Diffuse Interstitial Pneumonitis Clinicopathologic Correlations in 20 Patients Treated with Prednisone/Azathioprine
RICHARD H. WINTERBAUER, SAMUEL P. HAMMAR,
h4.D
M.D.
KEITH 0. HALLMAN. M.D. JAMES E. HAYS, Ph.D. NEELEY, E. PARDEE, M.D. EDWARD
H. MORGAN, M.D.
JOHN D. ALLEN, M.D. KENNETH D. MOORES, M.D. WILLIAM BUSH, M.D. JOHN H. WALKER, M.D. Seattle, Washington
From the Departments of Medicine and Patho@y, The f&son Clinic, Seattle, Washington. This study was supported by a grant from the Virginia Mason Research Center. Requests for reprints should be addressed to Dr. Richard Winterbauer. The Mason Clinic, 1100 Ninth Avenue, P.O. Box 900. Seattle, Washington 98111. Manuscript accepted May 3, 1978.
Twenty patients with diffuse interstitial pulmonary disease diagnosed by open lung biopsy received combined prednisonelatathioprine therapy. Twelve patients demonstrated improvement with therapy. Each patient’s clinical presentation, roentgenologic features and pathologic findings were correlated with their therapeutic response. Patients with an illness of one year’s duration or less had a more favorable response to therapy than patients with a greater than two year duration of illness. Patients with associated extrathoracic abnormalities (anemia, glomerulltis, hepatopathy) exhibited a better therapeutic response than those with only pulmonary disease. The biopsy material from each patient was quantitatively graded on 20 morphologic variables. Statistical analysis using multiple linear regression revealed that a single variable, degree of interstitial fibrosis, was more than 90 per cent accurate in separating those responsive to therapy from those who failed to respond. Patients who respond to treatment had less interstitial fibrosis. Neither the amount of alveolar septal inflammation nor intra-alveolar cellular reaction was discriminatory in predicting response to therapy. A beneficial response to therapy was reflected in both improved lung volumes and gas exchange. Eight patients appeared to have a selective beneficial effect from azathioprine. Diffuse interstitial pneumonitis is a syndrome best characterized by its clinical and morphologic variability, unpredictable course and resistance to treatment. Although a sudden onset with rapid progression to death in three to four months was emphasized in the original report by Hamman and Rich [ 11, subsequent experience has confirmed a long-term course with insidious progression and survival greater than 10 years in some patients [2]. The initial pathologic descriptions have been broadened to include five distinct pathologic variants according to the classification of Liebow [3]. The heterogeneity in natural history and histology offer an intriguing opportunity to correlate the prognosis and therapeutic outcome of the disease with specific clinical and histologic features [4-61. The present study is a prospective analysis of patients whose interstitial pneumonitis was confirmed by open lung biopsy and who were given a therapeutic protocol of combined prednisone/azathioprine. The goals of the study are (1) to identify clinical and histologic variables which correlate with the patient’s prognosis and response to therapy, (2) to assess the influence of intralobar and interlobar sampling variation in formulating clinicopathologic correlations, and (3) to evaluate the influence of combined prednisone/azathioprine therapy on the progress of disease.
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TABLE I
PNEUMONITIS-WINTERBAUER
Morphologic Variables Biopsy Specimens
ET AL.
Used to Grade
Obliteration of alveolar spaces Obliteration of terminal and respiratory bronchioles Interstitial fibrosis Intra-alveolar fibrosis Interstitial plasma cells Interstitial lymphocytes Interstitial polymorphonuclear leukocytes Interstitial eosinophils Interstitial macrophages Intra-alveolar macrophages Intra-alveolar plasma cells Intra-alveolar lymphocytes Intra-alveolar polymorphonuclear leukocytes Intra-alveolar eosinophils Alveolar lining cell hypertrophy and hyperplasia Obliteration of pulmonary capillary bed Bronchiolitis obliterans Vascular medial hypertrophy Vascular intimal fibrosis Microscopic honeycombing
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
MATERIALS
AND METHODS
Study Population. The study group consisted of 20 patients with a histologic diagnosis of diffuse interstitial pneumonitis who were seen at our institution between February 1974 and June 1977. Each patient was interviewed, examined and followed by one of us. Patients with interstitial pulmonary fibrosis associated with collagen vascular disease, pneumoconiosis or a postinfectious etiology, such as the diffuse scarring seen after Pneumocystis carinii or influenza viral pneumonia, were eliminated. Each patient had to exhibit clinical evidence of disease progression to be included in the study group. Rapidly progressive pulmonary symptoms in association with newly discovered diffuse pulmonary infiltrates were seen in 13 patients. However, seven patients had clinical and roentgenographic evidence of disease for two and a half to seven years prior to biopsy. These patients demonstrated disease progression through sequential pulmonary function tests and/or serial chest roentgenograms. Patients with known disease for over two years’ duration who had no evidence of progression on sequential testing were excluded from the study. Only patients available for regular follow-up were entered into the study group. Informed consent was obtained from all study participants. A standardized history was obtained from each of the study patients. The time of onset of pulmonary symptoms, time of initial chest roentgenographic abnormality, occupational history, medications taken in the two years prior to the onset of disease, history of drug allergies, history of previous pulmonary disease, smoking history and family history were all recorded. Serologic Studies. Serologic studies routinely performed included tests for antinuclear antibody (ANA) and rheumatoid factor (bentonite flocculation test-BFT), and serum protein
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electrophoresis. Quantitative immunoglobulins were measured by radial immunodiffusion for immunoglobulin G (IgG), A (IgA) and M (IgM). In addition, the patient’s serum was screened for precipitating antibodies to Micropolyspora faeni, Thermoactinomyces vulgaris, pigeon products, Aspergillus species and Sitophilus granarius by Ouchterlony gel-diffusion technics. The third (C3) and fourth (C4) factors of complement were measured by radial immunodiffusion technics. The results are expressed in milligrams per deciliter with the normal range 105 to 180 mg/dl for C3 and 10 to 40 mg/dl for C4. Pulmonary Function Tests. Pulmonary function tests were performed prior to therapy and repeated at three month intervals through the first year of therapy. Subsequent pulmonary tests were performed when clinically indicated. Measurement of the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV,) were determined with an Ohio Model 780 spirometer. The tracings were recorded in triplicate, and the highest result was accepted and corrected to standard temperature and pressure, dry. The diffusing capacity for carbon monoxide (DLCO) was measured by the steady-state method of Bates [ 71. Measurements were repeated until two consecutive values varied by less than 1 ml/min/mm Hg. Brachial artery blood samples were obtained with the patient at rest and breathing room air, and at the end of 4 minutes of exercise on a bicycle ergometer with a work load of 400 kg/m. The exercise arterial blood specimen was obtained at the completion of maximal effort for patients who could not complete the exercise test. Measurements included arterial oxygen tension (PaOp), arterial carbon dioxide tension (PaCOz), pH, hematocrit, arterial oxygen saturation (SaOP) and base excess. The alveolar air equation, PA02 = PlOsPaCOs (F102 + 1-FIOP)/R, was used to calculate the resting alveolar-arterial oxygen gradient (D(A - a)O*). R was presumed to be 0.8. Physiologic dead space was determined with the Fowler technic, and the total right to left shunt was measured by the 100 per cent oxygen breathing method [8,9]. Physiologic dead space was expressed as a ratio to tidal volume (Vo:Vr - normal I 0.3) and total shunt as per cent of cardiac output (normal 1: 1000. Three patients had detectable ANA in their serums. The most common serologic abnormality was the polyclonal gammopathy found on serum protein electrophoresis in 15 patients. Increases in the gamma and alpha* globulins were most common, but there was no recognizable diagnostic pattern. Quantitative serum immunoglobulins were abnormal in 12 of the 19 patients tested. Isolated increases in serum IgA was seen in five patients, and five others had a combination of elevated IgA levels with an increase in IgG or, less commonly, IgM. Two patients (Cases 13 and 18) had isolated elevations of the IgM level. C3 and C4 levels were normal in 10 of the 16 patients in whom they were measured. In six patients, serum complement levels were elevated. No patient had hypocomplementemia. Results of Therapy. The therapeutic protocol was initiated in 20 patients. However, in three patients (Cases 3, 4 and 7) an azathioprine associated fever and/or skin rash developed necessitating discontinuation of the drug. The therapeutic response was defined as improved if the patient’s vital capacity increased by more than 20 per cent with therapy. Patients failing to meet this criterion make up the unimproved group. Twelve of 20 patients (Cases 1 through 12, Table II) were improved. Only two deaths occurred in the 12 improved patients through a mean 30 month follow-up (range 15 to 44 months). One patient (Case 1) died of recurrent lymphoma 22 months after interstitial pneumonitis was recognized. Through one year of combined prednisone/azathioprine therapy the patient’s vital capacity had improved from 1.20 liters to 3.80 liters. One patient (Case 6) died from respiratory failure after the development of sequential superinfections, initially tuberculosis and ultimately pulmonary aspergillosis. In contrast, seven of the eight patients in the unimproved group died during a mean 13 month follow-up. Four patients (Cases 17 through 20) died from progressive
INTERSTITIAL
TABLE Ill
PNEUMONITIS-WINTERBAUER
ET AL.
A Comparison of Pulmonary Function Before and After Treatment in 16 Patients Who Completed One Year of Therapy (mean f SE) Results
Study
FVC
(% pred)
FEV,(FEV,:FVC%) DLCO
(% pred)
Pa02 (rest) PaCOs (rest) D(A - a)O, (rest) PaOs (exercise) PaCO* (exercise) Vo:Vr (rest) Vo:Vr (exercise) Anatomic shunt
Before
2.09 (58) f0.233 1.74 (79) f0.18 7.5 (45) f0.0639 65.5 f3.08 35.5 f0.97 41.4 63.688 53.2 f3.584 36.7 f1.48 0.44 f0.037 0.44 f0.043 13.7 f1.249
After
2.89 (80) f0.285 2.13 (74) f0.19 8.2 (49) f0.874 75.2 f2.864 34.6 f1.54 30.3 f2.906 59.6 f4.555 37.9 f2.83 0.45 f0.036 0.38 f0.043 10.3 f0.351
p Value
0.006 0.04 0.161 0.004 0.62 0.004 0.038 0.70 0.203 0.053 0.010
NOTE: FVC = forced vital capacity, FEV, 1 second forced expiratorv volume, DLCO = steady state carbon monoxide diffusing capacity, PaOs = arterial partial pressure of oxygen, PaC02 = arterial partial pressure of carbon dioxide, D(A - a& = alveolar-arterial oxygen gradient at rest, VWVT = ratio of dead space to tidal volume. Figures in parentheses are per cents
respiratory failure in the fourth to sixth month of treatment. Four others (Cases 13, 14, 15 and 16) demonstrated progressive loss of lung function despite a year of therapy. Two of these patients (Cases 14 and 15) ultimately died of respiratory failure; one (Case 16) died of an intercurrent acute myocardial infarction, and only one (Case 13) is still alive at the time of this report. The difference in the death rates of the improved versus unimproved groups is highly significant (p = 0.0032). A comparison of the pretreatment pulmonary function test results and pulmonary function after one year of treatment for the 16 patients who survived 12 months or longer is listed in Table III. There was a statistically significant improvement in mean forced vital capacity from 2.09 to 2.89 liters (p = O.OOS),a 38 per cent increase. The mean PaOp at rest breathing room air increased from 65 mm Hg before therapy to 75 mm Hg after one year of treatment (p = 0.004) with no change in the simultaneously measured PaCO2. There was also an increase in the Pa02 with exercise from 53 mm Hg to 59 mm Hg. The improved oxygenation during exercise occurred in the face of a greater physical effort by most patients in their post-treatment exercise testing.
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spite prednisone and azathioprine therapy make up the fourth subset. The subsets are too small to allow valid statistical analysis. However, the temporal sequence of improvement suggests that azathioprine was of benefit in eight of 13 patients who completed nine months of combined therapy. This included the four patients who had clinical deterioration when receiving prednisone alone and who showed improvement with the addition of azathioprine, and also the four steroid-responsive patients who showed additional improvement with azathioprine. Patients treated with prednisone alone showed a rapid initial improvement in pulmonary
‘O0C
‘11
, 1:
PREBIOPSY
,DURATlfN,,OF
3
6 MONTHS
THERAqy
1
9
12
&ire 2. Mean vital capacity measurements at three monl intervals for the 76 patients who completed one year or therapy.
The mean improvement in Pa02 at rest was greater than the improvement in exercise oxygenation, so the fall in PaOp with exercise actually increased from a mean of 12 mm Hg to 16 mm Hg with therapy. The mean D (A-a)02 at rest decreased from 41 mm Hg to 30 mm Hg (p = 0.004) and the mean anatomic shunt from 13.6 per cent to 10.2 per cent (p = 0.01) during treatment. Improvement in pulmonary function was usually matched by roentgenographic improvement. Ten of the 12 improved patients demonstrated improvement on the chest film. Figure 2 shows the vital capacity measurements at three month intervals for 16 patients treated for one year. The treated group is divided into four subsets represented in Figure 3. The three patients treated with prednisone alone increased their mean vital capacity from 44 per cent of predicted to 83 per cent in the first three months of treatment, with no further improvement through nine months of maintenance therapy. Five patients, ultimately receiving combined therapy, had an initial increase in forced vital capacity from 46 per cent of predicted to 67 per cent of predicted with prednisone alone, and four demonstrated additional improvement in the vital capacity with the use of azathioprine. The mean forced vital capacity increased to 82 per cent of predicted with azathioprine. The third subset included four patients with an acute illness of one to seven months’ duration, and minimal reduction of the forced vital capacity at the time of biopsy. These four patients exhibited a further reduction in the forced vital capacity from 83 per cent of predicted to 64 per cent of predicted during three months of prednisone therapy. With the use of azathioprine, the mean forced vital capacity returned to 84 per cent of predicted. The four patients who showed progressive loss of function de-
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f.J 40
% loo-
0 -I 2
go-
5
60-
C STEROID UNRESPONSIVE AZATHIOPRINE RESPONSIVE
)
70 60 I 50 .r^:. n
PREBIOPSY
3
6 MONTHS
9 0
12
AZATHIOPRINE PREDNISONE
Figure 3. Therapeutic subsets of patients completing on: year of therapy include three patients treated with prednisone alone (A), five patients responsive to both prednisone and azathioprine (B), four patients with loss of function with prednisone alone but improvement with the addition of azathioprine (Q, and four patients refractory to both prednisone and azathoprine (0).
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function with no further improvement after three months, i.e., 94 per cent of the improvement measured at one year is present in the three month tests. In contrast, the eight patients who appeared to respond to azathioprine therapy showed only 11 per cent of their total improvement during the three months of prednisane therapy with 89 per cent occurring subsequent to azathioprine therapy. The difference in the per cent of total improvement occurring in the first three months of therapy is statistically significant (p = 0.04). Therapy was discontinued at one year in seven of 13 patients receiving combined prednisone/azathioprine therapy. Five patients who showed improvement with treatment have demonstrated clinical stability 10 to 32 months without therapy (mean = 19 months). One patient in the improved group and one in the unimproved group exhibited.deterioration requiring reinstitution of therapy. Therapy was continued until the time of death in four patients (Cases 6, 14, 15 and 16). Prednisone therapy was discontinued at one year in Cases 5 and 12 but referring physicians have elected to continue azathioprine therapy and both patients maintain their improvement with azathioprine alone. Treatment was associated with a number of side effects. One patient (Case 20) became acutely psychotic while receiving high dose prednisone therapy necessitating a rapid reduction in dose. Six patients manifested myopathy, systemic hypertension, gastrointestinal intolerance or dependent edema singly or in combination when receiving only prednisone. Symptoms were diminished with dose reduction, and in no instance was prednisone therapy discontinued. Azathioprine therapy was discontinued in three patients because of fever, skin rash and/or intractable diarrhea. In one patient (Case 11) obstructive jaundice developed during the seventh month of combined prednisone/ azathioprine therapy. Needle biopsy of the liver disclosed intrahepatic cholestasis. The jaundice resolved and liver function returned to normal with discontinuation of azathioprine therapy. The entire syndrome recurred with resumption of azathioprine therapy and disappeared not to recur when azathioprine was permanently withdrawn. The single infectious complication was the development of pulmonary tuberculosis in one patient (Case 6) when receiving combined prednisone/azathioprine therapy. The patient was known to be tuberculin-positive and did not receive lsoniazid prophylaxis through physician error. Aspergillus infection eventually developed in the tuberculous cavity and was a significant factor in the patient’s death. Hemopoietic suppression from azathioprine was notably absent in the study group. Although mild leukopenia necessitated a dose reduction in one patient (Case 6). no other patient exhibited clinically significant suppression of platelets or leukocytes. Two newly dis-
TABLE IV _____.
PNEUMONITIS - WlMTERBRlJER ET Al
Correlation Between Response to Therapy and Clinical Features in 20 Patients -~.-.-.__-.~~ __ _ .__ _ .____ Variable
Age Sex Duration of symptoms Associated disease Bentonite flocculation test Antinuclear antibody Elevation of serum complement level Elevation of immunoglobulin levels Presence of allergic alveolitis precipitins -----. --._...--__._-_.._
Correlation Coeflicient - __ -.
p Value ~__.
0.171 0.392 -0.671 0 636 -0.245 -0.202 -0.200
0.531 0.140 0.007 0.009 0.368 0.455 0.539
-0.186
0.509
0 232 ~___
0.389
_.^_._.
covered malignancies have occurred in the study group to date. One patient (Case 1) was found to have stage I adenocarcinoma of the prostate 18 months after lung biopsy. Another patient (Case 14) had a peripheral lung nodule and hilar enlargement shortly prior to death. Postmortem examination revealed a peripheral bronchioloalveolar cell carcinoma which had metastasized to the hilar nodes. Clinical Correlation with Response to Therapy. The correlation between clinical features of the illness and improvement in vital capacity with therapy is listed in Table IV. The patient’s age, sex, the presence or absence of antinuclear antibody and/or rheumatoid factor, an increase in the serum complement and in quantitative immunoglobulins bore no relationship to the therapeutic outcome. Only the duration of symptoms prior to therapy and the presence of extrathoracic disease manifestations (anemia, glomerulitis and abnormal liver function) correlated with the therapeutic response. The patients with the briefest illness showed the greatest improvement. The mean duration of illness in the 12 patients who showed improvement was 4.7 months with only two patients (Cases 6 and 9) having symptoms for one year or longer. In contrast, the mean duration of symptoms was 49.3 months in the eight patients who showed no improvement with only one patient ill less than a year. Clinicopathologic Correlations. The individual patient’s mean score on each of 20 histologic variables was correlated with their improvement or lack of improvement with therapy. Inspection of regression coefficients and corresponding standard errors indicated three variables were effective in separating patients who showed improvement from those who did not, i.e., (1) interstitial fibrosis, (2) vascular intimal fibrosis, and (3) honeycombing. The multiple correlation resulting from the regression against these three variables for Pathologist 1 was +0.84. The multiple correlation for Pathologist 2 was -f-0.89. The single most important histologic variable is interstitial fibrosis. Patients who
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responded to therapy had less interstitial fibrosis than those who failed to improve with treatment. Utilizing the degree of interstitial fibrosis as a single variable Pathologist 1 could accurately predict the response to therapy of 18 of 20 patients and Pathologist 2 correctly categorized 19 of 20 patients. A predictive formula was developed for each pathologist. Utilizing a regression coefficient of 0.475 for Pathologist 1 with a constant of -0.730 and a maximum likelihood cutoff point of 0.446 (0.446 + 0.730/0.475 = 2.48) revealed that a mean rating for interstitial fibrosis of 2.48 was the dividing score for response to therapy. Patients with a mean score of less than 2.48 would be expected to show a good response to therapy, and patients with a mean score greater than 2.48 would probably have a poor response. The predictive formula for Pathologist 2 was (0.462 + 1.319/0.657 = 2.71) with 2.71 the dividing score for response to therapy. The severity of the changes on the chest film before biopsy did not correlate with the degree of interstitial fibrosis (correlation co-efficient 0.269, p = 0.256). However, the predominant pattern did correlate with the degree of fibrosis. The six patients with a ground glass pattern had a mean grade of 1.85 for interstitial fibrosis compared to 2.97 for the seven patients with a reticular pattern and 2.59 for the seven patients with a reticulonodular pattern (correlation coefficient 0.572, p = 0.015). Patients with a ground glass pattern, in turn, had a better response to therapy than those with the other two patterns. There was no significant correlation between the ground glass pattern and intra-alveolar cell accumulation. There was considerable intra- and interlobar variation in diagnosis when the classification of Liebow (UIP = usual interstitial pneumonitis, DIP = desquamative interstitial pneumonitis, BIP = bronchiolitis obliterans interstitial pneumonitis, LIP = lymphocytic interstitial pneumonitis, GIP = giant cell interstitial pneumonitis) was applied to the pathologic material. Pathologist 1 applied more than one diagnostic category to 19 of 37 lobes (5 1.4 per cent) and Pathologist 2 to 25 of 37 (67.6 per cent). Pathologist 2, for example, diagnosed two areas of usual interstitial pneumonitis, three areas of desquamative interstitial pneumonitis and one area of lymphocytic interstitial pneumonitis in reviewing three slides from the biopsy specimen of the upper lobe of the left lung of one patient (Case 11) (Figure 4). Giant cell interstitial pneumonitis was not recognized in any of the 444 regions examined. Pathologist 1 applied three or more diagnostic categories to different areas within the same lobe in four of the 37 biopsy specimen whereas Pathologist 2 used three or more diagnostic categories in nine lobes. Both pathologists found the intralobe variation and use of multiple diagnostic categories more frequent in patients who showed
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clinical improvement than in those who did not (40.5 per cent versus 10.8 per cent for Pathologist 1, and 45.9 per cent versus 18.9 per cent for Pathologist 2). COMMENTS In a retrospective analysis of 96 patients seen over a 17 year interval Stack and colleagues [2] emphasized the therapeutic response to corticosteroids as “the most important factor determining the prognosis in a new patient presenting with incapacitating dyspnea due to cryptogenic fibrosing alveolitis.” Eleven of their 69 patients (16 per cent) demonstrated significant improvement with prednisolone therapy, and eight of these 11 were still alive five years after diagnosis. The fiveyear survival for patients unresponsive to cor-ticosteroid therapy was only 20 per cent. Sixty per cent of our patient group showed improvement with therapy, and the response to therapy again proved to be the primary determinant of prognosis. Ten of 12 patients who showed improvement are alive through a mean 30 month follow-up whereas seven of eight patients who failed to show improvement with therapy died. The increased frequency of beneficial response to therapy in our patients could be attributed to several factors. Our initial prednisone dosage of 100 mg daily, for instance, was considerably higher than the 20 to 40 mg of prednisolone utilized by Stack et al. [ 21. A factor of great potential significance is differences in disease activity between the two study populations. The definition of disease activity is a perplexing but important issue in interstitial pneumonitis. Our experience has suggested that a number of patients suffer diffuse alveolar damage through some unknown but apparently self-limited mechanism. Such patients may exhibit a continuum from mild to severe disease but no progression with time. Therapy in these subjects is fruitless. The definition of our study group included criteria designed to eliminate patients without progressive disease. The patient group of Stack et al. [2], however, was not defined by disease activity. A lack of disease activity could explain their finding that patients with long-standing symptoms (more than 4 years) had a better prognosis, as six of seven such patients survived more than five years. In contrast, five of our seven patients with disease of more than 2 years’ duration at the time of biopsy were dead in 15 months. An accurate definition of disease activity is crucial to further investigation of interstitial pneumonitis; hopefully, new technics such as gallium-67 citrate lung scanning and analysis of cellular reactions in bronchoalveolar lavage fluid will provide a means of quantitating disease activity in the future [4]. The increased response to therapy in the current study may in part be due to the use of azathioprine.
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Figure 4. Case 11. lntralobar histologic variatibn seen in the biopsy specimen of the upper lobe of the left lung. A, a region showing large accumulations of macrophages within alveolar spaces with slight alveolar septal thickening. Regional diagnosis-DIP. 6, this region of the same biopsy specimen shows a diffuse septal infiltrate of lymphocytes and some plasma cells. Regional diagnosis-LIP. C, a third region demonstrates complete obliteration of the usual architecture and replacement of normal tissue by dense cellular fibrous connective tissue. Regional diagnosis--UP. Hematoxylin and eosin stain; magnification X 100, reduced by 3 1 per cent.
Although the current study does not provide any statistical assessment of the effects of azathioprine, the three month stagger between initiating administration of the two drugs provided a pattern of response which suggested that azathioprine was beneficial in eight patients. Our previous experience with prednisone showed that patients who showed improvement demonstrated a maximal response by three months. This course of events was duplicated by the three patients
in the current study who were treated with prednisone alone. In contrast, four of five patients responsive to prednisone who then received azathioprine showed additional improvement in pulmonary function through nine months of combined therapy. Even more convincing were the four patients who failed to show improvement with prednisone therapy but demonstrated significant improvement with the addition of azathioprine.
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The previously reported experience with azathioprine in the treatment of interstitial pneumonitis is meager. Brown and Turner-Warwick [ 1 l] in 1971 described five patients with cryptogenic fibrosing alveolitis treated with azathioprine. Azathioprine was given in a dose of 2 to 3 mg/kg to two patients with long-standing (four to 12 years) disease uninfluenced by corticosteroids, two patients with steroid-responsive disease who had side effects from long-term maintenance corticosteroid therapy and one patient with rapidly progressive interstitial pneumonitis in whom severe idiopathic osteoporosis contraindicated the use of steroids. The latter patient, receiving azathioprine alone, had symptomatic and physiologic improvement before the development of thrombocytopenia forced discontinuation of the drug after 15 weeks. Neither patient with steroid-resistant disease showed improvement with the addition of azathioprine. However, azathioprine did provide effective maintenance therapy with reduction in prednisone requirements for both patients with steroid-responsive disease. Azathioprine therapy had to be discontinued in two further patients at three weeks and eight weeks, respectively, because of fever and/or diarrhea and vomiting. The only subsequent experience was the report by Weese and colleagues [ 121 in 1975 of two patients with corticosteroid-resistant fibrosing alveolitis who appeared to respond to azathioprine therapy. Their first patient was a 62 year old man with a progressive reduction in total lung capacity and Pa02 through six months of prednisone therapy; the addition of azathioprine, 200 mg a day, resulted in stabilization of his lung function. A similar result was achieved in a 45 year old man with progressive loss of lung function through 40 months of triamcinolone therapy (8 to 24 mg/day). Stabilization of symptoms and pulmonary function for 27 months followed the addition of 200 mg a day of azathioprine. The correlation between histology at biopsy and response to therapy of fibrosing alveolitis has been the object of debate. Scadding and Hinson [5] analyzed 16 patients with fibrosing alveolitis diagnosed by open biopsy. The biopsy findings were interpreted without knowledge of the clinical course for degree of thickening of the alveolar walls, intra-alveolar cellular accumulation, excess lymphoid follicles in the periphery of the lung and uniformity of the changes. Alveolar wall thickening was the single discriminatory variable correlated with prognosis. Only one death occurred in the eight patients with slight alveolar wall thickening compared to four deaths in the eight with prominent alveolar wall thickening. Three of seven with slight alveolar wall thickening showed improvement with prednisolone therapy, but none of seven patients with prominent alveolar thickening responded to prednisolone. Patients with minimal alveolar wall thickening showed a more homogeneous pattern throughout the
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biopsy specimen. Stack and associates [2] also found a correlation between the degree of fibrosis and response to therapy in 16 of their patients with open lung biopsy. Six of nine patients with minimal septal fibrosis but a highly cellular interstitial and intra-alveolar pattern responded to corticosteroid therapy and one of seven patients with marked septal fibrosis and honeycombing responded to steroid therapy. The role of sampling variation is emphasized by contrasting these conclusions from open lung biopsies to the Mayo Clinic experience with transbronchoscopic lung biopsy [ 131. Their analysis of 73 patients with interstitial fibrosis, including 27 patients who died from their disease, showed no difference in the survival of patients with “no or slight fibrosis” compared to those with “moderate or severe fibrosis.” Our results support the predictive role of lung biopsy in fibrosing alveolitis and further define the histologic criteria for separating responders from nonresponders. The single variable, interstitial fibrosis, proved to be equal to any combination of variables in separating responders from nonresponders. The degree of interstitial and/or intra-alveolar cellular reaction was not accurate in predicting the therapeutic response in our patients. Others, however, have emphasized that a marked cellular histologic reaction is frequently, if not invariably, associated with minimal septal fibrosis, a good response to therapy and hence a good prognosis [2,14]. The pathologic material from our patients showed great variation in the mix of fibrous and cellular reaction. Several patients demonstrated striking intraalveolar and interstitial cellular reactions in the presence of severe septal fibrosis. Our results would indicate the response to therapy in these patients is predicated on the degree of fibrosis and not the degree of inflammation. The current study emphasizes the pitfalls of sampling variation in utilizing biopsy specimens to predict the response to therapy. Analysis of the variation within a lobe frequently showed wide discrepancy in the histologic ratings. In contrast to Scadding and Hinson’s [5] conclusion that patients with minimal septal fibrosis had the most homogeneous pathologic pattern, the least variation in histology was seen in patients with the greatest fibrosis in our study group. Patients with lower mean scores for fibrosis showed much greater histologic variation in both septal fibrosis and cellular reaction. The response to therapy was better in patients showing wider histologic variability underlying the need to observe multiple areas for accurate prognosis. Our results indicate that a small biopsy specimen, such as a single transbronchial biopsy, would be most accurate in diagnosing the nonresponder with severe, homogeneous septal fibrosis and least accurate in the responder with widespread histologic variation. It is important to note that the variation within a lobe was essentially
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identical to the variation between lobes. In none of the 12 patients with biopsies of two or three lobes was there a recognizable difference in the histology between lobes. Thus, open biopsies of multiple lobes added little to the information obtained from a large open biopsy of a single lobe. Sparing of the upper lobes is a frequently mentioned roentgenologic finding in cryptogenic fibrosing alveolitis [4]. Twelve of the patients with multiple lobe biopsies in our study group had both an upper and lower lung biopsy site. Despite the fact that the plain chest film showed a gradient of involvement with relative sparing of the upper lobe in seven, the histologic changes in the upper lobe were identical to those found in the adjacent lower and/or middle lobe. The discrepancy between roentgenographic and histologic abnormalities suggests that sparing of the upper lobe on the roentgenogram is an artifact, perhaps related to the smaller lung volume in the upper portion of the chest. Liebow [3] has subdivided interstitial pneumonitis of unknown cause histopathologically into usual interstitial pneumonitis, bronchiolitis obliterans interstitial pneumonitis, desquamative interstitial pneumonitis, lymphocytic interstitial pneumonitis and giant cell interstitial pneumonitis. The classification has few clinical correlates save that patients with desquamative interstitial pneumonia have a better response to corticosteroid therapy and hence a better prognosis [ 141. Scadding and Hinson [5] argue that the separation of desquamative interstitial pneumonitis and usual interstitial pneumonitis is artificial and that both patterns are found frequently in the same lung, probably representing different phases of the same process. Our results also indicate that the separation of usual interstitial pneumonitis, lymphocytic interstitial pneumonitis and bronchiolitis obliterans interstitial pneumonitis is not clear, and that multiple histologic patterns frequently coexist. Each of the 444 regions of lung examined were assigned a “single best” diagnostic category according to the Liebow classification. There was marked regional variation in diagnosis. More than one diagnostic category was applied in 27 of 37 lobes. Histologic variation was again more common in the group responsive to therapy with 50 per cent of regions showing usual interstitial pneumonitis, 24 per cent desquamative interstitial pneumonitis, 14 per cent bronchiolitis obliterans interstitial pneumonitis and 11 per cent normal. Eighty-six per cent of the regions examined showed usual interstitial pneumonitis in the nonresponding group with 10 per cent desquamative interstitial pneumonitis, 1 per cent lymphocytic interstitial pneumonitis, 1 per cent bronchiolitis obliterans interstitial pneumonitis and 1 per cent normal. The variation of histologic grading between pathologists was greater using the Liebow classification than when quantitating the specific histologic variables. Utilizing the Liebow classification, the
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ET AL.
pathologists differed in the most frequent regional diagnosis in five patients, leading to a discrepancy in their final diagnosis. In 195 1 Austrian and associates [ 151 described the “classic” physiologic concept of idiopathic pulmonary fibrosis. These investigators coined the term “alveolar-capillary block,” suggesting that the hypoxemia of idiopathic pulmonary fibrosis was secondary to an anatomic barrier to oxygen due to a thickened alveolar interstitium. Subsequent studies have demonstrated that ventilation-perfusion imbalance is the major cause of hypoxemia with a true diffusion barrier playing a minor role [ 16,171. Only recently have the histologic findings at biopsy been correlated with pulmonary function abnormalities. Green et al. [6] found positive correlations between the grade of fibrosis and resting PaOz, vital capacity, rest and exercise D (A - a)Os, exercise Pa02, maximal expiratory flow rate and total lung capacity in descending order of significance. Neither the resting single breath nor the exercise steady state diffusing capacity showed a significant correlation with the degree of fibrosis. Crystal et al. [4] found a good correlation between the degree of pulmonary fibrosis in 18 patients with an open lung biopsy and the coefficient of retraction, a decrease in Pa02 with exercise and a change in D (A - a)O, with exercise. Their results, however, failed to confirm a correlation between vital capacity, total lung capacity, resting Pa02 and resting alveolar-arterial oxygen gradient. The diffusing capacity again lacked correlation with the degree of fibrosis. These investigators emphasized exercise testing as the most sensitive method of following temporal changes in the fibrotic process. To obviate differences between patients other than the degree of pulmonary fibrosis, these workers related the changes in PaOz and D (A a)Oz with exercise to oxygen consumption (i/,-,,) and expressed their results as AP02:Ai/02 and QD(A a)02:AQo2. The current study demonstrates improvement in both pulmonary mechanics and gas exchange in patients responsive to therapy. The group with improvement was defined as showing a greater than 20 per cent improvement in vital capacity after one year of treatment, but these subjects also demonstrated statistically significant improvement in PaOz at rest, PaO, with exercise, D(A - a)O, at rest and anatomic shunt. Most patients with an increase in vital capacity under therapy demonstrated measurable improvement in gas exchange, and no patient demonstrated improved gas exchange without a simultaneous increase in vital capacity. However, there was not a statistically significant correlation between the increase in lung volume and the magnitude of improvement in gas exchange in the group responsive to therapy. Longer follow-up will be necessary to determine which measurements correlate best with long-term prognosis.
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REFERENCES 1. 2. 3.
4.
5.
6.
7. 8. 9.
672
Hamman L, Rich AR: Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 74: 173, 1944. Stack HR. Choo-Kang YFJ, Heard BE: The prognosis of cryptogenic fibrosing alveolitis. Thorax 27: 535, 1972. Liebow AA: New concepts and entities in pulmonary disease, in The Lung, (Liebow AA, Smith DE, eds), Baltimore, Williams 8 Wilkens. 1967, p 332. Crystal RG, Fulmer JO. Roberts WC, et al.: Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic. cytologic and biochemical aspects. Ann Intern Med 85: 769, 1976. Soadding JG. Hinson KFW: Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs). Correlation of histology at biopsy with prognosis. Thorax 22: 29 1, 1967. Green GM, Graham WGB, Hanson JS, et al.: Correlated studies of interstitial pulmonary disease. Chest (suppl8) 69: 263, 1976. Bates DV: The uptake of carbon monoxide in health and in emphysema. Clin Sci 11: 21, 1952. Fowler WS: The respiratory deadspace. Am J Physiol 154: 405, 1948. Davidson FF, Glazier JB, Murray JF: The components of the alveolar-arterial oxygen tension difference in normal subjects and in patients with pneumonia and obstructive disease. Am J Med 52: 754, 1972.
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10.
11.
12.
13.
14. 15.
16.
17.
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do Pica AG, Reddan WG, Chmelik F, et al.: The value of precipitating antibodies in screening for hypersensitivity pneumonitis. Am Rev Respir Dis 113: 451, 1976. Brown CH, Turner-Warwick M: The treatment of cryptogenic fibrosing alveolitis with immunosuppressant drugs. 0 J Med 158: 289. 1971. Weese WC, Levine BW. Kazemi H: Interstitial lung disease resistant to corticosteroid therapy. Report of three cases treated with azathioprine or cyclophosphamide. Chest 67: 57, 1975. De Remee RA, Harrison EG, Anderson, HA: The concept of classic interstitial pneumonitis-fibrosis (CIP-F) as a clinicopathologic syndrome. Chest 61: 213, 1972. Liebow AA, Steer A, Billingsley JG: Desquamative interstitial pneumonia. Am J Med 39: 369, 1965. Austrian R, et al.: Clinical and physiologic features of some types of pulmonary diseases with impairment of alveolarcapillary diffusion. The syndrome of “alveolar-capillary block.” Am J Med 11: 667, 1951. Finley TN, Swenson EW, Comroe JH. Jr: The cause of arterial hypoxemia at rest in patients with “alveolar-capillary block syndrome.” J Clin Invest 41: 618, 1962. Wagner PD. Dantzker DR. Dueck R. et al.: Distribution of ventilation-perfusion ratios in patients with interstitial lung disease. Chest 69 (suppl): 256, 1976.
RICHARD H. WINTERBAUER, SAMUEL P. HAMMAR,
h4.D
M.D.
KEITH 0. HALLMAN. M.D. JAMES E. HAYS, Ph.D. NEELEY, E. PARDEE, M.D. EDWARD
H. MORGAN, M.D.
JOHN D. ALLEN, M.D. KENNETH D. MOORES, M.D. WILLIAM BUSH, M.D. JOHN H. WALKER, M.D. Seattle, Washington
From the Departments of Medicine and Patho@y, The f&son Clinic, Seattle, Washington. This study was supported by a grant from the Virginia Mason Research Center. Requests for reprints should be addressed to Dr. Richard Winterbauer. The Mason Clinic, 1100 Ninth Avenue, P.O. Box 900. Seattle, Washington 98111. Manuscript accepted May 3, 1978.
Twenty patients with diffuse interstitial pulmonary disease diagnosed by open lung biopsy received combined prednisonelatathioprine therapy. Twelve patients demonstrated improvement with therapy. Each patient’s clinical presentation, roentgenologic features and pathologic findings were correlated with their therapeutic response. Patients with an illness of one year’s duration or less had a more favorable response to therapy than patients with a greater than two year duration of illness. Patients with associated extrathoracic abnormalities (anemia, glomerulltis, hepatopathy) exhibited a better therapeutic response than those with only pulmonary disease. The biopsy material from each patient was quantitatively graded on 20 morphologic variables. Statistical analysis using multiple linear regression revealed that a single variable, degree of interstitial fibrosis, was more than 90 per cent accurate in separating those responsive to therapy from those who failed to respond. Patients who respond to treatment had less interstitial fibrosis. Neither the amount of alveolar septal inflammation nor intra-alveolar cellular reaction was discriminatory in predicting response to therapy. A beneficial response to therapy was reflected in both improved lung volumes and gas exchange. Eight patients appeared to have a selective beneficial effect from azathioprine. Diffuse interstitial pneumonitis is a syndrome best characterized by its clinical and morphologic variability, unpredictable course and resistance to treatment. Although a sudden onset with rapid progression to death in three to four months was emphasized in the original report by Hamman and Rich [ 11, subsequent experience has confirmed a long-term course with insidious progression and survival greater than 10 years in some patients [2]. The initial pathologic descriptions have been broadened to include five distinct pathologic variants according to the classification of Liebow [3]. The heterogeneity in natural history and histology offer an intriguing opportunity to correlate the prognosis and therapeutic outcome of the disease with specific clinical and histologic features [4-61. The present study is a prospective analysis of patients whose interstitial pneumonitis was confirmed by open lung biopsy and who were given a therapeutic protocol of combined prednisone/azathioprine. The goals of the study are (1) to identify clinical and histologic variables which correlate with the patient’s prognosis and response to therapy, (2) to assess the influence of intralobar and interlobar sampling variation in formulating clinicopathologic correlations, and (3) to evaluate the influence of combined prednisone/azathioprine therapy on the progress of disease.
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TABLE I
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Morphologic Variables Biopsy Specimens
ET AL.
Used to Grade
Obliteration of alveolar spaces Obliteration of terminal and respiratory bronchioles Interstitial fibrosis Intra-alveolar fibrosis Interstitial plasma cells Interstitial lymphocytes Interstitial polymorphonuclear leukocytes Interstitial eosinophils Interstitial macrophages Intra-alveolar macrophages Intra-alveolar plasma cells Intra-alveolar lymphocytes Intra-alveolar polymorphonuclear leukocytes Intra-alveolar eosinophils Alveolar lining cell hypertrophy and hyperplasia Obliteration of pulmonary capillary bed Bronchiolitis obliterans Vascular medial hypertrophy Vascular intimal fibrosis Microscopic honeycombing
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
MATERIALS
AND METHODS
Study Population. The study group consisted of 20 patients with a histologic diagnosis of diffuse interstitial pneumonitis who were seen at our institution between February 1974 and June 1977. Each patient was interviewed, examined and followed by one of us. Patients with interstitial pulmonary fibrosis associated with collagen vascular disease, pneumoconiosis or a postinfectious etiology, such as the diffuse scarring seen after Pneumocystis carinii or influenza viral pneumonia, were eliminated. Each patient had to exhibit clinical evidence of disease progression to be included in the study group. Rapidly progressive pulmonary symptoms in association with newly discovered diffuse pulmonary infiltrates were seen in 13 patients. However, seven patients had clinical and roentgenographic evidence of disease for two and a half to seven years prior to biopsy. These patients demonstrated disease progression through sequential pulmonary function tests and/or serial chest roentgenograms. Patients with known disease for over two years’ duration who had no evidence of progression on sequential testing were excluded from the study. Only patients available for regular follow-up were entered into the study group. Informed consent was obtained from all study participants. A standardized history was obtained from each of the study patients. The time of onset of pulmonary symptoms, time of initial chest roentgenographic abnormality, occupational history, medications taken in the two years prior to the onset of disease, history of drug allergies, history of previous pulmonary disease, smoking history and family history were all recorded. Serologic Studies. Serologic studies routinely performed included tests for antinuclear antibody (ANA) and rheumatoid factor (bentonite flocculation test-BFT), and serum protein
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electrophoresis. Quantitative immunoglobulins were measured by radial immunodiffusion for immunoglobulin G (IgG), A (IgA) and M (IgM). In addition, the patient’s serum was screened for precipitating antibodies to Micropolyspora faeni, Thermoactinomyces vulgaris, pigeon products, Aspergillus species and Sitophilus granarius by Ouchterlony gel-diffusion technics. The third (C3) and fourth (C4) factors of complement were measured by radial immunodiffusion technics. The results are expressed in milligrams per deciliter with the normal range 105 to 180 mg/dl for C3 and 10 to 40 mg/dl for C4. Pulmonary Function Tests. Pulmonary function tests were performed prior to therapy and repeated at three month intervals through the first year of therapy. Subsequent pulmonary tests were performed when clinically indicated. Measurement of the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV,) were determined with an Ohio Model 780 spirometer. The tracings were recorded in triplicate, and the highest result was accepted and corrected to standard temperature and pressure, dry. The diffusing capacity for carbon monoxide (DLCO) was measured by the steady-state method of Bates [ 71. Measurements were repeated until two consecutive values varied by less than 1 ml/min/mm Hg. Brachial artery blood samples were obtained with the patient at rest and breathing room air, and at the end of 4 minutes of exercise on a bicycle ergometer with a work load of 400 kg/m. The exercise arterial blood specimen was obtained at the completion of maximal effort for patients who could not complete the exercise test. Measurements included arterial oxygen tension (PaOp), arterial carbon dioxide tension (PaCOz), pH, hematocrit, arterial oxygen saturation (SaOP) and base excess. The alveolar air equation, PA02 = PlOsPaCOs (F102 + 1-FIOP)/R, was used to calculate the resting alveolar-arterial oxygen gradient (D(A - a)O*). R was presumed to be 0.8. Physiologic dead space was determined with the Fowler technic, and the total right to left shunt was measured by the 100 per cent oxygen breathing method [8,9]. Physiologic dead space was expressed as a ratio to tidal volume (Vo:Vr - normal I 0.3) and total shunt as per cent of cardiac output (normal 1: 1000. Three patients had detectable ANA in their serums. The most common serologic abnormality was the polyclonal gammopathy found on serum protein electrophoresis in 15 patients. Increases in the gamma and alpha* globulins were most common, but there was no recognizable diagnostic pattern. Quantitative serum immunoglobulins were abnormal in 12 of the 19 patients tested. Isolated increases in serum IgA was seen in five patients, and five others had a combination of elevated IgA levels with an increase in IgG or, less commonly, IgM. Two patients (Cases 13 and 18) had isolated elevations of the IgM level. C3 and C4 levels were normal in 10 of the 16 patients in whom they were measured. In six patients, serum complement levels were elevated. No patient had hypocomplementemia. Results of Therapy. The therapeutic protocol was initiated in 20 patients. However, in three patients (Cases 3, 4 and 7) an azathioprine associated fever and/or skin rash developed necessitating discontinuation of the drug. The therapeutic response was defined as improved if the patient’s vital capacity increased by more than 20 per cent with therapy. Patients failing to meet this criterion make up the unimproved group. Twelve of 20 patients (Cases 1 through 12, Table II) were improved. Only two deaths occurred in the 12 improved patients through a mean 30 month follow-up (range 15 to 44 months). One patient (Case 1) died of recurrent lymphoma 22 months after interstitial pneumonitis was recognized. Through one year of combined prednisone/azathioprine therapy the patient’s vital capacity had improved from 1.20 liters to 3.80 liters. One patient (Case 6) died from respiratory failure after the development of sequential superinfections, initially tuberculosis and ultimately pulmonary aspergillosis. In contrast, seven of the eight patients in the unimproved group died during a mean 13 month follow-up. Four patients (Cases 17 through 20) died from progressive
INTERSTITIAL
TABLE Ill
PNEUMONITIS-WINTERBAUER
ET AL.
A Comparison of Pulmonary Function Before and After Treatment in 16 Patients Who Completed One Year of Therapy (mean f SE) Results
Study
FVC
(% pred)
FEV,(FEV,:FVC%) DLCO
(% pred)
Pa02 (rest) PaCOs (rest) D(A - a)O, (rest) PaOs (exercise) PaCO* (exercise) Vo:Vr (rest) Vo:Vr (exercise) Anatomic shunt
Before
2.09 (58) f0.233 1.74 (79) f0.18 7.5 (45) f0.0639 65.5 f3.08 35.5 f0.97 41.4 63.688 53.2 f3.584 36.7 f1.48 0.44 f0.037 0.44 f0.043 13.7 f1.249
After
2.89 (80) f0.285 2.13 (74) f0.19 8.2 (49) f0.874 75.2 f2.864 34.6 f1.54 30.3 f2.906 59.6 f4.555 37.9 f2.83 0.45 f0.036 0.38 f0.043 10.3 f0.351
p Value
0.006 0.04 0.161 0.004 0.62 0.004 0.038 0.70 0.203 0.053 0.010
NOTE: FVC = forced vital capacity, FEV, 1 second forced expiratorv volume, DLCO = steady state carbon monoxide diffusing capacity, PaOs = arterial partial pressure of oxygen, PaC02 = arterial partial pressure of carbon dioxide, D(A - a& = alveolar-arterial oxygen gradient at rest, VWVT = ratio of dead space to tidal volume. Figures in parentheses are per cents
respiratory failure in the fourth to sixth month of treatment. Four others (Cases 13, 14, 15 and 16) demonstrated progressive loss of lung function despite a year of therapy. Two of these patients (Cases 14 and 15) ultimately died of respiratory failure; one (Case 16) died of an intercurrent acute myocardial infarction, and only one (Case 13) is still alive at the time of this report. The difference in the death rates of the improved versus unimproved groups is highly significant (p = 0.0032). A comparison of the pretreatment pulmonary function test results and pulmonary function after one year of treatment for the 16 patients who survived 12 months or longer is listed in Table III. There was a statistically significant improvement in mean forced vital capacity from 2.09 to 2.89 liters (p = O.OOS),a 38 per cent increase. The mean PaOp at rest breathing room air increased from 65 mm Hg before therapy to 75 mm Hg after one year of treatment (p = 0.004) with no change in the simultaneously measured PaCO2. There was also an increase in the Pa02 with exercise from 53 mm Hg to 59 mm Hg. The improved oxygenation during exercise occurred in the face of a greater physical effort by most patients in their post-treatment exercise testing.
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‘i
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spite prednisone and azathioprine therapy make up the fourth subset. The subsets are too small to allow valid statistical analysis. However, the temporal sequence of improvement suggests that azathioprine was of benefit in eight of 13 patients who completed nine months of combined therapy. This included the four patients who had clinical deterioration when receiving prednisone alone and who showed improvement with the addition of azathioprine, and also the four steroid-responsive patients who showed additional improvement with azathioprine. Patients treated with prednisone alone showed a rapid initial improvement in pulmonary
‘O0C
‘11
, 1:
PREBIOPSY
,DURATlfN,,OF
3
6 MONTHS
THERAqy
1
9
12
&ire 2. Mean vital capacity measurements at three monl intervals for the 76 patients who completed one year or therapy.
The mean improvement in Pa02 at rest was greater than the improvement in exercise oxygenation, so the fall in PaOp with exercise actually increased from a mean of 12 mm Hg to 16 mm Hg with therapy. The mean D (A-a)02 at rest decreased from 41 mm Hg to 30 mm Hg (p = 0.004) and the mean anatomic shunt from 13.6 per cent to 10.2 per cent (p = 0.01) during treatment. Improvement in pulmonary function was usually matched by roentgenographic improvement. Ten of the 12 improved patients demonstrated improvement on the chest film. Figure 2 shows the vital capacity measurements at three month intervals for 16 patients treated for one year. The treated group is divided into four subsets represented in Figure 3. The three patients treated with prednisone alone increased their mean vital capacity from 44 per cent of predicted to 83 per cent in the first three months of treatment, with no further improvement through nine months of maintenance therapy. Five patients, ultimately receiving combined therapy, had an initial increase in forced vital capacity from 46 per cent of predicted to 67 per cent of predicted with prednisone alone, and four demonstrated additional improvement in the vital capacity with the use of azathioprine. The mean forced vital capacity increased to 82 per cent of predicted with azathioprine. The third subset included four patients with an acute illness of one to seven months’ duration, and minimal reduction of the forced vital capacity at the time of biopsy. These four patients exhibited a further reduction in the forced vital capacity from 83 per cent of predicted to 64 per cent of predicted during three months of prednisone therapy. With the use of azathioprine, the mean forced vital capacity returned to 84 per cent of predicted. The four patients who showed progressive loss of function de-
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f.J 40
% loo-
0 -I 2
go-
5
60-
C STEROID UNRESPONSIVE AZATHIOPRINE RESPONSIVE
)
70 60 I 50 .r^:. n
PREBIOPSY
3
6 MONTHS
9 0
12
AZATHIOPRINE PREDNISONE
Figure 3. Therapeutic subsets of patients completing on: year of therapy include three patients treated with prednisone alone (A), five patients responsive to both prednisone and azathioprine (B), four patients with loss of function with prednisone alone but improvement with the addition of azathioprine (Q, and four patients refractory to both prednisone and azathoprine (0).
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function with no further improvement after three months, i.e., 94 per cent of the improvement measured at one year is present in the three month tests. In contrast, the eight patients who appeared to respond to azathioprine therapy showed only 11 per cent of their total improvement during the three months of prednisane therapy with 89 per cent occurring subsequent to azathioprine therapy. The difference in the per cent of total improvement occurring in the first three months of therapy is statistically significant (p = 0.04). Therapy was discontinued at one year in seven of 13 patients receiving combined prednisone/azathioprine therapy. Five patients who showed improvement with treatment have demonstrated clinical stability 10 to 32 months without therapy (mean = 19 months). One patient in the improved group and one in the unimproved group exhibited.deterioration requiring reinstitution of therapy. Therapy was continued until the time of death in four patients (Cases 6, 14, 15 and 16). Prednisone therapy was discontinued at one year in Cases 5 and 12 but referring physicians have elected to continue azathioprine therapy and both patients maintain their improvement with azathioprine alone. Treatment was associated with a number of side effects. One patient (Case 20) became acutely psychotic while receiving high dose prednisone therapy necessitating a rapid reduction in dose. Six patients manifested myopathy, systemic hypertension, gastrointestinal intolerance or dependent edema singly or in combination when receiving only prednisone. Symptoms were diminished with dose reduction, and in no instance was prednisone therapy discontinued. Azathioprine therapy was discontinued in three patients because of fever, skin rash and/or intractable diarrhea. In one patient (Case 11) obstructive jaundice developed during the seventh month of combined prednisone/ azathioprine therapy. Needle biopsy of the liver disclosed intrahepatic cholestasis. The jaundice resolved and liver function returned to normal with discontinuation of azathioprine therapy. The entire syndrome recurred with resumption of azathioprine therapy and disappeared not to recur when azathioprine was permanently withdrawn. The single infectious complication was the development of pulmonary tuberculosis in one patient (Case 6) when receiving combined prednisone/azathioprine therapy. The patient was known to be tuberculin-positive and did not receive lsoniazid prophylaxis through physician error. Aspergillus infection eventually developed in the tuberculous cavity and was a significant factor in the patient’s death. Hemopoietic suppression from azathioprine was notably absent in the study group. Although mild leukopenia necessitated a dose reduction in one patient (Case 6). no other patient exhibited clinically significant suppression of platelets or leukocytes. Two newly dis-
TABLE IV _____.
PNEUMONITIS - WlMTERBRlJER ET Al
Correlation Between Response to Therapy and Clinical Features in 20 Patients -~.-.-.__-.~~ __ _ .__ _ .____ Variable
Age Sex Duration of symptoms Associated disease Bentonite flocculation test Antinuclear antibody Elevation of serum complement level Elevation of immunoglobulin levels Presence of allergic alveolitis precipitins -----. --._...--__._-_.._
Correlation Coeflicient - __ -.
p Value ~__.
0.171 0.392 -0.671 0 636 -0.245 -0.202 -0.200
0.531 0.140 0.007 0.009 0.368 0.455 0.539
-0.186
0.509
0 232 ~___
0.389
_.^_._.
covered malignancies have occurred in the study group to date. One patient (Case 1) was found to have stage I adenocarcinoma of the prostate 18 months after lung biopsy. Another patient (Case 14) had a peripheral lung nodule and hilar enlargement shortly prior to death. Postmortem examination revealed a peripheral bronchioloalveolar cell carcinoma which had metastasized to the hilar nodes. Clinical Correlation with Response to Therapy. The correlation between clinical features of the illness and improvement in vital capacity with therapy is listed in Table IV. The patient’s age, sex, the presence or absence of antinuclear antibody and/or rheumatoid factor, an increase in the serum complement and in quantitative immunoglobulins bore no relationship to the therapeutic outcome. Only the duration of symptoms prior to therapy and the presence of extrathoracic disease manifestations (anemia, glomerulitis and abnormal liver function) correlated with the therapeutic response. The patients with the briefest illness showed the greatest improvement. The mean duration of illness in the 12 patients who showed improvement was 4.7 months with only two patients (Cases 6 and 9) having symptoms for one year or longer. In contrast, the mean duration of symptoms was 49.3 months in the eight patients who showed no improvement with only one patient ill less than a year. Clinicopathologic Correlations. The individual patient’s mean score on each of 20 histologic variables was correlated with their improvement or lack of improvement with therapy. Inspection of regression coefficients and corresponding standard errors indicated three variables were effective in separating patients who showed improvement from those who did not, i.e., (1) interstitial fibrosis, (2) vascular intimal fibrosis, and (3) honeycombing. The multiple correlation resulting from the regression against these three variables for Pathologist 1 was +0.84. The multiple correlation for Pathologist 2 was -f-0.89. The single most important histologic variable is interstitial fibrosis. Patients who
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responded to therapy had less interstitial fibrosis than those who failed to improve with treatment. Utilizing the degree of interstitial fibrosis as a single variable Pathologist 1 could accurately predict the response to therapy of 18 of 20 patients and Pathologist 2 correctly categorized 19 of 20 patients. A predictive formula was developed for each pathologist. Utilizing a regression coefficient of 0.475 for Pathologist 1 with a constant of -0.730 and a maximum likelihood cutoff point of 0.446 (0.446 + 0.730/0.475 = 2.48) revealed that a mean rating for interstitial fibrosis of 2.48 was the dividing score for response to therapy. Patients with a mean score of less than 2.48 would be expected to show a good response to therapy, and patients with a mean score greater than 2.48 would probably have a poor response. The predictive formula for Pathologist 2 was (0.462 + 1.319/0.657 = 2.71) with 2.71 the dividing score for response to therapy. The severity of the changes on the chest film before biopsy did not correlate with the degree of interstitial fibrosis (correlation co-efficient 0.269, p = 0.256). However, the predominant pattern did correlate with the degree of fibrosis. The six patients with a ground glass pattern had a mean grade of 1.85 for interstitial fibrosis compared to 2.97 for the seven patients with a reticular pattern and 2.59 for the seven patients with a reticulonodular pattern (correlation coefficient 0.572, p = 0.015). Patients with a ground glass pattern, in turn, had a better response to therapy than those with the other two patterns. There was no significant correlation between the ground glass pattern and intra-alveolar cell accumulation. There was considerable intra- and interlobar variation in diagnosis when the classification of Liebow (UIP = usual interstitial pneumonitis, DIP = desquamative interstitial pneumonitis, BIP = bronchiolitis obliterans interstitial pneumonitis, LIP = lymphocytic interstitial pneumonitis, GIP = giant cell interstitial pneumonitis) was applied to the pathologic material. Pathologist 1 applied more than one diagnostic category to 19 of 37 lobes (5 1.4 per cent) and Pathologist 2 to 25 of 37 (67.6 per cent). Pathologist 2, for example, diagnosed two areas of usual interstitial pneumonitis, three areas of desquamative interstitial pneumonitis and one area of lymphocytic interstitial pneumonitis in reviewing three slides from the biopsy specimen of the upper lobe of the left lung of one patient (Case 11) (Figure 4). Giant cell interstitial pneumonitis was not recognized in any of the 444 regions examined. Pathologist 1 applied three or more diagnostic categories to different areas within the same lobe in four of the 37 biopsy specimen whereas Pathologist 2 used three or more diagnostic categories in nine lobes. Both pathologists found the intralobe variation and use of multiple diagnostic categories more frequent in patients who showed
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clinical improvement than in those who did not (40.5 per cent versus 10.8 per cent for Pathologist 1, and 45.9 per cent versus 18.9 per cent for Pathologist 2). COMMENTS In a retrospective analysis of 96 patients seen over a 17 year interval Stack and colleagues [2] emphasized the therapeutic response to corticosteroids as “the most important factor determining the prognosis in a new patient presenting with incapacitating dyspnea due to cryptogenic fibrosing alveolitis.” Eleven of their 69 patients (16 per cent) demonstrated significant improvement with prednisolone therapy, and eight of these 11 were still alive five years after diagnosis. The fiveyear survival for patients unresponsive to cor-ticosteroid therapy was only 20 per cent. Sixty per cent of our patient group showed improvement with therapy, and the response to therapy again proved to be the primary determinant of prognosis. Ten of 12 patients who showed improvement are alive through a mean 30 month follow-up whereas seven of eight patients who failed to show improvement with therapy died. The increased frequency of beneficial response to therapy in our patients could be attributed to several factors. Our initial prednisone dosage of 100 mg daily, for instance, was considerably higher than the 20 to 40 mg of prednisolone utilized by Stack et al. [ 21. A factor of great potential significance is differences in disease activity between the two study populations. The definition of disease activity is a perplexing but important issue in interstitial pneumonitis. Our experience has suggested that a number of patients suffer diffuse alveolar damage through some unknown but apparently self-limited mechanism. Such patients may exhibit a continuum from mild to severe disease but no progression with time. Therapy in these subjects is fruitless. The definition of our study group included criteria designed to eliminate patients without progressive disease. The patient group of Stack et al. [2], however, was not defined by disease activity. A lack of disease activity could explain their finding that patients with long-standing symptoms (more than 4 years) had a better prognosis, as six of seven such patients survived more than five years. In contrast, five of our seven patients with disease of more than 2 years’ duration at the time of biopsy were dead in 15 months. An accurate definition of disease activity is crucial to further investigation of interstitial pneumonitis; hopefully, new technics such as gallium-67 citrate lung scanning and analysis of cellular reactions in bronchoalveolar lavage fluid will provide a means of quantitating disease activity in the future [4]. The increased response to therapy in the current study may in part be due to the use of azathioprine.
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Figure 4. Case 11. lntralobar histologic variatibn seen in the biopsy specimen of the upper lobe of the left lung. A, a region showing large accumulations of macrophages within alveolar spaces with slight alveolar septal thickening. Regional diagnosis-DIP. 6, this region of the same biopsy specimen shows a diffuse septal infiltrate of lymphocytes and some plasma cells. Regional diagnosis-LIP. C, a third region demonstrates complete obliteration of the usual architecture and replacement of normal tissue by dense cellular fibrous connective tissue. Regional diagnosis--UP. Hematoxylin and eosin stain; magnification X 100, reduced by 3 1 per cent.
Although the current study does not provide any statistical assessment of the effects of azathioprine, the three month stagger between initiating administration of the two drugs provided a pattern of response which suggested that azathioprine was beneficial in eight patients. Our previous experience with prednisone showed that patients who showed improvement demonstrated a maximal response by three months. This course of events was duplicated by the three patients
in the current study who were treated with prednisone alone. In contrast, four of five patients responsive to prednisone who then received azathioprine showed additional improvement in pulmonary function through nine months of combined therapy. Even more convincing were the four patients who failed to show improvement with prednisone therapy but demonstrated significant improvement with the addition of azathioprine.
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The previously reported experience with azathioprine in the treatment of interstitial pneumonitis is meager. Brown and Turner-Warwick [ 1 l] in 1971 described five patients with cryptogenic fibrosing alveolitis treated with azathioprine. Azathioprine was given in a dose of 2 to 3 mg/kg to two patients with long-standing (four to 12 years) disease uninfluenced by corticosteroids, two patients with steroid-responsive disease who had side effects from long-term maintenance corticosteroid therapy and one patient with rapidly progressive interstitial pneumonitis in whom severe idiopathic osteoporosis contraindicated the use of steroids. The latter patient, receiving azathioprine alone, had symptomatic and physiologic improvement before the development of thrombocytopenia forced discontinuation of the drug after 15 weeks. Neither patient with steroid-resistant disease showed improvement with the addition of azathioprine. However, azathioprine did provide effective maintenance therapy with reduction in prednisone requirements for both patients with steroid-responsive disease. Azathioprine therapy had to be discontinued in two further patients at three weeks and eight weeks, respectively, because of fever and/or diarrhea and vomiting. The only subsequent experience was the report by Weese and colleagues [ 121 in 1975 of two patients with corticosteroid-resistant fibrosing alveolitis who appeared to respond to azathioprine therapy. Their first patient was a 62 year old man with a progressive reduction in total lung capacity and Pa02 through six months of prednisone therapy; the addition of azathioprine, 200 mg a day, resulted in stabilization of his lung function. A similar result was achieved in a 45 year old man with progressive loss of lung function through 40 months of triamcinolone therapy (8 to 24 mg/day). Stabilization of symptoms and pulmonary function for 27 months followed the addition of 200 mg a day of azathioprine. The correlation between histology at biopsy and response to therapy of fibrosing alveolitis has been the object of debate. Scadding and Hinson [5] analyzed 16 patients with fibrosing alveolitis diagnosed by open biopsy. The biopsy findings were interpreted without knowledge of the clinical course for degree of thickening of the alveolar walls, intra-alveolar cellular accumulation, excess lymphoid follicles in the periphery of the lung and uniformity of the changes. Alveolar wall thickening was the single discriminatory variable correlated with prognosis. Only one death occurred in the eight patients with slight alveolar wall thickening compared to four deaths in the eight with prominent alveolar wall thickening. Three of seven with slight alveolar wall thickening showed improvement with prednisolone therapy, but none of seven patients with prominent alveolar thickening responded to prednisolone. Patients with minimal alveolar wall thickening showed a more homogeneous pattern throughout the
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biopsy specimen. Stack and associates [2] also found a correlation between the degree of fibrosis and response to therapy in 16 of their patients with open lung biopsy. Six of nine patients with minimal septal fibrosis but a highly cellular interstitial and intra-alveolar pattern responded to corticosteroid therapy and one of seven patients with marked septal fibrosis and honeycombing responded to steroid therapy. The role of sampling variation is emphasized by contrasting these conclusions from open lung biopsies to the Mayo Clinic experience with transbronchoscopic lung biopsy [ 131. Their analysis of 73 patients with interstitial fibrosis, including 27 patients who died from their disease, showed no difference in the survival of patients with “no or slight fibrosis” compared to those with “moderate or severe fibrosis.” Our results support the predictive role of lung biopsy in fibrosing alveolitis and further define the histologic criteria for separating responders from nonresponders. The single variable, interstitial fibrosis, proved to be equal to any combination of variables in separating responders from nonresponders. The degree of interstitial and/or intra-alveolar cellular reaction was not accurate in predicting the therapeutic response in our patients. Others, however, have emphasized that a marked cellular histologic reaction is frequently, if not invariably, associated with minimal septal fibrosis, a good response to therapy and hence a good prognosis [2,14]. The pathologic material from our patients showed great variation in the mix of fibrous and cellular reaction. Several patients demonstrated striking intraalveolar and interstitial cellular reactions in the presence of severe septal fibrosis. Our results would indicate the response to therapy in these patients is predicated on the degree of fibrosis and not the degree of inflammation. The current study emphasizes the pitfalls of sampling variation in utilizing biopsy specimens to predict the response to therapy. Analysis of the variation within a lobe frequently showed wide discrepancy in the histologic ratings. In contrast to Scadding and Hinson’s [5] conclusion that patients with minimal septal fibrosis had the most homogeneous pathologic pattern, the least variation in histology was seen in patients with the greatest fibrosis in our study group. Patients with lower mean scores for fibrosis showed much greater histologic variation in both septal fibrosis and cellular reaction. The response to therapy was better in patients showing wider histologic variability underlying the need to observe multiple areas for accurate prognosis. Our results indicate that a small biopsy specimen, such as a single transbronchial biopsy, would be most accurate in diagnosing the nonresponder with severe, homogeneous septal fibrosis and least accurate in the responder with widespread histologic variation. It is important to note that the variation within a lobe was essentially
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identical to the variation between lobes. In none of the 12 patients with biopsies of two or three lobes was there a recognizable difference in the histology between lobes. Thus, open biopsies of multiple lobes added little to the information obtained from a large open biopsy of a single lobe. Sparing of the upper lobes is a frequently mentioned roentgenologic finding in cryptogenic fibrosing alveolitis [4]. Twelve of the patients with multiple lobe biopsies in our study group had both an upper and lower lung biopsy site. Despite the fact that the plain chest film showed a gradient of involvement with relative sparing of the upper lobe in seven, the histologic changes in the upper lobe were identical to those found in the adjacent lower and/or middle lobe. The discrepancy between roentgenographic and histologic abnormalities suggests that sparing of the upper lobe on the roentgenogram is an artifact, perhaps related to the smaller lung volume in the upper portion of the chest. Liebow [3] has subdivided interstitial pneumonitis of unknown cause histopathologically into usual interstitial pneumonitis, bronchiolitis obliterans interstitial pneumonitis, desquamative interstitial pneumonitis, lymphocytic interstitial pneumonitis and giant cell interstitial pneumonitis. The classification has few clinical correlates save that patients with desquamative interstitial pneumonia have a better response to corticosteroid therapy and hence a better prognosis [ 141. Scadding and Hinson [5] argue that the separation of desquamative interstitial pneumonitis and usual interstitial pneumonitis is artificial and that both patterns are found frequently in the same lung, probably representing different phases of the same process. Our results also indicate that the separation of usual interstitial pneumonitis, lymphocytic interstitial pneumonitis and bronchiolitis obliterans interstitial pneumonitis is not clear, and that multiple histologic patterns frequently coexist. Each of the 444 regions of lung examined were assigned a “single best” diagnostic category according to the Liebow classification. There was marked regional variation in diagnosis. More than one diagnostic category was applied in 27 of 37 lobes. Histologic variation was again more common in the group responsive to therapy with 50 per cent of regions showing usual interstitial pneumonitis, 24 per cent desquamative interstitial pneumonitis, 14 per cent bronchiolitis obliterans interstitial pneumonitis and 11 per cent normal. Eighty-six per cent of the regions examined showed usual interstitial pneumonitis in the nonresponding group with 10 per cent desquamative interstitial pneumonitis, 1 per cent lymphocytic interstitial pneumonitis, 1 per cent bronchiolitis obliterans interstitial pneumonitis and 1 per cent normal. The variation of histologic grading between pathologists was greater using the Liebow classification than when quantitating the specific histologic variables. Utilizing the Liebow classification, the
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pathologists differed in the most frequent regional diagnosis in five patients, leading to a discrepancy in their final diagnosis. In 195 1 Austrian and associates [ 151 described the “classic” physiologic concept of idiopathic pulmonary fibrosis. These investigators coined the term “alveolar-capillary block,” suggesting that the hypoxemia of idiopathic pulmonary fibrosis was secondary to an anatomic barrier to oxygen due to a thickened alveolar interstitium. Subsequent studies have demonstrated that ventilation-perfusion imbalance is the major cause of hypoxemia with a true diffusion barrier playing a minor role [ 16,171. Only recently have the histologic findings at biopsy been correlated with pulmonary function abnormalities. Green et al. [6] found positive correlations between the grade of fibrosis and resting PaOz, vital capacity, rest and exercise D (A - a)Os, exercise Pa02, maximal expiratory flow rate and total lung capacity in descending order of significance. Neither the resting single breath nor the exercise steady state diffusing capacity showed a significant correlation with the degree of fibrosis. Crystal et al. [4] found a good correlation between the degree of pulmonary fibrosis in 18 patients with an open lung biopsy and the coefficient of retraction, a decrease in Pa02 with exercise and a change in D (A - a)O, with exercise. Their results, however, failed to confirm a correlation between vital capacity, total lung capacity, resting Pa02 and resting alveolar-arterial oxygen gradient. The diffusing capacity again lacked correlation with the degree of fibrosis. These investigators emphasized exercise testing as the most sensitive method of following temporal changes in the fibrotic process. To obviate differences between patients other than the degree of pulmonary fibrosis, these workers related the changes in PaOz and D (A a)Oz with exercise to oxygen consumption (i/,-,,) and expressed their results as AP02:Ai/02 and QD(A a)02:AQo2. The current study demonstrates improvement in both pulmonary mechanics and gas exchange in patients responsive to therapy. The group with improvement was defined as showing a greater than 20 per cent improvement in vital capacity after one year of treatment, but these subjects also demonstrated statistically significant improvement in PaOz at rest, PaO, with exercise, D(A - a)O, at rest and anatomic shunt. Most patients with an increase in vital capacity under therapy demonstrated measurable improvement in gas exchange, and no patient demonstrated improved gas exchange without a simultaneous increase in vital capacity. However, there was not a statistically significant correlation between the increase in lung volume and the magnitude of improvement in gas exchange in the group responsive to therapy. Longer follow-up will be necessary to determine which measurements correlate best with long-term prognosis.
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REFERENCES 1. 2. 3.
4.
5.
6.
7. 8. 9.
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Hamman L, Rich AR: Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 74: 173, 1944. Stack HR. Choo-Kang YFJ, Heard BE: The prognosis of cryptogenic fibrosing alveolitis. Thorax 27: 535, 1972. Liebow AA: New concepts and entities in pulmonary disease, in The Lung, (Liebow AA, Smith DE, eds), Baltimore, Williams 8 Wilkens. 1967, p 332. Crystal RG, Fulmer JO. Roberts WC, et al.: Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic. cytologic and biochemical aspects. Ann Intern Med 85: 769, 1976. Soadding JG. Hinson KFW: Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs). Correlation of histology at biopsy with prognosis. Thorax 22: 29 1, 1967. Green GM, Graham WGB, Hanson JS, et al.: Correlated studies of interstitial pulmonary disease. Chest (suppl8) 69: 263, 1976. Bates DV: The uptake of carbon monoxide in health and in emphysema. Clin Sci 11: 21, 1952. Fowler WS: The respiratory deadspace. Am J Physiol 154: 405, 1948. Davidson FF, Glazier JB, Murray JF: The components of the alveolar-arterial oxygen tension difference in normal subjects and in patients with pneumonia and obstructive disease. Am J Med 52: 754, 1972.
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10.
11.
12.
13.
14. 15.
16.
17.
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do Pica AG, Reddan WG, Chmelik F, et al.: The value of precipitating antibodies in screening for hypersensitivity pneumonitis. Am Rev Respir Dis 113: 451, 1976. Brown CH, Turner-Warwick M: The treatment of cryptogenic fibrosing alveolitis with immunosuppressant drugs. 0 J Med 158: 289. 1971. Weese WC, Levine BW. Kazemi H: Interstitial lung disease resistant to corticosteroid therapy. Report of three cases treated with azathioprine or cyclophosphamide. Chest 67: 57, 1975. De Remee RA, Harrison EG, Anderson, HA: The concept of classic interstitial pneumonitis-fibrosis (CIP-F) as a clinicopathologic syndrome. Chest 61: 213, 1972. Liebow AA, Steer A, Billingsley JG: Desquamative interstitial pneumonia. Am J Med 39: 369, 1965. Austrian R, et al.: Clinical and physiologic features of some types of pulmonary diseases with impairment of alveolarcapillary diffusion. The syndrome of “alveolar-capillary block.” Am J Med 11: 667, 1951. Finley TN, Swenson EW, Comroe JH. Jr: The cause of arterial hypoxemia at rest in patients with “alveolar-capillary block syndrome.” J Clin Invest 41: 618, 1962. Wagner PD. Dantzker DR. Dueck R. et al.: Distribution of ventilation-perfusion ratios in patients with interstitial lung disease. Chest 69 (suppl): 256, 1976.
