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Whipple Disease Revealed by Lung InvolvementWhipple Disease Revealed by Lung Nodules: A Case Report and Literature Review FREE TO VIEW

Geoffrey Urbanski, MD; Philippe Rivereau, MD; Laure Artru, MD; Florence Fenollar, MD, PhD; Didier Raoult, MD, PhD; Xavier Puéchal, MD, PhD
Author and Funding Information

From the Center for Rare Systemic Auto-immune Diseases (Drs Urbanski, Artru, and Puéchal), the Department of Rheumatology, and the Department of Respiratory Diseases (Dr Rivereau), Le Mans General Hospital, Le Mans; and Unité des rickettsies (Drs Fenollar and Raoult), Faculté de Médecine, Université de la Méditerranée, Marseille, France.

Correspondence to: Xavier Puéchal, MD, PhD, National Referral Center for Rare Systemic and Autoimmune Diseases, Necrotizing Vasculitides, Université Paris V-Descartes, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 27, rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France; e-mail: xavier.puechal@cch.aphp.fr


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


© 2012 American College of Chest Physicians


Chest. 2012;141(6):1595-1598. doi:10.1378/chest.11-1812
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We report the case of a man with a history of intermittent fever and arthritis who presented with a dry cough and associated lung involvement, who was eventually given the diagnosis of Whipple disease. The pulmonary symptoms preceded the development of GI manifestations. Five years later, periodic acid-Schiff (PAS)-positive macrophages were identified in duodenal biopsy specimens and polymerase chain reaction for Tropheryma whipplei was positive in the duodenum, stools, saliva, and cerebrospinal fluid. Pulmonary T whipplei was retrospectively confirmed by positive PAS staining and immunoreactivity to specific antibodies in endobronchial biopsy specimens. Antibiotic treatment was followed by remission. A literature review identified eight other cases of Whipple disease presenting with lung parenchymal involvement, predominantly interstitial lung disease (ILD), and without initial GI symptoms. In the absence of GI symptoms, a diagnosis of Whipple disease should be considered in middle-aged men presenting with ILD or lung nodules, if the patient has a history of unexplained arthralgia and/or fever. The association of mediastinal adenopathy or pleural effusion offers additional concern. Whipple disease may be fatal in the absence of treatment, but prolonged antibiotic treatment often leads to complete remission.

Figures in this Article

Whipple disease is a rare infectious disease caused by a bacterium, Tropheryma whipplei. The classic form has a prodromal stage characterized by arthritis and a steady-state stage with diarrhea and weight loss.1 The prevalence of pulmonary involvement in Whipple disease has been estimated to be 30% to 40%. Pleural effusion and mediastinal adenopathy have been reported in 28% and 12% of cases, respectively, but lung parenchymal involvement is rare. Pulmonary involvement generally occurs late in the course of the disease but, in rare cases, it may be the presenting feature. We report a case of Whipple disease presenting with lung nodules and review previously reported cases in which lung parenchymal involvement was the presenting feature of the disease.

A 40-year-old man reported intermittent fever beginning in May 2001. In March 2002, he started to complain of dry cough. Intermittent arthritis began, with synovial fluid obtained from the knee containing 2,240 leukocytes/μL, of which 92% were polymorphonuclear cells. In October 2004, a chest radiograph was normal but CT scan disclosed several parenchymal nodules, which were primarily subpleural (Fig 1A). BAL fluid contained 4×104 lymphocytes/μL (27%), 74% of which were CD4+. Pulmonary function tests, including carbon monoxide diffusion capacity, gave normal results. Endobronchial biopsy specimens revealed nonspecific inflammation. In April 2007, the patient underwent GI endoscopy. Duodenal biopsy specimens revealed periodic acid-Schiff (PAS)-positive macrophages. Polymerase chain reaction (PCR) for Tropheryma whipplei was positive in the duodenal biopsy specimens, stools, saliva, and cerebrospinal fluid specimens. The patient was treated with a combination of doxycycline, trimethoprim-sulfamethoxazole, and hydroxychloroquine for 2 years. The symptoms disappeared after 15 days of treatment. The patient had no more fever, arthralgia, or cough with a 4.6-year follow-up period.

Figure Jump LinkFigure 1. A, One of the nodules located in the upper lobe of the left lung at CT scan revealed Whipple disease. B, Immunohistochemical staining with polyclonal rabbit anti-Tropheryma whipplei antibody and Mayer hemalum counterstaining showed T whipplei in bronchial biopsy specimen (arrows) (original magnification ×200). C, Same as B but with original magnification ×400. (Figure courtesy of Hubert Lepidi, MD)Grahic Jump Location

A follow-up examination 2 years after the end of treatment showed no evidence of disease. All PCR results on similar biologic specimens showed no evidence of the organism. A control CT scan showed the persistence of the lung nodules without any change. A retrospective study of the bronchial biopsy specimens revealed PAS staining and immunoreactivity with anti-T whipplei antibodies (Figs 1B, 1C), confirming the presence and suggesting the involvement of T whipplei in the pathogenesis of the presenting lung disease.

Literature Review

Published cases of Whipple disease with lung parenchymal involvement were identified by a computerized MEDLINE search of articles published from 1950 to 2010. The cases had to fulfill the following criteria to be retained for the literature analysis: (1) the diagnosis of Whipple disease had to be confirmed, (2) there had to be an absence of GI symptoms at the time of first respiratory symptom or chest radiographic abnormality, and (3) evidence of parenchymal abnormalities had to be documented on chest radiographs or CT scans.

Immunohistochemical Staining

Several slides of samples from the endobronchial biopsy specimens were immunostained for T whipplei with the use of a polyclonal rabbit antibody, as already described in other tissues (Fig 1).1,2 Although not yet widely available, immunohistochemical staining provides direct visualization of the bacilli, with greater sensitivity and specificity than does PAS staining.1 It can be used retrospectively on fixed samples.

In addition to our case, we identified eight published cases of Whipple disease with lung parenchymal involvement without GI symptoms.3-9 Including the present case, the nine cases comprised eight men and one woman, with a mean age of 47.2 years (range, 30.7-59 years) at the onset of respiratory symptoms (Table 1). These demographic features are consistent with those usually reported for this disease, occurring principally in middle-aged white men.1

Table Graphic Jump Location
Table 1 —Characteristics and Outcomes of Nine Patients Reported in the Literature With Whipple Disease and Lung Parenchymal Abnormalities but No Digestive Symptoms

Anti-Tw = anti-Tropheryma whipplei; F = female; M = male; − = negative; PAS = periodic acid-Schiff; PCR = polymerase chain reaction; + = positive.

A characteristic prodromal phase was observed before the onset of respiratory symptoms in six patients, for a period lasting a mean of 5 years (range, 0.4-11.0 years). In the other three patients, prodromal and pulmonary symptoms appeared simultaneously.3-5 Seven patients (77.8%) presented with arthralgia or migratory arthritis, and the rheumatic symptoms were the first to occur in five patients. Other prodromal features included intermittent fever in six patients and cutaneous granulomatosis lesions in three.4-6

The clinical respiratory features included shortness of breath in six patients (66.7%), dry cough in five patients (55.6%), and chest pain in two patients (22.2%). In one case, radiographic abnormalities preceded the onset of clinical symptoms.3 Evidence of interstitial lung disease (ILD) was present in six patients, showing either a nodular8 or a reticulonodular3 pattern in one patient each, or a reticular6,7 and an undetermined pattern in two patients each.5,9 Pulmonary nodules were reported in one patient,4 with several large rounded lesions in both lung fields. Moreover, three patients presented bilateral pleural effusions,5,7 and three cases had mediastinal adenopathies.3,5,8 Four endobronchial biopsies were performed: One revealed PAS-positive macrophages4 and one, noncaseating granuloma.3 Of four lung biopsy specimens, two showed noncaseating granuloma8,9 and the other two, fibrosis.7,8 One lung biopsy specimen, in addition to revealing a granuloma, also showed positive PAS staining and the characteristic bacilli on electron microscopy.9 A mediastinal node biopsy specimen showed noncaseating granuloma, and positive results were obtained for T whipplei PCR, although PAS staining was negative.5 To our knowledge, this case is the first to be described extensively in which T whipplei involvement has been demonstrated by positive immunostaining with anti-T whipplei antibodies.

GI symptoms followed the discovery of lung disease in seven cases (77.8%), whereas two patients (this patient and the patient reported by Kelly et al4) received the diagnosis before the onset of intestinal manifestations. The patients had diarrhea, often associated with weight loss, abdominal pain, and malabsorption. In these patients, the mean time between the onset of prodromal symptoms and the diagnosis of Whipple disease was 6.5 years (range, 0.4-14 years), which is consistent with the literature.1 Consequently, the patients had advanced disseminated disease at the time of diagnosis.

In the nine patients, the mean follow-up period was 16.1 months (range, 0-51 months) and the survival rate was 88.9%. The symptoms disappeared within 4.3 weeks (range, 1-8 weeks) in all the patients treated with antibiotics. One patient died in a cachexic state from pneumonia. He had presented with arthralgia, micronodular ILD, diarrhea, and weight loss.7 Whipple disease was established on autopsy.

In patients presenting with lung involvement associated with arthralgia and fever, sarcoidosis is a possible alternative diagnosis. Moreover, granulomas may occur in both diseases but corticosteroid treatment is known to adversely affect this disease.10

In cases of suspected Whipple disease with or without pulmonary involvement, duodenal biopsy with PAS staining is indicated, even in the absence of intestinal clinical symptoms. It is also essential to perform PCR for T whipplei PCR on stool samples, saliva, and frozen biopsy specimens from the bronchi and duodenum. This is more sensitive than PAS staining. In our case, the bronchial location of the bacterium was confirmed retrospectively by immunohistochemical analysis with anti-T whipplei antibodies. This technique, or PCR analysis, may make it possible to obtain a diagnosis retrospectively, even from fixed bronchial biopsy specimens.

In conclusion, even in the absence of GI symptoms, a diagnosis of Whipple disease should be considered in middle-aged men presenting with ILD or lung nodules if they have a history of unexplained arthralgia and/or fever. This is further supported by the presence of mediastinal adenopathies or pleural effusion, or evidence of granuloma. Whipple disease may be fatal in the absence of treatment but is responsive to antibiotic treatment.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Raoult is a co-inventor of two patents without any commercial application or derivative products. He is also a shareholder in the company INODIAG. Drs Urbanski, Rivereau, Artru, Fenollar, and Puéchal have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Hubert Lepidi, MD, from our lab, for providing Figure 1.

ILD

interstitial lung disease

PAS

periodic acid-Schiff

PCR

polymerase chain reaction

Fenollar F, Puéchal X, Raoult D. Whipple’s disease. N Engl J Med. 2007;3561:55-66. [CrossRef] [PubMed]
 
Baisden BL, Lepidi H, Raoult D, Argani P, Yardley JH, Dumler JS. Diagnosis of Whipple disease by immunohistochemical analysis: a sensitive and specific method for the detection ofTropheryma whipplei(the Whipple bacillus) in paraffin-embedded tissue. Am J Clin Pathol. 2002;1185:742-748. [CrossRef] [PubMed]
 
Pequignot H, Morin Y, Grandjouan MS, et al. Sarcoidosis and Whipple’s disease. Association? Relation? [in French]. Ann Med Interne (Paris). 1976;12711:797-806. [PubMed]
 
Kelly CA, Egan M, Rawlinson J. Whipple’s disease presenting with lung involvement. Thorax. 1996;513:343-344. [CrossRef] [PubMed]
 
Dzirlo L, Hubner M, Müller C, et al. A mimic of sarcoidosis. Lancet. 2007;3699575:1832. [CrossRef] [PubMed]
 
Nahon S, Marie L, Maurer C, et al. Whipple’s disease manifesting as atypical respiratory manifestations [in French]. Gastroenterol Clin Biol. 2009;3312:1073-1075. [CrossRef] [PubMed]
 
Symmons DP, Shepherd AN, Boardman PL, Bacon PA. Pulmonary manifestations of Whipple’s disease. Q J Med. 1985;56220:497-504. [PubMed]
 
Cho C, Linscheer WG, Hirschkorn MA, Ashutosh K. Sarcoidlike granulomas as an early manifestation of Whipple’s disease. Gastroenterology. 1984;874:941-947. [PubMed]
 
Winberg CD, Rose ME, Rappaport H. Whipple’s disease of the lung. Am J Med. 1978;655:873-880. [CrossRef] [PubMed]
 
Mahnel R, Kalt A, Ring S, Stallmach A, Strober W, Marth T. Immunosuppressive therapy in Whipple’s disease patients is associated with the appearance of gastrointestinal manifestations. Am J Gastroenterol. 2005;1005:1167-1173. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. A, One of the nodules located in the upper lobe of the left lung at CT scan revealed Whipple disease. B, Immunohistochemical staining with polyclonal rabbit anti-Tropheryma whipplei antibody and Mayer hemalum counterstaining showed T whipplei in bronchial biopsy specimen (arrows) (original magnification ×200). C, Same as B but with original magnification ×400. (Figure courtesy of Hubert Lepidi, MD)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Characteristics and Outcomes of Nine Patients Reported in the Literature With Whipple Disease and Lung Parenchymal Abnormalities but No Digestive Symptoms

Anti-Tw = anti-Tropheryma whipplei; F = female; M = male; − = negative; PAS = periodic acid-Schiff; PCR = polymerase chain reaction; + = positive.

References

Fenollar F, Puéchal X, Raoult D. Whipple’s disease. N Engl J Med. 2007;3561:55-66. [CrossRef] [PubMed]
 
Baisden BL, Lepidi H, Raoult D, Argani P, Yardley JH, Dumler JS. Diagnosis of Whipple disease by immunohistochemical analysis: a sensitive and specific method for the detection ofTropheryma whipplei(the Whipple bacillus) in paraffin-embedded tissue. Am J Clin Pathol. 2002;1185:742-748. [CrossRef] [PubMed]
 
Pequignot H, Morin Y, Grandjouan MS, et al. Sarcoidosis and Whipple’s disease. Association? Relation? [in French]. Ann Med Interne (Paris). 1976;12711:797-806. [PubMed]
 
Kelly CA, Egan M, Rawlinson J. Whipple’s disease presenting with lung involvement. Thorax. 1996;513:343-344. [CrossRef] [PubMed]
 
Dzirlo L, Hubner M, Müller C, et al. A mimic of sarcoidosis. Lancet. 2007;3699575:1832. [CrossRef] [PubMed]
 
Nahon S, Marie L, Maurer C, et al. Whipple’s disease manifesting as atypical respiratory manifestations [in French]. Gastroenterol Clin Biol. 2009;3312:1073-1075. [CrossRef] [PubMed]
 
Symmons DP, Shepherd AN, Boardman PL, Bacon PA. Pulmonary manifestations of Whipple’s disease. Q J Med. 1985;56220:497-504. [PubMed]
 
Cho C, Linscheer WG, Hirschkorn MA, Ashutosh K. Sarcoidlike granulomas as an early manifestation of Whipple’s disease. Gastroenterology. 1984;874:941-947. [PubMed]
 
Winberg CD, Rose ME, Rappaport H. Whipple’s disease of the lung. Am J Med. 1978;655:873-880. [CrossRef] [PubMed]
 
Mahnel R, Kalt A, Ring S, Stallmach A, Strober W, Marth T. Immunosuppressive therapy in Whipple’s disease patients is associated with the appearance of gastrointestinal manifestations. Am J Gastroenterol. 2005;1005:1167-1173. [CrossRef] [PubMed]
 
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