INTERSTITIAL PULMONARY FIBROSIS

INTERSTITIAL P U L M O N A R Y FIBROSIS William

B. Ford, M.D.*

J. W. Giacobine, M.D., H. R. Madoff, M.D.,

Murray Sachs, M.D., Pittsburgh,

and

Pa.

T

HIS report records our experiences with 34 patients with interstitial pul­ monary fibrosis to emphasize the importance of lung biopsy in diagnosis and to compare a series of patients treated with steroids with a series of patients treated symptomatically without steroids. HISTORY

Hamman and Rich12 first observed interstitial fibrosis as a new and unusual pulmonary disease in 3 cases seen from 1931 to 1933, and discussed 4 cases of the acute diffuse form of it in 1944. They mentioned that following their earlier brief report at a meeting of the American Clinical and Climatological Association in 1935, Soper and Finney each discussed a patient with symptoms and histologie findings resembling their cases. In 1956, Grant, Hillis, and Davidson 11 reviewed 36 cases from the literature and reported 3 more. In 1957, Rubin and Lubliner 21 analyzed these 39 cases and recorded 15 more that they had personally observed. In only 6 of the 39 previously reported cases had the diagnosis been ascertained by lung biopsy, and 5 of their own 15 cases were so affirmed. A review of the literature up to the present discloses 138 cases, and in only 75 has the diagnosis been substantiated by lung biopsy. DIAGNOSTIC CRITERIA

The 34 patients included in this report fulfill the following criteria, in order of their importance : 1. Histological study of the lung biopsy reveals changes consistent with the disease and for no other specific entity. The specimen exhibited neither a culture nor a stain positive for a specific organism. 2. There is a history of unremitting progression of dyspnea. 3. Chest film discloses diffuse reticular and/or fibronodular infiltrates con­ sistent with pulmonary fibrosis. 4. Bronchoscopy is negative for gross abnormalities. Presented at the Kastern Section Meeting of the American Thoracic Society, Philadelphia. Pa., Oct. 27, 1962. Received for publication Dec. 3, 1963. *Address: 3515 Fifth Avenue, Pittsburgh, Pa. 15213. 799

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5. Sputum cultures are negative for significant pathogens. 6. Skin testing with histoplasmin, coccidiodin, blastomycin, and P P D was negative. (Nine of this group of patients had a positive PPD, but there were no histologie findings on lung biopsy to support the diagnosis of tuberculosis.) Interstitial fibrosis was diagnosed either by lung biopsy or by autopsy. Of the 17 patients diagnosed by lung biopsy, 15 were immediately treated with corticosteroids. Furstenberg 10 has suggested that the illness be divided into three groups, according to duration of illness: acute, up to 6 months; chronic, up to 2 years or more; subacute, more than 6 months but less than 2 years. In our series of cases in which there were lung biopsies, 5 were acute, 6 were subacute, and 6 were chronic, by Furstenberg's criteria. The earliest and most prominent clinical signs and symptoms of the disease are cough, fever, and progressive dyspnea. The later signs may include digital clubbing, cyanosis, and weight loss. Progressive dyspnea was present in all cases. Twelve patients suffered from an initial productive cough which later became nonproductive. Eight of these patients had short febrile episodes, and one patient suffered hemoptysis. A lung biopsy is not an innocuous procedure ; however, it is easily performed by way of a short left submammary incision and excision of the tip of the lingula of the upper lobe of the left lung. No complications occurred in the 17 patients who underwent lung biopsies. In acute cases, the pleura was only slightly thickened, and adhesions, if present, were filmy and easily lysed by blunt dissection. Pleuropericardial adhesions were usually absent. Pressure on the cut surface of the lung caused the appearance of a thin serosanguineous fluid. The cut surface was granular and brownish gray. In chronic cases, a thickened white pleura with dense adhesions was present. There were usually pleuropericardial adhesions, and, in addition, two of these exhibited subpleural emphysematous blebs. The transected lung was gray, dry, and fibrotic. One biopsied lung showed honeycombing grossly. The x-ray findings are not absolute, but suggest the characteristics of interstitial pulmonary fibrosis. Diffuse, uniform, reticular mottling is usually seen with symmetrical, small nodulation. In chronic cases, spherical cystic areas may be seen along the periphery. As the disease progresses, the cardiac silhouette begins to assume a right ventricular hypertrophy contour. In this series, several patients exhibited a bilateral, reticular, granular infiltration with some irregular nodularities of the lower lobe. In other cases, entire pulmonary fields were involved in a dense, diffuse, reticular pattern. The infiltration bocame confluent in most of the terminal patients (Figs. 1-6). PATHOLOGIC

ANATOMY

In general, the lungs removed at autopsy showed, on transection, brownish discoloration with granular, honeycombed surfaces. They were contracted, in­ elastic, and heavier than water. In 7 of the 17 cases, there were small pulmonary emboli, and it was usual for the same lung to show a variety of histological changes of the disease.

Fig. 1.—A chest x-ray film made in the posteroanterior projection which shows diffuse reticular striations with multiple small calcific hilar opacities and with modera'e flattening of each leaf of the diaphragm. The transverse Assure is easily seen. The inAltration in the lower lobe area seems confluent in the anteromedial basal segment. Fig. 2.—A chest x-ray Aim made in the posteroanterior projection which shows diffuse bilaterial reticular striations with confluent lesions in the left lower lobe area and with bilateral hilar opacities.

Fig. 3.—Made after 10 weeks of corticosteroid therapy and with complete regression of symptoms, this ι centgenogram shows some regression of the reticular striations and of the conglomérant disease in the left lower lobe. Fig. 4.—X-ray Aim which shows bilateral diffuse reticular striations along with conglomér­ ant shadows along the right hilum and large spherical opacity in the left hilum.

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Pig-. 5.—Roentgenogram made 36 months after steroid therapy shows a regression of the linear striations and of the right hilar confluent shadow. The left hilum shows no essential change. Fig. 6.—A posteroanterior projection made after one year of corticosteroid therapy using the same technique shows hyperlucent pulmonary fields without the heavy reticular striations. The short fissure and the multiple calciflc hilar lesions show no change.

Totten 2c believes that these cases do not represent a specific disease entity. I t is well-known that the lung is capable of a limited number of generally similar reactions to a variety of stimuli. This is substantiated by at least two sets of observations: (1) in the human disease states of known varied etiology, the anatomic changes may be nearly identical (viz., Hand-Schüller-Christian disease, scleroderma, berylliosis, sarcoidosis, and, even, anthracosilicosis), (2) in experimental animals, similar end results may be seen following a variety of etiological agents (viz., roentgen irradiation, virus infections, metallic acids, chromâtes, and creosote). The limited number of cases studied fell into three groups: (1) in 7 cases the lesions were diffuse, (2) in 3 cases the lesions were focal, and (3) in 2 cases the lesions were focal and diffuse. Fibrosis and inflammation were conspicuous in an interstitial location since the alveolar walls were thickened (Fig. 7). The fibrosis varied from dense collagenous tissue through fibrous connective tissue with adult fibroblasts to very young fibrous tissue with delicate fibrils and plump fibroblasts. The in­ flammation was characterized principally by lymphocytes, with plasma cells admixed, in some cases. Neutrophils were rarely seen, and then were chiefly entrapped in the mucus within bronchi or bronchioles. Macrophages were conspicuous in many cases but appeared principally within alveoli, as is com­ monly seen when stasis occurs in the lung. The majority contained lipid vacuoles

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and/or dust particles. Occasional multinucleated forms were seen. Cholesterol clefts were prominent in one case, and calcific spherules were seen only in the same case. Epithelial proliferation, either alveolar or bronchiolar or both, was seen in all cases to varying degrees. This was roughly, but not invariably, correlated with the degree of fibrosis and inflammation. Prominent alveolar lining cells

Fig. 7.—Diffuse interstitial fibrosis with both fibrosis and mononuclear infiltration contri­ buting to thickening of alveolar walls. Lipid—filled histiocytes and calcific deposits (black amorphous vessels) in alveolar spaces.

Fig.

8.—Diffuse

chronic

interstitial

fibrosis with prominent epithelium.

proliferation

of

bronchiolar

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Fig. 9.—Focal interstitial pneumonitis with mild fibrosis. Note relatively uninvolved lung in upper right.

were seen in all cases and were striking in some. Bronchiolar proliferation was seen less often, but was quite prominent in 3 cases (Fig. 8). Some degree of vascular change was seen in all cases. This consisted of intimai thickening, medial hypertrophy, or adventitial fibrosis. Proliferation of smooth muscle elements was noted in most cases and was striking in some. Attempts to identify specific organisms in these cases by culture or staining methods were uniformly negative. Most anatomists agree that the interstitial component of lung includes the alveolar wall, the interlobular septa, and the connective tissue around the bronchioles and the capillaries. Smith 23 states that fibrous tissue cells were rarely seen in normal alveolar cells, and he classifies chronic interstitial fibrosis into four stages: (1) thickening of the alveolar walls due to dilatation of the capillaries and swelling of the epithelial cells with edema, (2) a proliferation of the reticulin fibers in the alveolar walls, (3) the appearance of excess collagen in the alveolar walls, and (4) contraction of the fibrous tissue causing the lung to be compact and honeycombed (Fig. 9). ETIOLOGY

The etiology of chronic interstitial fibrosis remains unknown, although many factors related to the disease have been investigated. It is known that nitrous fumes (N0 2 ) cause an acute illness with pulmonary fibrosis, although acute necrotizing bronchiolitis is predominately found. Radiation will produce pulmonary fibrosis, but a history of this therapy obviates a diagnosis of chronic interstitial fibrosis of unknown etiology. Waddell, Sniffen, and Sweet29 have found high concentrations of cholesterol within the parenchyma of some patients,

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and Anderson and Foraker 1 have stated that there may be inciting factors leading to interstitial fibrosis associated with lipoid pneumonia and lymphohematogenous spread of carcinoma. Solomon25 has found that a secondary pul­ monary fibrosis occurs with pulmonary venous hypertension. Asbestos oxide and silica dioxide exposure show some degree of pulmonary interstitial fibrosis at various stages. Hamman and Rich12 believe that hypersensitivity may be a factor in causing the disease. Working on this hypothesis, Read20 prepared an anti-rat lung serum which causes pulmonary histologie changes similar to diffuse interstitial fibrosis when injected into a rat. He, therefore, believes that autoimmunity may be important as an etiologic factor in this disease entity. A diffuse thickening of the alveolar wall is also found in alveolar cell carcinoma. 3 The pulmonary changes occurring in prolonged therapy with hexamethonium 0 and with connective tissue diseases resemble chronic interstitial fibrosis.7 This is particularly true with rheumatoid arthritis. 21 · 2 * Other investigators consider virus infections as possible etiologic factors. 4 · 15 Therefore, the etiology remains obscure in any given case unless pertinent clinical and laboratory data are present to support one of the defined etiological processes. CLINICAL F I N D I N G S

The pathologic physiology has been defined by Baldwin, Cournand, and Richards. 2 The alveolar membrane thickening was found to be a primary ab­ normality responsible for a diffusion defect and a reduced arterial oxygen tension. The blood carbon dioxide tension usually remained within normal limits. The pulmonary function studies, however, disclosed a reduction in pulmonary compliance, and a diminished vital capacity with no evidence of expiratory ventilatory obstruction. Impaired diffusion is more common than the reduction of vital capacity. 31 Holland and Blacket14 studied 5 patients with the HammanRich syndrome with detailed spirometry. These showed a Γβάμοίίοη in lung volume with no emphasis on a particular subdivision reduction. The decreased ventilation was due largely to an increase in the physiologic dead space. In terminal stages, pulmonary circulation is also involved in the development of pulmonary hypertension and cor pulmonale. The clinical differential diagnosis may include connective tissue diseases, lymphohematogenous spread of carcinoma, cardiac decompensation, mycotic infection, unresolved pneumonias, pneumoconiosis, bronchiolar carcinoma, sarcoidosis, and the hexamethonium lung. Clinical diagnosis of interstitial fibrosis should be suspected on the basis of history, physical examination, and chest roentgenograms. An occupational history of prolonged exposure to coal, silica dioxide asbestos, bauxite, beryllium, or nitrous dioxide should exclude the diagnosis of chronic interstitial fibrosis of unknown etiology, as should a preceding knowl­ edge of tuberculosis or mycotic disease. A physical examination disclosing deforming arthritis, multiple metastatic nodules, evidence of scleroderma, or obvious cardiac decompensation would be most helpful in differentiating idiopathic pulmonary fibrosis from any of the previously mentioned disease states.

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THERAPY

Several authors during the past decade have reported that corticosteroid therapy is beneficial if given early in cases of diffuse interstitial fibrosis.8-19·21·28 A smaller proportion of patients display some improvement in pulmonary func­ tion,5- 18 as shown by objective studies, and there are, indeed several reports of patients showing evidence of roentgenographic clearing with corticosteroids. 5 - 9 - 19 > 22 Such a response seems reasonable in the early and formative stages of the fibrosis, but, unfortunately, one rarely sees these patients during the early disease process. Nevertheless, people with mature fibrosis, which is found by histological study, may benefit clinically from corticosteroids.16 Similarly, pa­ tients with long-standing fibrosis treated in the same manner are relatively unresponsive, 13 - 17 > 30 although an occasional patient may show some beneficial effects.18 If, indeed, hypersensitivity plays a significant role in the genesis of interstitial pulmonary fibrosis, it becomes readily apparent that some patients with long-standing cases will improve. 27 If, however, the etiology is related to iibrocystic dysplasia of the lung or pulmonary venous hypertension, it is again obvious that, even in the early phases of fibrosis, corticosteroids would not be beneficial. Since we are dealing with a disease of possible varying etiology and since many of these patients are responsive to corticosteroids, it seems logical that we should give the patient every opportunity for at least symptomatic relief with corticosteroids. In the literature and in our experience, dosages vary greatly. Duration of the therapy also varies from several days to several years before beneficial effects result. There is a recent trend to give larger doses; therefore, our series of patients has been treated with a high initial dose (an average of 70 mg. of prednisone per day) with gradual reduction in 3 months to a dose of 5 mg. of prednisone per day. Some patients in this group showed complete symptomatic relief while others revealed that a suppression of the progress of the disease is possible with steroids; 3 of the patients returned to work with complete relief, and with associated roentgen regression of the disease, 7 patients have had symptomatic suppression of the progress of the disease without roentgen re­ gression. Two children died rapidly despite corticosteroids, and 3 adult patients had an ingravescent course and died between 4 and 15 months after the initial treatment. Two patients did not receive steroids and are not showing a sympto­ matic progression of their disease. It is very encouraging and perhaps significant that all of the group with acute disease had quick remission of the disease on corticosteroid therapy, and are still doing very well. The autopsied patients without steroid therapy survived for an average of 20 months; whereas, the patients reported here on steroid therapy have an average longevity of 31 months to date. SUMMARY

Thirty-four cases of interstitial pulmonary fibrosis are presented, 17 in which the diagnosis was proved by lung biopsy, and 17 in which the diagnosis

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was verified at autopsy. Pertinent historical sources and findings are presented. Gross and histologie findings are discussed, and emphasis is placed on the nonspecificity of the lesions described. Predominant histological findings were fibrosis and inflammation in the interstitial spaces with thickened alveolar walls. Epithelial proliferation, both alveolar and bronchiolar, was seen in all cases to varying degrees. X-ray findings consisted of diffuse uniform reticular mottling with sym­ metrical small nodulation predominantly in the lower lung fields. All 34 patients met the following criteria : 1. Histological study of lung biopsy specimen revealed changes consistent with the disease and negative for any other specific entity. The specimen did not show a culture or stain positive for a specific organism. 2. There was a history of unremitting progression of dyspnea. 3. Chest roentgenogram disclosed diffuse reticular and/or fibronodular in­ filtrates consistent with pulmonary fibrosis. 4. Bronchoscopy was negative for gross abnormalities. 5. Sputum cultures were negative for significant pathogens. 6. Skin testing with histoplasmin, coccidiodin, blastomycin, and P P D was negative. (Nine of this group of patients had a positive PPD but no histologie findings on lung biopsy to support the diagnosis of tuberculosis.) The possible etiological factors are discussed. Emphasis is placed on hypersensitivity to some agent or material as being pertinent in the genesis of this disease. Pertinent pulmonary pathophysiologie defects are described. Fifteen of the 17 patients who had lung biopsies received cortieosteroid therapy. Ten of these 15 patients had symptomatic improvement. Possible explanation for this improvement is presented. On the basis of this improvement, it is recommended that corticosteroids be given a trial in all patients with this disease if a specific contraindication to such therapy does not exist. The authors wish to extend appreciation for support in the development of the article both in an advisory capacity and use of patients to Arthur M. Phillips, M.D., Weirton, West Virginia, for criticism and suggestions to Sol Katz, M.D., Chief, Medical Service VA Hospital, Washington, D. C , and Oscar Auerbach, M.D., Senior Clinical Investigator, VA Hospital, East Orange, N. J., and for editorial assistance to Miss Susanne Silberstein. REFERENCES

1. Anderson, A. E., Jr., and Foraker, A. G. : Morphological Aspects of Interstitial Pulmonary Fibrosis, A. M. A. Arch. Path. 70: 79, 1960. 2. Baldwin, E. deF., Cournand, A., and Richards, D. W., J r . : Pulmonary Insufficiency; A Study of 39 Cases of Pulmonary Fibrosis, Medicine 28: 1, 1949. 3. Beaver, D. L., and Shapiro, J . L.: A Consideration of Chronic Pulmonary Parenchymal Inflammation and Alveolar Cell Carcinoma With Regard to a Possible Etiologic Relationship, Am. J . Med. 2 1 : 879, 1956. 4 Cross K. R. : Diffuse Interstitial Pneumonitis ; Acute, Fibrosing, and Focal Healing Patterns, A. M. A. Arch. Path. 63: 132, 1957. 5. Doctor, L., and Snider, G. L. : Diffuse Interstitial Pulmonary Fibrosis Associated With Arthritis, Am. Rev. Resp. Dis. 85: 413, 1962. 6. Doniach, I., Morrison, B., and Steiner, R. E.: Lung Changes During Hexamethonium Therapy for Hypertension, Brit. Heart J . 16: 101, 1954. 7. Ellman, P., and Cudkowicz, L. : Pulmonary Manifestations in the Diffuse Collagen Diseases, Thorax 9: 46, 1954.

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8. Fleishman, S. J., Bosman, A. R., and Fuller, D. N. : Diffuse Interstitial Fibrosis of the Lungs, Am. J . Med. 24: 823, 1958. 9. Freedman, A., and Deaton, W. R., J r . : Diffuse Interstitial Fibrosis of the Lungs (Hamman-Rich Syndrome) : Successful Palliation of a Case With Steroid Therapy, Dis. Chest 34: 557, 1958. 10. Furstenberg, N. E. : Diffuse Interstitial Fibrosis of the Lung, Postgrad. Med. 27: 24, 1960. 11. Grant, I. W. B., Hillis, B. R., and Davidson, J . : Diffuse Interstitial Fibrosis of the Lungs (Hamman-Rich Syndrome), Am. Rev. Tuberc. 74: 485, 1956. 12. Hamman, L., and Rich, A. R. : Acute Diffuse Interstitial Fibrosis of the Lungs, Bull. Johns Hopkins Hosp. 74: 177, 1944. 13. Hoff, H. R.: The Hamman-Rich Syndrome, New England J . Med. 259: 81, 1958. 14. Holland, R. A. B., and Blacket, R. B. : Pulmonary Function in the Hamman-Rich Syndrome, Am. J . Med. 29: 955, 1960. 15. McCordock, H. A., and Muckenfuss, R. S.: The Similarity of Virus Pneumonia in Animals to Epidemic Influenza and Interstitial Broncho-pneumonia in Man, Am. J . Path. 9: 221, 1933. 16. Maxwell, W. M., and Campbell, P . E . : Hamman-Rich Syndrome (Diffuse Interstitial Pulmonary Fibrosis) M. J . Australia 47: 616, 1960. 17. Muschenheim, C. : Some Observations on the Hamman-Rich Disease, Am. J . M. Se. 241: 279, 1961. 18. Nahmias, B. B., Churchwell, A. G., and Bowles, F . N. : Diffuse Interstitial Fibrosis (Hamman-Rich Syndrome), Am. J . Med. 3 1 : 154, 1961. 19. Pinney, C. T., and Harris, H. W. : Hamman-Rich Syndrome. Report of a Case Diagnosed Antemortem by Lung Biopsy and Successfully Treated With Long-Term Cortisone Therapy, Am. J . Med. 20: 308, 1956. 20. Read, J . : The Pathogenesis of the Hamman-Rich Syndrome: A Review From the Stand­ point of Possible Allergic Etiology, Am. Rev. Tuberc. 78: 353, 1958. 21. Rubin, E. H., and Lubliner, R.: The Hamman-Rich Syndrome: Review of the Literature and Analysis of 15 Cases, Medicine 36: 397, 1957. 22. Schechter, M. M. : Diffuse Interstitial Fibrosis of the Lungs, Am. Rev. Tuberc. 68: 603, 1953. 23. Smith, K. V.: Chronic Diffuse Interstitial Pneumonia and Diffuse Interstitial Pulmonary Fibrosis, M. J . Australia 2: 244, 1961. 24. Smith, W. W., and Rothermich, N. O. : Diffuse Interstitial Fibrosis Complicating Rheu­ matoid Arthritis, Ohio M. J. 53: 773, 1957. 25. Solomon, M. : Interstitial Pulmonary Fibrosis Secondary to Pulmonary Venous Hyper­ tension, J . A. M. A. 174: 464, 1960. 26. Totten, Robert, M.D., Assoc. Prof. Pathology, University of Pittsburgh, and Pathologist, Presbyterian-University Hospital, Pittsburgh, Pa. : Personal communication. 27. Tuft, L., and Girsh, L. S.: Diffuse Interstitial Pulmonary Fibrosis (Hamman-Rich Syndrome) in an Allergic Patient, Am. J . M. Se. 235: 60, 1958. 28. Van Slyck, E. J . : Diffuse Interstitial Pulmonary Fibrosis (Hamman-Rich Syndrome), Dis. Chest 3 1 : 593, 1957. 29. Waddell, W. R., Sniffen, R. C , and Sweet, R. H . : Chronic Pneumonitis; I t s Clinical and Pathologic Importance. Report of Ten Cases Showing Interstitial Pneumonitis and Unusual Cholesterol Deposits, J . THORACIC SURG. 18: 707, 1949. 30. Wildberger, H. L., and Barclay, W. R. : Diffuse Interstitial Pulmonary Fibrosis, Ann. Int. Med. 4 3 : 1127, 1955. 31. Zohman, L. R., and Williams, M. H., J r . : Cardiopulmonary Function in Pulmonary Fibrosis, Am. Rev. Resp. Dis. 80: 700, 1959.