Interstitial Lung Disease Resistant to Corticosteroid Therapy: Report of Three Cases Treated with Azathioprine or Cyclophosphamide

doi:10.1378/chest.67.1.57

Chest

Volume 67, Issue 1, January 1975, Pages 57-60

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Three patients with severe progressive interstitial lung disease refractory to steroid therapy were treated with immunosuppressive drugs. Biopsy material of one showed mainly fibrosis, while that of the second showed interstitial pneumonitis as well; both patients received azathioprine. Cyclophosphamide was employed in the third patient with systemic vasculitis and massive hemoptysis. All patients had reduced lung volumes and abnormal gas exchange, which continued to worsen on high doses of steroids. In patients 1 and 2, there was long-term stabilization of lung function, while pulmonary physiologic abnormalities in the patient with vasculitis reverted to normal on five months of cyclophosphamide. Although the etiology of most forms of interstitial lung disease is unknown, several reports suggest at least a partial immunologic basis. Abatement in progression of disease in this small series would suggest that a trial of immunosuppressive drugs be considered in interstitial lung disease when steroid therapy fails.

Section snippets

MATERIALS AND METHODS

All patients were studied in the pulmonary unit of the Massachusetts General Hospital and were attended by at least one of us. Lung function tests were performed at intervals in the course of their illness.

Vital capacity and the first-second forced expiratory volume (FEV₁) were determined in a 9-liter Collins spirometer. Peak expiratory flow rate (PFR) was measured with a peak flow meter.^* Total lung capacity and its subdivisions were

CASE 1

A 62-year-old industrial engineer had reported slowly progressive dyspnea over several years such that, by 1971, he had to rest after climbing one flight of stairs. In July 1972, he reported shortness of breath at rest and a cough productive of scant, whitish sputum. Empiric treatment for “pneumonia” did not improve symptoms, and he was referred to the Massachusetts General Hospital in August 1972. Past medical history was unremarkable except for a hiatal hernia managed symptomatically and

DISCUSSION

Even with histologic diagnosis, the progress of interstitial pulmonary fibrosis cannot invariably be predicted.5, 6 Consequently, in evaluation of drug therapy for a disease that can undergo spontaneous exacerbation and remissions, it is difficult to separate drug effect from natural course of the disease. In our three patients, however, we were impressed that coincident with the use of immunosuppressive agents there was marked abatement (both clinical and physiologic) in previously rapidly

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Cited by (26)

Long-Term Treatment With Azathioprine and Mycophenolate Mofetil for Myositis-Related Interstitial Lung Disease
2019, Chest
The efficacy of azathioprine (AZA) and mycophenolate mofetil (MMF) for interstitial lung disease (ILD) has been described, but mainly in connective tissue disease-associated ILD. The objective of this study was to evaluate the effect of AZA and MMF on lung function and prednisone dose in myositis-related ILD (M-ILD).
In this retrospective study, patients with M-ILD seen at Johns Hopkins and treated with AZA or MMF and no other steroid-sparing agents were included. Linear mixed-effects models adjusted for sex, age, antisynthetase antibody, and smoking status were used to compare the change in FVC % predicted, diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted, and prednisone dose.
Sixty-six patients with M-ILD were treated with AZA and 44 with MMF. At treatment initiation, mean FVC % predicted and Dlco % predicted were significantly lower in the AZA group than in the MMF group. In both groups, FVC % predicted improved and the prednisone dose was reduced over 2 to 5 years; however, for Dlco % predicted, only the AZA group improved. The adjusted model showed no significant difference in posttreatment FVC % predicted or Dlco % predicted between groups (mean difference of 1.9 and –8.2, respectively), but a 6.6-mg lower dose of prednisone at 36 months in the AZA group. Adverse events were more frequent with AZA than MMF (33.3% vs 13.6%; P = .04).
In M-ILD, AZA treatment was associated with improved FVC % predicted and Dlco % predicted, and lower prednisone dose. Patients treated with MMF had improved FVC % predicted and lower prednisone dose. After 36 months, patients treated with AZA received a lower prednisone dose than those treated with MMF.
Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: A prospective study in patients who failed to respond to corticosteroids
2000, Chest
Citation Excerpt :
Unfortunately, a sustained response to cyclophosphamide therapy was evident in only 1 patient; 7 patients remained in stable condition and the conditions of 11 patients deteriorated while receiving cyclophosphamide. The reported use of cyclophosphamide is limited to a few anecdotal reports and two controlled studies.1,46,78,1213,1415,1617,1819,2021,2230,3435 Unfortunately, from these disparate studies, the efficacy of cyclophosphamide is difficult to assess for the following reasons: the uncontrolled, retrospective, or anecdotal nature of the study6,712,1416,1718,2021,2230,35; the unbalanced disease severity and substantial crossover between groups8; the varying diagnostic criteria without consistent use of lung biopsy4,67,1112,1718,29; the inclusion of patients with CTD who may exhibit better response to cytotoxic treatment6,1415,1630; the variable treatment regimens and follow-up14,1517,2021,30; the concurrent use of corticosteroids8,1214,1516,1820,2122,30; and the variable criteria used to assess response to therapy.6,812,1516,1920,2122,30
To prospectively examine the role of cyclophosphamide in patients with idiopathic pulmonary fibrosis that is unresponsive to or intolerant of high-dose steroid treatment.
Prospective study.
Tertiary referral center.
Nineteen patients with biopsy specimen-proven usual interstitial pneumonia who failed to respond (n = 16) or experienced adverse effects (n = 3) from corticosteroid treatment (1 mg/kg/d for 3 months).
Steroid therapy was tapered quickly, and oral cyclophosphamide, 2 mg/kg/d, was prescribed (mean duration of treatment, 6.0 ± 0.9 months).
In 10 patients, response to therapy was determined by pretreatment and posttreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function, including exercise saturation) scores (CRP). Response was defined as a > 10-point drop in CRP; stable as ± 10-point change in CRP; and nonresponders as > 10-point rise in CRP. In nine patients, physiologic criteria were used to assess response; significant changes in pulmonary function were defined as follows: total lung capacity,± 10% of baseline value; FVC, ± 10% of baseline value, diffusion capacity of the lung for carbon monoxide, ± 20% of baseline value; and resting pulse oximetry, ± 4% of baseline value. Patients who died while receiving or shortly after discontinuing cyclophosphamide were classified as nonresponders (n = 2). Among 19 patients treated with cyclophosphamide, only 1 patient demonstrated sustained response; 7 patients remained stable and 11 deteriorated while receiving the drug. Toxicity associated with cyclophosphamide was substantial; more than two thirds of the patients developed drug-related adverse effects, and almost half discontinued the drug prematurely due to side effects. In the remaining patients, cyclophosphamide therapy was discontinued due to lack of improvement or progressive deterioration.
Cyclophosphamide therapy is of limited efficacy in patients with idiopathic pulmonary fibrosis who fail to respond or who experience adverse effects from corticosteroid treatment, and adverse effects often complicate its use.
Cryptogenic fîbrosing alveolitis: A clinicopathological entity
1996, Current Diagnostic Pathology
Cryptogenic fibrosing alveolitis (CFA) is now recognized as a distinct clinico-pathological entity albeit of unknown aetiology and uncertain pathogenesis. The histological pattern has been well described as an inflammatory and fibrosing process, though with wide variation in the degree of involvement in different parts of the lung and between individual cases. The end-stage disease is a honeycomb lung, with the sub-pleural position of the honeycombing being instantly diagnostic. The use of the term CFA as a diagnosis in biopsies simply showing interstitial fibrosis should be avoided, as this diagnosis labels the patient as having a chronic terminal condition and may result in inappropriate treatment with powerful immunosuppresive drugs. Currently, the diagnosis of CFA requires careful histological assessment of either open or thoracoscopic lung biopsies; it should not be made on specimens obtained by transbronchial biopsy.
Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis
1992, Chest
Study Objective: To determine the safety and efficacy of intravenous cyclophosphamide for patients with idiopathic pulmonary fibrosis.
Design: Nonrandomized, open-labeled study of efficacy in symptomatic patients.
Setting: Patients were treated as outpatients in a referral clinic.
Patients: All patients had idiopathic pulmonary fibrosis with symptoms of dyspnea on exertion. Patients had either worsening disease or contraindication to corticosteroids.
Intervention: Thirty-three patients were treated with intravenous cyclophosphamide every two weeks. Initial dosage was 500 mg, and the dose was escalated provided the total white blood cell count remained greater than 3,000 cells per cubic millimeter. The maximum dose administered was 1,000 to 1,800 mg of cyclophosphamide. Corticosteroid therapy was tapered as tolerated by the patient.
Measurements and Results: Patients were treated for at least six months or until death. For the 33 patients, 18-month probability of survival was >50 percent. For those patients surviving six months, there was a significant rise in the vital capacity (from 1.6±.61 L [mean±SD] to 1.8±.52 L, p<0.01) which persisted for at least 18 months of treatment. This was associated with a significant fall in the average prednisone dosage from 32 ± 13.0 mg/day to 4 ± 10.4 mg/day (p<0.01) by 12 months. Only one patient required hospitalization for possible drug-related toxic reaction.
Conclusions: Intermittent, intravenous cyclophosphamide therapy was associated with improved pulmonary function and reduced corticosteroid dosage in patients with idiopathic pulmonary fibrosis who survived at least six months after institution of therapy.
The treatment of idiopathic pulmonary fibrosis
1991, Chest
Immune complexes, gallium lung scans, and bronchoalveolar lavage in idiopathic interstitial pneumonitis-fibrosis. A structure-function clinical study
1983, Chest

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Supported by NIH grants no. HL06664 and HL05767. Presented in part at the Annual Meeting, American College of Chest Physicians, Toronto, Ontario, Canada, October 25, 1973.

Manuscript received April 25; revision accepted June 4.

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Chest

Clinical InvestigationsInterstitial Lung Disease Resistant to Corticosteroid Therapy: Report of Three Cases Treated with Azathioprine or Cyclophosphamide

Section snippets

MATERIALS AND METHODS

CASE 1

DISCUSSION

Lancet

Carbon monoxide uptake and pulmonary diffusion capacity in normal subjects at rest and during exercise

J Clin Invest

Patterns of lung dysfunction in chronic beryllium disease

Am Rev Resp Dis

Mechanism of postural hypoxemia in asymptomatic smokers

Am Rev Resp Dis

The prognosis of cryptogenic fibrosing alveolitis

Thorax

Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs). Correlation of histology at biopsy with prognosis

Thorax

The pathogenesis of the Hamman-Rich syndrome. A review from the standpoint of possible allergic etiology

Am Rev Tuberc

Auto-antibody studies in interstitial pulmonary fibrosis

Br Med J

Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs): Two cases with autoimmune features

Thorax

Clinical Investigations
Interstitial Lung Disease Resistant to Corticosteroid Therapy: Report of Three Cases Treated with Azathioprine or Cyclophosphamide