Whipple's disease: a rare case of malabsorption.

Whipple's disease is a chronic, rare, multisystemic, infectious entity, described for the first time in 1907. Its aetiological agent is the Gram-negative rod, Tropheryma whipplei, which was isolated for the first time in 2001 from a cardiac valve of a patient with endocarditis. We present the case of a 71-year-old man, who came into the emergency room complaining of anorexia, weakness, abdominal pain and diarrhoea with haematochezia and presented disseminated palpable purpuric lesions, predominantly in the lower limbs. The upper endoscopy showed a duodenal vasculitis and the biopsy of that location revealed aspects suggestive of Whipple's disease. We started him on antibiotics according to the recent orientations with progressive clinical and analytical improvement, although he developed an immune reconstitution syndrome, which lasted for 2 weeks.

Tropheryma whipplei infection (Whipple's disease) in a patient after liver transplantation.

Whipple's disease (WD) is a rare infection caused by the bacterium Tropheryma whipplei that can affect multiple organs and most commonly occurs in the immunocompetent host. Only 3 cases of WD have been reported in the setting of immunosuppression for organ transplantation. Here, we report the first case of WD, to our knowledge, in a patient after liver transplantation with comorbid graft-versus-host-disease. We discuss the diagnostic challenges in this setting and the value of electron microscopy and in situ hybridization methods for confirming the infection. WD may be under-diagnosed in immunosuppressed transplant patients because the disease can present with atypical clinical and histological features that suggest other conditions.

Intrafamilial circulation of Tropheryma whipplei, France.

Tropheryma whipplei, which causes Whipple disease, has been detected in 4% of fecal samples from the general adult population of France. To identify T. whipplei within families, we conducted serologic and molecular studies, including genotyping, on saliva, feces, and serum from 74 relatives of 13 patients with classic Whipple disease, 5 with localized chronic T. whipplei infection, and 3 carriers. Seroprevalence was determined by Western blot and compared with 300 persons from the general population. We detected T. whipplei in 24 (38%) of 64 fecal samples and 7 (10%) of 70 saliva samples from relatives but found no difference between persons related by genetics and marriage. The same circulating genotype occurred significantly more often in families than in other persons. Seroprevalence was higher among relatives (23 [77%] of 30) than in the general population (143 [48%] of 300). The high prevalence of T. whipplei within families suggests intrafamilial circulation.

Whipple's disease in mentally retarded patients: report of two cases.

Of 21 patients diagnosed with Whipple's disease (WD) by polymerase chain reaction (PCR), 3 were mentally retarded. We describe 2 of these patients, both of whom had WD in the central nervous system. WD was confirmed with PCR on blood and, for 1 patient, also on cerebrospinal fluid (CSF).

Decreased levels of interleukin-12p40 in the serum of patients with Whipple's disease.

BACKGROUND: An impaired production of interleukin (IL)-12 and T cell interferon-gamma (IFN-gamma) of in vitro stimulated monocytes has been discussed as a pathogenic factor in Whipple's disease (WD). It is unclear whether this defect of cellular immunity is translated to the humoral immune system and to serum correlates. METHODS: We analyzed the serum of 40 patients with Whipple's disease in various degrees of disease activity by sandwich enzyme-linked immunosorbent assay for differences in cytokine and cell adhesion molecule concentrations compared with age- and sex-matched controls. RESULTS: We observed a highly significant reduction of IL-12p40 levels (patients, 0.18+/-0.05 ng/ml (mean+/-SEM); controls, 3.19+/-0.39 ng/ml; p<0.01) in all stages of disease activity, whereas the concentration of IL-12p70 was comparable with controls. Furthermore, we observed a slight decrease in tumour necrosis factor alpha (TNF-alpha) concentrations in the serum of patients (patients, 6.36+/-0.90 pg/ml; controls, 10.5+/-1.23 pg/ml; p<0,05). The levels of other cytokines such as IFN-gamma, IL-2, IL-13 and transforming growth factor beta, as well as soluble cell adhesion molecules lymphocyte function-associated antigen 3 and intercellular adhesion molecule 1, were not significantly different compared with controls. Levels of immunoglobulin G2 (IgG2) measured in the serum of WD patients were below normal in 24 of 29 patients and were even below the 95% confidence interval in 10 patients. CONCLUSION: Our data demonstrate a persistent defect of the cellular immune response with decreased serum concentrations of IL-12p40 and TNF-alpha and decreased IgG2 levels in a large group of WD patients. These data support as in vivo finding the results obtained in previous investigations with stimulated monocytes/lymphocytes. The isolated decrease in IL-12p40 may hint at possible defects in the IL-12/IFN-gamma promoter system.

[New etiologies responsible for infective endocarditis with negative blood cultures]. / Etiologie emergenti responsabili di endocarditi infettive con emocolture negative.

The prevalence of infective endocarditis with negative blood cultures varies in the different series from 5 to 25%. There are certain explanations of negative blood culture endocarditis: previous incorrect antibiotic therapy before obtaining blood samples (antibiotic treatment inhibits the growth of germs, and therefore bacteremia, without sterilizing the vegetations); infective endocarditis due to fastidious microorganism, that is of difficult cultivation and identification; infective endocarditis due to cell-dependent organism (e.g. Coxiella burnetii); infective endocarditis due to fungi; non-infectious involvement of the endocardium (at times with vegetations) during the course of certain disease. We underline three etiologies (Coxiella burnetii, Bartonella species and Whipple's disease bacterium) because their study have constituted the stimulus for the introduction into clinical evaluation of patients with suspected infective endocarditis of different diagnostic approaches, based on a correct sequential application of blood cultures, serodiagnosis and molecular microbiology.

[An unusual case of morbid weight loss]. / Kóros soványság ritka esete.

A 47 year old patient was admitted because of 20 kg weight loss and microcytic anaemia. There wasn't any important disease in his medical history. During examinations it has been found microcytic anaemia, hypoproteinaemia, low serum potassium, elevated prothrombin INR value, malabsorption and mild hepatosplenomegaly. After precluding the possibility of malignant disorders and any other chronic diseases, examinations have cleared Whipple-disease.

Impaired monocyte function in patients succesfully treated for Wipple's disease

Peripheral blood mononuclear cells (monocytes) from patients with Whipple's disease in long-term remission were tested for their ability to handle intracellular microorganisms. Phagocytosis and lysis of Candida tropicalis by monocytes of patients (n=12) andcontrols (n=8) were quantified after 30 min of incubation. Phagocytosis was similar in both groups but intracellular Killing of Candida tropicalis was significativily lower in patients (p<0.001). We concluded that our study showed an in vitro defect in the intracellular Killing function of monocytes in subjects in remission many years after diagnosis of Whipple's disease. The defective function did not seem to be related to relapse or to the susceptibility to other infections.

Impaired monocyte function in patients successfully treated for Whipple's disease.

Peripheral blood mononuclear cells (monocytes) from patients with Whipple's disease in long-term remission were tested for their ability to handle intracellular microorganisms. Phagocytosis and lysis of Candida tropicalis by monocytes of patients (n = 12) and controls (n = 8) were quantified after 30 min of incubation. Phagocytosis was similar in both groups but intracellular killing of Candida tropicalis was significatively lower in patients (p < 0.001). We concluded that our study showed an in vitro defect in the intracellular killing function of monocytes in subjects in remission many years after diagnosis of Whipple's disease. The defective function did not seem to be related to relapse or to the susceptibility to other infections.

Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease.

Several small studies have indicated an impaired cell mediated immune response as a possible cause for the delayed elimination of the bacteria in Whipple's disease. A specific defect, however, has not been defined. We examined the expression of cell surface molecules and mitogenic responses of peripheral blood mononuclear cells in 27 patients with Whipple's disease at different disease stages by indirect immunofluorescence and by measurement of [3H]thymidine incorporation, respectively. E-rosette formation and cutaneous reaction to seven recall antigens were determined. Matched healthy donors served as controls. We found a significantly reduced number of cells expressing the complement receptor 3 alpha-chain (= CD11b) in all patients. In florid disease, the number of activated cells (in particular CD58 positive cells) was increased and CD4/CD8 ratios were diminished. Proliferation to phytohemagglutinin and to sheep red blood cells was reduced at all stages of the disease. Serum of control persons reversed this decreased responsiveness especially in patients with active disease. Skin reaction was hypoergic in all patients. Determination of CD58 positive cells increased in patients with active disease may be useful to define the activity of the disease and the duration necessary for treatment. Transient inhibiting serum activities may impair the CD2/CD58 interaction. The reduction of cells expressing CD11b, the decreased proliferation, and the cutaneous hypoergy indicate a persisting defect of cell mediated immunity in vivo and in vitro. These defects may contribute to the impaired ability of patients with Whipple's disease to eliminate bacteria.

Whipple's disease with axial and peripheral joint destruction.

A seropositive white man had follow-up for 16 years with a diagnosis of palindromic rheumatism. Treatment had included parenteral gold, methotrexate, prednisone, hydroxychloroquine sulfate, and penicillamine before diarrhea led to a biopsy-proven diagnosis of Whipple's disease. Clinical and radiographic criteria for ankylosing spondylitis were met. In addition to classic Whipple's arthropathy, he had the combined but singular findings of pancarpal destruction and cervical apophyseal fusion. HLA typing revealed the B7 antigen. This case illustrates the pitfalls in diagnosis of a chronic polyarthritis that has, as a typical feature, a long latency before manifesting its more specific signs and symptoms (ie, diarrhea, malabsorption, and hyperpigmentation). Care should be taken during evaluation of any disease with atypical and nonspecific features (eg, positive rheumatoid factor in a patient with polyarthritis) and one should continue to reevaluate the original impression while confirmatory evidence is lacking. Moreover, the roentgenographic findings of pancarpal narrowing, apophyseal fusion, and advanced iliofemoral joint disease, in addition to sacroiliitis and syndesmophyte formation, challenge the generally held notion that Whipple's arthropathy is a nondestructive joint disease.

Whipple's disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients.

Whipple's disease is a chronic systemic illness, the optimal treatment of which remains poorly defined. In our analysis of a 30-year, 29-patient experience with Whipple's disease at the Mayo Clinic, the frequent initial manifestations of diarrhea, weight loss, arthritis, and lymphadenopathy correlated with findings reported previously by other investigators. Antibiotic therapy yielded rapid symptomatic and biochemical improvement, and histologic changes in the small bowel occurred subsequently. Despite antimicrobial therapy, relapses in patients with Whipple's disease are common, and the central nervous system is considered the most serious site of involvement for recurrence. Administration of an antibiotic agent that is able to cross the blood-brain barrier may be more important in preventing relapse than prolonged duration of initial antimicrobial therapy.

Impaired bacterial degradation by monocytes and macrophages from a patient with treated Whipple's disease.

A patient with Whipple's disease is described, and multiparameter flow cytometric examinations of several of the patient's phagocyte functions 3 and 9 mo after the start of oxytetracycline therapy are reported. Almost no intracellular degradation of Escherichia coli or Streptococcus pyogenes proteins and DNA occurred after ingestion by the patient's monocytes and macrophages. In addition, only minor digestion of phagocytized zymosan particles was detected. The mononuclear intracellular degradation was equally impaired 3 and 9 mo after the start of therapy. The monocyte and macrophage phagocytosis and intracellular killing, and all granulocyte phagocyte functions tested, were normal. The impaired mononuclear degradation of ingested material that was measured is consistent with the accumulation of periodic acid-Schiff-positive bacterial degradation products seen in macrophages of affected tissues in vivo, and suggests a key role of macrophage dysfunction in the pathogenesis of Whipple's disease.

Monocyte procoagulant activity in Whipple's disease.

We have studied the expression of procoagulant activity by the circulating mononuclear cells of four patients with Whipple's disease. There was a spontaneous expression of procoagulant activity in two patients with active untreated Whipple's disease. This activity was shown to originate in the monocyte fraction of the mononuclear cells and was demonstrated to cleave prothrombin directly. This prothrombinase activity was not Factor Xa, because it was not neutralized by anti-Factor X serum and was not inhibited by an established panel of Factor Xa inhibitors. The prothrombinase activity was not expressed by the monocytes of these patients following 8 weeks of antibiotic therapy, by which time the patients' symptoms resolved, and was not found in two patients previously treated for Whipple's disease who were in clinical remission or in normal subjects. Serial studies in one patient with active disease showed that monocytes failed to express increased prothrombinase within 2 weeks of antibiotic therapy. A second procoagulant activity was produced in response to endotoxin (LPS) by cells from controls and patients with Whipple's disease and was identified as thromboplastin. These observations suggest that circulating monocytes of patients with active Whipple's disease are endogenously stimulated to express prothrombinase activity, which may contribute, at least in part, to the pathophysiology of this condition.

Thrombocytosis in Whipple's disease.

Three men with Whipple's disease had platelet counts of 729,000-1,142,000 per mm3, which fell to normal as their illness responded to antibiotic therapy. Reports on Whipple's disease and hospital charts from the largest published series reveal thrombocytosis in 11 of the 24 patients whose counts were recorded. The prevalence of anemia, marrow infiltration, and classic manifestations of Whipple's disease did not differ between patients with and without thrombocytosis. The thrombocytosis of Whipple's disease is similar to that of celiac sprue, Crohn's disease, and ulcerative colitis.