Whipple's Disease: A Systematic Review of the Literature

Introduction: Whipple's disease is a chronic systemic disease with a predilection for the digestive system, especially the small intestine. It was first described in 1907 by George H. Whipple, who named it intestinal lipodystrophy. It is caused by a gram-positive bacterium belonging to the Actinomycetaceae family called Tropheryma whipplei. Objective: To characterize patients with Whipple's disease. Materials and methods: A systematic literature review was carried out using the DeCS terms enfermedad de Whipple (Whipple's disease) or (Tropheryma whipplei) in the Pubmed/Medline, Scopus, Scielo, Science Direct, Embase, Cochrane Library, BIREME, Proquest, and Redalyc databases; 123 articles were analyzed. Results: 123 published articles corresponding to case reports and series were examined, noting a higher prevalence in males (70.6%). The most frequent manifestations were joint symptoms (61%), followed by weight loss (47.1%) and diarrhea (43.4%). The most used diagnostic method was polymerase chain reaction (PCR) (63.2%), followed by biopsy (50.7%) and pathological examination with PAS (periodic acid Schiff) granules (47.8%). The management most used was antibiotic therapy with a predominance of trimethoprim/sulfamethoxazole and ceftriaxone. Conclusions: Whipple's disease has a low prevalence, occurs more frequently in white people, mainly affects the elderly, has a predilection for the male sex, and is characterized as a chronic systemic disease with a predilection for the digestive system, especially the small intestine.

Introducción: la enfermedad de Whipple es una enfermedad crónica sistémica con predilección por el aparato digestivo, especialmente el intestino delgado. Fue descrita por vez primera en 1907 por George H. Whipple, quien la denominó lipodistrofia intestinal. Es causada por una bacteria grampositiva perteneciente a la familia de los Actinomycetaceae denominada Tropheryma whipplei. Objetivo: caracterizar a los pacientes con enfermedad de Whipple. Materiales y métodos: se realizó una revisión sistemática de la literatura, de los términos DeCS enfermedad de Whipple (whipple Disease) o (Tropheryma whipplei) en las bases de datos Pubmed/Medline, Scopus, Scielo y Science Direct, Embase, Cochrane Library, BIREME, Proquest y Redalyc; se analizaron 123 artículos. Resultados: se analizaron 123 artículos publicados que correspondían a reportes y series de casos en los cuales se evidenció una mayor prevalencia en varones (70,6%). Las manifestaciones más frecuentes fueron los síntomas articulares (61%), seguidos de pérdida de peso (47,1%) y diarrea (43,4%). El método diagnóstico más usado fue la reacción en cadena de la polimerasa (PCR) (63,2%), seguido por la biopsia (50,7%) y, por último, examen anatomopatológico con gránulos PAS (ácido peryódico de Schiff) (47,8%). El manejo más empleado fue la antibioticoterapia con predominio de trimetoprima/sulfametoxazol y ceftriaxona. Conclusiones: la enfermedad de Whipple tiene una baja prevalencia, se presenta con mayor frecuencia en personas de raza blanca, afecta principalmente a los adultos mayores, tiene predilección por el sexo masculino y se caracteriza por ser una enfermedad crónica sistémica con predilección por el aparato digestivo, especialmente el intestino delgado.

Enfermedad de whipple e hipertensión pulmonar reversible / Whipple's disease and reversible pulmonary hypertension

Resumen La enfermedad de Whipple es una enfermedad multisistémica crónica, causada por la bacteria Tropherima whipplei. Se han descripto aproximadamente 1200 casos en la literatura. La incidencia mundial se estima en 9.8 casos por millón de personas. Los datos provenientes de Sudamérica y Europa muestran que afecta a varones de mediana edad. Se cree que los factores inmunológicos del huésped son los que influyen en el curso de la infección y no el genotipo del agente. Dado que las características clínicas no suelen ser específicas y el espectro de manifestaciones en órganos individuales puede ser subestimado, el diagnóstico sigue siendo muy difícil. Presentamos un caso confirmado por histopatología con compromiso multisistémico. Consideramos importante su difusión dados los escasos casos documentados en Sudamérica y la relevancia de tener presente la sospecha diagnóstica para el abordaje terapéutico precoz que mejora el pronóstico de esta rara enfermedad.

Abstract Whipple's disease is a chronic mutisystem disease caused by the bacteria Tropherima whipplei. Approximately 1200 cases have been described in the literature. The worldwide incidence is estimated at 9.8 cases per million people. Data from South America and Europe show that it affects middle-aged males. It is believed that host immunological factors rather than agent genotypic traits influence the course of the infection. Since the clinical characteristics are usually nonspecific and the wide spectrum of manifestations in individual organs may be underestimated, the diagnosis remains challenging. We present a case with multisystem compromise confirmed by histopathology. We consider its publication important given the few cases documented in South America and the relevance of bearing in mind the importance of an early diagnosis for a prompt treatment that improves the prognosis of this rare disease.

Tropheryma whipplei as the cause of acute pneumonia / 中华检验医学杂志

Tropheryma whipplei (TW) is an opportunistic pathogen that can cause Whipple′s disease (WD). Recently, the biomedical field is concerned about whether the bacteria cause pneumonia. When BALF was detected by PCR, the TW positive rate was about 6.1%. Etiology status is generally described as “associated” or “probable”. Immunocompromised status is the susceptible factor; Different species of the same genus have been reported. The current method may have missed detection. All relevant information needs further study. This article reviews the acute pneumonia caused by TW and the detection technology.

Whipple's disease: a fatal mimic

Whipple's Disease, a rare diagnosis caused by the slow-growing bacterium Tropheryma whipplei, most often presents with the classically described signs of malabsorption due to gastrointestinal colonization. However, it can also have signs and symptoms that clinically overlap with rheumatic diseases, potentially resulting in misdiagnosis. Furthermore, treatment with modern potent biologic immunosuppressive agents and classic disease modifying anti-rheumatic drugs (DMARDs) can lead to serious exacerbation of undiagnosed infections. We present the case of a middle-aged woman with long term complaints of arthalgias, who was diagnosed with seronegative rheumatoid arthritis and subsequently treated for almost 7 years with such immunosuppressive therapies. The patient's disease course included chronic diarrhea that abruptly intensified and culminated in fatal hypovolemic shock/sepsis. A diagnosis of WD was made by autopsy examination, wherein several organ systems were found to be heavily involved by Tropheryma whipplei organisms, and their identification was confirmed with histochemical and molecular evaluation. Notably, most bacterial organisms were located deeply in the submucosa/muscularis of affected organs, a practical reminder to practicing pathologists that challenges the classic histopathologic description of Whipple disease as an infiltration of predominantly lamina propria, and the potential for sampling bias in typically superficial endoscopic biopsies during routine procedures.

Enfermedad de Whipple en paciente con fiebre de origen desconocido / Whipple's disease in a patient with fever of unknown origin

La enfermedad de Whipple es una entidad multisistémica de origen infeccioso causada por una bacteria Gram positiva perteneciente a la familia de los actinomicetos denominada Tropheryma whippleii. Constituye una causa infecciosa infrecuente de fiebre de origen desconocido. Se presenta el caso de un paciente masculino de 65 años con cuadro febril de 3 años de evolución, poliartralgias, edema en miembros inferiores, adenopatías periféricas y diarreas ocasionales. Se describen la evolución clínica, los estudios de laboratorio, imagenológicos e histológicos que permitieron hacer el diagnóstico de enfermedad de Whipple. Se considera que la publicación de este caso es importante pues contribuye a mantener presente esta enfermedad entre las posibilidades diagnósticas de los pacientes con fiebre de origen desconocido, aún por lo atípico de esta forma de presentación(AU)

Whipple's disease is a multisystem entity of infectious origin caused by a Gram-positive bacterium called Tropheryma whippleii of the actinomycetes family. This is an infrequent infectious disease causing fever of unknown origin. We present the case of a 65-year-old male patient with a 3-year history of fever, polyarthralgia, lower limb edema, peripheral lymphadenopathy, and occasional diarrhea. The clinical evolution, the laboratory results, imaging and histological studies that allowed the diagnosis of Whipple's disease are described. The publication of this case is considered important because it contributes to keep this disease into account among the diagnostic possibilities of patients with fever of unknown origin, since the atypical nature of this form of presentation(AU)

Doença de Whipple: relato de caso / Whipple's Disease: a case report

Descrevemos um caso de doença de Whipple diagnosticada em paciente com síndrome diarreica crônica, emagrecimento intenso, pesquisa de DNA da Tropheryma whipplei positiva em fluido biológico e resposta excelente ao tratamento antibiótico.

A case of Whipple's disease diagnosed in a patient with chronic diarrhea syndrome, intense weight loss, positive DNA searching for Tropheryma whipplei, and excellent clinical response to antibiotic therapy is described.

Doença de Whipple: rara causa de má absorção intestinal - relato de caso / Whipple's Disease: a rare cause of intestinal malabsorption - case report

A doença de Whipple é uma infecção sistêmica rara, causada pela bactéria gram-positiva Tropheryma whipplei, usualmente encontrada no solo. Acomete com maior frequência homens, entre 40 e 60 anos. Tem como característica ser uma doença com sintomas inespecíficos, o que dificulta seu diagnóstico. No presente estudo, relatamos o caso de um paciente do sexo masculino, 57 anos, que apresentava como sintomas principais diarreia e perda de peso significativa. Realizada investigação diagnóstica durante internação, onde a endoscopia digestiva alta confirmou o diagnóstico, com biópsia compatível com doença de Whipple. O paciente do presente estudo foi a óbito no décimo dia de internação. Entretanto, a doença quando diagnosticada precocemente apresenta bom prognóstico, sendo importante considerar doença de Whipple no diagnóstico diferencial de doenças disabsortivas. O tratamento é baseado em antibioticoterapia prolongada.

Whipple's disease is a rare systemic infection caused by gram-positive bacterium Tropheryma whipplei, usually found in soil. It affects more often men between 40 and 60 years. Its characteristic is a disease with specific symptoms, which makes diagnosis difficult. In this study, we report the case of a male patient, 57, who had as main symptoms diarrhea and significant weight loss. Held diagnostic investigation during hospitalization, where endoscopy confirmed the diagnosis with a biopsy compatible with Whipple's disease. The patient in this study died on the tenth day of hospitalization. However, the disease when diagnosed early has a good prognosis, it is important to consider Whipple's disease in the differential diagnosis of malabsorptive diseases. Treatment is based on prolonged antibiotic therapy.

Manifestações clínicas e diagnóstico da doença de Whipple: relato de caso / Clinical manifestations and diagnosis of Whipple?s disease:case report

A doença de Whipple é uma infecção multissistêmica rara, cujo agentecausal é um bacilo Gram-positivo, Tropheryma whippelii. Caracteriza-se por fase prolongada de sintomatologia inespecífica, o que faz postergar o seu diagnóstico. A doença evolui com boa resposta à antibioticoterapia, com boa evolução clínica e laboratorial, mas se não tratada adequadamente pode ser grave e fatal. Este relato descreve umcaso de doença de Whipple, com manifestações sistêmicas. Relato de caso: paciente masculino, 60 anos de idade, há um ano com perda de 15 kg, diarreia, anorexia, poliartralgia e palidez cutaneomucosa. Seu peso era de 45 kg e o índice de massa corpóreo de 18,7. A propedêutica completa revelou: hemoglobina de 8,12 g/dL, sorologias virais e marcadores de doença celíaca negativos; tomografia de abdome: linfonodomegaliaem cadeias mesentéricas e paraórticas; endoscopia digestiva alta revelou áreas de pangastrite enantematosa e biópsia com histopatológico compatível com doença de Whipple, colonoscopia sem alterações. Iniciado tratamento com ceftriaxone seguido por sulfametoxazol-trimetoprim. Evoluiu com melhora, mantendo acompanhamento em ambulatório. Conclusão: a doença de Whipple pode ser fatal se não diagnosticadae tratada de maneira correta. A resposta terapêutica é boa e ocorre nas duas primeiras semanas de tratamento com antibiótico.

Whipple?s disease is a rare multisystemic infection whose causative agent is the Gram-positive bacillus Tropheryma whippelii. It is characterized by a prolonged phase of nonspecific symptoms that delays diagnosis. The disease evolves with good response to antibiotic therapy, good clinical and laboratory evolution, however, if not properly treated it can be serious and fatal. This report describes a case of Whipple?s disease withsystemic manifestations. Case report: male patient, 60 years of age, 15 kg weight loss in one year, diarrhea, anorexia, poly arthralgia, and cutaneous-mucosa pallor. His weight was 45 kg with 18.7 body mass index. The complete propaedeutics revealed: 8.12 g/dL hemoglobin, negative viral serology and celiac disease markers; CT scan of abdomen:lymphadenopathy in mesenteric and para-aortic chains; upper gastrointestinal endoscopy revealed areas of enanthematous pangastritis and biopsy with histopathologic findings compatible with Whipple?s disease, colonoscopy without alterations. Treatment wasstarted with ceftriaxone and followed by sulfamethoxazole-trimethoprim. Patient evolved with improvement maintaining ambulatory monitoring. Conclusion: the Whipple?s disease can be fatal if not diagnosed and treated properly. The therapeutic response is good and occurs in the first two weeks of treatment with antibiotics.

Tumoural form of Whipple's disease simulating carcinomatosis

Whipple's disease is a rare disease caused by the actinomycete bacteria Tropheryma whipplei, which cause intestinal infection. The most common symptoms are chronic diarrhoea, weight loss, abdominal pain, arthritis and neurological abnormalities, which can be fatal. This paper reports a case of a 57-year-old Brazilian woman with diarrhoea, vomiting, abdominal pain, appetite loss, intermittent fever, malaise, weight loss and malnutrition. Migratory polyarthralgia and recurrent visual scotomas preceded the symptoms. The retroperitoneal pseudotumour formation finding was associated with prolonged wasting syndrome, which did not respond to usual therapies, thus leading to the investigation of carcinomatosis disease. After laparotomy, biopsy and histochemical study of the lesions with negative results for malignancy, we proceeded to the investigation of Whipple's disease, which was then confirmed. The patient improved clinically and started gaining weight after using ceftriaxone (IV).

Whipple's disease in an Afro-Caribbean national / Enfermedad de whipple en un nacional afrocaribeño

Whipple's disease is a rare multi-organ infectious disease caused by Tropheryma whipplei. It is fatal without treatment. We report on a 40-year old Afro-Jamaican man who presented with a six-month history of weight loss and diarrhoea. Investigations revealed iron deficiency anaemia and hypoalbuminaemia. Upper gastrointestinal endoscopy revealed white patchy lesions in the duodenum. The duodenal biopsy showed broadening and thickening of the villi by a dense infiltrate of foamy histiocytes within the lamina propria and focally extending into the attached submucosa. Periodic Acid-Schiff stains were positive. Electron microscopy was confirmatory and polymerase chain reaction testing conclusively identified the organisms as T whipplei. Antibiotic treatment resulted in resolution of symptoms. Although the diagnosis of Whipple's disease is difficult, increased awareness should lead to an increase in reported cases with the improvements in diagnostic capabilities.

La enfermedad deWhipple es una rara enfermedad infecciosa multiorgánica causada por el Tropheryma whipplei. Es fatal sin tratamiento. Reportamos un hombre afro-jamaicano de 40 años que se presentó con una historia de seis meses de pérdida de peso y diarrea. Las investigaciones revelaron hipoalbuminemia y anemia ferropénica. La endoscopia gastrointestinal superior reveló lesiones blancas irregulares en el duodeno. La biopsia duodenal mostró la ampliación y engrosamiento de las vellosidades por un denso infiltrado de histiocitos espumosos dentro de la lámina propia, que se extienden hasta la submucosa adjunta. Las tinciones con ácido peryódico de Schiff fueron positivas. La microscopia electrónica fue confirmatoria y la prueba de la reacción en cadena de la polimerasa, identificó los organismos como T whipplei de forma concluyente El tratamiento antibiótico trajo como resultado la resolución de los síntomas. Si bien el diagnóstico de la enfermedad de Whipple es difícil, un aumento de la conciencia debe conducir a un aumento en los reportes de casos divulgados que reflejan un mejoramiento en la capacidad para hacer el diagnóstico.

Whipple's disease: rare disorder and late diagnosis / Doença de Whipple: patologia rara e de diagnóstico tardio

Whipple's disease is a rare systemic infectious disorder caused by the bacterium Tropheryma whipplei. We report the case of a 61-year-old male patient who presented to emergency room complaining of asthenia, arthralgia, anorexia, articular complaints intermittent diarrhea, and a 10-kg weight loss in one year. Laboratory tests showed the following results: Hb = 7.5 g/dL, albumin = 2.5 mg/dL, weight = 50.3 kg (BMI 17.4 kg/m²). Upper gastrointestinal endoscopy revealed areas of focal enanthema in the duodenum. An endoscopic biopsy was suggestive of Whipple's disease. Diagnosis was confirmed based on a positive serum polymerase chain reaction. Treatment was initiated with intravenous ceftriaxone followed by oral trimethoprim-sulfamethoxazole. After one year of treatment, the patient was asymptomatic, with Hb = 13.5 g/dL, serum albumin = 5.3 mg/dL, and weight = 70 kg (BMI 24.2 kg/m²). Whipple's disease should be considered a differential diagnosis in patients with prolonged constitutional and/or gastrointestinal symptoms. Appropriate antibiotic treatment improves the quality of life of patients.

Doença de Whipple é uma rara infecção sistêmica causada pelo Tropheryma whipplei. Caracteriza-se por fase prolongada de sintomas inespecíficos, levando longo período até o seu diagnóstico. Sem tratamento, pode ser grave e fatal, mas com antibioticoterapia tem ótima resposta clínica e laboratorial. Relatamos o caso de paciente masculino, 61 anos, internado por astenia, anorexia, diarréia intermitente e perda de 10 kg em um ano. Apresentava-se com hemoglobina (Hb) 7,5 g/dL, albumina de 2,5 mg/dL, peso 50,3 kg (IMC 17,4). Endoscopia digestiva alta com áreas de enantema focal da mucosa duodenal e biópsia compatível com doença de Whipple. O diagnóstico foi confirmado com PCR sérica positiva, sendo instituído tratamento com ceftriaxone seguido de sulfametoxazol-trimetropim. Após um ano de tratamento, encontrava-se assintomático, com Hb 13,5 g/dL, albumina sérica de 5,3 mg/dL e peso de 70 kg. Doença de Whipple deve fazer parte da lista de diagnósticos diferenciais em pacientes com sintomas constitucionais e/ou com queixas gastrointestinais com evolução prolongada. O tratamento antibiótico pode curar a infecção, recuperando a qualidade de vida do paciente.

Doença de Whipple: relato de caso ­ recentes avanços no diagnóstico e tratamento / Whipple's disease: case report - recent advances in diagnosis and treatment

Os autores relatam um caso de Doença de Whipple em paciente do sexo masculino, de 55 anos, que apresentava predominância de sintomas gastrintestinais e importante comprometimento do estado geral, caquexia e anemia. O diagnóstico foi confirmado por exame histopatológico. Após o tratamento com antibióticos, observou-se excelente evolução clínica. Salientam-se a importância e a atualidade do diagnóstico, visto que, apesar de doença pouco frequente, é potencialmente fatal e responde drasticamente ao tratamento com antibióticos.

Detection of Tropheryma whipplei DNA in Joint Fluid of Patients with Arthritis by Polymerase Chain Reaction / 감염과화학요법

BACKGROUND: Whipple's disease is a chronic systemic infection caused by Tropheryma whipplei which chiefly involves gastrointestinal tract and joints. Because arthritis is often the first sign of Whipple's disease, Whipple's disease may be misdiagnosed in the early stage of illness as non-infectious inflammatory arthritis. Rheumatoid arthritis may also be caused by infectious agents, including T. whipplei. To elucidate the relationship between T. whipplei infection and various arthritis, we examined T. whipplei DNA in Korean patients by polymerase chain reaction (PCR). MATERIALS AND METHODS: With two T. whipplei-specific primers dervied from the partial heat shock protein 65 gene sequence, PCR was performed on 56 joint fluid samples:33 samples from RA patients, 18 samples from OA patients, and 5 samples from patients with other unflammatory arthritis. In addition, the same method was applied to find out the DNA of T. whipplei in 8 normal adults' saliva and 22 patients' gastric juice. Due to the difficulty in obtaining the reference strain of T. whipplei, the PCR was performed without the positive control. RESULTS: The PCR method did not reveal T. whipplei in joint fluid from 56 patients with arthropathies, 8 samples from saliva, and 22 samples from gastric juice. CONCLUSION: Though technical errors can not be excluded as a cause of absence of a positive case, our results suggest that T. whipplei infection may not be a common cause of various arthritis in Korea; T. whipplei may be associated with inflammatory arthritis indirectly by immune-mediated mechanism rather than by direct joint invasion. The examination of specimens other than joint fluid could be helpful and the study of larger number of patient is highly desirable.

Detection of Tropheryma whipplei DNA in Joint Fluid of Patients with Arthritis by Polymerase Chain Reaction / 감염과화학요법

BACKGROUND: Whipple's disease is a chronic systemic infection caused by Tropheryma whipplei which chiefly involves gastrointestinal tract and joints. Because arthritis is often the first sign of Whipple's disease, Whipple's disease may be misdiagnosed in the early stage of illness as non-infectious inflammatory arthritis. Rheumatoid arthritis may also be caused by infectious agents, including T. whipplei. To elucidate the relationship between T. whipplei infection and various arthritis, we examined T. whipplei DNA in Korean patients by polymerase chain reaction (PCR). MATERIALS AND METHODS: With two T. whipplei-specific primers dervied from the partial heat shock protein 65 gene sequence, PCR was performed on 56 joint fluid samples:33 samples from RA patients, 18 samples from OA patients, and 5 samples from patients with other unflammatory arthritis. In addition, the same method was applied to find out the DNA of T. whipplei in 8 normal adults' saliva and 22 patients' gastric juice. Due to the difficulty in obtaining the reference strain of T. whipplei, the PCR was performed without the positive control. RESULTS: The PCR method did not reveal T. whipplei in joint fluid from 56 patients with arthropathies, 8 samples from saliva, and 22 samples from gastric juice. CONCLUSION: Though technical errors can not be excluded as a cause of absence of a positive case, our results suggest that T. whipplei infection may not be a common cause of various arthritis in Korea; T. whipplei may be associated with inflammatory arthritis indirectly by immune-mediated mechanism rather than by direct joint invasion. The examination of specimens other than joint fluid could be helpful and the study of larger number of patient is highly desirable.