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Page 4 Bronchiolar
Airway Disorders and Bronchiolitis Obliterans
Connective Tissue Bronchiolitis Obliterans Connective tissue bronchiolitis obliterans occurs most commonly in women with rheumatoid arthritis and has a particularly poor prognosis, often a fatal outcome within three years. This airflow lesion has also been reported in other connective tissue disorders including lupus erythematosus, ankylosing spondylitis, Sjogren's syndrome, and scleroderma. The clinical features are identical to idiopathic bronchiolitis obliterans. Dyspnea may be severe and physical examination indicates early inspiratory crackles. The chest film is normal or shows hyperinflation. Physiologically there is severe airflow obstruction. Histologically, a pattern of constrictive bronchiolitis or intraluminal granulation tissue polyps is seen, the latter has a more favorable course. In general, this lesion represents a poor prognostic sign in the connective tissue disorders, whether it is the combination of the two disorders or whether there is an accelerated, progressive form of bronchiolitis obliterans is not known. The underlying disorder must be managed as well as possible, and a course of high-dose corticosteroid therapy can be used for severe pulmonary involvement or for exacerbations of the pulmonary lesion. Bronchiolitis obliterans rarely occurs in men with rheumatoid arthritis. Schwarz and associates (47) described a 62 year-old man with no evidence of active rheumatological disease and a serum rheumatoid factor of 1:1256 who suddenly developed airflow obstruction. Lung biopsy showed that the majority of the terminal and respiratory bronchioles had intense inflammatory infiltration. The alveolar walls were spared. This infiltrate caused reduction of the bronchial lumen, resulting in a polypoid appearance to the bronchial lining. There was peribronchiolar inflammatory infiltrate with destruction of the subepithelial elastic layer. These findings suggest that bronchiolitis obliterans may be seen prior to active rheumatological symptoms and as the only manifestation of rheumatoid arthritis. The finding of constrictive bronchiolitis in patients with rheumatoid arthritis has usually been associated with a poor prognosis; however, a favorable two-year outcome was reported among a group of seven patients treated with erythromycin (48). Drug-Related Bronchiolitis Obliterans Drug-related bronchiolitis obliterans has generally been reported in association with rheumatoid arthritis. Histologically, the lesion is usually constrictive bronchiolitis although intraluminal granulation tissue polyps are also seen. Cough with no sputum production is the first symptom, then dyspnea about two weeks later. Early inspiratory crackles are heard, the chest roentgenogram is normal, and there is severe airflow obstruction with FEV1 values often less than one liter. The penicillamine-related constrictive bronchiolitis usually has a poor prognosis, sometimes requiring lung transplantation for management (49). There is report of a 32 year-old woman who had taken penicillamine for slightly less than one year and then developed progressive dyspnea with an FEV1 of 0.9 liters (50). Transbronchial biopsy showed thickening of the bronchiolar wall with varying degrees of fibrosis and lymphocytic infiltration and fragmentation of bronchiolar elastic fibers. Intraluminal plugs of granulation tissue were not seen. Alveoli were normal. Although the prognosis is usually poor, stabilization occurred in this patient after discontinuing the penicillamine and treatment with corticosteroid therapy. Gold therapy for patients with rheumatoid arthritis may cause bronchiolitis obliterans, but the cause and effect relationship between gold therapy and bronchiolitis obliterans is difficult to establish. There are several reasons for this difficulty. Bronchiolitis obliterans occurs in patients with rheumatoid arthritis who have not been treated. Airflow obstruction as measured by pulmonary function testing in patients with rheumatoid arthritis has been documented. Most patients with possible drug-induced lung toxicity do not have a lung biopsy; thus, the histologic lesion is often not characterized. Fatal bronchiolitis obliterans has been reported in a 12 year-old girl with juvenile rheumatoid arthritis after a six month course of intramuscular gold (51). A high pitched inspiratory ìsqueakî was heard over the right hemathorax. The FEV1 was 0.5 liters. An open lung biopsy indicated occlusion of small bronchioles by lymphocytes, a peribronchiolar lymphoid infiltrate and mild peribronchiolar fibrosis. A polyp of organizing inflammatory reaction was noted in one of the terminal bronchioles. There was no response to prednisone and Cytoxan. A single lung transplant failed because of organ rejection. She died after a double lung transplant. Pathological findings of the native lung showed extensive scarring with bronchiolar obliteration and multiple granulomatous lesions consistent with rheumatoid nodules. Although, cause and effect is difficult to confirm, the possibility of drug-related bronchiolitis obliterans continues to be important clinically. Patients with a connective tissue disorder receiving these medications who develop unexplained cough or dyspnea should be promptly evaluated. Bone Marrow Transplantation Bronchiolitis Obliterans Bone marrow transplantation bronchiolitis obliterans occurs in allogeneic bone marrow recipients who have had graft-versus-host disease. It is seen in two to ten percent of patients who develop chronic-versus-host-disease (52). In the majority of patients, bronchiolitis obliterans is preceded by typical findings of graft-versus-host disease, including skin rash, mucositis, sicca, and angiitis, usually occurring within three months after transplantation. Six months later, cough develops, then progressive dyspnea. The chest radiograph is normal in 80 percent of patients at this late stage, and the FEV1 is severely reduced with no improvement after bronchodilator inhalation. Response to therapy is poor once severe airflow obstruction has been established. Late onset and severe airflow obstruction indicate a poor prognosis. From a review of 17 biopsy specimens of the lung showing graft-versus-host disease in bone marrow transplant recipients, Yousem categorized the morphological changes into four categories (53). The categories included three with diffuse alveolar damage (DAD); seven with lymphocytic bronchitis/bronchiolitis (BIP) with interstitial pneumonitis; two with bronchiolitis obliterans organizing pneumonia (BOOP); and five with cicatricial bronchiolitis obliterans. The histological findings of the five patients with bronchiolitis obliterans indicated that the lumens of airways were obliterated by dense fibrous scar tissue and the atretic airways were identified only by their location adjacent to arterioles. All five patients had cough and shortness of breath, two died from bronchiolitis obliterans, one is alive with disease and two had double lung transplants. It was noted that this lesion may reflect irreversible pulmonary graft-versus-host disease. Obliterative bronchiolitis has been reported in children who have undergone allogeneic bone marrow transplantation (54). Among a group of six children, a three year-old girl developed grade one graft-versus-host disease during her early transplant course and CMV pneumonia at six weeks. Seven months after transplant, an obstructive chronic bronchiolitis was suspected, Aspergillus fumigatus, Candida albicans and CMV were isolated from the bronchial lavage and long-term treatment was instituted. Perfusion scintigraphy and CT of the lungs were consistent with obstructive bronchiolitis. One year and two months after transplant, the patient died form respiratory insufficiency. Lung Transplantation Bronchiolitis Obliterans Heart-lung transplant bronchiolitis obliterans emerged as the most important clinical complication among heart-lung transplant recipients in the mid 1980's. It has been reported that the frequency of bronchiolitis obliterans is similar among recipients of all types of lung transplantation including heart-lung, double lung or single lung transplantation (55), thus it is classified as lung-transplant bronchiolitis obliterans. Lung transplant bronchiolitis obliterans probably represents a form of chronic rejection. It continues to occur in about 20 to 50 percent of long-term survivors and mortality remains high. Among 135 heart-lung transplants and 61 lung transplants in 184 patients, the prevalence of obliterative bronchiolitis was 64 percent for heart-lung transplantation and 68 percent after lung transplantation (56). Obliterative bronchiolitis occurred in 28%, 49%, 56% and 71% of these patients at one, two, three and five years respectively after lung transplantation. The frequency and severity of the acute rejection episode was the highest risk factor. Treatment consisted of augmented immunosuppression. Analysis of the 73 patients with obliterative bronchiolitis indicated a 10-year survival of only 17 percent compared to 56 percent for patients without obliterative bronchiolitis. In a study of 26 single lung transplant recipients that survived longer than six months, 15 developed bronchiolitis obliterans (57). Three patterns of decrement in FEV1 were identified. A rapid onset and a relentless progressive course characterized the first; the second was characterized by a similar rapid onset and initial rapid decline, but then stabilization; and the third pattern was characterized by an insidious onset and course. The onset was 12 months, 15 months, and 30 months respectively. All patients in the first group were oxygen-dependent after nine months and none of them survived more than 13 months beyond their diagnosis of bronchiolitis obliterans. Patients in the second and third group had a lower mortality rate. In an additional study of risk factors among recipients of single, double, or heart-lung transplantation, it was found that those who had more than three episodes of acute rejection in any 12 month period, there was eventually a 100% incidence of bronchiolitis obliterans (58). These findings suggested that acute rejection is as marker and possibly a factor in chronic airway-directed rejection. These authors also noted that spirometry, especially FEF25-75, was useful as a noninvasive indicator of bronchiolitis obliterans when combined with a normal chest radiograph and the absence of cytologic or microbiologic evidence of infection. Organizing pneumonia was studied by comparing a group of 12 lung transplant recipients who developed obliterative bronchiolitis with 13 who had stable lung function (59). Clinical or histologic evidence of pulmonary rejection occurring after the first month was more frequent in patients with obliterative bronchiolitis, and organizing pneumonia associated with acute rejection was also seen more frequently. It was concluded that the coexistence of organizing pneumonia with pulmonary rejection in the fist year post transplantation is a strong predictive factor for the development of obliterative bronchiolitis. Seasonal variation was found in a group of 49 lung transplant recipients who developed bronchiolitis obliterans (60). The mean onset of the lesion was 507 days after transplantation. It was found that the onset of this complication occurred in 47 percent of patients during the first quarter of the year compared to 27 percent, 24 percent, and only 2 percent for the subsequent quarters. Effective therapeutic options continued to be explored. Augmented immunotherapy may alter the decrease in FEV1 in a rapid and sustained manner (61). A randomized control trial is needed for confirmation. In a study of aerosolized cyclosporine, 7 of 9 patients showed improvement in rejection histology and stabilization of FEV1 (62). Lung transplantation has been utilized as therapeutic management for transplant-related obliterative bronchiolitis. In a group of 72 patients who underwent retransplantation, results have somewhat improved (63). The actuarial survival rate was 43% at one year and 35% at two years. It was concluded that pulmonary retransplantation is appropriate only in selected patients with obliterative bronchiolitis who are ambulatory and have their procedure at experienced centers. Among a group of 160 patients that received lung retransplantation, those who had a retransplantation because of obliterative bronchiolitis, the prognosis was poor (64). Only 31 percent were free of the bronchiolitis obliterans syndrome at the third year compared to 83 percent of patients who underwent retransplantation because of other indications.
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