Diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease: Data from the French Tw-IRD registry.

OBJECTIVES: Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease. METHODS: We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease. RESULTS: Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases. CONCLUSIONS: Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation.

Clinical and laboratory predictors and prevalence of immune reconstitution inflammatory syndrome in patients with Whipple's disease.

OBJECTIVES: Whipple's disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time. METHODS: Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not. RESULTS: Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h, P < 0.01), platelet (PLT; 234 × 109 /L vs 363 × 109 /L, P < 0.01), and body mass index (22.0 ± 2.0 kg/m2 vs 19.8 ± 3.0 kg/m2 , P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72-1.00) and PLT ≤ 327 × 109 /L (AUROC 0.85, 95% CI 0.70-1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time. CONCLUSIONS: Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades.

Patients with Whipple's disease have a high prevalence of Helicobacter pylori infection.

INTRODUCTION: Whipple's disease is a rare systemic infection due to an impaired immunological response against T. whipplei in genetically predisposed individuals. Since we previously noted development of H. pylori related complications in some patients with Whipple's disease, our aim was to study the prevalence of H. pylori infection and H. pylori related disorders in Whipple's disease. METHODS: Whipple's disease patients diagnosed from Jan-2002 to Dec-2021 and two controls per patient, matched for age, gender, ethnicity and year of H. pylori testing were enrolled. RESULTS: 34 patients with Whipple's disease and 68 controls were enrolled. H. pylori infection (13/34 vs 8/68, p<0.01), H. pylori-related gastritis (p<0.01) and gastric atrophy (p = 0.01) were significantly more common in patients with Whipple's disease than controls. H. pylori infection and Whipple's disease were diagnosed synchronously in 6/13 patients, and during follow-up in the remaining 7. Interestingly, these last 7 patients were all on trimethoprim-sulfamethoxazole long-term therapy. Two patients developed H. pylori-related gastric malignancies during follow-up. No patients on doxycycline developed H. pylori infection. CONCLUSIONS: H. pylori infection and related disorders are common in patients with Whipple's disease and should always be excluded both at time of diagnosis and during follow-up. These findings should be taken into account when selecting antibiotics for Whipple's disease long-term prophylaxis.

Tropheryma whipplei Intestinal Colonization in Migrant Children, Greece.

We obtained fecal samples from migrant children <12 years of age throughout hotspots in Greece and tested them for Tropheryma whipplei by using a quantitative PCR assay. We identified 6 genotypes of T. whipplei, 4 of which are newly described. Our findings suggest a high prevalence of T. whipplei in these regions.

Whipple's disease review, prevalence, mortality, and characteristics in the United States: A cross-sectional national inpatient study.

Whipple's disease is a rare multiorgan systemic disease caused by Tropheryma whipplei infection that may present with a wide range of signs and symptoms. This study aim to comprehensively review and determine the inpatient prevalence, mortality, risk factors, and reasons for hospitalization of patients with Whipple's disease. ICD-10 codes were used to identify admissions with Whipple's disease during the years 2016 to 2018. Characteristics of admissions with and without Whipple's disease were compared. The most common reasons for hospitalization were identified in admissions with Whipple's disease. The prevalence of Whipple's disease was 4.6 per 1 million hospitalizations during the study period. Whipple's disease admissions were significantly older than other hospitalizations, with a mean age of 60.2 ±â€…1.6 years compared to 50.0 ±â€…0.1. Males were more likely to have Whipple's disease and represented approximately two-thirds of hospitalizations. A disproportionate number of admissions occurred in the Midwest. Patients with Whipple's disease were most commonly admitted for gastrointestinal disease, followed by systemic infection, cardiovascular/circulatory disease, musculoskeletal disease, respiratory disease, and neurological disease. High mortality was seen in admissions for central nervous system (CNS) disease. Whipple's disease has heterogeneous presentations for inpatient admissions, and disproportionately affects older males. High hospitalization rates in the Midwest support environmental and occupational disease transmission likely from the soil. Hospitalists should be aware of the various acute, subacute, and chronic presentations of this disease, and that acute presentations may be more common in the inpatient setting.

Tropheryma whipplei intestinal colonization in immunocompromised children in Iran: a preliminary study.

Aim & method:Tropheryma whipplei causes Whipple's disease. Children are reservoirs of this bacterium. The aim of this study was to investigate the presence of T. whipplei in children with immunodeficiency in central Iran from July 2018 to February 2019. Stool samples were tested by SYBR Green and Taq-Man real-time PCR assays. For confirmation, the isolated DNA was sequenced. Results: One hundred and thirty children were enrolled. Acute lymphocytic leukemia was the most reported immunodeficient disease (77%), followed by non-Hodgkin lymphoma and retinoblastoma. Thirteen (10%) children had T. whipplei DNA in the stool; 11.4% of the children under 5 years old were positive. Conclusion: This is the first study showing the circulation of T. whipplei in Iran.

Tropheryma whipplei Infection (Whipple Disease) in the USA.

BACKGROUND: Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA. AIMS: To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection. METHODS: Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids. RESULTS: Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11-75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%). CONCLUSIONS: TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.

Epidemiology of Whipple's Disease in the USA Between 2012 and 2017: A Population-Based National Study.

OBJECTIVE: Prior studies on the epidemiology of Whipple's disease are limited by small sample size and case series design. We sought to characterize the epidemiology of Whipple's disease in the USA utilizing a large population-based database. METHODS: We queried a commercial database (Explorys Inc, Cleveland, OH), an aggregate of electronic health record data from 26 major integrated healthcare systems in the USA. We identified a cohort of patients with a diagnosis of Whipple's disease based on systemized nomenclature of medical terminology (SNOMED CT) codes. We calculated the overall and age-, race-, ethnicity, and gender-based prevalence of Whipple's disease and prevalence of associated diagnoses using univariate analysis. RESULTS: A total of 35,838,070 individuals were active in the database between November 2012 and November 2017. Of these, 350 individuals had a SNOMED CT diagnosis of Whipple's disease, with an overall prevalence of 9.8 cases per 1 million. There was no difference in prevalence based on sex. However, prevalence of Whipple's disease was higher in Caucasians, non-Hispanics, and individuals > 65 years old. Individuals with a diagnosis of Whipple's disease were more likely to have associated diagnoses/findings of arthritis, CNS disease, endocarditis, diabetes, malignancy, dementia, vitamin D deficiency, iron deficiency, chemotherapy, weight loss, abdominal pain, and lymphadenopathy. CONCLUSIONS: To our knowledge, this is the largest study to date examining the epidemiology of Whipple's disease. In this large population-based study, the overall prevalence of Whipple's disease in the USA is 9.8 cases per 1 million people. It affects men and women at similar rates and is more common in Caucasians, non-Hispanics, and people > 65 years old.

Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections.

Whipple's disease is a rare infectious disease that can be fatal if left untreated. The disease is caused by infection with Tropheryma whipplei, a bacterium that may be more common than was initially assumed. Most patients present with nonspecific symptoms, and as routine cultivation of the bacterium is not feasible, it is difficult to diagnose this infection. On the other hand, due to the generic symptoms, infection with this bacterium is actually quite often in the differential diagnosis. The gold standard for diagnosis used to be periodic acid-Schiff (PAS) staining of duodenal biopsy specimens, but PAS staining has a poor specificity and sensitivity. The development of molecular techniques has resulted in more convenient methods for detecting T. whipplei infections, and this has greatly improved the diagnosis of this often missed infection. In addition, the molecular detection of T. whipplei has resulted in an increase in knowledge about its pathogenicity, and this review gives an overview of the new insights in epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Tropheryma whipplei infections.

Tropheryma whipplei associated with diarrhoea in young children.

Tropheryma whipplei was detected in preliminary studies in faeces of young children with diarrhoea and also in faeces of asymptomatic persons, not only in Europe but also in Africa. In this study, the link between this bacterium and the presence of acute diarrhoea was evaluated in a large group of children. From December 2009 to January 2013, rectal swabs collected from 3796 children in the emergency departments of university hospitals in Marseille, France, were analysed: 555 children (245 female and 310 male, from 6 days to 6 years old) with acute diarrhoea defined as at least three loose stools per day for <1 week and 3241 children (1444 female and 1797 male, from 22 days to 6 years old) without diarrhoea. Specific quantitative real-time PCR was performed to detect the presence of T. whipplei and of two enteric pathogens Clostridium difficile and Giardia duodenalis. Tropheryma whipplei was significantly more common in children with diarrhoea (22/555, 4%) than without (56/3241, 1.7%; p 0.001). Neither C. difficile nor G. duodenalis showed this association. For C. difficile, 39 of 531 (7.3%) children with diarrhoea were positive versus 184 of 3119 (5.9%) of children without diarrhoea (p 0.25). For G. duodenalis, 2 of 529 (0.37%) children with diarrhoea were positive versus 5 of 3119 (0.16%) children without diarrhoea (p 0.26). Tropheryma whipplei was found more commonly in autumn. Tropheryma whipplei is significantly associated with diarrhoea in children, suggesting that the bacterium may be a cause of acute diarrhoea.

High prevalence of asymptomatic carriers of Tropheryma whipplei in different populations from the North of Spain / Alta prevalencia de portadores asintomáticos de Tropheryma whipplei en distintas poblaciones del norte de España

INTRODUCTION: Tropheryma whipplei is the causative agent of Whipple disease. T. whipplei has also been detected in asymptomatic carriers with a very different prevalence. To date, in Spain, there are no data regarding the prevalence of T. whipplei in a healthy population or in HIV-positive patients, or in chronic fatigue syndrome (CFS). Therefore, the aim of this work was to assess the prevalence of T. whipplei in stools in those populations. METHODS: Stools from 21 HIV-negative subjects, 65 HIV-infected, and 12 CFS patients were analysed using real time-PCR. HIV-negative and positive subjects were divided into two groups, depending on the presence/absence of metabolic syndrome (MS). Positive samples were sequenced. RESULTS: The prevalence of T. whipplei was 25.51% in 98 stool samples analysed. Prevalence in HIV-positive patients was significantly higher than in HIV-negative (33.8% vs. 9.09%, p = 0.008). Prevalence in the control group with no associated diseases was 20%, whereas no positive samples were observed in HIV-negative patients with MS, or in those diagnosed with CFS. The prevalence observed in HIV-positive patients without MS was 30.35%, and with MS it was 55.5%. The number of positive samples varies depending on the primers used, although no statistically significant differences were observed. CONCLUSIONS: There is a high prevalence of asymptomatic carriers of T. whipplei among healthy and in HIV-infected people from Spain. The role of T. whipplei in HIV patients with MS is unclear, but the prevalence is higher than in other populations

INTRODUCCIÓN: Tropheryma whipplei es el agente etiológico de la enfermedad de Whipple. También se ha detectado, con diferentes prevalencias, en portadores asintomáticos. Hasta la fecha, en España, no hay datos sobre su prevalencia en población sana, en pacientes VIH o con síndrome de fatiga crónica (SFC). Por ello, el objetivo de este trabajo fue evaluar la prevalencia de T. whipplei en heces en dichas poblaciones. MÉTODOS: Se analizaron heces de 21 sujetos VIH-negativos, de 65 pacientes VIH-positivos y de 12 con SFC mediante PCR a tiempo real. Los sujetos VIH-negativos y VIH-positivos se dividieron en 2 grupos dependiendo de la presencia/ausencia de síndrome metabólico (SM). Las muestras positivas se secuenciaron. RESULTADOS: De 98 muestras analizadas, la prevalencia de T. whipplei fue del 25,51%. La prevalencia en pacientes VIH-positivos fue significativamente mayor que en los negativos (33,8% vs. 9,09%, p = 0,008). Dentro del grupo control (no VIH) la prevalencia fue del 20% en el grupo sin patologías asociadas, mientras que no se observó ningún positivo en los que presentaban SM ni en los pacientes con SFC. La prevalencia en pacientes VIH-positivos sin SM fue del 30,35%, y del 55,5% en pacientes con SM. El número de muestras positivas varió dependiendo de las dianas utilizadas, aunque no se observaron diferencias significativas. CONCLUSIONES: Existe una alta prevalencia de portadores asintomáticos de T. whipplei en individuos sanos y también en pacientes VIH. El papel de T. whipplei en pacientes VIH con SM no está claro, pero la prevalencia es más alta que en otras poblaciones

Tropheryma whipplei as a Cause of Epidemic Fever, Senegal, 2010-2012.

The bacterium Tropheryma whipplei, which causes Whipple disease in humans, is commonly detected in the feces of persons in Africa. It is also associated with acute infections. We investigated the role of T. whipplei in febrile patients from 2 rural villages in Senegal. During June 2010-March 2012, we collected whole-blood finger-prick samples from 786 febrile and 385 healthy villagers. T. whipplei was detected in blood specimens from 36 (4.6%) of the 786 febrile patients and in 1 (0.25%) of the 385 apparently healthy persons. Of the 37 T. whipplei cases, 26 (70.2%) were detected in August 2010. Familial cases and a potential new genotype were observed. The patients' symptoms were mainly headache (68.9%) and cough (36.1%). Our findings suggest that T. whipplei is a cause of epidemic fever in Senegal.

Tropheryma whipplei in children with diarrhoea in rural Ghana.

Tropheryma whipplei has been hypothesized to be able to cause diarrhoea, but data from young children are scarce. In this hospital-based case-control study 534 stool samples of children aged between 2 months and 15 years from rural Ghana were analysed for the presence of T. whipplei. Overall stool prevalence of T. whipplei was high (27.5%). Although there was no difference in T. whipplei carriage overall between cases and controls, cases aged between 0 and 12 months carried T. whipplei in their stool twice as often as controls without diarrhoea. The results from this study may support the hypothesis that T. whipplei can cause diarrhoea in first-time infection.

High prevalence of asymptomatic carriers of Tropheryma whipplei in different populations from the North of Spain.

INTRODUCTION: Tropheryma whipplei is the causative agent of Whipple disease. T. whipplei has also been detected in asymptomatic carriers with a very different prevalence. To date, in Spain, there are no data regarding the prevalence of T. whipplei in a healthy population or in HIV-positive patients, or in chronic fatigue syndrome (CFS). Therefore, the aim of this work was to assess the prevalence of T. whipplei in stools in those populations. METHODS: Stools from 21 HIV-negative subjects, 65 HIV-infected, and 12 CFS patients were analysed using real time-PCR. HIV-negative and positive subjects were divided into two groups, depending on the presence/absence of metabolic syndrome (MS). Positive samples were sequenced. RESULTS: The prevalence of T. whipplei was 25.51% in 98 stool samples analysed. Prevalence in HIV-positive patients was significantly higher than in HIV-negative (33.8% vs. 9.09%, p=0.008). Prevalence in the control group with no associated diseases was 20%, whereas no positive samples were observed in HIV-negative patients with MS, or in those diagnosed with CFS. The prevalence observed in HIV-positive patients without MS was 30.35%, and with MS it was 55.5%. The number of positive samples varies depending on the primers used, although no statistically significant differences were observed. CONCLUSIONS: There is a high prevalence of asymptomatic carriers of T. whipplei among healthy and in HIV-infected people from Spain. The role of T. whipplei in HIV patients with MS is unclear, but the prevalence is higher than in other populations.

Prevalence of Whipple's disease in north-western Italy.

Whipple's disease (WD) is a rare systemic infection due, in genetically susceptible individuals, to Tropheryma whipplei, a heterogeneous Gram-positive actinobacteria. Although it has already been recognised that WD affects mainly middle-aged Caucasian men, the prevalence of WD is virtually unknown. The annual incidence of WD in the general population is said to be less than 1 per 1,000,000, but scientific evidence for these figures is still lacking. On the basis of the number of patients recorded with a diagnosis of Whipple's disease in the regional registers for rare diseases of Lombardia, Liguria and Piemonte-Valle d'Aosta regions, we studied the prevalence of WD in the north-western part of Italy. Forty-six patients with Whipple's disease were recorded in these regions (13 females; mean age at diagnosis 52.1 ± 11.1 years). Since 16,130,725 inhabitants live in these four regions, prevalence of WD in the general population is 3/10(6) and almost 30% of the patients are females. WD is certainly a rare disease but it also affects women in a considerable proportion of cases.

High prevalence of Tropheryma whipplei in Lao kindergarten children.

BACKGROUND: Tropheryma whipplei is a bacterium commonly found in feces of young children in Africa, but with no data from Asia. We estimated the prevalence of T. whipplei carriage in feces of children in Lao PDR (Laos). METHODS/PRINCIPAL FINDINGS: Using specific quantitative real-time PCR, followed by genotyping for each positive specimen, we estimated the prevalence of T. whipplei in 113 feces from 106 children in Vientiane, the Lao PDR (Laos). T. whipplei was detected in 48% (51/106) of children. Those aged ≤ 4 years were significantly less frequently positive (17/52, 33%) than older children (34/54, 63%; p< 0.001). Positive samples were genotyped. Eight genotypes were detected including 7 specific to Laos. Genotype 2, previously detected in Europe, was circulating (21% of positive children) in 2 kindergartens (Chompet and Akad). Genotypes 136 and 138 were specific to Chompet (21% and 15.8%, respectively) whereas genotype 139 was specific to Akad (10.55%). CONCLUSIONS/SIGNIFICANCE: T. whipplei is a widely distributed bacterium, highly prevalent in feces of healthy children in Laos. Further research is needed to identify the public health significance of this finding.

Are prevalent self-reported cardiovascular disorders associated with delayed recovery from whiplash-associated disorders: a population-based cohort study.

OBJECTIVES: The aim of this cohort study was to investigate the association between self-reported cardiovascular disorders (CVD) and recovery from whiplash-associated disorder (WAD) after a traffic collision. MATERIALS AND METHODS: This study was based on the Saskatchewan Government Insurance cohort, including individuals over 18 years of age, who made a traffic-injury claim or received health care after a traffic injury, between 1997 and 1999. Participants completed a baseline questionnaire and were followed up by telephone interviews at 6 weeks, 3 months, 6 months, 9 months, and 12 months after injury. Our sample includes a subcohort of 6011 participants who reported WAD (defined as answering "yes" to the question "Did the accident cause neck or shoulder pain") at baseline. The outcome, self-perceived recovery, was measured at all follow-up interviews. The presence of CVD and its effect on health was classified into 3 exposure categories: (1) CVD absent, (2) CVD present with no or mild effect on health, and (3) CVD present with moderate or severe effect on health. The association between CVD and recovery from WAD was assessed with Cox regression, and adjusted for potential confounders. RESULTS: We found a crude association between comorbid CVD with moderate or severe effect on health in women. However, the adjusted association was weak and potentially affected by residual confounding. We found no association in men. DISCUSSION: Our results suggest that CVD does not have an impact on the recovery of individuals with WAD.

[Whipple's disease]. / Whipples sygdom.

Whipple's disease (WD) is a rare, chronic, systemic infection caused by the bacterium Tropheryma whipplei. New molecular techniques and epidemiological data over the latest decade have contributed to better understanding of this infection. The classical form of WD is characterized by arthritis followed years after by diarrhoea, weight loss and malabsorption but other clinical forms without intestinal involvement have been described. Prompt recognition and treatment of the infection is important, as the disease can be fatal if untreated. New studies are required to establish the optimal therapy regimen.

Common subclinical hypothyroidism during Whipple's disease.

BACKGROUND: Classic Whipple's disease is caused by T. whipplei and likely involves genetic predispositions, such as the HLA alleles DRB1*13 and DQB1*06, that are more frequently observed in patients. T. whipplei carriage occurs in 2-4% of the general population in France. Subclinical hypothyroidism, characterized by high levels of TSH and normal free tetra-iodothyronine (fT4) dosage, has been rarely associated with specific HLA factors. METHODS: We retrospectively tested TSHus in 80 patients and 42 carriers. In cases of dysthyroidism, we tested the levels of free-T4 and anti-thyroid antibodies, and the HLA genotypes were also determined for seven to eight patients. RESULTS: In this study, 72-74% of patients and carriers were male, and among the 80 patients, 14 (17%) individuals had a high level of TSH, whereas none of the carriers did (p<0. 01). In the 14 patients with no clinical manifestations, the T4 levels were normal, and no specific antibodies were present. Four patients treated with antibiotics, without thyroxine supplementation, showed normal levels of TSHus after one or two years. One patient displayed a second episode of subclinical hypothyroidism during a Whipple's disease relapse five years later, but the subclinical hypothyroidism regressed after antibiotic treatment. HLA typing revealed nine alleles that appeared more frequently in patients than in the control cohort, but none of these differences reached significance due to the small size of the patient group. CONCLUSION: Regardless of the substratum, classic Whipple's disease could lead to subclinical hypothyroidism. We recommend systematically testing the TSH levels in patients with Whipple's disease.