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A 63-Year-Old Woman With Progressive Dyspnea After Remission of Lymphoma FREE TO VIEW

Tomoe Nishihara, MD; Hiroshi Nakano, MD, PhD; Hiroko Nogami, MD, PhD; Katsuyuki Katahira, MD; Akiko Ishimatsu, MD; Naozumi Hashimoto, MD, PhD; Toyoharu Yokoi, MD, PhD; Tomoaki Iwanaga, MD, PhD
Author and Funding Information

This article has been published as a case report in Japanese (Nishihara T, Katahira K, Nogami H, et al. Ann Jpn Resp Soc. 2014;3[2]:281-286) (used by permission).

aDepartment of Psychosomatic Medicine, National Hospital Organization, Fukuoka National Hospital, Fukuoka, Japan

bDepartment of Psychosomatic Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

cDepartment of Respiratory Medicine, National Hospital Organization, Fukuoka National Hospital, Fukuoka, Japan

dDepartment of Respiratory Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

eDepartment of Respiratory Medicine, Graduate School of Medical Science, Nagoya University, Nagoya, Japan

fDepartment of Pathology, Nagoya Ekisaikai Hospital, Nagoya, Japan

CORRESPONDENCE TO: Hiroshi Nakano, MD, PhD, Department of Respiratory Medicine, Fukuoka National Hospital, 4-39-1, Yakatabaru, Minami-ku, Fukuoka-city, Fukuoka, 811-1394, Japan


Copyright 2017, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(3):e57-e62. doi:10.1016/j.chest.2017.01.023
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Case Presentaion  A 63-year-old woman visited our hospital for a further evaluation of progressive dyspnea. She had developed a progressive airflow obstruction after 3 years’ remission of non-Hodgkin’s lymphoma (follicular mixed cell type), which had been treated with chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The patient’s primary care physician had diagnosed her as having COPD and bronchial asthma and had treated her with medications including inhaled corticosteroids, tiotropium, and oral erythromycin. Her dyspnea had gradually worsened, however, and she had a score of 4 on the modified Medical Research Council dyspnea scale at the time of admission to our hospital.

Figures in this Article

The patient’s arterial oxygen saturation (measured with a pulse oximeter) was 94% on room air. Early inspiratory crackles were heard on auscultation over almost all the lung fields. The lung sound analysis is shown in Figure 1. The remainder of the physical examination was unremarkable.

Figure 1
Figure Jump LinkFigure 1 A, B. Phonopneumogram during resting breathing. A, Spectrogram of lung sounds from six sites on the chest wall. The vertical lines at the very early phase of inspiration represent crackles. B, Time waveforms of lung sounds occurring during the first breath shown in panel A. The waveforms of the crackles differed according to the recording site.Grahic Jump Location

The patient’s CBC count and basic chemistry panel were normal. An arterial blood gas analysis showed mild hypoxemia with hypercapnia (Pao2, 69 mm Hg; Paco2, 49 mm Hg; and pH, 7.44). No ST-segment changes were seen on 12-lead ECG, and her echocardiogram revealed normal cardiac function. Results of pulmonary function testing revealed severe airflow obstruction (FEV1, 33% predicted) and the absence of a bronchodilator response. The diffusing capacity was normal. The patient’s chest radiographs were normal; high-resolution chest CT findings are shown in Figure 2.

Figure 2
Figure Jump LinkFigure 2 High-resolution chest CT scans obtained at expiration show a mosaic pattern.Grahic Jump Location

What is the diagnosis?

What study should be considered to make the diagnosis?

Diagnosis: Bronchiolitis obliterans or obliterative bronchiolitis; open lung biopsy is required for the diagnosis

Bronchiolitis obliterans (BO) or obliterative bronchiolitis is a small airways disease that results in airflow limitation and progressive dyspnea. “Constrictive bronchiolitis” is the term used for the pathologic diagnosis. The histopathologic findings are characterized by subepithelial inflammation and fibrotic narrowing of the bronchioles, eventually resulting in the obliteration of the lumen. These findings are distinct from those of inflammatory proliferative bronchiolitis, which involves the distal bronchioles with polypoid lesions and extends into the alveolar spaces; this condition is referred to as BO with organizing pneumonia (or, more currently, as cryptogenic organizing pneumonia).

The pathogenesis of BO is complex and may involve multiple immune mechanisms. Several sources of injury to the airway can be associated with the development of BO, including viral respiratory infection, chronic gastroesophageal reflex, and long-standing exposure to air pollutants as well as alloimmune immunologic insults. The fact that diverse medical conditions and exposures can result in BO suggests it may be a final common pathway of various insults to small airway epithelial cells and subepithelial structures. Recent studies have recognized that diverse mechanisms contribute to the development of BO after lung transplantation, including alloimmune T-cell reactivity, humoral immunity, autoimmunity, innate immunity, and response to environmental insults.

BO is a major consequence of bone marrow, lung, and heart-lung transplantations. BO affects > 70% of long-term survivors of lung transplantation. BO syndrome is the term used for clinical diagnosis of transplant-related BO, which is defined according to obstructive ventilator impairment. Nontransplant-related BO is rare and can mimic asthma or COPD, which reportedly occurs during the course of autoimmune disease, after viral or mycoplasma infection, after the ingestion or inhalation of certain drugs or toxic agents, and as a cryptogenic illness. BO caused by drugs is rare, and reports of causative drugs have been limited to penicillamine, gold, and possibly 5-fluorouracil. Two factors from the literature suggest a possible link between malignant lymphoma and BO. One is the fact that patients with malignant lymphoma complicated by paraneoplastic pemphigus (a rare autoimmune disease) may present with BO with a frequency as high as 30%. The other is that there is at least one previous case report of BO after treatment with rituximab for malignant lymphoma.

Clinically, progressive dyspnea and nonproductive coughing are typical manifestations of BO. Chest physical examinations may be normal or may reveal early inspiratory crackles or squawks. These adventitious sounds reflect sudden opening of obstructed airways during inspiration. The timing of crackles is very important; early inspiratory crackles indicate obstructive lung disease, whereas late inspiratory crackles (Velcro crackles) indicate restrictive lung disease, including idiopathic pulmonary fibrosis. The early inspiratory timing, as well as its gravitational independence, reflects a relatively central location of airway obstruction, compared with Velcro crackles in idiopathic pulmonary fibrosis.

A chest radiograph is often normal or may show hyperinflation. Results of pulmonary function testing typically reveal irreversible airflow obstruction. Diffusing capacity of the lungs for carbon monoxide is usually normal in BO. High-resolution CT imaging may produce a mosaic pattern consisting of high- and low-density areas that represent bronchiolar air trapping. As a cause of the mosaic pattern of lung attenuation, there are three different processes: patchy infiltrative disease, patchy perfusion secondary to vascular disease, and diffuse small airways disease, including BO. Expiratory imaging may be helpful in distinguishing small airways disease from other processes; accentuation of the mosaic pattern at end-expiration indicates air trapping due to small airways disease.

The pathologic involvement of constrictive bronchiolitis may be patchy, making a diagnosis based on transbronchial biopsy results difficult. When the clinical diagnosis is unclear, an open lung biopsy may be necessary. Unfortunately, regardless of the cause, BO remains an irreversible process that is associated with a poor survival outcome, and no effective treatment has yet been established. The early detection of BO makes it possible to use an immunosuppressant treatment option, usually consisting of high-dose corticosteroids and cyclosporine or tacrolimus. In addition, recent advances have revealed that macrolides (azithromycin), statins, and extracorporeal photopheresis offer some beneficial immunomodulatory effects for BO syndrome, resulting in a slower decline in FEV1 or improved survival. Once the establishment of constrictive fibrosis has led to a severe obstructive disorder, supportive care remains the mainstay of treatment.

Clinical Course

The present case involves a nontransplant patient, but her clinical history and auscultation findings of early inspiratory coarse crackles heard over extensive lung fields provided telling diagnostic clues. The mosaic pattern on lung CT scan suggested BO, which was confirmed by results of open lung biopsy using video-assisted thoracic surgery. The extensive degree of constrictive fibrosis (Fig 3) decreased the likelihood of benefit from immunosuppressant therapy, and the patient was therefore treated with home oxygen and positive pressure ventilation.

Figure 3
Figure Jump LinkFigure 3 A, B. Hematoxylin-eosin staining shows that the alveoli and small pulmonary vessels were mostly normal, whereas a bronchiole adjacent to the pulmonary artery was severely obliterated by fibrosis (A, ×100 magnification; B, ×200 magnification). C, Elastica van Gieson staining shows the increased subepithelial deposition of collagen in the bronchioles (×200). Black, elastic fiber; red, collagen. D, Masson trichrome staining shows the involvement of constrictive fibrosis in the bronchioles (×200). Red, muscle fiber; blue, collagen.Grahic Jump Location

  • 1.

    BO is a progressive obstructive lung disease that frequently occurs in patients after transplantation and rarely occurs in patients with other conditions.

  • 2.

    BO should be considered as a differential diagnosis of irreversible airflow obstruction of unknown etiology.

  • 3.

    The presence of early inspiratory crackles or squawks in a patient with progressive exertional dyspnea may indicate a need to suspect BO.

  • 4.

    Mosaic patterns in high-resolution CT scans are very helpful for the diagnosis of BO. Expiratory enhancement of this pattern can differentiate BO from other possible conditions, including patchy infiltrative disease and patchy perfusion secondary to vascular disease.

  • 5.

    An open lung biopsy is required for a diagnosis in nontransplant cases, whereas a clinical diagnosis of BO syndrome, defined according to pulmonary function changes, can be made for posttransplant patients.

Financial/nonfinancial disclosure: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.


Figures

Figure Jump LinkFigure 1 A, B. Phonopneumogram during resting breathing. A, Spectrogram of lung sounds from six sites on the chest wall. The vertical lines at the very early phase of inspiration represent crackles. B, Time waveforms of lung sounds occurring during the first breath shown in panel A. The waveforms of the crackles differed according to the recording site.Grahic Jump Location
Figure Jump LinkFigure 2 High-resolution chest CT scans obtained at expiration show a mosaic pattern.Grahic Jump Location
Figure Jump LinkFigure 3 A, B. Hematoxylin-eosin staining shows that the alveoli and small pulmonary vessels were mostly normal, whereas a bronchiole adjacent to the pulmonary artery was severely obliterated by fibrosis (A, ×100 magnification; B, ×200 magnification). C, Elastica van Gieson staining shows the increased subepithelial deposition of collagen in the bronchioles (×200). Black, elastic fiber; red, collagen. D, Masson trichrome staining shows the involvement of constrictive fibrosis in the bronchioles (×200). Red, muscle fiber; blue, collagen.Grahic Jump Location

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