Interstitial Lung Disease Resistant to Corticosteroid Therapy* Report of Three Cases Treated with Azathioprine or Cyclophosphamide William C. Weese, M.D.,t Barry W. Levine, M.D.,§ and Homayoun Kazemi, M.D.II 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 bad reduced lung volumes and abnormal gas exchange, which continued to worsen on bigb doses of steroids. In patients 1 and 2, there was long-term stabili-
zation of lung function, while pulmonary physiologic abnormalities in the patient with vasculitis reverted to normal on five months of cyclophosphamide. Ahhough 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.
The classification, interstitial lung disease, includes a heterogeneous group of disorders resulting from injury to one or more components of the alveolar-capillary membrane from the alveolar epithelium to the capillary endothelium. More than 150 causes have been defined, though in most cases the disorder is idiopathic. With or without a specific etiology, the clinician often empirically treats with steroids with a variable response. Usually, the course remains progressive. In some instances of interstitial lung disease, nonspecific tissue antibodies and immunologic disorders have been demonstrated and suggest an immunologic basis for this group of diseases. Recently, we encountered three patients with interstitial lung disease who deteriorated despite intensive steroid therapy. On the possibility of an underlying immunologic defect, immunosuppressive drugs were initiated. Our experience with azathioprine and cyclophosphamide in these patients and the rationale for their use follows.
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 ( FEV 1 ) were detennined in a 9-liter Collins spirometer. Peak expiratory flow rate ( PFR) wa.~ measured with a peak flow meter. 0 Total lung eapacity and its subdivisions wt•re measured by the two-step helium dilution nwthod. While the patient wa.~ in tht• reeumbent position under 2 pereent proeaine local anesthesia, a Riley needle was inserted in a brachial artery. The subject breathed in a closed system through a Hans-Rudolf valve. Alveolar air wa.~ s;unpled just distal to the expiratory valve during a brief voluntary forced expiration given at the end of nom1al expiration. Arterial blood wa.~ obtained in heparinized syringes. Alveolar Po2 and Pcoz and arterial pH, Po-! and Pco2 were determined in duplicate at 37°C with appropriate elec:trodes.t ~1easurements were made while the subject breathed room air and after seven minutes of breathing 100 percent oxygen. Carbon monoxide diffusing capacity ( DLco) was detem1ined by the steady state method. 1 Physiologic dead space was calculated from the modified Bohr equation.:! These techniques a.~ performed in this laboratory have been presented previously.:t.4
MATERIALS AND METHODS
All patients were studied in the pulmonary unit of the Massachusetts General Hospital and were attended by at •From the Medical Services ( Puhnonary Unit), Massachusetts General Hospital and Harvard Medical School, Boston. 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. !Instructor in Medicine. §Assistant Professor of Medicine. I[Associate Professor of Medicine. Manuscript received April25; revision accepted June 4. Rewint requests: Dr. Kazemi, Pulmonary Unit, Massachusetts General Hospital. Boston 02114
CHEST, 67: 1, JANUARY, 1975
CASE REPORTS CASE
1
A 62-year-old industrial engineer had reported slowly progressive dyspnea over several years such that, hy 1971, he had to rest after climbing one flight of stairs. In July 1972, lw reported shortness of breath at rest and a cough productive of scant, whitish sputum. Empiric treabnent for "pnemnonia" did not improve symptoms, and he wa~ referred to the Massachusetts General Hospital in August 1972. Past medical history was unremarkable except for a hiatal hernia managed symptomatically and essential hypertension treated intermittently with chlorthiazide. He had smoked 1" packages of cigarettes daily for 20 years and had stopped smoking in 0 Air-Med Specialties, Ltd., Harlow, Essex, England. tModels 123 and 125A, lnstnm1entation Laboratory, Cambridge, Mass.
INTERSTITIAL LUNG DISEASE RESISTANT TO CORTICOSTEROID THERAPY 57
Table 1-Ca.e 1: Record of a 62-Year-Old-Man * Dr ugH
Predicted Values
9/72
10/72
3/73
Prcdnisonl'
0
40 mg
40 mg
Azathioprine
0
0
0
2.88
2.99
2.08
Total lung capacity
6.35 liters
DLco
20 ml/mm Hg/min
Vo/VT
80 mm Hg
95 95
PaCOt (room air)
38-42 mm Hg
36
A-aD02 (on 100% Ot)
zation of lung function, while pulmonary physiologic abnormalities in the patient with vasculitis reverted to normal on five months of cyclophosphamide. Ahhough 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.
The classification, interstitial lung disease, includes a heterogeneous group of disorders resulting from injury to one or more components of the alveolar-capillary membrane from the alveolar epithelium to the capillary endothelium. More than 150 causes have been defined, though in most cases the disorder is idiopathic. With or without a specific etiology, the clinician often empirically treats with steroids with a variable response. Usually, the course remains progressive. In some instances of interstitial lung disease, nonspecific tissue antibodies and immunologic disorders have been demonstrated and suggest an immunologic basis for this group of diseases. Recently, we encountered three patients with interstitial lung disease who deteriorated despite intensive steroid therapy. On the possibility of an underlying immunologic defect, immunosuppressive drugs were initiated. Our experience with azathioprine and cyclophosphamide in these patients and the rationale for their use follows.
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 ( FEV 1 ) were detennined in a 9-liter Collins spirometer. Peak expiratory flow rate ( PFR) wa.~ measured with a peak flow meter. 0 Total lung eapacity and its subdivisions wt•re measured by the two-step helium dilution nwthod. While the patient wa.~ in tht• reeumbent position under 2 pereent proeaine local anesthesia, a Riley needle was inserted in a brachial artery. The subject breathed in a closed system through a Hans-Rudolf valve. Alveolar air wa.~ s;unpled just distal to the expiratory valve during a brief voluntary forced expiration given at the end of nom1al expiration. Arterial blood wa.~ obtained in heparinized syringes. Alveolar Po2 and Pcoz and arterial pH, Po-! and Pco2 were determined in duplicate at 37°C with appropriate elec:trodes.t ~1easurements were made while the subject breathed room air and after seven minutes of breathing 100 percent oxygen. Carbon monoxide diffusing capacity ( DLco) was detem1ined by the steady state method. 1 Physiologic dead space was calculated from the modified Bohr equation.:! These techniques a.~ performed in this laboratory have been presented previously.:t.4
MATERIALS AND METHODS
All patients were studied in the pulmonary unit of the Massachusetts General Hospital and were attended by at •From the Medical Services ( Puhnonary Unit), Massachusetts General Hospital and Harvard Medical School, Boston. 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. !Instructor in Medicine. §Assistant Professor of Medicine. I[Associate Professor of Medicine. Manuscript received April25; revision accepted June 4. Rewint requests: Dr. Kazemi, Pulmonary Unit, Massachusetts General Hospital. Boston 02114
CHEST, 67: 1, JANUARY, 1975
CASE REPORTS CASE
1
A 62-year-old industrial engineer had reported slowly progressive dyspnea over several years such that, hy 1971, he had to rest after climbing one flight of stairs. In July 1972, lw reported shortness of breath at rest and a cough productive of scant, whitish sputum. Empiric treabnent for "pnemnonia" did not improve symptoms, and he wa~ referred to the Massachusetts General Hospital in August 1972. Past medical history was unremarkable except for a hiatal hernia managed symptomatically and essential hypertension treated intermittently with chlorthiazide. He had smoked 1" packages of cigarettes daily for 20 years and had stopped smoking in 0 Air-Med Specialties, Ltd., Harlow, Essex, England. tModels 123 and 125A, lnstnm1entation Laboratory, Cambridge, Mass.
INTERSTITIAL LUNG DISEASE RESISTANT TO CORTICOSTEROID THERAPY 57
Table 1-Ca.e 1: Record of a 62-Year-Old-Man * Dr ugH
Predicted Values
9/72
10/72
3/73
Prcdnisonl'
0
40 mg
40 mg
Azathioprine
0
0
0
2.88
2.99
2.08
Total lung capacity
6.35 liters
DLco
20 ml/mm Hg/min
Vo/VT
80 mm Hg
95 95
PaCOt (room air)
38-42 mm Hg
36
A-aD02 (on 100% Ot)
