Case Report

Bronchiolitis obliterans Organizing Pneumonia: A Distinct Pulmonary Complication in Cystic Fibrosis
Martin Häusler^a, Rainer Meilicke^b, Stefan Biesterfeld^c, Heiner Kentrup^a, Frank Friedrichs^a, Gregor Kusenbach<sup>a

a</sup>Department of Pediatrics,
^bDepartment of Medical Immunology/Microbiology and
^cDepartment of Pathology, University Hospital, RWTH Aachen, Germany

Address of Corresponding Author

Respiration 2000;67:316-319 (DOI: 10.1159/000029517)

 Outline

• Key Words
• Abstract
• Introduction
• Case Report
• Discussion
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

  Key Words

• Mycobacteria, atypical
• Bronchiolitis obliterans organizing pneumonia
• Cystic fibrosis
• Lung disease
• Lung inflammation

  Abstract

Organizing pneumonia in cystic fibrosis has hitherto been considered a nonspecific reparative process. We report on an adult patient with cystic fibrosis and histologically proven bronchiolitis obliterans organizing pneumonia, who experienced sustained clinical improvement under corticosteroid therapy. This case suggests that bronchiolitis obliterans organizing pneumonia may be a distinct pulmonary complication in cystic fibrosis and improve with specific therapy.

Copyright © 2000 S. Karger AG, Basel

 introduction

Bronchiolitis obliterans organizing pneumonia (BOOP) is histologically characterized by granulation tissue, extending from small airways into alveolar ducts and alveoli. It causes flu-like symptoms, dry cough, dyspnea, hypoxemia, fever, weight loss, a restrictive defect in lung function, and patchy infiltrations on chest X-rays, symptoms which do not respond to antibiotics but to corticosteroids [1, 2, 3, 4]. BOOP may be idiopathic, occur secondary to triggers like drugs, infectious or toxic agents and inhalation of mold spores, is associated with hematologic, autoimmune or immunodeficiency disorders and may complicate lung, renal or bone marrow transplantation [1, 2, 3, 4, 5, 6, 7]. The histopathologic features of BOOP are observed in about 10% of patients with cystic fibrosis (CF) [6]. However, this is not considered a distinct pulmonary complication which might require special attention and therapy but a chronic reparative reaction [2].

 case report

In the male patient (born in 1975, homozygous F508, nonsmoking) CF was diagnosed at the age of 7 months because of recurrent bronchitis and steatorrhea. Pulmonary infection with Pseudomonas aeruginosa, Aspergillus fumigatus and Staphylococcus aureus occurred in early infancy. From July 1993 serum antibody titers to protease, elastase and exotoxin of P. aeruginosa increased and Mycobacterium abscessus was repeatedly isolated from sputum samples. The clinical status, however, was stable until March 1995, and antimycobacterial therapy was not initiated.

In April 1995 recurrent fever, persistent dry cough, pleuritic chest pain, night sweat, a decrease of transcutaneous oxygen saturation values from 95 to 92% and rapid progressive breathlessness on exertion occurred. Values of forced expiratory volume in 1 s (50% predicted), forced vital capacity (70%) and total lung capacity (90%), however, remained unchanged. Laboratory inflammation markers were only slightly elevated, and body weight did not decrease (weight 57 kg; height 168 cm). When compared with the preceding 5 years, chest X-rays gave no indication of an unusual pulmonary complication: there were peribronchial thickening, bronchiectasis, an increase in interstitial markings and pulmonary hyperinflation but no peripheral patchy air space consolidation or abscess formation. The tuberculin skin test was negative. Negative antibody titers to and skin testing for A. fumigatus as well as normal IgE concentrations excluded allergic bronchopulmonary aspergillosis. No further microbial agents but M. abscessus, P. aeruginosa and A. fumigatus were isolated from sputum samples. Empiric antibiotic therapy, however, failed to improve the patient's symptoms. As pulmonary colonization with M. abscessus does not prove nontuberculous mycobacterial lung disease [8], it was decided to perform a thoracoscopic lung biopsy, aimed at evaluating the clinical importance of M. abscessus. A biopsy of the lingula, which is accurate and safe for a diagnosis of diffuse lung disease, was taken [9]. Surprisingly, microbiology, histopathology and immunohistochemistry (staining for IgG, IgA, fibronectin and collagen III) did not confirm nontuberculous mycobacterial disease but showed acute BOOP (fig. 1). This included early stages of acute BOOP, as demonstrated by fibrinoid inflammatory cell clusters which are characterized by the intra-alveolar accumulation of lymphocytes, alveolar space foam cells and intra- as well as extracellular immunoglobulins [10]. Neither peribronchial granulomas, abscesses, necrosis, hyaline membranes, honeycombing, vasculitis or marked eosinophilia, nor morphologic changes of alveolar epithelial cells indicative of acute viral infection were found. Laboratory investigations excluded the presence of autoantibodies indicative of collagen vascular diseases, of autoantibodies to dsDNA, hep-2 cells, neutrophil cytoplasmic antigens, cardiolipins and basement membrane, of circulating immune complexes and of rheumatoid factors. Antibody titers to influenza, parainfluenza, adenovirus, cytomegalovirus, hepatitis B, Epstein-Barr and respiratory syncytial viruses as well as to Mycoplasma pneumoniae were not increased. HIV infection was ruled out. In vitro immunoglobulin synthesis and lymphocyte proliferation (³H thymidine incorporation) were normal.

Fig. 1. Histopathologic examination documenting the typical characteristics of BOOP [1, 2, 5, 6, 10]. Granulation tissue in respiratory bronchioles, alveolar ducts and alveoli, showing a patchy distribution. The bronchoalveolar architecture is preserved. G = Intra-alveolar granulation tissue; A = free alveolar space. Arrowheads represent interstitial mononuclear infiltration. HE. Bar: 200 µm.

High-dose prednisolone therapy (1-2 mg/kg per day for 10 weeks) with ensuing low-dose maintenance therapy resulted in a rapid clinical improvement. Within 6 months and despite no accompanying antimycobacterial therapy, an increase was recorded in the forced expiratory volume in 1 s (to 61%), forced vital capacity (to 77%), total lung capacity (to 100%) and transcutaneous oxygen saturation values (to 98%). Antibody titers to exoenzymes of P. aeruginosa decreased. No severe side effects of corticosteroid therapy were observed. A high-resolution CT scan (HRCT) of the chest, performed 6 weeks after the beginning of prednisolone therapy, confirmed peribronchial thickening and bronchiectasis but did not reveal peripheral patchy infiltrations. Now, 4 years later, the patient is still being treated with 5 mg of prednisolone every second day. Despite persisting mycobacterial colonization and no antimycobacterial therapy, the symptoms have not relapsed. Chest X-rays showed slowly progressive bronchiectasis; the lung function has remained stable.

 discussion

This is the first patient with CF where acute BOOP was diagnosed and effectively treated during his lifetime. Diagnosis was based on three major findings: on the clinical symptoms that were characteristic of BOOP but uncommon for differential diagnoses like inflammatory airflow obstruction, on the good response to corticosteroids and, most importantly, on open lung biopsy [1, 2, 3, 4, 5]. In this process histopathology revealed even early stages of acute BOOP simultaneously with the clinical deterioration and ruled out differential diagnoses like chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis, extrinsic allergic alveolitis, diffuse alveolar damage or Wegener's granulomatosis [2, 5, 11, 12]. A decrease in pulmonary function values and characteristic radiological findings were not observed. However, this has previously been reported in non-CF patients [1, 4, 6]. Furthermore, preexisting lung disease may have masked discrete radiological signs, and HRCT, the most sensitive radiological diagnostic tool to reveal discrete lung disease in CF [13], was performed after a delay of 6 weeks.

Both BOOP and chronic lung disease in CF are characterized by an increased inappropriate immune response; both diseases may show interstitial inflammation as well as a good response to immunosuppressive therapy, and triggering factors for BOOP, like drug therapy and pulmonary infections, are present in many patients with CF [1, 2, 3, 4, 6, 10, 11]. Histopathologic characteristics of BOOP have already been found in patients with CF, and the hypothesis that this might contribute to lung disease is not new [6]. However, this suggestion was based on postmortem investigations, and organizing pneumonia in CF was hitherto considered a chronic reparative reaction [2]. Even ground glass opacities have already been reported in chest HRCT images of patients with CF [13]. However, BOOP was not considered in these patients. Therefore, the present case gives first evidence that BOOP may acutely complicate lung disease in CF in vivo, and, similar to inflammatory airflow obstruction, require immunosuppressive therapy.

In our patient the impact of different triggers for BOOP remains uncertain [1, 2, 3, 4, 5, 6, 7]: collagen vascular and severe immunodeficiency diseases were excluded. Oxygen, which may be toxic to alveoli, was never applied. Although intravenous cefotaxime and tobramycin therapy, oral supplementation of vitamin E, A and K, of pancreatic enzymes and of mucolytics as well as inhalation of salbutamol and DNAse were not discontinued after the diagnosis of BOOP, the patient recovered and suffered no relapses. Furthermore, signs of acute viral disease were absent. Before manifestation of BOOP the frequency of pulmonary exacerbations had not increased and the rise in antibody titers in response to P. aeruginosa is a nonspecific finding in CF. Finally, mycobacterial colonization of the lung is rare in CF and the prognostic impact is unknown [8]. Granulomatous pneumonia with caseous necrosis, which may be accompanied by organizing pneumonia, was observed in all cases of histologically proven nontuberculous mycobacterial lung disease [8]. In our patient, neither granulomas nor nontuberculous mycobacteria were found in lung tissue. Therefore, antimycobacterial therapy was not initiated. Although sputum samples continued to be positive for M. abscessus, P. aeruginosa and A. fumigatus, he experienced a sustained clinical improvement.

In the absence of atypical mycobacteria or in the case of a severe underlying lung disease - the patient had previously shown an exceptionally mild pulmonary disease - lung biopsy would not have been performed, BOOP would not have been diagnosed and empirical corticosteroid treatment might have been started. This indicates that BOOP in CF might be more frequent than commonly assumed, that symptoms of BOOP may be difficult to distinguish from further CF-related findings, and that it may also occur in patients with moderate lung disease. BOOP should be considered in patients with atypical clinical complaints, like dry cough, pleuritic chest pain, night sweat or acute pulmonary deterioration refractory to established therapy as well as in patients showing patchy infiltrations on chest X-rays or CT scans. Short-term high-dose corticosteroid therapy may be followed by long-term low-dose therapy in one third of patients with BOOP [1, 4]. Considering the serious side effects of immunosuppression a clear-cut diagnosis is essential, with early HRCT of the chest possibly being useful [12]. However, even in patients without chronic lung disease the diagnostic accuracy of radioimaging is limited [12]. In many cases lung biospy may be the only reliable method. In patients with contraindications to empiric corticosteroid therapy and in patients with relapsing or refractory disease, lung biopsy may be indispensable.

BOOP may be an important pulmonary complication in CF. The good response to immunosuppressive therapy encourages intensified search of and research on this new aspect of lung disease in CF.

  References

1.

Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA: Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312:152-158.

2.

Colby TV: Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992;102:38S-43S.

3.

Costabel U, Guzman J, Teschler H: Bronchiolitis obliterans with organising pneumonia: Outcome. Thorax 1995;50(suppl 1):S59-S64.

4.

King TE Jr, Mortenson RL: Cryptogenic organizing pneumonitis. The North American experience. Chest 1992;102:8S-13S.

5.

Kitaichi M: Differential diagnosis of bronchiolitis obliterans organizing pneumonia. Chest 1992;102:44S-49S.

6.

Tomashefski JF Jr, Konstan MW, Bruce MC, Abramowsky CR: The pathologic characteristics of interstitial pneumonia cystic fibrosis. A retrospective autopsy study. Am J Clin Pathol 1989;91:522-530.

7.

Epler GR: Heterogeneity of bronchiolitis obliterans organizing pneumonia. Curr Opin Pulm Med 1998;4:93-97.

8.

Tomashefski JF Jr, Stern RC, Demko CA, Doershuk CF: Nontuberculous mycobacteria in cystic fibrosis. An autopsy study. Am J Respir Crit Care Med 1996;154:523-528.

9.

Wetstein L: Sensitivity and specificity of lingular segmental biopsies of the lung. Chest 1986;90:383-386.

10.

Peyrol S, Cordier JF, Grimaud JA: Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia. Cell-matrix patterns. Am J Pathol 1990;137:155-170.

11.

Greenberger PA: Immunologic aspects of lung diseases and cystic fibrosis. JAMA 1997;278:1924-1930.

12.

Johkoh T, Müller NL, Cartier Y, Kavanagh PV, Hartman TE, Akira M, Ichikado K, Ando M, Nakamura H: Idiopathic interstitial pneumonias: Diagnostic accuracy of thin-section CT in 129 patients. Radiology 1999;211:555-560.

13.

Santamaria F, Grillo G, Guidi G, Rotondo A, Raia V, deRitis G, Sarnelli P, Caterino M, Greco L: Cystic fibrosis: When should high-resolution computed tomography of the chest be obtained. Pediatrics 1998;101:908-913.

  Author Contacts

M. Häusler, MD
Department of Pediatrics, University Hospital RWTH Aachen
Pauwelsstrasse 30
D-52074 Aachen (Germany)
Tel. +49 241 8088773, Fax +49 241 8888484, E-Mail Haeusler@RWTH-Aachen.de

  Article Information

Received: Received: May 25, 1999
Accepted after revision: September 5, 1999
Number of Print Pages : 4
Number of Figures : 1, Number of Tables : 0, Number of References : 13

  Publication Details

Respiration (International Review of Thoracic Diseases)
Founded 1944 as 'Schweizerische Zeitschrift für Tuberkulose und Pneumonologie' by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger, continued 1962-1967 as 'Medicina Thoracalis'

Vol. 67, No. 3, Year 2000 (Cover Date: May-June 2000)

Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025-7931 (print), 1423-0356 (Online)

For additional information: http://www.karger.com/journals/res

  Drug Dosage / Copyright

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.