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Pulmonary Sarcoidosis
Pulmonary Sarcoidosis MARTIN M. CUMMINGS, M.D.* EDWARD DUNNER, M.D.**
ALTHOUGH the clinical manifestations of sarcoidosis were first described more than 80 years ago, the cause of the disease remains obscure. After Hutchinson 13 first described the disease in 1875, Besnier1 in 1889, Boeck2 in 1899 and Schaumann25 in 1917, each reported observations which more clearly defined certain clinical and pathologic features of the disease. Heerfordt,11 and more recently, Lofgren,17 Garland and Thompson, 9 and Longcope and Pierson 19 have made further contributions to the description of the disease. A definition of sarcoidosis was constructed by a Subcommittee of the National Research Council in 1948 and re-defined in October 1956.t As sarcoidosis has become recognized more frequently in the United States, many reports have brought into clearer focus the criteria for diagnosis, but unfortunately, they have shed little light on the cause of the disease. ETIOLOGY
Sarcoidosis has been observed in many parts of the world. In Europe, and particularly in Scandinavia where the Negro population is low, the
* Director, Research Service, Veterans Administration, Washington, D.C. ** Chief, Clinical Studies Division, Research Service, Veterans Administration, Washington, D.G.
t "Sarcoidosis is a systemic disease, or group of diseases, of undetermined etiology and pathogenesis. Histologically, it is marked by the presence of epithelioid-cell tubercles, showing little or no necrosis. Varying types of inclusions in giant cells may be present but are not pathognomonic. A similar histological picture may be found in certain other diseases, especially in infectious granulomas and in beryllium poisoning. Clinically, the disease most commonly involves lymph nodes, lungs, skin, eyes, liver, spleen and phalangeal bones. The course is usually chronic and constitutional symptoms vary markedly. More specific symptoms, when present, relate to the tissues and organs involved. "The diagnosis of sarcoidosis is based upon the above clinical features associated with a compatible histological picture, provided beryllium poisoning and known infectious processes can be excluded. "Spontaneous clinical recovery, with or without recognizable fibrosis, may result, or sarcoidosis may persist for years with varying functional alteration of the tissues or organs involved, or the disease may follow a progressive course ending fatally." 163
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Martin M. Cummings, Edward Dunner
disease occurs more commonly in the white race. In the United States, on the other hand, the disease occurs more commonly in Negroes. There seemingly are very few cases among American Indians. Few cases of the disease have been reported from Negroid Africa, which may only reflect a lack of familiarity with or lack of interest in the disease on that continent. The Chinese seem to be peculiarly exempt. The disease has been observed in children above seven years of age, rarely earlier, but its onset occurs most frequently between the ages of 20 and 40 years. Both sexes appear to be affected with equal frequency, although various reports disagree on this point. Many clinicians have argued that sarcoidosis is a manifestation of tuberculosis because the lesions resemble miliary tubercles histologically. They also point out that patients with sarcoidosis not infrequently die of tuberculosis. However, the rarity of demonstration of tubercle bacilli within the lesions and the frequent occurrence of negative skin reactions to tuberculin (60 to 70 per cent) would tend to disfavor the argument that the disease is a manifestation of tuberculosis. Patients with sarcoidosis appear to be equally unresponsive to other skin-testing antigens (Friou,8 Sones and IsraeP7). Those "vho believe that sarcoidosis is not related to tuberculosis argue that the rarity of caseation necrosis makes it most unlikely that the disease is due to Mycobacterium tuberculosis. Many other theories relative to the cause of the disease have been advanced and considered. Leprosy, brucellosis, syphilis, and infections due to viruses, fungi, protozoa and helminths have been considered to be inciting causes, but no proof has been advanced to support these hypotheses. Concepts of the cause of the disease have been reviewed by J acques 14 and Longcope. 18 Refvem22 analyzed tissue obtained from patients with sarcoidosis and suggested that calcareous spar found in certain soil types may be a possible etiologic agent. He also demonstrated that quartz particles and other foreign bodies may provoke localized sarcoid formation. Refvem's studies also led him to suggest that the epithelioid cell formation occurs when the primary irritant is an antigen capable of stimulating antibodies which contain or accumulate phospholipid. More recently the similarity of sarcoidosis to berylliosis and to histoplasmosis has been described. 12 , 6 EPIDEMIOLOG Y
It has been most difficult to determine the true incidence or prevalence of sarcoidosis, since most reports in the literature deal with small numbers of cases usually seen in hospitals situated in large cities. Freiman, 7 in 1948, reviewed the literature and suggested that there were more than 1000 cases of sarcoidosis in the United States. Since recognition of the disease may be difficult, its true incidence is undoubtedly much higher than currently suspected. Indeed, the Veterans Administration already has collected several thousand cases from among its population group.
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165
After the observation of Ransmeier21 that sarcoidosis among the military occurred predominantly in personnel from the southeastern part of the country, Michael and his associates,2°' 10 made an intensive epidemiologic study of the disease. They reviewed the records of 350 veterans who had sarcoidosis during W orld War 11, and confirmed the fact that most of these patients were born in the southeastern part of the United States. The birthplaces were strikingly rural, especially when population densities were considered. The incidence of the disease in Negro veterans was 20 times as great as it was in white veterans when calculated by number of instances of the disease per 100,000 inductees. These authors suggested that the environment of the area in which the disease was endemic might be responsible for the geographic distribution, and they postulated that the distribution could be related to the type of soil predominant in the southeastern part of the United States. Sarcoidosis was diagnosed in 1700 patients who had been seen in Veterans Administration hospitals between 1949 and 1956. The case records of 1194 of these patients diagnosed during the five-year period 1949-1954, were reviewed. 3 , 5 Information concerning age, race, sex, place and date of birth was analyzed. The most striking finding was the geographic distribution of· the disease, revealing an endemic area in eastern United States. To this degree, this study confirmed the earlier observation on distribution made by Michael et al. on a group of service men with sarcoidosis. The major difference between these studies was the finding among veterans of significant numbers of patients with sarcoidosis in New England and the North Central States. A review of ecologic factors which correlated with the distribution of this disease suggested that some aspect of the eastern forest distribution, where pine is the predominant tree, might be an important enviornmental factor related to the etiology of the disease. The distribution of birthplaces of veteran patients diagnosed as having sarcoidosis correlated better with pine forests than it did with the sandy soil distribution suggested by Gentry et al. as a possible factor related to the geographic concentration of patients with sarcoidosis. Pine pollen was suggested as a possible inciting agent. 4 However, proof is still lacking to establish it as a cause, in whole or in part, of the clinical disease or syndrome. PATHOLOGY
The disease is characterized by granuloma formation. The lesions are composed of epithelioid cell collections with multinucleated giant cells interspersed. The giant cells often contain doubly refractile bodies (Schaumann 24 ) with histochemical evidence that they are calcium salts (Johnson 15 ). The protoplasm of the giant cells at times also contain small basophilic inclusion bodies known as asteroid bodies because of their configuration. Necrosis is rare, caseation does not occur. Histologically the lesions appear to heal by fibrosis and hyalinization.
166
Martin M. Cummings, Edward Dunner
The granulomas may be widely scattered throughout many organs or may be found as a single well-defined infiltrating mass in one site. Such lesions have been noted in the lungs, lymph nodes, liver, spleen, kidney, endocrine glands, skin, mucous membrane, lacrimal and salivary glands, tonsil, eye, prostate, testis, bone and voluntary muscle. On occasion the bone marrow will reveal epithelioid cell nests. PATHOLOGICAL PHYSIOLOGY
Physiologic disturbances reflect the principal sites of involvement. Extensive pulmonary sarcoidosis may induce pulmonary fibrosis and ultimately cor pulmonale. Impaired diffusion of gases through the lung may be detected by modern pulmonary function measurements. Dyspnea, cough and fatigue are early manifestations of pulmonary involvements. Arrhythmia and heart failure may result from myocardial involvement. Involvement of the endocrines may produce diabetes insipidus (pituitary) or myxedema (thyroid). Adrenal involvement is rare. Kidney involvement may lead to renal insufficiency and at times frank uremia. The finding of renal calculi associated with hypercalcinemia and hypercalcinuria is not uncommon. Loss of vision may result from the uveoparotid involvement. Involvement of the terminal phalangeal bones rarely leads to symptoms or deformities. The cutaneous lesions may be disfiguring but do not cause symptoms as a rule. CLINICAL FEATURES
Almost any organ or tissue of the body may be affected, but the extent to which this takes place varies considerably. Symptoms may be absent despite the enlargement of a few superficial lymph nodes or the presence of abnormal shadows in the lung discovered in a routine x-ray of the chest. When constitutional symptoms are present the extent of the pulmonary lesions are, as a rule, out of all proportion to the symptomatic complaints. In a series of 175 patients with histologic evidence of sarcoidosis admitted to Veterans Administration hospitals, symptoms which could be related to sarcoidosis were present in all but 10 per cent of the patients. A most frequent symptom was nonproductive cough which occurred in the morning or at night. In patients in whom the cough was productive, the sputum was described as mucoid, white to yellow in color. In order of decreasing frequency this was followed by weight loss, dyspnea, fatigue and chest pain. Night sweats and arthralgia may also occur. Occasionally, a paroxysm of coughing caused hemoptysis, emesis or syncope. Physical signs consist of diffuse rales and rhonchi when the lungs are involved. Clubbing of the fingers is rare. Signs of pulmonary hypertension may be found in long-standing cases. The lungs and hilar lymph nodes were involved in 97 per cent of the
Pulmonary Sarcoidosis
167
patients reviewed. Lesions may occur in any part of the respiratory tract from the mucous membrane of the nose and accessory facial sinuses to the alveolar walls. Involvement of the bones of the hands and feet are not common findings, although some reports suggest that they occur in 10 to 15 per cent of cases. Shadows due to involvement of hilar lymph nodes bilaterally, and the right paratracheallymph nodes, form the classical x-ray picture of early pulmonary sarcoidosis. An excellent description of bilateral hilar lymphadenopathy and the erythema nodosum which is often associated with it has been reported by Lofgren. 16 Erythema nodosum is more uncommon in sarcoidosis as it occurs in the United States when compared with European experience. LABORATORY FINDINGS
The results of clinical laboratory tests performed in this group of 175 veteran patients are shown in the table below. Hyperglobulinemia occurred most frequently (88 per cent). In order of decreasing frequency this was followed by increased serum calcium, increased alkaline phosphatase, leukopenia and eosinophilia. RESULTS OF LABORATORY TESTS IN PATIENTS WITH HISTOLOGIC EVIDENCE OF SARCOIDOSIS NO. OF PATIENTS TESTED
Protein@mia (greater than 7.9) A/G ratio (less than 2.1). . . . . . . . . . . . . . . . . . . . . . . .. " Alkaline-phosphatase (greater than 5 B.U.) Serum calcium (greater than 11) Leukopenia (less than 5000) Eosinophilia (greater than 7) . . . . . . . . . . . . . . . . . . . "
166 162 78 113 175 175
PER CENT OJ;"' THOSE TEf::TED
30 88
29
35
29
16
DIAGNOSIS
The diagnosis of sarcoidosis is dependent upon the thorough exclusion of infectious granulomatous diseases, neoplasms and certain pneumoconioses as well as the availability of tissue (biopsy) confirmation. A biopsy compatible with sarcoidosis may not be considered unequivocal proof of the diagnosis, since beryllium poisoning and histoplasmosis may evoke the same type of histological response. Enlarged hilar and tracheobronchial lymph nodes of sarcoidosis are difficult to differentiate from Hodgkin's disease, lymphosarcoma and tuberculosis (Longcope). Skin lesions are easily confused with lupus and tuberculosis. Involvement of the eye closely mimics tuberculosis and syphilis. A negative tuberculin test and repeatedly negative sputum cultures for tubercle bacilli strongly point away from tuberculosis. Parotid
168
Martin M. Cummings, Edward Dunner
involvement along with iridocyclitis or uveitis is more commonly associated with sarcoidosis. Peribronchial infiltrations radiating from the hilum associated with "potato-like" bilateral lymph node involvement are the most characteristic x-ray findings. Miliary lesions and nodular masses scattered throughout the lungs may also be found. These x-ray shadows change significantly with exacerbations and remissions of the disease. These findings, when accompanied by hyperglobulinemia, hypercalcemia and eosinophilia point to the diagnosis of sarcoidosis. A negative tuberculin reaction is additional comforting confirmative evidence. Pathological confirmation of the clinical diagnosis is usually made from biopsy of lymph nodes, lung, liver or skin. The only test thought to be specific for sarcoidosis is the NickersonKveim cutaneous reaction. Its practical value is some,vhat diminished because it may often take "veeks or months for the reaction to appear. Since the antigen used is crude and unstandardized (homogenate of sarcoidosis lymph node or spleen) it is necessary to biopsy the cutaneous site of injection to be certain the reaction is a sarcoid granuloma and not a foreign body reaction (Siltzbach26 ). There is a pressing need for a purified standardized extract or antigen to be used as a diagnostic test. COURSE AND PROGNOSIS
The course of the disease is notably variable. In the lungs, progression of the disease by x-ray obEervation may give rise to peribronchial infiltrations, to nodular masses scattered bilaterally throughout the parenchyma or to diffuse and confluent infiltrations. Spontaneous remission can occur. As progression of the disease occurs, the infiltrating lesions become fibrotic and frequently result in emphysema which, when sufficiently pronounced, produces extreme degrees of dyspnea and cyanosis. Fibrosis of the lesions may give rise to an alveolar capillary block ,vith impairment of pulmonary compliance resulting in pulmonary hypertension and cor pulmonale. Secondary infections are common, and a certain proportion of the patients develop rapidly progressive pulmonary tuberculosis. Other complications such as histoplasmosis, coccidioidomycosis and aspergillosis have been described but are not common. In spite of the comparatively favorable prognosis in the majority of the cases with hilar lymphadenopathy (Scadding23 ), pulmonary sarcoidosis is not as benign a disease as it is generally stated to be. Of 540 patients admitted to Veterans Administration hospitals ,vith a diagnosis of sarcoidosis between the years 1949 and 1951,84 (15 per cent) died within a five year period. Autopsy was performed in 50 of these 84 patients. In 19 of the 50 autopsied cases tuberculosis, carcinoma (usually metastatic), Hodgkin's disease and tuberculosis were found to have been confused with sar-
Pulmonary Sarcoidosis
169
coidosis. This indicates that a clinical diagnosis even supported by biopsy may at times be in error. The most frequent case of death was cor pulmonale. Tuberculosis was found in nine of the 50 patients studied at necropsy. It is difficult to deterlnine whether the 19 patients who demonstrated no evidence of sarcoidosis at death represent a group who had complete resolution of their disease process during this five year period or whether they never had the disease at the outset.
TREATMENT While there is no kno\vn definitive therapy, steroids are currently the popular method of treatment. Conclusions as to the benefits of this therapeutic procedure are difficult to evaluate because of the spontaneous remissions which frequently occur in sarcoidosis. Steroids cannot be expected to affect irreversible fibrosis but frequently do result in symptomatic improvement. The duration of treatment should be individualized based upon the severity of symptoms and the initial response. Exacerbation after cessation of therapy may occur especially if the length of treatment is too short. Best results appear to be obtained "Tith sustained use of the newer corticosteroids. Antituberculosis drugs such as streptomycin, isoniazid and paraaminosalicylic acid (PAS) do not affect the course of the disease. There are conflicting opinions relative to the necessity of adding these drugs to cortisone as prophylaxis against the hypothetical development of tuberculosis in patients with sarcoidosis. In the absence of a positive tuberculin reaction, it would appear unnecessary to give antituberculosis drugs.
REFERENCES 1. Besnier, E.: Lupus pernio de la face; synovitis fongeuses (scrofulotuberculeuses) symetriques des extremites superieures. Ann. de dermat. et syph. 10: 333, 1889. 2. Boeck, C.: Multiple Benign Sarkoid of Skin. J. Cutan. Dis. 17: 543 (Dec.) 1899. 3. Cummings, M. M., Dunner, E., Schmidt, R. H. Jr. and Barnwell, J. B.: Concepts of Epidemiology of Sarcoidosis. Postgraduate Med. 19: 437 (May) 1956. 4. Cummings, M. M. and Hudgins, P. C.: Chemical Constituents of Pine Pollen and Their Possible Relationship to Sarcoidosis. Am. J. M. Se. 236: 311, 1958. 5. Dunner, E., Cummings, M. M., Williams, J. H. Jr., Schmidt, R. H. Jr. and Barnwell, J. B.: A New Look at Sarcoidosis. J. South. M. A. 50: 1141 (Sept.) 1957. 6. Fisher, A. M. (Discussion): Some Clinical and Pathological Features Observed in Sarcoidosis. Tr. Am. Climatol. & Clin.. A. 59: 73,1947. 7. Freiman, ]). C.: Sarcoidosis. New England J. Med. 239: 664 (Oct. 28) 1948; ibid. 239: 709 (Nov. 4) 1948; ibid. 239: 743 (Nov. 11) 1948. 8. Friou, G. J.: A Study of the Cutaneous Reactions to Oidiomycin, Trichophytin, and Mumps Skin Test Antigens in Patients with Sarcoidosis. Yale J. BioI. Med. 24:533,1952. 9. Garland, H. C. and Thompson, J. C.: Uveo-parotid Tuberculosis (Febris Uveoparotidea of Heerfordt). Quart. J. Med. 2:157 (April) 1933. 10. Gentry, J. T., Nitowsky, H. M. and Michael, M. Jr.: Studies on the Epidemiology
170 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
Martin M. Cummings, Edward Dunner
of Sarcoidosis in the United States; the Relationship to Soil Areas and to Urban-Rural Residence. J. Clin. Invest. 34: 1839, 1955. Heerfordt, C. F.: tJber eine "Febris Uveo-parotideasubchronica" an der Glandula Parotis und der Ulvea des Auges lokalisiert und haufig mit Parsen cerebrospinaler Nerven kompliziert. Arch. f. Ophth. 70: 254, 1909. Higgins, H. L.: Pulmonary Sarcoidosis. Connecticut M. J. 11: 330 (May) 1947. Hutchinson, J.: Cases of Mortimer's Malady (Lupus Vulgaris Multiplex Nonulcerans et Non-serpiginosus). Arch. Surge (London) 9: 307, 1898. Jacques, W. E.: Sarcoidosis; a review and a proposed etiologic concept. Arch. Path. 53: 558 (June) 1952. Johnson, Frank: Personal communication. Lofgren, S.: Erythema N odosum. Studies on Etiology and Pathogenesis in 185 Adult Cases. Acta med. scandinav. (supp. 174) 1946. Lofgren, S.: Primary Pulmonary Sardoidosis. I. Early Signs and Symptoms. Acta med. scandinav. 145: 424, 1953. Longcope, W. T.: Sarcoidosis. Veterans Admin. Techn. Bull. TB-73, May 10, 1951, p. 1. Longcope, W. T. and Piersoll, J. W.: Boeck's Sarcoid (Sarcoidosis). Bull. Johns Hopkins Hosp. 60: 223 (April) 1937. . Michael, M. Jr., Cole, R. M., Beeson, P. B. and Olson, B. J.: Sarcoidosis; Preliminary Report on a Study of 350 Cases with Special Reference to Epidemiology. Am. Rev. Tuberc. 62: 403 (Oct.) 1950. Ransmeier, J. C.: Minutes of the Conference on Sarcoidosis. National Research Council, Division of Medical Sciences, p. 5, February 11, 1948. Refvem, 0.: Pathogenesis of Boeck's Disease (Sarcoidosis). Acta med. scandinav. (supp. 294) 149: 1, 1954. Scadding, J. G.: Discussion on Sarcoidosis. Proc. Roy. Soc. Med. 49: 799, 1956. Schaumann, J.: Lymphogranulomatosis Benigna in Light of Prolonged Clinical Observations and Autopsy Findings. Brit. J. Dermat. 48: 399, 1936. Schaumann, J. : Etude sur le lupus pernio et ses rapports avec les sarcoides et la tuberculose. Ann. de dermat. et syph. 6: 357, 1916-1917. Siltzbach, L. E. and Ehrlich, J. C.: The Nickerson-Kveim Reaction in Sarcoidosis. Am. J. Med. 16: 790, 1954. Sones, M. and Israel, H. L. : Altered Immunologic Reactions in Sarcoidosis. Ann. Intern. Med. 4-0: 260, 1954.
ALTHOUGH the clinical manifestations of sarcoidosis were first described more than 80 years ago, the cause of the disease remains obscure. After Hutchinson 13 first described the disease in 1875, Besnier1 in 1889, Boeck2 in 1899 and Schaumann25 in 1917, each reported observations which more clearly defined certain clinical and pathologic features of the disease. Heerfordt,11 and more recently, Lofgren,17 Garland and Thompson, 9 and Longcope and Pierson 19 have made further contributions to the description of the disease. A definition of sarcoidosis was constructed by a Subcommittee of the National Research Council in 1948 and re-defined in October 1956.t As sarcoidosis has become recognized more frequently in the United States, many reports have brought into clearer focus the criteria for diagnosis, but unfortunately, they have shed little light on the cause of the disease. ETIOLOGY
Sarcoidosis has been observed in many parts of the world. In Europe, and particularly in Scandinavia where the Negro population is low, the
* Director, Research Service, Veterans Administration, Washington, D.C. ** Chief, Clinical Studies Division, Research Service, Veterans Administration, Washington, D.G.
t "Sarcoidosis is a systemic disease, or group of diseases, of undetermined etiology and pathogenesis. Histologically, it is marked by the presence of epithelioid-cell tubercles, showing little or no necrosis. Varying types of inclusions in giant cells may be present but are not pathognomonic. A similar histological picture may be found in certain other diseases, especially in infectious granulomas and in beryllium poisoning. Clinically, the disease most commonly involves lymph nodes, lungs, skin, eyes, liver, spleen and phalangeal bones. The course is usually chronic and constitutional symptoms vary markedly. More specific symptoms, when present, relate to the tissues and organs involved. "The diagnosis of sarcoidosis is based upon the above clinical features associated with a compatible histological picture, provided beryllium poisoning and known infectious processes can be excluded. "Spontaneous clinical recovery, with or without recognizable fibrosis, may result, or sarcoidosis may persist for years with varying functional alteration of the tissues or organs involved, or the disease may follow a progressive course ending fatally." 163
164
Martin M. Cummings, Edward Dunner
disease occurs more commonly in the white race. In the United States, on the other hand, the disease occurs more commonly in Negroes. There seemingly are very few cases among American Indians. Few cases of the disease have been reported from Negroid Africa, which may only reflect a lack of familiarity with or lack of interest in the disease on that continent. The Chinese seem to be peculiarly exempt. The disease has been observed in children above seven years of age, rarely earlier, but its onset occurs most frequently between the ages of 20 and 40 years. Both sexes appear to be affected with equal frequency, although various reports disagree on this point. Many clinicians have argued that sarcoidosis is a manifestation of tuberculosis because the lesions resemble miliary tubercles histologically. They also point out that patients with sarcoidosis not infrequently die of tuberculosis. However, the rarity of demonstration of tubercle bacilli within the lesions and the frequent occurrence of negative skin reactions to tuberculin (60 to 70 per cent) would tend to disfavor the argument that the disease is a manifestation of tuberculosis. Patients with sarcoidosis appear to be equally unresponsive to other skin-testing antigens (Friou,8 Sones and IsraeP7). Those "vho believe that sarcoidosis is not related to tuberculosis argue that the rarity of caseation necrosis makes it most unlikely that the disease is due to Mycobacterium tuberculosis. Many other theories relative to the cause of the disease have been advanced and considered. Leprosy, brucellosis, syphilis, and infections due to viruses, fungi, protozoa and helminths have been considered to be inciting causes, but no proof has been advanced to support these hypotheses. Concepts of the cause of the disease have been reviewed by J acques 14 and Longcope. 18 Refvem22 analyzed tissue obtained from patients with sarcoidosis and suggested that calcareous spar found in certain soil types may be a possible etiologic agent. He also demonstrated that quartz particles and other foreign bodies may provoke localized sarcoid formation. Refvem's studies also led him to suggest that the epithelioid cell formation occurs when the primary irritant is an antigen capable of stimulating antibodies which contain or accumulate phospholipid. More recently the similarity of sarcoidosis to berylliosis and to histoplasmosis has been described. 12 , 6 EPIDEMIOLOG Y
It has been most difficult to determine the true incidence or prevalence of sarcoidosis, since most reports in the literature deal with small numbers of cases usually seen in hospitals situated in large cities. Freiman, 7 in 1948, reviewed the literature and suggested that there were more than 1000 cases of sarcoidosis in the United States. Since recognition of the disease may be difficult, its true incidence is undoubtedly much higher than currently suspected. Indeed, the Veterans Administration already has collected several thousand cases from among its population group.
Pulmonary Sarcoidosis
165
After the observation of Ransmeier21 that sarcoidosis among the military occurred predominantly in personnel from the southeastern part of the country, Michael and his associates,2°' 10 made an intensive epidemiologic study of the disease. They reviewed the records of 350 veterans who had sarcoidosis during W orld War 11, and confirmed the fact that most of these patients were born in the southeastern part of the United States. The birthplaces were strikingly rural, especially when population densities were considered. The incidence of the disease in Negro veterans was 20 times as great as it was in white veterans when calculated by number of instances of the disease per 100,000 inductees. These authors suggested that the environment of the area in which the disease was endemic might be responsible for the geographic distribution, and they postulated that the distribution could be related to the type of soil predominant in the southeastern part of the United States. Sarcoidosis was diagnosed in 1700 patients who had been seen in Veterans Administration hospitals between 1949 and 1956. The case records of 1194 of these patients diagnosed during the five-year period 1949-1954, were reviewed. 3 , 5 Information concerning age, race, sex, place and date of birth was analyzed. The most striking finding was the geographic distribution of· the disease, revealing an endemic area in eastern United States. To this degree, this study confirmed the earlier observation on distribution made by Michael et al. on a group of service men with sarcoidosis. The major difference between these studies was the finding among veterans of significant numbers of patients with sarcoidosis in New England and the North Central States. A review of ecologic factors which correlated with the distribution of this disease suggested that some aspect of the eastern forest distribution, where pine is the predominant tree, might be an important enviornmental factor related to the etiology of the disease. The distribution of birthplaces of veteran patients diagnosed as having sarcoidosis correlated better with pine forests than it did with the sandy soil distribution suggested by Gentry et al. as a possible factor related to the geographic concentration of patients with sarcoidosis. Pine pollen was suggested as a possible inciting agent. 4 However, proof is still lacking to establish it as a cause, in whole or in part, of the clinical disease or syndrome. PATHOLOGY
The disease is characterized by granuloma formation. The lesions are composed of epithelioid cell collections with multinucleated giant cells interspersed. The giant cells often contain doubly refractile bodies (Schaumann 24 ) with histochemical evidence that they are calcium salts (Johnson 15 ). The protoplasm of the giant cells at times also contain small basophilic inclusion bodies known as asteroid bodies because of their configuration. Necrosis is rare, caseation does not occur. Histologically the lesions appear to heal by fibrosis and hyalinization.
166
Martin M. Cummings, Edward Dunner
The granulomas may be widely scattered throughout many organs or may be found as a single well-defined infiltrating mass in one site. Such lesions have been noted in the lungs, lymph nodes, liver, spleen, kidney, endocrine glands, skin, mucous membrane, lacrimal and salivary glands, tonsil, eye, prostate, testis, bone and voluntary muscle. On occasion the bone marrow will reveal epithelioid cell nests. PATHOLOGICAL PHYSIOLOGY
Physiologic disturbances reflect the principal sites of involvement. Extensive pulmonary sarcoidosis may induce pulmonary fibrosis and ultimately cor pulmonale. Impaired diffusion of gases through the lung may be detected by modern pulmonary function measurements. Dyspnea, cough and fatigue are early manifestations of pulmonary involvements. Arrhythmia and heart failure may result from myocardial involvement. Involvement of the endocrines may produce diabetes insipidus (pituitary) or myxedema (thyroid). Adrenal involvement is rare. Kidney involvement may lead to renal insufficiency and at times frank uremia. The finding of renal calculi associated with hypercalcinemia and hypercalcinuria is not uncommon. Loss of vision may result from the uveoparotid involvement. Involvement of the terminal phalangeal bones rarely leads to symptoms or deformities. The cutaneous lesions may be disfiguring but do not cause symptoms as a rule. CLINICAL FEATURES
Almost any organ or tissue of the body may be affected, but the extent to which this takes place varies considerably. Symptoms may be absent despite the enlargement of a few superficial lymph nodes or the presence of abnormal shadows in the lung discovered in a routine x-ray of the chest. When constitutional symptoms are present the extent of the pulmonary lesions are, as a rule, out of all proportion to the symptomatic complaints. In a series of 175 patients with histologic evidence of sarcoidosis admitted to Veterans Administration hospitals, symptoms which could be related to sarcoidosis were present in all but 10 per cent of the patients. A most frequent symptom was nonproductive cough which occurred in the morning or at night. In patients in whom the cough was productive, the sputum was described as mucoid, white to yellow in color. In order of decreasing frequency this was followed by weight loss, dyspnea, fatigue and chest pain. Night sweats and arthralgia may also occur. Occasionally, a paroxysm of coughing caused hemoptysis, emesis or syncope. Physical signs consist of diffuse rales and rhonchi when the lungs are involved. Clubbing of the fingers is rare. Signs of pulmonary hypertension may be found in long-standing cases. The lungs and hilar lymph nodes were involved in 97 per cent of the
Pulmonary Sarcoidosis
167
patients reviewed. Lesions may occur in any part of the respiratory tract from the mucous membrane of the nose and accessory facial sinuses to the alveolar walls. Involvement of the bones of the hands and feet are not common findings, although some reports suggest that they occur in 10 to 15 per cent of cases. Shadows due to involvement of hilar lymph nodes bilaterally, and the right paratracheallymph nodes, form the classical x-ray picture of early pulmonary sarcoidosis. An excellent description of bilateral hilar lymphadenopathy and the erythema nodosum which is often associated with it has been reported by Lofgren. 16 Erythema nodosum is more uncommon in sarcoidosis as it occurs in the United States when compared with European experience. LABORATORY FINDINGS
The results of clinical laboratory tests performed in this group of 175 veteran patients are shown in the table below. Hyperglobulinemia occurred most frequently (88 per cent). In order of decreasing frequency this was followed by increased serum calcium, increased alkaline phosphatase, leukopenia and eosinophilia. RESULTS OF LABORATORY TESTS IN PATIENTS WITH HISTOLOGIC EVIDENCE OF SARCOIDOSIS NO. OF PATIENTS TESTED
Protein@mia (greater than 7.9) A/G ratio (less than 2.1). . . . . . . . . . . . . . . . . . . . . . . .. " Alkaline-phosphatase (greater than 5 B.U.) Serum calcium (greater than 11) Leukopenia (less than 5000) Eosinophilia (greater than 7) . . . . . . . . . . . . . . . . . . . "
166 162 78 113 175 175
PER CENT OJ;"' THOSE TEf::TED
30 88
29
35
29
16
DIAGNOSIS
The diagnosis of sarcoidosis is dependent upon the thorough exclusion of infectious granulomatous diseases, neoplasms and certain pneumoconioses as well as the availability of tissue (biopsy) confirmation. A biopsy compatible with sarcoidosis may not be considered unequivocal proof of the diagnosis, since beryllium poisoning and histoplasmosis may evoke the same type of histological response. Enlarged hilar and tracheobronchial lymph nodes of sarcoidosis are difficult to differentiate from Hodgkin's disease, lymphosarcoma and tuberculosis (Longcope). Skin lesions are easily confused with lupus and tuberculosis. Involvement of the eye closely mimics tuberculosis and syphilis. A negative tuberculin test and repeatedly negative sputum cultures for tubercle bacilli strongly point away from tuberculosis. Parotid
168
Martin M. Cummings, Edward Dunner
involvement along with iridocyclitis or uveitis is more commonly associated with sarcoidosis. Peribronchial infiltrations radiating from the hilum associated with "potato-like" bilateral lymph node involvement are the most characteristic x-ray findings. Miliary lesions and nodular masses scattered throughout the lungs may also be found. These x-ray shadows change significantly with exacerbations and remissions of the disease. These findings, when accompanied by hyperglobulinemia, hypercalcemia and eosinophilia point to the diagnosis of sarcoidosis. A negative tuberculin reaction is additional comforting confirmative evidence. Pathological confirmation of the clinical diagnosis is usually made from biopsy of lymph nodes, lung, liver or skin. The only test thought to be specific for sarcoidosis is the NickersonKveim cutaneous reaction. Its practical value is some,vhat diminished because it may often take "veeks or months for the reaction to appear. Since the antigen used is crude and unstandardized (homogenate of sarcoidosis lymph node or spleen) it is necessary to biopsy the cutaneous site of injection to be certain the reaction is a sarcoid granuloma and not a foreign body reaction (Siltzbach26 ). There is a pressing need for a purified standardized extract or antigen to be used as a diagnostic test. COURSE AND PROGNOSIS
The course of the disease is notably variable. In the lungs, progression of the disease by x-ray obEervation may give rise to peribronchial infiltrations, to nodular masses scattered bilaterally throughout the parenchyma or to diffuse and confluent infiltrations. Spontaneous remission can occur. As progression of the disease occurs, the infiltrating lesions become fibrotic and frequently result in emphysema which, when sufficiently pronounced, produces extreme degrees of dyspnea and cyanosis. Fibrosis of the lesions may give rise to an alveolar capillary block ,vith impairment of pulmonary compliance resulting in pulmonary hypertension and cor pulmonale. Secondary infections are common, and a certain proportion of the patients develop rapidly progressive pulmonary tuberculosis. Other complications such as histoplasmosis, coccidioidomycosis and aspergillosis have been described but are not common. In spite of the comparatively favorable prognosis in the majority of the cases with hilar lymphadenopathy (Scadding23 ), pulmonary sarcoidosis is not as benign a disease as it is generally stated to be. Of 540 patients admitted to Veterans Administration hospitals ,vith a diagnosis of sarcoidosis between the years 1949 and 1951,84 (15 per cent) died within a five year period. Autopsy was performed in 50 of these 84 patients. In 19 of the 50 autopsied cases tuberculosis, carcinoma (usually metastatic), Hodgkin's disease and tuberculosis were found to have been confused with sar-
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coidosis. This indicates that a clinical diagnosis even supported by biopsy may at times be in error. The most frequent case of death was cor pulmonale. Tuberculosis was found in nine of the 50 patients studied at necropsy. It is difficult to deterlnine whether the 19 patients who demonstrated no evidence of sarcoidosis at death represent a group who had complete resolution of their disease process during this five year period or whether they never had the disease at the outset.
TREATMENT While there is no kno\vn definitive therapy, steroids are currently the popular method of treatment. Conclusions as to the benefits of this therapeutic procedure are difficult to evaluate because of the spontaneous remissions which frequently occur in sarcoidosis. Steroids cannot be expected to affect irreversible fibrosis but frequently do result in symptomatic improvement. The duration of treatment should be individualized based upon the severity of symptoms and the initial response. Exacerbation after cessation of therapy may occur especially if the length of treatment is too short. Best results appear to be obtained "Tith sustained use of the newer corticosteroids. Antituberculosis drugs such as streptomycin, isoniazid and paraaminosalicylic acid (PAS) do not affect the course of the disease. There are conflicting opinions relative to the necessity of adding these drugs to cortisone as prophylaxis against the hypothetical development of tuberculosis in patients with sarcoidosis. In the absence of a positive tuberculin reaction, it would appear unnecessary to give antituberculosis drugs.
REFERENCES 1. Besnier, E.: Lupus pernio de la face; synovitis fongeuses (scrofulotuberculeuses) symetriques des extremites superieures. Ann. de dermat. et syph. 10: 333, 1889. 2. Boeck, C.: Multiple Benign Sarkoid of Skin. J. Cutan. Dis. 17: 543 (Dec.) 1899. 3. Cummings, M. M., Dunner, E., Schmidt, R. H. Jr. and Barnwell, J. B.: Concepts of Epidemiology of Sarcoidosis. Postgraduate Med. 19: 437 (May) 1956. 4. Cummings, M. M. and Hudgins, P. C.: Chemical Constituents of Pine Pollen and Their Possible Relationship to Sarcoidosis. Am. J. M. Se. 236: 311, 1958. 5. Dunner, E., Cummings, M. M., Williams, J. H. Jr., Schmidt, R. H. Jr. and Barnwell, J. B.: A New Look at Sarcoidosis. J. South. M. A. 50: 1141 (Sept.) 1957. 6. Fisher, A. M. (Discussion): Some Clinical and Pathological Features Observed in Sarcoidosis. Tr. Am. Climatol. & Clin.. A. 59: 73,1947. 7. Freiman, ]). C.: Sarcoidosis. New England J. Med. 239: 664 (Oct. 28) 1948; ibid. 239: 709 (Nov. 4) 1948; ibid. 239: 743 (Nov. 11) 1948. 8. Friou, G. J.: A Study of the Cutaneous Reactions to Oidiomycin, Trichophytin, and Mumps Skin Test Antigens in Patients with Sarcoidosis. Yale J. BioI. Med. 24:533,1952. 9. Garland, H. C. and Thompson, J. C.: Uveo-parotid Tuberculosis (Febris Uveoparotidea of Heerfordt). Quart. J. Med. 2:157 (April) 1933. 10. Gentry, J. T., Nitowsky, H. M. and Michael, M. Jr.: Studies on the Epidemiology
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of Sarcoidosis in the United States; the Relationship to Soil Areas and to Urban-Rural Residence. J. Clin. Invest. 34: 1839, 1955. Heerfordt, C. F.: tJber eine "Febris Uveo-parotideasubchronica" an der Glandula Parotis und der Ulvea des Auges lokalisiert und haufig mit Parsen cerebrospinaler Nerven kompliziert. Arch. f. Ophth. 70: 254, 1909. Higgins, H. L.: Pulmonary Sarcoidosis. Connecticut M. J. 11: 330 (May) 1947. Hutchinson, J.: Cases of Mortimer's Malady (Lupus Vulgaris Multiplex Nonulcerans et Non-serpiginosus). Arch. Surge (London) 9: 307, 1898. Jacques, W. E.: Sarcoidosis; a review and a proposed etiologic concept. Arch. Path. 53: 558 (June) 1952. Johnson, Frank: Personal communication. Lofgren, S.: Erythema N odosum. Studies on Etiology and Pathogenesis in 185 Adult Cases. Acta med. scandinav. (supp. 174) 1946. Lofgren, S.: Primary Pulmonary Sardoidosis. I. Early Signs and Symptoms. Acta med. scandinav. 145: 424, 1953. Longcope, W. T.: Sarcoidosis. Veterans Admin. Techn. Bull. TB-73, May 10, 1951, p. 1. Longcope, W. T. and Piersoll, J. W.: Boeck's Sarcoid (Sarcoidosis). Bull. Johns Hopkins Hosp. 60: 223 (April) 1937. . Michael, M. Jr., Cole, R. M., Beeson, P. B. and Olson, B. J.: Sarcoidosis; Preliminary Report on a Study of 350 Cases with Special Reference to Epidemiology. Am. Rev. Tuberc. 62: 403 (Oct.) 1950. Ransmeier, J. C.: Minutes of the Conference on Sarcoidosis. National Research Council, Division of Medical Sciences, p. 5, February 11, 1948. Refvem, 0.: Pathogenesis of Boeck's Disease (Sarcoidosis). Acta med. scandinav. (supp. 294) 149: 1, 1954. Scadding, J. G.: Discussion on Sarcoidosis. Proc. Roy. Soc. Med. 49: 799, 1956. Schaumann, J.: Lymphogranulomatosis Benigna in Light of Prolonged Clinical Observations and Autopsy Findings. Brit. J. Dermat. 48: 399, 1936. Schaumann, J. : Etude sur le lupus pernio et ses rapports avec les sarcoides et la tuberculose. Ann. de dermat. et syph. 6: 357, 1916-1917. Siltzbach, L. E. and Ehrlich, J. C.: The Nickerson-Kveim Reaction in Sarcoidosis. Am. J. Med. 16: 790, 1954. Sones, M. and Israel, H. L. : Altered Immunologic Reactions in Sarcoidosis. Ann. Intern. Med. 4-0: 260, 1954.