosal and mural causes of malabsorption are abundant, and include gluten-sensitive enteropathy, tropical sprue, autoimmune enteropathy, and HIV/AIDS-related enteropathy, as well as mural conditions such as systemic sclerosis. Finally, microbial causes of malabsorption include bacterial overgrowth, Whipple's disease, and numerous infections or infestations that are most frequently seen in immunocompromised patients. An overview of the most common and interesting entities in each of these categories follows, along with a discussion of current concepts. Mucosal conditions and microbial causes of malabsorption are given special attention.

Chronic myelitis from Whipple's disease of the spinal cord is extremely rare. The differential diagnosis includes chronic inflammatory lesions, viral or bacterial infections, and tumours of the spinal cord. Here we present a 50-year-old man with mild sensory deficits because of a large lesion of the cervical spinal cord who markedly showed improvement during probatory antibiotic therapy. PCR and jejunal biopsy were initially negative and only later confirmed the diagnosis of Whipple's disease. Clinical and neuroradiological criteria are suggested which may be of help in the early diagnosis of spinal Whipple's disease before confirmation by molecular biology or histology.

SUMMARY A case with transient, almost complete sleep loss caused by cerebral manifestation of Whipple's disease (WD) is presented. Cerebral WD is rare and in most cases occurs after gastrointestinal infection. In our case, a progressive and finally almost complete sleep loss was the initial and predominant symptom. Polysomnographic studies in several consecutive nights and over 24 h showed a total abolition of the sleep–wake cycle with nocturnal sleep duration of less than 15 min. Endocrine tests revealed hypothalamic dysfunction with flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin. Cerebrospinal fluid (CSF) hypocretin was reduced. [18F]Deoxyglucose positron emission tomography (FDG-PET) revealed hypermetabolic areas in cortical and subcortical areas including the brainstem, which might explain sleep pathology and vertical gaze palsy. In the course of treatment with antibiotics and additional carbamazepine for 1 year, insomnia slowly and gradually improved. Endocrine investigations at 1-year follow-up showed persistent flattening of circadian rhythmicity. The FDG-PET indicated normalized metabolism in distinct regions of the brain stem which paralleled restoration of sleep length. The extent of sleep disruption in this case of organic insomnia was similar to cases of familial fatal insomnia, but was at least partially reversible with treatment.

Whipple's disease is a rare systemic disease with symptoms dominated by diarrhea, weight loss, arthralgia or arthritis and abdominal pain. Whipple's disease is limited to humans and the disease is caused by infection with the gram-positive bacterium, Tropheryma whippelii. PCR determinations suggest that T. whippelii is an environmental actinomycete but studies on the organism have been limited due to the inability to culture the organism in vitro. Most patients are male Caucasians older than 50 years of age living in North and South America, England, continental Europe and Australia. The cellular immune system appears to control T. whippelii and patients with cellular immune defects appear to be more susceptible to Whipple's disease. The disease affects the gastrointestinal tract, the central nervous system, cardiovascular system and musculoskeletal system; however, other organs also may be affected. Whipple's disease can be treated with antibiotics effective against gram-positive bacteria but relapses are common. Untreated Whipple's disease is usually fatal. Although the mode of transmission of T. whippelii in humans is unclear, it possibly occurs through the fecal-oral route and food and/or water may be the source of the organism.

We describe 2 patients presenting with polyarthritis in whom the synovial fluid (1 patient) or synovial tissue (1 patient) was positive for Tropheryma whippelii, the Whipple's disease-associated bacillus, when examined by polymerase chain reaction (PCR) and DNA sequencing. Histopathologic findings were consistent with articular Whipple's disease in the synovial fluid of 1 patient and the synovial tissue of the other. In both patients, bowel mucosal specimens were negative for Whipple's disease features by histologic and PCR methods. One patient was positive for T whippelii in the peripheral blood. Control synovial fluid specimens from 40 patients with other arthritides, including Lyme arthritis, were negative. Sequencing of a 284-basepair region of the 16S ribosomal RNA gene confirmed that the sequence is closely related to the known T whippelii sequence. Both patients responded to treatment with antibiotics.

Many cases of central nervous system (CNS) Whipple's disease are not diagnosed until postmortem. Few reviews of CNS Whipple's disease have delineated the frequencies of abnormalities on neurological examination, cerebrospinal fluid studies, neuroimaging, and intestinal biopsy studies. Guidelines for diagnosis and treatment have not been proposed. In this review we present 3 new cases of CNS Whipple's disease and summarize the literature to determine the frequencies of neurological signs and abnormalities on diagnostic testing. We propose guidelines for diagnostic screening, selection for biopsy, and treatment. Review of the 84 cases of CNS Whipple's disease (81 in the literature, 3 new) revealed that 80% of the patients had systemic signs. Cognitive changes were frequent (71%), and 47% with cognitive changes also had psychiatric signs. Oculomasticatory myorhythmia and oculo-facial-skeletal myorhythmia, pathognomic for CNS Whipple's disease, were present in 20% of patients, and were always accompanied by a supranuclear vertical gaze palsy. Tissue biopsy was a sensitive technique; 89% of those who had biopsies had positive biopsy results. Diagnosis and treatment of definite CNS Whipple's disease should be based on the presence of pathognomic signs (oculomasticatory myorhythmia or oculo-facial-skeletal myorhythmia) or positive biopsy or polymerase chain reaction results. Possible CNS Whipple's disease should be diagnosed in the setting of unexplained systemic symptoms and neurological signs (supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations). Those with possible CNS Whipple's disease should undergo small-bowel biopsy.

Whipple's disease (WD) is a rare disorder caused by the gram-positive actinomycete Tropheryma whippelii (1). An oral route of acquisition is presumed (2). WD is a chronic systemic infection morphologically characterized by foamy PAS-positive macrophages. This case report depicts the diagnosis and clinical management of a woman who presented with atypical cardial manifestations of WD and died from severe cardiac impairment by Tropheryma whippelii which was confirmed by polymerase chain reaction. Histological assessment of myocardial specimens obtained at autopsy showed PAS-positive macrophages accumulating within foci of interstitial myocardial fibrosis. Immunohistochemical staining demonstrated myocarditis with lymphocytes and neutrophilic granulocytes, which has not been reported so far in the course of WD.

The clinical picture of neurological involvement in Whipple's disease (WD) may resemble progressive supranuclear palsy (PSP). We looked for WD pathogen DNA in the cerebrospinal fluid of 9 patients with a clinical diagnosis of PSP. The analysis was negative for all samples, showing that WD is not commonly involved in the aetiopathogenesis of PSP.

A case of Whipple's disease occurring in a 63-year-old woman is reported. Cervical lymphadenopathy and vague constitutional symptoms were soon followed by diarrhea and weight loss. Supraclavicular lymph node exeresis suggested the initial diagnosis, which was confirmed by intestinal biopsy. The concurrence of cystic spaces, PAS-positive foamy histiocytes and epithelioid granulomas is considered by the authors to provide a useful histological clue in the diagnosis of lymph node involvement in Whipple's disease. Pathologists must be aware of such an un-conventional presentation of this rare entity and therefore include it within the differential diagnosis of cervical and/or axillary lymphadenopathies.

Background: Cutaneous findings other than hyperpigmentation are rare in Whipple’s disease. Case report: We present the case of a 59-year-old man previously diagnosed with Whipple’s disease by duodenal biopsy, who developed red-brown, painful, subcutaneous nodules on the buttocks, thighs, arms and legs. Biopsy of these nodules showed a septal panniculitis and foamy macrophages containing PAS-positive, diastase resistant intracytoplasmic material, characteristic of Whipple’s disease and similar to that observed in the duodenal biopsy. Ultrastructurally, this material in the histiocytes corresponded to degenerated bacilli. Conclusions: This is the fourth documented case of subcutaneous involvement by Whipple’s disease. One should consider the possibility of Whipple’s disease in any patient who presents with symptoms compatible with that condition who demonstrates septal panniculitis with a large amount of foamy histiocytes.

Infection with Tropheryma whippelii, the causative agent of Whipple's disease, involves nearly every organ. Involvement of bone marrow may be an overlooked area of Whipple's disease. We report a case of lymphoma-like Whipple's disease with bone marrow involvement together with a brief review of the literature on this topic. Despite minimal documentation, bone marrow may be commonly involved in Whipple's disease and, although not specific, diastase-resistant periodic acid-Schiff (PAS)-positive macrophages in bone marrow may offer an important clue to diagnosis using PAS histology of upper endoscopic biopsies, polymerase chain reaction or electron microscopy.

We report here a new case of oculomasticatory syndrome related to systemic Whipple's disease. The patient presented typical ophthalmoparesis associated with ocular myorhythmia consisting of 1 Hz convergent oscillations of both eyes. The masticatory involvement was remarkable and consisted of a permanent bruxism leading to severe tooth abrasions. Possible pathophysiology of such a disorder is discussed.

A problem of management in Whipple's Disease. K. P. Lim, A. S-Y Leong and A. Kerr Grant, Aust. N.Z. J. Med., 1981, 11, pp. 5&59. A patient with Whipple's disease did not respond to appropriate antibiotic treatment. A therapeutic response was obtained by a combination of tetracycline and prednisolone

A case of Whipple's disease is described where the lymphatics in the regional lymph nodes appear to be obstructed by embolized macrophages, containing the characteristic PAS positive bacillary material. It is suggested that the regional lymphangiectasia in Whipple's disease may in part result from such cellular embolism.

The cellular immune system was tested in nine patients with Whipples' disease. Three patients had active disease, and six had been in remission for up to 10 years. Intradermal delayed hypersensitivity reactions to candidin, trichophytin, tuberculin and varidase, T-cell counts as determined by E-rosettes, allogeneic stimulation of lymphocytes in the mixed lymphocyte culture, and mitogenic activation of lymphocytes by concanavalin A, phytohaemagglutinin and by pokeweed mitogen, were tested in the patients and compared with control subjects. HLA typing was performed in all patients. The reaction to tuberculin and varidase, the T-cell counts and the activation of lymphocytes by concanavalin A were significantly reduced in patients with active disease and in patients during remission. The reaction to candidin and trichophytin was poor even in the controls. The mean results of the mixed lymphocyte culture, phytohaemagglutinin, and pokeweed mitogen activation tests were not significantly different from the controls. In patients with active disease the mixed lymphocyte culture reaction and the T-cell counts were less than in patients in remission. The results suggest a persistent defect of T-cells in patients with Whipple's disease, a defect that is more severe in patients with active disease. The finding of HLA B27 in four of thenine patients supports the hypothesis of primary rather than secondary impairment of the cellular immune system in Whipple's disease.

Progressive hypersomnia, memory disturbance, and vertical ophthalmoplegia developed in a 63-year-old woman. The diagnosis of Whipple's disease of the central nervous system was suggested by her presentation and results of studies using magnetic resonance imaging. Despite a one-month course of antibiotics, active Whipple's disease, localized to the central nervous system, was found at autopsy.

A fifth case of oculomasticatory myorthythmia associated with cerebral Whipple's disease is reported. This peculiar abnormal movement has never been described in association with cerebral dysfunction other than Whipple's disease. The present case exhibited rhythmic convergence of the eyes and synchronous (1–2 Hz) contractions of the masticatory muscles and of the proximal and distal skeletal muscles. These abnormal movements occurred 13 years after the beginning of the disease. They were persistent and unchanged until the death of the patient 3 months later. No treatment was effective to suppress the involuntary movements (clonazepam, baclofen, antibiotics). Associated neurological signs included global supranuclear ophthalmoplegia, facial weakness, bilateral ptosis, absent gag reflex, and intellectual deterioration.

Neurologic and electrophysiologic findings in a 57-year-old man with Whipple's disease are reported. The patient had severe proximal weakness and weight loss of more than 20 kg. Conventional electromyography and nerve conduction studies suggested mild neuropathy in distal segments of lower limbs and myopathy in proximal muscles. Automatic analysis of the electromyogram in proximal muscles was consistent with myopathy. Conduction velocity of muscle fibers in situ showed low propagation velocity of the impulse. Weakness, weight loss, and all the electrophysiologic parameters improved after treatment, including a compression of the peroneal nerve at the knee, perhaps related to weight loss (slimmer's paralysis).

Arthritis usually precedes the other manifestations of Whipple’s disease (WD). During this “lead time,” which may extend as long as 35 years (l), the correct diagnosis may be virtually impossible without recourse to synovial biopsy. There are scattered accounts of subcutaneous nodules with Whipple’s disease, but only a single published report of a nodule biopsy-a brief notation that “the changes were consistent with rheumatoid arthritis” (2). This is a report of a patient with a nodule that followed the onset of oligoarthritis by 3 years and preceded the appearance of diarrhea and weight loss by 12 years. Biopsy of the nodule utilizing electron microscopy disclosed specific diagnostic features of Whipple’s disease.

Summary: Whipple's disease involving the pericardium: Pathological confirmation during life. R. E. Vlietstra, J. T. Lie, W. E. Kuhl, G. K. Danielson and M. K. Roberts, Aust. N.Z. J. Med., 1978, 8, pp. 649–651. Cardiac involvement in Whipple's disease has been a frequent autopsy finding but is rarely recognized clinically. We report here a patient, a 63-year-old man, in whom Whipple's disease was diagnosed in 1974, based on a seven-year history of arthralgia, one-year history of weight loss and steatorrhea, and diagnostic small bowel biopsy. Despite complete regression of all joint and bowel symptoms following a prolonged course of tetracycline therapy, the patient developed incapacitating congestive heart failure and signs of constrictive pericarditis, for which a thoracotomy and pericardectomy was performed. Histologic examination revealed fibrous pericarditis with mononuclear infiltrates, including PAS-positive histiocytes. The characteristic bacilliform bodies were identified by electron microscopy in the resected pericardium. This to our knowledge is the first such demonstration during life of Whipple's disease involving the heart.

Absence of PAS-positive macrophages In hepatic and lymph node granulomata in Whipple's disease. P. J. Torzillo, L. Bignold and G. A. Khan, Aust. N.Z. J. Med., 1982, 12, pp. 73–75. A patient with Whipple's disease presented with hepatic and lymph node granulomata which contained no PAS-positive macrophages but which disappeared after penicillin treatment. The absence of PAS-positive staining in the macrophages of hepatic granulomata in Whipple's disease has not previously been reported but does not negate the diagnosis.