Case 2 -

Whipple's Associated Pulmonary Disease Carol Farver Cleveland Clinic Foundation Cleveland, OH

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Clinical history The patient is a 41 year old female who presented with a three week history of shortness of breath and cough, productive of white sputum. She reported no history of fever, chills, or hemoptysis. Clinical exam revealed minimal bilateral wheezing. Laboratory tests revealed a microcytic anemia and a chest CT scan revealed diffuse infiltration and prominence of the mediastinal fat, bilateral numerous enlarged axillary lymph nodes (approx. 1cm) with diffuse mild pleural thickening of the mid and lower right lung. Lung windows showed diffuse interstitial changes with ill-defined, ground-glass opacities. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 Case 2 - Figure 2 Case 2 - Figure 3 Case 2 - Figure 4 Case 2 - Figure 5 Case 2 - Figure 6 Pathologic features The patient underwent a duodenal biopsy for her history of microcytic anemia followed by mediastinoscopic lymph node biopsies and a surgical lung biopsy. The duodenal biopsy revealed classic pathologic features of Whipple's disease confirmed by histochemical confirmation of PAS-positive bacilli within macrophages and ultrastructural location of bacillary forms. Lymph nodes from the mediastinoscopy contained lipogranulomas scattered throughout and the lung contained marked congestion, capillary dilatation and scattered poorly formed granulomas. The alveolar spaces contained eosinophilic material and around the bronchovascular areas were scattered foamy macrophages. Pulmonary arteries throughout the lung revealed muscular hypertrophy. PAS-positive bacilli were present in the lymph nodes, in rare histiocytes within the bronchus-associated lymphoid tissue (BALT) of the lung and in focal bronchiolar epithelium. An Oil Red-O stain performed on frozen lung tissue was positive for lipid within the dilated capillaries. Immunohistochemical studies confirmed the presence of many T. whipplei within the lymph nodes and within rare cells in the BALT and the bronchial epithelium. Polymerase chain reaction (PCR) performed on the lymph node also confirmed the presence of the organisms within the mediastinal lymph nodes. Final Diagnosis Whipple's associated pulmonary disease Discussion Whipple's disease (WD) is a rare infectious disease with systemic manifestations caused by Tropheryma whipplei, a gram-positive rod-shaped actinobacteria that is ubiquitous in the environment. WD, first described by George Hoyt Whipple in1907, has an estimated annual incidence of less than 1/100,000 and is more common in men than women [1]. It is now postulated that patients with WD may have a defective host defense, perhaps diminished macrophage activation that is specific for this organism as these patients are not affected by other infections [2]. These findings may explain the poorly formed granulomas that manifest in the lymph nodes of patients with this disease and the foamy macrophages that contain abundant organisms seen in intestinal tissue, the liver, lymph nodes and the spleen. WD has long been thought of as predominantly a disease of the gastrointestinal tract, reflected in its original name of 'intestinal lipodystrophy'. However, it is now known that this disease involves a wide spectrum of organs including the heart, the kidney, the brain and the lungs. The most common clinical manifestations in decreasing order are weight loss (92%), steatorrhea (91%), anemia (85%), diarrhea (76%), arthralgias (67%), lymphadenopathy (60%) and abdominal pain (55%). CNS disease is the most serious and is found in 10-40% of patients, with dementia, decreasing level of consciousness, and memory impairment as the most common neurologic findings [1]. The histopathological features of the gastrointestinal disease include dilated villi of the duodenum with ecstatic lymph vessels. Foamy macrophages are found in the lamina propria with an abundance of PAS-positive and diastase-resistant bacilli. These same macrophages may be found in cerebrospinal fluid, brain tissue, lymph nodes, bone marrow, skin, liver and the eye. Other pathologic features frequently reported include an arteriopathy that has been reported in the small intestine serosa, liver, coronary arteries, lung and pancreas. This consists of a lymphocytic arteritis, intimal proliferation and mural scarring [3, 4]. Spectrum of Pulmonary Disease Approximately 30-40% of the patients with WD have lung involvement which usually manifests clinically as a chronic nonproductive cough, pleuritic chest pain and dyspnea. Imaging studies commonly show pleural effusions, bilateral pulmonary infiltrates and mediastinal lymphadenopathy [5, 6]. Pulmonary symptoms are rarely the initial manifestations of WD [7], however, the pleuritis may precede other symptoms [8]. The histopathological features of the pulmonary disease reported in these cases usually reveal collections of foamy macrophages around the bronchovascular area that have infiltrated the smooth muscle and mucosa of the bronchiole and a pleura infiltrated by a mix of lymphocytes and some plasma cells with fibrosis. Histochemical studies reveal large numbers of PAS-positive histiocytes in both areas [9]. The pathologic features of WD involvement found in this case, the dilatation of the capillaries by lipid coupled with the vasculopathy, has not been well-documented. The previous report that pathologically documented similar vascular pathology in the lung was by James et al who reported two cases of pulmonary involvement by WD with pulmonary arteries with intimal proliferation and media hypertrophy [3]. The etiology of these lesions is unclear. Some suggest that the vascular changes are a result of thrombosis caused by either vascular invasion by the T. whipplei organisms [10] or by increased viscosity of the lipid in the blood due to the malabsorption from the small bowel [11]. Differential Diagnosis for Pulmonary Whipple's associated pathology The pathologic differential diagnosis of WD involving the lung includes disease that may cause lipogranulomas such as lipid pneumonia, lipid storage diseases (Niemann-Pick and Gaucher's) or perhaps other infections that exhibit abundant foamy macrophages including malakoplakia, and non-tuberculous mycobacteria. Sarcoidosis should also be considered, although sarcoidal granulomas are usually more well formed. Also, the pathology in the mediastinal lymph nodes of sarcoidosis is usually more extensive and significant hyalinization may be present. The impressive vascular changes found in this lung may be confused with a pulmonary hypertensive arteriopathy. The presence of other pathology including lipogranulomas and capillary congestion/dilatation in cases of WD may help to distinguish this from a primary vascular disease. Also, clinical evidence for significant pulmonary hypertension such as right-sided heart failure and elevated PA pressures has not been documented in WD. Diagnostic Methods Tropheryma whipplei is very difficult to culture, making diagnosis difficult. The most common method of diagnosis is small bowel biopsy and demonstration of the periodic acid-Schiff (PAS)-positive, diastase-resistant bacilli within the tissue. This diagnosis can be confirmed by demonstrating the characteristic bacillary bodies using electron microscopy. In addition, molecular studies can confirm the presence of the bacilli in the tissue, using a polymerase chain reaction (PCR) assay for the 16S ribosomal RNA genes of T. whipplei. Immunohistochemical studies are now available that are species specific. The pattern of immunoreactivity is granular and intracellular and is reported to be similar to the pattern seen with the PAS stain, but is more sensitive, picking up some cases that were negative by PAS stain [12]. Treatment The main aim of therapy for WD is to eradicate the organism from the area of primary infection, usually the intestine. Given the small number of cases of this infection, definitive treatment guidelines are not available. Empiric data suggests that an induction period of intravenous treatment with ceftriaxone or meropenem followed by long term treatment with trimethoprim-sulfamethoxazole orally is the most successful therapy, though treatment failures are well-documented [13]. Clinical response is usually quite rapid with disappearance of general symptoms, abdominal pain, cessation of diarrhea, and weight gain. References Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D. Whipple's disease: new aspects of pathogenesis and treatment. Lancet Infect Disease 2008;8:179-190. Marth T, Schneider T. Whipple disease. Curr Opin Gastroenterol 2008;2492):141-148. James T, Bulkley BH. Whipple bacilli within the tunica media of pulmonary arteries. Chest 1984;86(3):454-458. James T. On the wide spectrum of abnormalities in the coronary arteries of Whipple's disease. Coron Artery Dis 2001;12:115-125. Symmons DP, Shepherd AN, Boardman PL, Bacon PA. Pulmonary manifestations of Whipple's disease; QJMed 1985;56(220):497-504. Enzinger FM, Helwig EG. Whipple's disease: a review of the literature and report of fifteen cases. Virchows Arch A Pathol Anat Histopathol 1963;336:238-269. Kelly CA, Egan M, Rawlinson J. Whipple's disease presenting as lung involvement. Thorax 1996;51(3):343-344. Pastor BM, Geerken RG. Whipple's disease presenting as pleuropericarditis. Am J Med 1973;55(6):827-831. Winberg CD, Rose ME, Rappaport H. Whipple's disease of the lung. Am J Med 1978;65(5):873-880. Peschard S, Brinkane A, Bergheul S, Crickx L, Gaudin B, Morecelet M, Levy R. Whipple disease associated with pulmonary arterial hypertension. Jarisch-Herxheimer reaction after antibiotic therapy. Presse Med 2001;30(31):1549-1551. Adams CWM, Ayres J, Fagg NLK, Hicks BH. Lymph-vessel embolism in a case of Whipple's disease. Histopathology 1985;9: 109-115. Baisden B, Lepidi H, Raoult D, Argani P. Diagnosis of Whipple disease by immunohistochemical analysis: a sensitive and specific method for the detection of Tropheryma whipplei (the Whipple Bacillus) in paraffin-embedded tissue. Am J Clin Path 2002;188:742-748. Bakkali N, Fenollar F, Biswas S, Rolain JM, Raoult D. Acquired resistance to trimethoprim-sulfamethoxazole during Whipple disease and expression of the causative target gene. J Infect Dis 2008;198(1):101-108.