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(Chest. 2000;118:253-256.)
© 2000 American College of Chest Physicians

Recurrent, Self-Limited, Menstrual-Associated Bronchiolitis Obliterans Organizing Pneumonia*

Mordechai Yigla, MD; Ofer Ben-Itzhak, MD; Anna Solomonov, MD; Luda Guralnik, MD and Ilana Oren, MD

* From the Division of Pulmonary Medicine (Drs. Yigla and Solomonov), the Department of Pathology (Dr. Ben-Itzhak), the Department of Diagnostic Radiology (Dr. Guralnik), and the Department of Internal Medicine A (Dr. Oren), Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Correspondence to: Mordechai Yigla, MD, Division of Pulmonary Medicine, Rambam Medical Center, POB 9602, Haifa 31096, Israel; e-mail: m_yigla{at}rambam.health.gov.il


   Abstract
TOP
 Abstract
Introduction
 Case Report
 Discussion
 References
 
A 39-year-old woman presented with recurrent acute illness, characterized by high-grade fever, pleuritic chest pain, and unilateral nodular infiltrate on chest radiograph. During the follow-up period, there were six similar episodes, each starting 2 to 3 days prior to her menstrual period and resolving within 5 to 10 days. Persistent symptoms in the seventh episode led us to perform an open lung biopsy; the specimen showed histologic changes compatible with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP). To the best of our knowledge, this is the first report describing BOOP in association with a menstrual period. This exceptional case emphasizes the wide and unexpected spectrum of this disease.

Key Words: bronchiolitis obliterans organizing pneumonia • menstruation


   Introduction
TOP
 Abstract
 Introduction
Case Report
 Discussion
 References
 
Bronchiolitis obliterans organizing pneumonia (BOOP) is an important cause of respiratory morbidity. Histologic findings include granulation tissue plugs within the lumen of the small airways, sometimes with complete obstruction of these airways, and granulation tissue extending into alveolar ducts and alveoli.1 Affected patients present with a flu-like illness, respiratory symptoms, impaired pulmonary function, and diffuse patchy lung infiltrates.2 Left untreated, BOOP tends to progress gradually over weeks, although rapid deterioration to respiratory failure and spontaneous remissions has been described.3 4 5 6 7 8 BOOP has been described in association with infections, malignancy, connective tissue disorders, organ transplantation, radiation therapy, certain medications, and other conditions.9 10 11 12 13 14 15 16 17 18 19 20 21 In a thorough review of the literature, we did not find any reports describing a possible association between BOOP and menstruation. We describe a 39-year-old woman with menstrual-associated BOOP.


   Case Report
TOP
 Abstract
 Introduction
 Case Report
Discussion
 References
 
A 39-year-old woman presented to her primary physician with severe right-sided pleuritic chest pain, a fever of 39.5°C, and a dry cough with duration of 2 days. There was no history of smoking, but there was a history of multiple pregnancies and abortions, along with two normal deliveries. Her pregnancies were not associated with respiratory symptoms, and, more recently, she has been using oral contraception. There was no history of connective tissue disorders or a recent infectious disease. She worked as a secretary and had no occupational exposure to toxic fumes.

On physical examination, she appeared ill, although her BP, pulse rate, and respiration rate were normal. Lung auscultation revealed only a few crackles in the right lung base. CBC count was normal without eosinophilia, and the results of renal and liver function tests were within normal limits. Chest radiography showed a mass-like opacity in the lower third of the right lung (Fig 1 , top). Oral antibiotic therapy with macrolides and cephalosporines for presumed pneumonia was started, with a favorable response after 5 days of therapy.



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  		Figure 1. Chest radiographs taken during the first and the second episodes, demonstrating a mass-like opacity in the right (top) and the left lung (bottom).

 
The patient was referred to the pulmonary clinic 1 month later with another episode of acute illness, characterized by similar clinical and radiographic features. Again, physical examination findings were normal and a chest radiograph revealed unilateral infiltrate, this time in the left lower lobe (Fig 1 , bottom). Results of routine blood tests were normal except for an erythrocyte sedimentation rate elevated to 110 mm in the first hour. Arterial blood gases and complete pulmonary function test results were also normal. The symptoms resolved within 1 week of antibiotic treatment. In the next 5 months, there were five more such episodes. In three of these episodes, the patient received antibiotic treatment with macrolides and cephalosporines for presumed pneumonia, with resolution of her symptoms within 5 to 10 days. Between episodes, she was free of symptoms and chest radiographs were normal, although she complained of persistent fatigue with a weight loss of 5 kg.

During the third episode, extensive diagnostic workup was performed. Pulmonary CT scan revealed unilateral irregular consolidation in the right middle lobe with mild widening of the relevant bronchi (Fig 2 ). Immunologic studies, fiberoptic bronchoscopy, and fine-needle aspiration of the lesion in the right lung did not demonstrate malignant cells or any infectious agent.



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  		Figure 2. Chest CT scan at the level of the inferior pulmonary ligament performed during the seventh episode, demonstrating bilateral irregular consolidations in the right middle lobe and in the lingula.

 
After the third episode, we noted that all the previous episodes had started 2 to 3 days prior to the onset of menstruation, and association of her illness to the menstrual period was suspected for the first time. An atypical form of pulmonary endometriosis was presumed, and this episode resolved with nonsteroidal anti-inflammatory drugs with a similar pattern of response. During the following 3 months, she received monthly IM injections of a gonadotropin-releasing hormone antagonist. During the next two menstrual periods, she was free of symptoms, but the next three menses were associated with three similar episodes. Persistence of the seventh episode beyond 2 weeks led us to perform an open lung biopsy.

Lung biopsy specimens showed lung tissue with scattered dark-brown areas. Histologic sections showed diffuse areas of organizing loose tissue plugs composed of lymphocytes, macrophages, granulocytes, and fibroblasts, filling airspaces and a few bronchioli (Fig 3 ). In other areas, an excess of alveolar macrophages and thickening of alveolar septa by mononuclear cells and granulocytes were noted. In only a few areas was nearly normal lung tissue seen. A diagnosis of BOOP was established, and oral steroid therapy (prednisone, 30 mg/d) was started, with complete resolution of her symptoms and the radiographic findings within a few weeks. The patient stopped the steroid therapy after 8 months due to disabling side effects. During 20 months of follow-up, including 8 months on steroid treatment and 12 months off steroid treatment, the patient remains symptom free and her radiographic findings have returned to normal.



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  		Figure 3. Loose organizing connective tissue plugs fill and obliterate airspaces. Adjacent alveolar septa contain leukocytes and some show prominence of type 2 pneumocytes (hematoxylin-eosin, original x 250).

 

   Discussion
TOP
 Abstract
 Introduction
 Case Report
 Discussion
References
 
The causes of BOOP remain unknown in the majority of cases, but associated diseases and specific causes are being increasingly recognized.9 10 11 12 13 14 15 16 17 18 19 20 21 Today, BOOP is described in association with infectious diseases,9 10 drugs,11 12 immunologic and connective tissue disorders,13 14 bone marrow or solid-organ transplantation,15 16 HIV infection,17 radiation therapy,18 myelodysplastic syndrome,19 and malignant diseases.20 21 Men and women are equally affected, presenting with a flu-like illness, cough, and dyspnea. Bilateral patchy alveolar infiltrates are the most common radiographic findings.22 Generally, these infiltrates enlarge from their original site or new infiltrates appear as the clinical course progress.23 24 Pulmonary function tests show decreased flow rates and lung volumes, reduced diffusion capacity, and arterial hypoxemia. Oral steroid therapy for 1 year is the treatment of choice for patients with symptomatic progressive BOOP,3 and 65 to 80% of BOOP patients will respond to steroid therapy. Nonresponding disease is associated with a mortality rate of 5%, and relapses are associated with an insufficient amount or duration of steroid therapy.

Our patient’s presentation with recurrent acute illness, starting 2 to 3 days before menstruation, suggested an atypical form of pulmonary endometriosis. Failure of hormonal therapy directed at pulmonary endometriosis and persistence of the seventh episode led us to perform an open lung biopsy that disclosed the diagnosis of BOOP. This is a unique case of BOOP from several points of view. To our knowledge, it is the first report describing an association between BOOP and menstruation. Further clinical features, all of which are uncommon in BOOP patients, include the following: (1) presentation, acute episodes of high-grade fever and severe chest pain; (2) course, spontaneous exacerbations and remissions; (3) radiographic changes, unilateral and bilateral focal nodular infiltrate; (4) and history, stable respiratory status despite presumably ineffective treatment over 6 months. Atypical presentation, as was the case with our patient, raises the possibility of other conditions to be included in the differential diagnosis, such as hypersensitivity pneumonitis, that were not excluded completely.

Onset or aggravation of respiratory disorders in the premenstrual phase or during the menstrual period has been described in asthma,25 endometriosis,26 and lymphangioleiomyomatosis.27 The contribution of premenstrual hormonal changes to the pathogenesis of this condition is questionable, and the role of the hormonal manipulations is not clear yet. In this context, it is very difficult to explain both the premenstrual development of BOOP and the associated clinical features.

While uncommon, focal nodular infiltrates were described in 5 of 16 patients with idiopathic BOOP who had pulmonary involvement of the "pneumonia" type28 in the upper lungs, and all five patients underwent surgical excision. Focal lesions may represent an unusual variant of BOOP. Alternately, they might also represent a spectrum of idiopathic BOOP that eventually develops into typical patchy infiltrates, sometimes requiring steroid therapy for resolution.

Our patient received erythromycin, 2 g/d for 10 days, only during the first three episodes. Erythromycin has been used previously in a few patients with idiopathic BOOP, with promising results.29 Randomized control trials are needed for confirmation of the effectiveness of these agents. The cyclic pattern of disease noted in our patient, ie, relapses and remissions, is attributed to premenstrual hormonal changes rather than to treatment with erythromycin.

Left untreated, the respiratory status of BOOP patients tends to deteriorate with development of dyspnea, hypoxia, impaired pulmonary function test results and progressive alveolar infiltrates. Our patient experienced recurrent self-limited illness that did not affect her respiratory condition, although she did not receive appropriate treatment. Steroid therapy was followed by rapid clinical and radiologic improvement within a few weeks and complete recovery within 3 months. During 20 months of follow-up, including 12 months off steroid therapy, the patient remains well, without evidence of disease.


   Acknowledgements
 
The authors thank M. Perlmutter for her assistance in the preparation of this article.


   Footnotes
 
Abbreviation: BOOP = bronchiolitis obliterans organizing pneumonia

Received for publication January 27, 1999. Accepted for publication December 13, 1999.


   References
TOP
 Abstract
 Introduction
 Case Report
 Discussion
 References
 

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