Whipple's disease.

In recent years, it has become apparent that Tropheryma whipplei not only causes a chronic multisystemic infection which is often preceded by arthropathies for many years, well known as 'classical' Whipple's disease, but also clinically becomes manifest with localized organ affections and acute (transient) infections in children. T. whipplei is found ubiquitously in the environment and colonizes in some healthy carriers. In this review, we highlight new aspects of this enigmatic infectious disorder.

Tropheryma whipplei infection and Whipple's disease.

Recent advances in medical microbiology, epidemiology, cellular biology, and the availability of an expanded set of diagnostic methods such as histopathology, immunohistochemistry, PCR, and bacterial culture have improved our understanding of the clinical range and natural course of Tropheryma whipplei infection and Whipple's disease. Interdisciplinary and transnational research activities have contributed to the clarification of the pathogenesis of the disorder and have enabled controlled trials of different treatment strategies. We summarise the current knowledge and new findings relating to T whipplei infection and Whipple's disease.

Tropheryma whipplei , Immunosuppression and Whipple's Disease: From a Low-Pathogenic, Environmental Infectious Organism to a Rare, Multifaceted Inflammatory Complex.

BACKGROUND: The actinobacterium Tropheryma whipplei was detected 20 years ago by molecular techniques, and following its culture has been characterized as the cause of a systemic infection known as Whipple's disease (WD). T. whipplei occurs in the environment, is prevalent only in humans, is believed to be transmitted via oral routes and to be host dependent. KEY MESSAGES: The classical form of T. whipplei infection, i.e. classical WD (CWD), is rare. It is well defined as slowly progressing chronic infection with arthralgia, diarrhea and weight loss, mostly in middle-aged men. However, current research revealed a much broader spectrum of clinical features associated with T. whipplei infection. Thus, T. whipplei may cause acute and transient infections (observed primarily in children) and the bacterium, which is found in soil and water, occurs in asymptomatic carriers as well as in CWD patients in clinical remission. In addition, T. whipplei affects isolated and localized body compartments such as heart valves or the central nervous system. Subtle immune defects and HLA associations have been described. New findings indicate that the progression of asymptomatic T. whipplei infection to clinical WD may be associated with medical immunosuppression and with immunomodulatory conditions. This explains that there is a discrepancy between the widespread occurrence of T. whipplei and the rareness of WD, and that T. whipplei infection triggered by immunosuppression presents with protean clinical manifestations. CONCLUSIONS: This review highlights recent findings and the clinical spectrum of infection with T. whipplei and WD, focusing specifically on the role of host immunity and immunosuppression. Current concepts of the pathogenesis, diagnosis and therapy are discussed.

Sewage workers with low antibody responses may be colonized successively by several Tropheryma whipplei strains.

OBJECTIVES: Asymptomatic faecal carriage of Tropheryma whipplei, the agent of Whipple's disease, is reported among sewage workers. However, the potential development of such carriage is unknown. A 7-year follow-up of T. whipplei-carrying sewage workers is reported. METHODS: Nineteen sewage workers previously detected as faecal carriers of T. whipplei were followed to ascertain the chronicity of their carriage. Faeces were tested by molecular assays using quantitative real-time PCR specifically targeting T. whipplei. Serological anti-T. whipplei Western blotting was also performed. RESULTS: Seventy-nine percent (15/19) of workers exhibited a strong immune response against T. whipplei. Among these, five were followed for more than 1 year. Four maintained a strong response, with three carrying the same strain and one becoming negative. The fifth exhibited a decreased immune response, a negative faeces result, and subsequent carriage of another strain. Three individuals with low immune responses were also followed. Two never developed a response, with one carrying the same strain and one becoming negative and then positive with another strain; the third developed a strong response and became negative. CONCLUSIONS: Chronic T. whipplei carriers appear to be protected against reinfection, but those with low or decreasing antibody levels may be re-colonized by another strain.

Complicated Whipple's disease and endocarditis following tumor necrosis factor inhibitors.

AIM: To test whether treatment with tumor necrosis factor inhibitors (TNFI) is associated with complications of Tropheryma whipplei (T. whipplei) infection. METHODS: Because unexplained arthritis is often the first Whipple's disease (WD) symptom, patients may undergo treatment with TNFI before diagnosis. This may influence the course of infection with T. whipplei, which causes WD, because host immune defects contribute to the pathogenesis of WD. A literature search and cross referencing identified 19 reports of TNFI treatment prior to WD diagnosis. This case-control study compared clinical data in patients receiving TNFI therapy (group I, n = 41) with patients not receiving TNFI therapy (group II, n = 61). Patients from large reviews served as controls (group III, n = 1059). RESULTS: The rate of endocarditis in patient group I was significantly higher than in patient group II (12.2% in group I vs 1.6% in group II, P < 0.05), and group III (12.2% in group I vs 0.16% in group III, P < 0.01). Other, severe systemic or local WD complications such as pericarditis, fever or specific organ manifestations were increased also in group I as compared to the other patient groups. However, diarrhea and weight loss were somewhat less frequent in patient group I. WD is typically diagnosed with duodenal biopsy and periodic acid Schiff (PAS) staining. PAS-stain as standard diagnostic test had a very high percentage of false negative results (diagnostic failure in 63.6% of cases) in group I. Polymerase chain reaction (PCR) for T. whipplei was more accurate than PAS-stainings (diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01). CONCLUSION: TNFI trigger severe WD complications, particularly endocarditis, and lead to false-negative PAS-tests. In case of TNFI treatment failure, infection with T. whipplei should be considered.

Intravenous ceftriaxone, followed by 12 or three months of oral treatment with trimethoprim-sulfamethoxazole in Whipple's disease.

BACKGROUND: There is no agreement on how and for how long Whipple's disease should be treated. In a randomized trial it was shown that patients can be cured with ceftriaxone or meropenem followed by trimethoprim-sulfamethoxazole for 12 months. The present study tested whether trimethoprim-sulfamethoxazole for three months is sufficient. METHODS: In the time from July 2004 to July 2008, 40 untreated patients from central Europe were sequentially admitted to an open-label, non-randomized extension of the previous trial with essentially an identical protocol. The modified treatment consisted of 2 g ceftriaxone intravenously once daily for 14 days followed by oral trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 months. Primary endpoint was treatment efficacy compared with the previous study. RESULTS: Twelve months of treatment with trimethoprim-sulfamethoxazole was not more effective than 3 months as indicated by clinical findings, laboratory (p = 0.405, p = 0.631, resp.), and histological data (p = 0.456). 36 of 37 surviving patients including 14 with cerebrospinal infection were in remission without evidence of recurrence after a median follow-up time of 80 months. In one patient, Tropheryma whipplei arthritis recurred 63 months after initial therapy. Secondary endpoints indicate that histology of intestinal biopsies was a more useful indicator to determine eradication of T. whipplei than PCR. In submucosal and extra-intestinal tissue, the diagnostic value of the PCR was superior. Prospective data disclosed a heterogeneous spectrum of clinical presentation and course of Whipple's disease. CONCLUSION: This study indicates that ceftriaxone followed by three months of trimethoprim-sulfamethoxazole is highly efficacious in the treatment of Whipple's disease.

Cloning and characterization of the human SH3BP2 promoter.

SH3BP2 activating mutations lead to an unique clinical condition in which patients develop symmetrical bone resorptive lesions of the jaw, a condition termed cherubism. Due to this specific temporal sequence and location of bone resorption, we investigated the transcriptional regulation of SH3BP2 expression. Analyses of 5'- and 3'-serial promoter deletions defined the core promoter/regulatory elements, including two repressor sites (from -1,200 to -1,000 and from +86 to +115, respectively) and two activator sites (a PARP1 binding site from -44 to -21 and a second activator site from +57 to +86). We identified that PARP1 binds to DNA from -44 to -21 by Streptavidin-biotin purification and confirmed this binding by electrophoretic mobility shift assay (EMSA). Mutagenesis of the PARP1 binding site on the SH3BP2 promoter showed that this binding site is essential for SH3BP2 expression. EMSA and chromatin immunoprecipitation (ChIP) assays confirmed that PARP1 was able to bind to the SH3BP2 promoter in vitro and in vivo. Indeed, knockout of Parp1 in mice BMMs reduced expression of SH3BP2. These results demonstrate that PARP1 regulates expression of SH3BP2.

Efficacy of ceftriaxone or meropenem as initial therapies in Whipple's disease.

BACKGROUND & AIMS: Whipple's disease is a chronic infection caused by the actinomycete Tropheryma whipplei. We conducted a randomized controlled trial of the efficacy of antimicrobials that are able to cross the blood-brain barrier and to which T whipplei is susceptible. METHODS: Patients from central Europe with previously untreated Whipple's disease (n = 40) were assigned randomly to groups given daily infusions of either ceftriaxone (1 x 2 g, 20 patients) or meropenem (3 x 1 g, 20 patients) for 14 days, followed by oral trimethoprim-sulfamethoxazole for 12 months. The primary outcome measured was maintenance of remission for 3 years, determined by a composite index of clinical and laboratory data as well as histology. RESULTS: All patients were observed for the entire follow-up period (median, 89 mo; range, 71-128 mo); all achieved clinical and laboratory remission. Remission was maintained in all patients during the time of observation, except for 2 who died from unrelated causes. A single patient with asymptomatic cerebrospinal infection who was resistant to both treatments responded to chloroquine and minocycline. The odds ratio for the end point (remission for at least 3 years) was 0.95 (95% confidence interval, 0.05-16.29; P = 1.0). CONCLUSIONS: This was a randomized controlled trial to show that treatment with ceftriaxone or meropenem, followed by trimethoprim-sulfamethoxazole, cures patients with Whipple's disease. One asymptomatic individual with infection of the cerebrospinal fluid required additional therapy.

New insights into Whipple's disease - a rare intestinal inflammatory disorder.

Whipple's disease (WD) is a rare systemic infectious disorder caused by the actinomycete Tropheryma whipplei. This chronic disease, first described by Whipple as 'intestinal lipodystrophy', affects preferentially middle-aged white men who may present with weight loss, diarrhea, abdominal pain and arthralgia. Thus, it represents an important differential diagnosis of chronic diarrhea. A variety of other clinical patterns, such as involvement of the heart, lung, or central nervous system (CNS), are frequent. In addition, individuals with isolated heart valve involvement or asymptomatic carriers may be observed. The diagnosis often is established by small bowel biopsy, which is characterized by periodic acid-Schiff-positive inclusions representing the causative bacteria. T. whipplei can be detected by specific polymerase chain reaction, immunohistochemistry or electron microscopy and was cultured a few years ago. Several studies show that subtle defects of the cell-mediated immunity exist in active and inactive WD which may predispose individuals with a certain HLA type to a clinical manifestation of T. whipplei infection. As confirmed in a recent controlled trial, most patients respond well to a prolonged antibiotic treatment, but some patients with relapsing disease or CNS manifestation may have a poor prognosis. In the presentation, the relevance of WD in the differential diagnosis of chronic diarrhea and the new findings of this enigmatic rare disorder will be discussed.

The HLA alleles DRB1*13 and DQB1*06 are associated to Whipple's disease.

BACKGROUND & AIMS: Whipple's disease is a systemic, chronic, relapsing disorder caused by a combination of environmental (Tropheryma whipplei) and unknown host factors. Because it is a rare disease, the association between HLA type and Whipple's disease has been studied in only small numbers of patients; these studies have led to conflicting results. We aimed to investigate whether disease phenotype and outcome are associated with HLA type in 122 patients with Whipple's disease. METHODS: Genomic DNA was collected from 103 German, 11 Italian, and 8 Austrian patients with Whipple's disease, along with 62 healthy Austrian workers exposed to T whipplei (14 stool samples contained the bacterium). HLA class I and II alleles were identified by polymerase chain reaction analysis. Patient genotypes were compared with those of healthy German and Austrian populations; data for Italian controls were obtained from the Pavia HLA bone marrow donors' bank. RESULTS: HLA-DRB1*13 and DQB1*06 alleles occurred significantly more frequently in patients with Whipple's disease but not in healthy individuals who had been exposed to T Whipplei. The cumulative odds ratios for disease were 2.23 for the DRB1*13 allele (P < .0001) and 2.25 for the DQB1*06 allele (P < .0001). CONCLUSIONS: DRB1*13 and DQB1*06 alleles were found to be risk factors in the largest HLA study ever performed in patients with Whipple's disease.

Whipple's disease: new aspects of pathogenesis and treatment.

100 years after its first description by George H Whipple, the diagnosis and treatment of Whipple's disease is still a subject of controversy. Whipple's disease is a chronic multisystemic disease. The infection is very rare, although the causative bacterium, Tropheryma whipplei, is ubiquitously present in the environment. We review the epidemiology of Whipple's disease and the recent progress made in the understanding of its pathogenesis and the biology of its agent. The clinical features of Whipple's disease are non-specific and sensitive diagnostic methods such as PCR with sequencing of the amplification products and immunohistochemistry to detect T whipplei are still not widely distributed. The best course of treatment is not completely defined, especially in relapsing disease, neurological manifestations, and in cases of immunoreconstitution after initiation of antibiotic treatment. Patients without the classic symptoms of gastrointestinal disease might be misdiagnosed or insufficiently treated, resulting in a potentially fatal outcome or irreversible neurological damage. Thus, we suggest procedures for the improvement of diagnosis and an optimum therapeutic strategy.

Whipple disease.

PURPOSE OF REVIEW: The availability of and advantages in molecular technology and immunology have led to an improved understanding of the etiology and pathogenesis of Whipple disease. As this rare infection represents a model disease reflecting the input of novel findings into clinical medicine and therapy, this review intends to highlight newer findings and put them in context. RECENT FINDINGS: Sequencing of 16S rRNA allowed the phylogeny of the bacterium to be determined. The culture and subsequent genome analysis have led to improved diagnosis and monitoring of the disease, for example by PCR or immunohistochemistry. New experimental approaches hint of defects in T-cell and macrophage immunity in patients. Antibiotic therapy will soon be based on data from the first prospective therapy study. SUMMARY: Within a few years the findings from molecular genetics and immunology as well as concerted research activities from the European Consortium on Whipple Disease which established a data and material bank could be translated into clinical medicine. Thus, for patients with Whipple disease an improved basis for diagnosis and therapy have been achieved.

Genotyping reveals a wide heterogeneity of Tropheryma whipplei.

Tropheryma whipplei, the causative agent of Whipple's disease, is associated with various clinical manifestations as well as an asymptomatic carrier status, and it exhibits genetic heterogeneity. However, relationships that may exist between environmental and clinical strains are unknown. Herein, we developed an efficient genotyping system based on four highly variable genomic sequences (HVGSs) selected on the basis of genome comparison. We analysed 39 samples from 39 patients with Whipple's disease and 10 samples from 10 asymptomatic carriers. Twenty-six classic gastrointestinal Whipple's disease associated with additional manifestations, six relapses of classic Whipple's disease (three gastrointestinal and three neurological relapses), and seven isolated infections due to T. whipplei without digestive involvement (five endocarditis, one spondylodiscitis and one neurological infection) were included in the study. We identified 24 HVGS genotypes among 39 T. whipplei DNA samples from the patients and 10 T. whipplei DNA samples from the asymptomatic carriers. No significant correlation between HVGS genotypes and clinical manifestations of Whipple's disease, or asymptomatic carriers, was found for the 49 samples tested. Our observations revealed a high genetic diversity of T. whipplei strains that is apparently independent of geographical distribution and unrelated to bacterial pathogenicity. Genotyping in Whipple's disease may, however, be useful in epidemiological studies.

Antibodies to complement receptor 3 treat established inflammation in murine models of colitis and a novel model of psoriasiform dermatitis.

Prior studies indicated the ability of Abs to complement receptor 3 (CR3, CD11b/CD18) to suppress the production of IL-12 from immune cells. Therefore, we tested the ability of an anti-CR3 Ab (clone M1/70) to treat established IL-12-dependent Th1-mediated inflammation in murine models. Systemic administration of anti-CR3 significantly ameliorated established intestinal inflammation following the intrarectal administration of trinitrobenzene sulfonic acid (TNBS-colitis), as well as colitis and skin inflammation in C57BL/10 RAG-2(-/-) mice reconstituted with CD4+CD45RBhigh T cells. The hyperproliferative skin inflammation in this novel murine model demonstrated many characteristics of human psoriasis, and was prevented by the adoptive transfer of CD45RBlow T cells. In vitro and in vivo studies suggest that anti-CR3 treatment may act, at least in part, by directly inhibiting IL-12 production by APCs. Administration of anti-CR3 may be a useful therapeutic approach to consider for the treatment of inflammatory bowel disease and psoriasis in humans.

Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in patients with Whipple's disease.

Whipple's disease is a rare infectious disorder caused by Tropheryma whipplei. Major symptoms are arthropathy, weight loss, and diarrhea, but the CNS and other organs may be affected, too. The incidence of Whipple's disease is very low despite the ubiquitous presence of T. whipplei in the environment. Therefore, it has been suggested that host factors indicated by immune deficiencies are responsible for the development of Whipple's disease. However, T. whipplei-specific T cell responses could not be studied until now, because cultivation of the bacteria was established only recently. Thus, the availability of T. whipplei Twist-Marseille(T) has enabled the first analysis of T. whipplei-specific reactivity of CD4(+) T cells. A robust T. whipplei-specific CD4(+) Th1 reactivity and activation (expression of CD154) was detected in peripheral and duodenal lymphocytes of all healthy (16 young, 27 age-matched, 11 triathletes) and disease controls (17 patients with tuberculosis) tested. However, 32 Whipple's disease patients showed reduced or absent T. whipplei-specific Th1 responses, whereas their capacity to react to other common Ags like tetanus toxoid, tuberculin, actinomycetes, Giardia lamblia, or CMV was not reduced compared with controls. Hence, we conclude that an insufficient T. whipplei-specific Th1 response may be responsible for an impaired immunological clearance of T. whipplei in Whipple's disease patients and may contribute to the fatal natural course of the disease.

Immunosuppressive therapy in Whipple's disease patients is associated with the appearance of gastrointestinal manifestations.

OBJECTIVES: Whipple's disease is a rare chronic disorder, which is caused by systemic infection with Tropheryma whipplei. The first symptom of Whipple's disease usually is a nondestructive polyarthritis resembling in many aspects seronegative rheumatoid arthritis. This polyarticular inflammatory arthropathy preceding the diagnosis of Whipple's disease for several years frequently is treated with nonsteroidal antiinflammatory drugs (NSAIDs) and with immunosuppressive therapy. There is evidence that altered immune functions play a role in the manifestation of the disease and that Whipple's disease is associated with opportunistic infections. We therefore asked whether immunosuppressive treatment for arthropathy may alter the course of Whipple's disease. PATIENTS AND METHODS: In a series of 27 patients with Whipple's disease clinical data were documented and the patients were followed for 3-4 yr. The patients were classified into three groups according to their medication: (i) patients with immunosuppressive therapy preceding the diagnosis, (ii) patients with NSAIDs before diagnosis, and (iii) patients without such therapies. RESULTS: Arthropathies occurred in the mean 8 yr before diagnosis and were the first symptom in 63% of the patients. Gastrointestinal involvement usually became evident later on and frequently led to the diagnosis of Whipple's disease. In patients with immunosuppressive treatment, diarrhea occurred in the median 4 months after the initiation of such therapy and diagnosis of Whipple's disease was made after another 2 months. In contrast, other medical treatments were not closely followed by the onset of diarrhea. CONCLUSIONS: These results indicate an association between immunosuppressive therapy and the onset of diarrhea in Whipple's disease and thus support the concept that immunologic factors play a role in disease pathogenesis. Further investigation on the interaction of the immune system and Tropheryma whipplei infection are required to understand the factors contributing to the clinical manifestation of this rare disorder and possibly to introduce preventive interventions.

Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis.

BACKGROUND: It has been suggested that Crohn's disease (CD) is associated with an exaggerated T-helper 1 cytokine response manifested by increased production of interleukin (IL)-12. IL-12 is a heterodimeric protein comprising 2 disulfide-linked subunits designated p35 and p40. Recently, IL-12-related cytokines, IL-23 and IL-27, were described. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 whereas its p19 subunit is distantly related to IL-12p35. IL-27 consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. AIM: We sought to determine whether mucosal expression of IL-23p19 and IL-27p28 transcripts correlate with the inflammatory activity in inflammatory bowel disease (IBD). PATIENTS/METHODS: Messenger RNA expression in colonic mucosa from patients with Crohn's disease (CD; n = 37) and ulcerative colitis (UC; n = 19), and in non-IBD control subjects (specific colitis [SC]; n = 16) and normal, nondiseased control patients (n = 12) was measured by reverse-transcribed real-time polymerase chain reaction. RESULTS: IL-23p19 was significantly increased in inflamed mucosa in CD (P = 0.0377) and to a lesser extent also in UC patients but not in SC patients. Elevation of IL-23p19 transcript levels in CD correlated with the severity of endoscopic lesions. IL-27p28 transcripts and EBI3 transcripts were significantly elevated only in active CD. DISCUSSION: IL-23p19, IL-27p28, and EBI3 transcripts are strongly up-regulated in CD. The stimulatory effects of these cytokines on naive T cells in addition to a strongly synergistic action with IL-12 to trigger interferon-gamma production may contribute to the perpetuation of the inflammatory process in patients with CD. Notably, increased expression of IL-23 and IL-27 transcripts in CD suggests a T helper 1-dominated immunologic function in this disease.

Mucosal immune response to Tropheryma whipplei.

Whipple's disease is a rare infectious disease caused by the ubiquitously occurring Tropheryma whipplei in predisposed persons. Genetic or acquired defects in the mucosal and peripheral immune system become apparent as diminished Th1 immune functions with decreased production of IL-12 and IFN-gamma accompanied by an increased secretion of IL-4. These defects may enable T. whipplei to survive and replicate. The recently established cultivation of the bacterium in HEL cells and the isolation from infected intestinal biopsies enable a multitude of experimental possibilities which may lead to an improved diagnosis as well as understanding of the etiology and pathogenesis of Whipple's disease.

Whipple's disease.

Whipple's disease, or intestinal lipodystrophy, is a systemic infectious disorder affecting mostly middle-aged white men. Patients present with weight loss, arthralgia, diarrhoea, and abdominal pain. The disease is commonly diagnosed by small-bowel biopsy; the appearance of the sample is characterised by inclusions in the lamina propria staining with periodic-acid-Schiff, which represent the causative bacteria. Tropheryma whipplei has been classified as an actinomycete and has been propagated in vitro, which allows the possibility of improving diagnostic strategies, for example through antibody-based detection of the bacillus on duodenal tissue or in circulating monocytes. Cell-mediated immunity in active and inactive Whipple's disease has subtle defects that might predispose some individuals to symptomatic infection with this bacillus, which probably occurs ubiquitously. Although most patients respond well to empirical antibiotic treatment, some with relapsing disease have a poor outlook. The recent findings and concerted research might allow development of new strategies for diagnosis, treatment, and monitoring of patients with Whipple's disease.