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A mimic of sarcoidosis
Case Report
A mimic of sarcoidosis Larisa Dzirlo, Marianne Hubner, Christian Müller, Benedikt Blaha, Elisabeth Formann, Christoph Dellinger, Peter Petzelbauer, Leonhard Müllauer, Kurt Huber, Meinhard Kneussl, Michael Gschwantler Lancet 2007; 369: 1832 Fourth Department of Internal Medicine (Gastroenterology and Hepatology) (L Dzirlo MD, B Blaha MD, E Formann MD, Prof M Gschwantler MD), Second Department of Internal Medicine (Pulmonary Medicine) (M Hubner MD, Prof M Kneussl MD), Third Department of Internal Medicine (Cardiology) (Prof K Huber MD), and Department of Pathology (C Dellinger MD), Wilhelminenspital, Vienna, Austria; Department of Internal Medicine IV, Division of Gastroenterology and Hepatology (Prof C Müller MD), Department of Dermatology, Division of General Dermatology (Prof P Petzelbauer MD) and Institute of Clinical Pathology (Prof L Müllauer MD), Medical University of Vienna, Vienna, Austria Correspondence to: Dr Larisa Dzirlo, Fourth Department of Internal Medicine (Gastroenterology and Hepatology), Wilhelminenspital, Vienna, Austria [email protected]
In June, 1998, a 48-year-old man presented to the University Hospital of Vienna with large, red, partly ulcerated cutaneous plaques on the anterior surfaces of his lower legs. He also described shortness of breath on exertion. He had no other medical history of note. Biopsy of the plaques showed sarcoid-like granulomas. Radiography and CT of the chest showed enlarged mediastinal and hilar lymph nodes, and linear opacities on the basal lung fields, indicating pulmonary fibrosis. Mediastinoscopy was done, and biopsy samples were taken from the mediastinal lymph nodes. Histological analysis showed epithelioid cells, and a granulomatous lymphadenitis of sarcoid type. A diagnosis of sarcoidosis was made, and the patient was treated with corticosteroids. The ulcers healed, the plaques disappeared, and the shortness of breath became less severe. During the next 5 years, the patient was treated with varying doses of corticosteroids, as recommended by respiratory physicians. However, from November, 2003, his pulmonary function deteriorated, and responded neither to corticosteroids nor to azathioprine. CT of the chest showed that, since 1998, the mediastinal, hilar, and axillary lymph nodes had enlarged, the interstitial lung changes had progressed, and bilateral pleural effusions had developed. Histological analysis of the mediastinal lymph nodes revealed non-caseating granulomatous inflammation. In January, 2004, the patient developed chronic diarrhoea and malabsorption. During the next 3 months, his body weight decreased by 15 kg. In April, 2004, he was admitted to the intensive care unit of the Wilhelminen Hospital, with generalised oedema caused by hypoalbuminaemia (serum albumin 23·8 g/L). A protein-losing enteropathy was suspected. Gastroscopy showed villous atrophy of the duodenum, which had a pseudopolypous surface. Duodenal biopsy samples showed massive infiltration of the intestinal mucosa by macrophages, which were stained purple by periodic–acid/Schiff (PAS), leading to a diagnosis of Whipple’s disease. PCR testing for Tropheryma whipplei confirmed the diagnosis. After initial treatment with intravenous imipenem and ceftriaxone, the patient was given a combination of
Macrophage
Figure: Duodenal mucosa in Whipple’s disease The PAS-stained macrophages form a band on the left hand side. 1832
trimethoprim and sulfametrole for 18 months. After 8 weeks of antibiotic treatment, his gastrointestinal symptoms had resolved, so he could be discharged on supplemental oxygen, at a flow rate of 2–4 L/min. After 9 months of antibiotic treatment, his pulmonary function began to improve greatly. The biopsy samples of the skin plaques and mediastinal lymph nodes, taken in 1998, were analysed. The PAS staining and the PCR of the skin samples were negative, but the PCR of the lymph nodes was positive for T whipplei—which may have been a false positive result. However, it is likely, in our opinion, that the PCR was more sensitive than PAS-staining in detecting T whipplei in our patient, particularly as PAS-staining is often negative in extraintestinal Whipple’s disease.1 The PCR of the skin samples may have given a false negative result, because of the poor quality of the paraffin used to embed the specimen. The clinical course of the illness, and its response to antibiotic treatment, led us to conclude that our patient probably had Whipple’s disease in 1998, which was misdiagnosed as sarcoidosis. When last seen, in April, 2007, the patient was free of gastrointestinal symptoms, and had no respiratory symptoms, although he was not able to jog as far as he had before 1998. Whipple’s disease is a rare multisystem disorder, caused by infection with the bacterium T whipplei. Diagnostic tests include staining with PAS, electron microscopy, immunohistochemistry, and PCR, which detects species-specific bacterial-ribosomal RNA.2,3 The results of diagnostic tests can be contradictory and difficult to interpret.1,3 The clinical picture varies greatly: patients can present with arthralgia or with cardiac, pulmonary, endocrine, ophthalmological, neurological, or dermatological symptoms.3 Sarcoid-like granulomas in association with Whipple’s disease have been described in various organs; and Whipple’s disease has occasionally been reported to mimic sarcoidosis of the lung, and even to respond to corticosteroid treatment.4,5 In this case, pulmonary (and perhaps skin) disease resembling sarcoidosis may have preceded gastrointestinal symptoms by more than 5 years. We believe that Whipple’s disease should always be considered in the differential diagnosis of sarcoidosis, particularly when apparent sarcoidosis does not respond to treatment. References 1 Müller SA, Vogt P, Altwegg M, Seebach JD. Deadly carousel or difficult interpretation of new diagnostic tools for Whipple’s disease: case report and review of the literature. Infection 2005; 33: 39–42. 2 Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992; 327: 293–301. 3 Marth T, Raoult D. Whipple’s disease. Lancet 2003; 361: 239–46. 4 Cho C, Linscheer WG, Hirschkorn MA, Ashutosh K. Sarcoidlike granulomas as an early manifestation of Whipple’s disease. Gastroenterology 1984; 87: 941–47. 5 Scully RE, Mark EJ, McNeely WF, Ebeling SH, Phillips LD. Case records of the Massachusetts General Hospital. N Engl J Med 1997; 337: 1612–19. www.thelancet.com Vol 369 May 26, 2007
A mimic of sarcoidosis Larisa Dzirlo, Marianne Hubner, Christian Müller, Benedikt Blaha, Elisabeth Formann, Christoph Dellinger, Peter Petzelbauer, Leonhard Müllauer, Kurt Huber, Meinhard Kneussl, Michael Gschwantler Lancet 2007; 369: 1832 Fourth Department of Internal Medicine (Gastroenterology and Hepatology) (L Dzirlo MD, B Blaha MD, E Formann MD, Prof M Gschwantler MD), Second Department of Internal Medicine (Pulmonary Medicine) (M Hubner MD, Prof M Kneussl MD), Third Department of Internal Medicine (Cardiology) (Prof K Huber MD), and Department of Pathology (C Dellinger MD), Wilhelminenspital, Vienna, Austria; Department of Internal Medicine IV, Division of Gastroenterology and Hepatology (Prof C Müller MD), Department of Dermatology, Division of General Dermatology (Prof P Petzelbauer MD) and Institute of Clinical Pathology (Prof L Müllauer MD), Medical University of Vienna, Vienna, Austria Correspondence to: Dr Larisa Dzirlo, Fourth Department of Internal Medicine (Gastroenterology and Hepatology), Wilhelminenspital, Vienna, Austria [email protected]
In June, 1998, a 48-year-old man presented to the University Hospital of Vienna with large, red, partly ulcerated cutaneous plaques on the anterior surfaces of his lower legs. He also described shortness of breath on exertion. He had no other medical history of note. Biopsy of the plaques showed sarcoid-like granulomas. Radiography and CT of the chest showed enlarged mediastinal and hilar lymph nodes, and linear opacities on the basal lung fields, indicating pulmonary fibrosis. Mediastinoscopy was done, and biopsy samples were taken from the mediastinal lymph nodes. Histological analysis showed epithelioid cells, and a granulomatous lymphadenitis of sarcoid type. A diagnosis of sarcoidosis was made, and the patient was treated with corticosteroids. The ulcers healed, the plaques disappeared, and the shortness of breath became less severe. During the next 5 years, the patient was treated with varying doses of corticosteroids, as recommended by respiratory physicians. However, from November, 2003, his pulmonary function deteriorated, and responded neither to corticosteroids nor to azathioprine. CT of the chest showed that, since 1998, the mediastinal, hilar, and axillary lymph nodes had enlarged, the interstitial lung changes had progressed, and bilateral pleural effusions had developed. Histological analysis of the mediastinal lymph nodes revealed non-caseating granulomatous inflammation. In January, 2004, the patient developed chronic diarrhoea and malabsorption. During the next 3 months, his body weight decreased by 15 kg. In April, 2004, he was admitted to the intensive care unit of the Wilhelminen Hospital, with generalised oedema caused by hypoalbuminaemia (serum albumin 23·8 g/L). A protein-losing enteropathy was suspected. Gastroscopy showed villous atrophy of the duodenum, which had a pseudopolypous surface. Duodenal biopsy samples showed massive infiltration of the intestinal mucosa by macrophages, which were stained purple by periodic–acid/Schiff (PAS), leading to a diagnosis of Whipple’s disease. PCR testing for Tropheryma whipplei confirmed the diagnosis. After initial treatment with intravenous imipenem and ceftriaxone, the patient was given a combination of
Macrophage
Figure: Duodenal mucosa in Whipple’s disease The PAS-stained macrophages form a band on the left hand side. 1832
trimethoprim and sulfametrole for 18 months. After 8 weeks of antibiotic treatment, his gastrointestinal symptoms had resolved, so he could be discharged on supplemental oxygen, at a flow rate of 2–4 L/min. After 9 months of antibiotic treatment, his pulmonary function began to improve greatly. The biopsy samples of the skin plaques and mediastinal lymph nodes, taken in 1998, were analysed. The PAS staining and the PCR of the skin samples were negative, but the PCR of the lymph nodes was positive for T whipplei—which may have been a false positive result. However, it is likely, in our opinion, that the PCR was more sensitive than PAS-staining in detecting T whipplei in our patient, particularly as PAS-staining is often negative in extraintestinal Whipple’s disease.1 The PCR of the skin samples may have given a false negative result, because of the poor quality of the paraffin used to embed the specimen. The clinical course of the illness, and its response to antibiotic treatment, led us to conclude that our patient probably had Whipple’s disease in 1998, which was misdiagnosed as sarcoidosis. When last seen, in April, 2007, the patient was free of gastrointestinal symptoms, and had no respiratory symptoms, although he was not able to jog as far as he had before 1998. Whipple’s disease is a rare multisystem disorder, caused by infection with the bacterium T whipplei. Diagnostic tests include staining with PAS, electron microscopy, immunohistochemistry, and PCR, which detects species-specific bacterial-ribosomal RNA.2,3 The results of diagnostic tests can be contradictory and difficult to interpret.1,3 The clinical picture varies greatly: patients can present with arthralgia or with cardiac, pulmonary, endocrine, ophthalmological, neurological, or dermatological symptoms.3 Sarcoid-like granulomas in association with Whipple’s disease have been described in various organs; and Whipple’s disease has occasionally been reported to mimic sarcoidosis of the lung, and even to respond to corticosteroid treatment.4,5 In this case, pulmonary (and perhaps skin) disease resembling sarcoidosis may have preceded gastrointestinal symptoms by more than 5 years. We believe that Whipple’s disease should always be considered in the differential diagnosis of sarcoidosis, particularly when apparent sarcoidosis does not respond to treatment. References 1 Müller SA, Vogt P, Altwegg M, Seebach JD. Deadly carousel or difficult interpretation of new diagnostic tools for Whipple’s disease: case report and review of the literature. Infection 2005; 33: 39–42. 2 Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992; 327: 293–301. 3 Marth T, Raoult D. Whipple’s disease. Lancet 2003; 361: 239–46. 4 Cho C, Linscheer WG, Hirschkorn MA, Ashutosh K. Sarcoidlike granulomas as an early manifestation of Whipple’s disease. Gastroenterology 1984; 87: 941–47. 5 Scully RE, Mark EJ, McNeely WF, Ebeling SH, Phillips LD. Case records of the Massachusetts General Hospital. N Engl J Med 1997; 337: 1612–19. www.thelancet.com Vol 369 May 26, 2007