Case 2 -
Whipple's Associated Pulmonary Disease
Cleveland Clinic Foundation
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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
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.
Whipple's associated pulmonary disease
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
. 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 . 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 .
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
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
symptoms are rarely the initial manifestations of WD , however, the pleuritis may precede other
symptoms . 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
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 . 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  or by increased viscosity of the lipid in the blood due to the malabsorption from the
small bowel .
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.
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
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 . Clinical response
is usually quite rapid with disappearance of general symptoms, abdominal pain, cessation of diarrhea, and
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