Sarcoidosis: Clinical Features and Management

Sarcoidosis: Clinical Features and Management LOUIS E. SILTZBACH, M.D.*

INTRODUCTION Sarcoidosis is recognized as a fairly commonplace disorder but detection of cases is beset with certain difficulties. First, there is no known etiology and a causative agent cannot be identified to help establish the diagnosis. As a result, a number of disorders characterized by epithelioid-cell granulomas such as tuberculosis, beryllium disease, leprosy, brucellosis, some fungal diseases, and local "sarcoid reactions" are easily confused with sarcoidosis. t Second, sarcoidosis almost always begins silently, and very often it runs its entire course asymptomatic ally, so that many cases elude detection. Third, sarcoidosis presents an unusual and not universally recognized constellation of organ involvement. Hence, diagnosis is often delayed even after symptoms eventually do appear, months or even years after the onset. The symptoms may prompt the patient to visit anyone of several medical specialists, that is, an ophthalmologist, dermatologist, neurologist, rheumatologist, hematologist, etc., and unless the specialist is familiar with the variegated patterns of clinical sarcoidosis, he may continue to treat the patient for a local lesion for long periods unaware of the underlying systemic disorder. Historically, it was during World War II that the surprisingly frequent finding of silent bilateral hilar adenopathy in mass chest radiographic surveys among armed forces recruits in many different countries first called attention to the importance of presymptomatic Studies alluded to in this communication were supported by Grant AI-02272 from the National Institutes of Allergy and Infectious Diseases, United States Public Health Service. ·Clinical Professor of Medicine, The Mount Sinai School of Medicine; Head, Division of Thoracic Diseases, Department of Medicine, The Mount Sinai Hospital, New York, New York tSee definition of sarcoidosis, reference 1. Medical Clinics of North America - VD!. 51, No. 2, March, 1967

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sarcoidosis. Since then, surveys among Swedish army recruits have disclosed that sarcoidosis is twice as prevalent among them as is active tuberculosis. 2 In Denmark, mass radiographic surveys which were conducted among the general population in 1961-1962 revealed that asymptomatic cases of sarcoidosis outnumbered by four to one symptomatic cases which were being diagnosed in hospitals and clinics.:l • 4 Finally, autopsy observations in Malmo, Sweden, where the mean age of death is 75 to 85 years, showed that clinically unsuspected sarcoidosis was present in one of 150 autopsies, a prevalence of sarcoidosis at death which was ten times greater than that which is found in the general population of Sweden. 5 Doubtless, then, a silent course predominates in this disease. But unlike our situation with respect to poliomyelitis and mumps, we have neither a serologic test nor a skin test which is of any help in identifying patients who have completely recovered from sarcoidosis. The Kveim test is a valuable diagnostic tool in the active phase of sarcoidosis but it loses much of its diagnostic capacity when the lesions of sarcoidosis undergo resolution. 6 • 7

Sarcoidosis in the Community Rough estimates can be made of the entire pool of cases of sarcoidosis existing in a given community at anyone time. In Table 1, the percentage of undetected cases of sarcoidosis in the general population has been hypothetically placed at 80 per cent and of those currently detected at 20 per cent. The largest category among the undetected Table 1.

Sarcoidosis in the Community UNDETECTED SARCOIDOSIS

(80 per cent (?) of all cases in the community) Silent sarcoidosis, present but undetected: Intrathoracic lesions unrecognized because no chest radiograph is made Tuberculin response changing from positive to negative; negative cutaneous response to a battery of antigens of delayed hypersensitivity type Unexplained hypercalciuria and hypercalcemia, with normal chest radiograph Erythema nodosum with normal chest radiograph Silent sarcoidosis clinically regressed Symptomatic sarcoidosis including "burnt-out" cases not recognized during active stage in spite of symptoms SARCOIDOSIS DIAGNOSED IN CLINICS AND HOSPITALS

(20 per cent (?) of all cases in community)

Symptomless intrathoracic sarcoidosis detected in mass surveys Erythema nodosum cases with hilar node enlargement and a positive Kveim test Symptomatic biopsy-confirmed sarcoidosis of lungs, lymph nodes, eyes, skin, etc. in early and late phases Autopsy-disclosed cases of sarcoidosis, florid or "burnt out," unsuspected during life.

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group is that of patients with silent sarcoidosis whose former lesions have gone on to apparently complete regression. Such cases may no longer be detectable even with scrupulously carried-out autopsy observations. For the other categories of undetected cases, once sarcoidosis is suspected, the array of diagnostic techniques which are usually employed, e.g., chest radiography, organ biopsy, Kveim test, etc., can be applied to bring these cases of sarcoidosis to light.

The Timetable of Sarcoidosis To understand fully the great variety of clinical patterns and their management, one must possess an awareness of the way in which sarcoidosis evolves and of the chronological order of the successive clinical manifestations. From the very first, one must take into account the stage of sarcoidosis in which the patient may be presenting himself; i.e., whether the process is subacute or of less than two years' duration, or chronic, the later stage. Figure 1 presents a schema of the course of sarcoidosis in the manner of a timetable. It records during various periods of the life the changes in immunologic, clinical, radiographic and pathologic findings which may precede the onset of sarcoidosis or occur during it and after

Schema For Course Of Sarcoidosis Subacute MLN·EN lung other sub· eye

Organ involvement

chnical

parotid

PLN elevated g. glob. MLN scalene LN liver

Orgon biopsy

muscle skin scar

lung liver spleen skin eye

Chronic (2 yrs +) lung bone kidney damage etc

lung bronchus

PLN

lacrimal lung bronchus

skin

PLN palate

palate

IJ~ 4J\i\ ~~ ~~

X-ray Normal chest

[) ljD 1ja ~ ~a BHL

BHL

mottling

ill 0-2yrs.

BHL

mottling

ill 2-7yrs.

lung

bronchus skin PLN palate

~ ~

Dense fibrosis a bullae

Mottllng only

ill 7y,s. +

.... , Course of sarcoidosis

:.,

Genetic Susceptibility

:,

:i ~...........................;;'/ Age Immunological state

--0:j3Y';-, i4~Oy,; I Kveim- (?) Negative 1-100 TU

Kveim+(?) Positive 1-100 TU

....... 20-45yrs. Kveim + Negative 100 TU 0' weak positive

over 45y's. Kveim

+ or-

Negotive 100 TU 0' weak positive

Figure 1. Schema for course of sarcoidosis. MLN, Mediastinal lymph nodes. EN, Erythema nodosum. PLN, Peripheral lymph nodes. BHL, Bilateral hilar adenopathy. TV, Tuberculin units. (From Siltzbach, L. E.: Am. J. Med. 39:366, 1965.)

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recovery. The two lowest bars of the schema portray the immunologic state as reflected by tuberculin sensitivity and Kveim reactivity. Because ethnic factors appear to play a role in the attack rate of sarcoidosis, it is suggested that genetic susceptibility may exert a predisposing influence. As shown, the tuberculin reaction is usually negative from birth to age 13 and Kveim reactivity is probably also absent, although no relevant data are at hand covering this point. In the closer presymptomatic phase (ages 14 to 20 years or older), the tuberculin test may have become positive in a proportion of the subjects who later fall ill with clinical sarcoidosis. Whether Kveim reactivity may also be acquired before the illness is clinically apparent is, likewise, unknown. With the clinical onset of sarcoidosis, relative tuberculin insensitivity is manifested and this insensitivity may persist with apparent recovery. In short, aside from racial or ethnic susceptibility which mayor may not rest on a genetic base, the immunologic capacities of individuals who may later fall ill with sarcoidosis is no different during the years prior to illness than that of individuals who are unaffected, as Sutherland, Mitchell, and HartS have shown. The relative intracutaneous anergy to multiple antigens usually eliciting delayed-type hypersensitivity appears to be acquired either at the clinical onset or shortly before sarcoidosis becomes manifest and tuberculin sensitivity is not readily regained. Above these, the schema portrays the period of clinically recognizable sarcoidosis. Three courses of illness of varying duration and severity are charted; first, that of the mildest course lasting two years or less, represented by a solid line; second, a dotted curve showing the course of patients with disseminated sarcoidosis which lasts from two to seven years and undergoes slow healing often with residual scarring; third, the most chronic course with the poorest prognosis, marked with dashes, lasting more than seven years with substantial organ impair., ment by granuloma and scarring. Cases which prove to be fatal, relat:ively few in number, usually follow this course. Erythema Nodosum It is not known what stimulus triggers the usually silent explosion of epithelioid granulomas which first seed the mediastinal lymph nodes, lungs, liver, muscles, and bone marrow. A notable exception to this silent and insidious onset of sarcoidosis occurs among young women of Swedish, Puerto Rican, and Irish backgrounds. In these patients, sarcoidosis often is announced dramatically by an outbreak of erythema nodosum with or without accompanying polyarthritis - LMgren's syndromeY Concomitantly, one finds bilateral hilar adenopathy with right paratracheal node enlargement (Stage 1). If, at this time, one performs a biopsy of a scalene fat pad, mediastinal node, striated muscle, liver, or even of lung, characteristic noncaseating epithelioid cell tubercles are found. However, lesions in these organs remain clinically silent for months or even years until cumulative seedings with granuloma impair organ function and give rise to symptoms.

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Ordinarily, erythema nodosum represents a generalized sensitization phenomenon which follows upon exposure to the streptococcus, tubercle bacillus, lepra bacillus, Coccidioides immitis, and to certain drugs, particularly drugs in the sulfonamide family. Because, as mentioned, an attack of erythema nodosum not infrequently ushers in the clinical onset of sarcoidosis, especially in women, it would appear that the affected individual has recently been exposed to a new sensitizing agent. It is precisely for this reason that so much effort has been put into trying to uncover a microbial or chemical substance to which presumably the patient with recent sarcoidosis has become sensitized. Subacute and Chronic Sarcoidosis The three upper rows of the schema (Fig. 1), from above down, refer to organ involvement in sarcoidosis, to those areas from which biopsies of clinically evident lesions or blind biopsies can be made, and below these, to the radiographic patterns which are encountered as lung lesions progress. It is now generally accepted that, when first observed, patients fall into one of two large chronological subdivisions; those with subacute lesions estimated to be of less than two years' duration and those with chronic lesions of more than two years' duration. Only estimates of duration are possible because recently made chest radiographs which show no abnormality are seldom available, and only some patients suffer an initiating attack of erythema nodosum. As James 10 has stressed, patients in the subacute stage often exhibit the following characteristics: They are likely to have been discovered in the presymptomatic phase by means of routine or mass chest radiog~ raphy or by an initiating attack of erythema nodosum. They are usually less than 30 years old, display hilar adenopathy on chest x-ray (Stage 1), have a positive Kveim test and a negative tuberculin test, and exhibit noncaseating epithelioid cell granulomas in scalene fat pads or mediastinal nodes, or liver, muscle, or an old cutaneous scar. In the subacute stage the lesions are usually transient and patients have ~ good prognosis, going on to spontaneous remission in most instances. With respect to later developing ocular lesions, salivary and lacrimal gland enlargement, miliary or confluent pulmonary mottling (Stage 2), and peripheral lymphadenopathy, if they appear, they do so within the first or second year of the illness. These lesions, as well, will generally have a favorable outcome. When corticosteroid therapy is necessary, as in ocular lesions or in progressive lung lesions, response to therapy will generally be favorable in this stage but relapse after treatment is discontinued is high.!! In patients in the chronic stage when first discovered, the onset has been insidiOUS, with symptoms making their appearance only later in the course and persisting thereafter. It is these later symptoms, in fact, which usually first call attention to the illness at a time when lesions have already spread beyond the thorax. These patients are more likely to be over 30 years of age. Their chest x-rays show varying degrees of involvement of pulmonary parenchyma, usually with recession of the hilar adenopathy (Stage 3), and at a later stage, exhibit extensive

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fibrosis and bullae. The tuberculin test remains negative and Kveim reactivity may be lost. Palpable peripheral lymph nodes are present and cutaneous lesions appear, either nodular, plaquelike, or at times of a lupus pernio variety. There may be hepatosplenomegaly, hypercalcemia and eventually nephrocalcinosis, ocular lesions with keratoconjunctivitis sicca or chronic uveitis affecting both anterior and posterior chambers and terminating in secondary glaucoma, cataracts or phthisis bulbi. Less commonly noted are phalangeal bone cysts, central nervous system lesions (other than transient facial palsy), chronic myopathy and hypersplenism. Confirmatory tissue biopsy is obtained comparatively easily in the chronic stage from enlarged peripheral lymph nodes or from cutaneous lesions when present and from blind biopsy procedures such as bronchoscopic biopsy of bronchial wall and lung, and of normal-appearing palate. Liver biopsies are of limited use because many conditions besides sarcoidosis are associated with hepatic granulomas. Histologically, the noncaseating epithelioid tubercles may exhibit some degree of healing by hylinization and Schaumann bodies in the specimens removed in the chronic stage. Treatment with corticosteroid therapy is at best ameliorative, effecting symptomatic relief but relapse after discontinuation of therapy is frequent, especially in respect to cutaneous and pulmonary lesions. Five to 10 per cent of patients presenting in the chronic phase will succumb to cor pulmonale and pulmonary insufficiency during the first five years of observation. After five years, deaths from neoplasms and degenerative diseases outnumber deaths from sarcoidosis. In sum, the subacute and chronic stages of sarcoidosis differ considerably in respect to clinical findings, prognosis, and treatment. Clearly, the greater the proportion of patients detected in the presymptomatic stage of hilar adenopathy, the fewer patients there will be with extrathoracic dissemination and, in general, the better the prognosis will be and the less the need for therapy.

CLINICAL FEATURES OF SARCOIDOSIS-A SURVEY OF 311 CASES Between 1946 and 1961, 311 patients with sarcoidosis presenting a characteristic clinical picture which was associated with compatible organ biopsy findings or a microscopically positive Kveim test, or both, have been diagnosed at the Sarcoidosis Clinic at the Mount Sinai Hospital and were observed through June, 1965 for a period ranging from four months to 20 years (mean, 5.0 years). The 311 patients with biopsyconfirmed sarcoidosis were drawn from a total pool of 750 patients who had been referred for diagnosis because of the presence of a suspicion of sarcoidosis. The clinical features and the management of sarcoidosis presented here are based on observations of this series of patients. The factors of selection in the present series will become evident in the tables analyzing the clinical material.

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Sex, Age and Ethnic Background Table 2 shows that women outnumbered men by 2 to 1, a predominance similar to that recorded in several other series. Negroes constituted almost half the patients and that is a lesser proportion than has been reported in other series of cases published in the United States where the proportion of Negroes has reached as high as 87 per cent.12 Prevalence of sarcoidosis among Negroes in New York City is estimated by mass chest radiography to be approximately ten times the prevalence among Caucasians. Among the population of Puerto Rican background in New York City, of whom 95 per cent are Caucasian, the prevalence of sarcoidosis lies between that of Negroes and other Caucasians. Two of every three patients were under the age of 40 which is, as a whole, a characteristic age distribution. Duration of Disease Reflecting the large proportion of patients in this series detected in the presymptomatic stage, 78 per cent were in the subacute stage with an estimated duration of less than two years, and 22 per cent in the chronic stage. In a minority of patients, it was possible to obtain an accurate estimate of the duration because of an initiating attack of erythema nodosum or through the availability of a normal chest radiograph made within a year prior to the discovery of sarcoidosis. As anticipated, the proportion of patients with three or more systems involved was only 35 per cent, a lesser proportion than usually reported in other series. Mode of Onset Forty per cent of the patients in this study were referred for investigation because of an abnormality disclosed by a chest x-ray film made during the course of a routine examination or a mass survey. These patients had either no symptoms or relatively insignificant ones. Examination infrequently showed clinically evident dissemination to organs other than the lungs. In contrast, in the 60 per cent of patients whose illness came to light because of some symptom, evidence of clinically important extrathoracic involvement was common. Owing to the relatively high proportion of patients in this series with silent sarcoidosis, the prognosis for the group as a whole was somewhat better than that reported in other large series of patients with sarcoidosis in the United States. In patients with a symptomatic onset, the most troublesome and outstanding complaints at the onset were respiratory symptoms in 19 per cent, erythema nodosum, 11 per cent, ocular complaints in 7 per cent, and cutaneous sarcoids in 6 per cent. All patients with cutaneous sarcoids were already in the chronic stage. Constitutional symptoms, peripheral lymphadenopathy, salivary gland enlargement, and nervous system involvement were other modes of onset. Intrathoracic Sarcoidosis In spite of the systemic nature of the disorder, the intrathoracic (Text continued on page 492.)

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Table 2. 311 Patients with Sarcoidosis (1946-1961) NO. PATIENTS

PER CENT

Sex Males Females

100 211

32 68

Race Caucasian Negro Puerto Rican-born

146 54

III

36 47 17

Age Under 40 years Over 40 years

221 90

71 29

Estimated Duration of Disease Less than 2 years (subacute) More than 2 years (chronic)

243 68

78 22

Mode of Onset Routine chest radiography Respiratory symptoms Erythema nodosum Ocular symptoms Skin sarcoids Peripheral lymphadenopathy Arthralgias Fever, weight loss, weakness Parotid enlargement Nervous system involvement Hypersplenism Lacrimal gland enlargement Myalgia Hypercalcemia Cardiac failure Irregular cardiac rhythm Nasal stuffiness

124 59 33 22 20 14 10 9 6 4 3 2 1 1 1 1 1

40 19 11 7 6 5 3 3 2 1.2 0.9 0.6 0.3 0.3 0.3 0.3 0.3

Chest X-ray at Presentation Hilar adenopathy Hilar adenopathy plus mottling Mottling only Normal

133 108 44 26

43 35 14 8

62 31 27 12 11

38 19 16 7 7

8 4 10 165

5 2 6 100

First Histological Confirmation Peripheral lymph node Skin Scalene fat pad Liver Respiratory mucosa (including bronchial wall) Lung Muscle Other Total: Kveim site only

146

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SARCOIDOSIS: CLINICAL FEATURES AND MANAGEMENT

Table 2.

Patients with Sarcoidosis (1946-1961) (Continued) NO. PATIENTS

PER CENT

Extent of Dissemination 3 or more organ systems 1 or 2 organ systems

108 203

35 65

Organs Involved Intrathoracic Hilar nodes Lung parenchyma Peripheral lymph nodes Liver Eyes Skin sarcoids Spleen Erythema nodosum Bones of hands Salivary glands Lacrimal glands Joints Nervous system Kidney (hypercalcemia) Respiratory mucosa Muscle Myocardium Uterus

285 241 152 116 64 62 59 57 33 13/139 25 21 18 13 12 9 5 5 1

92 77 49 37 21 20 19 18 11 9 8 7 6 4 4 3 1.6 1.6 0.3

Kveim Test Results All patients positive Organ biopsy-confirmed positive

285/311 139/165

92 84

Tuberculin Status Positive 1 TU 10 TU 250 TU Total 1-250 TU

24 10 78 112

8 3 26 37

5 7 179 191

1.7 2.3 59 63

Laboratory Findings Serum globulin elevated Serum calcium elevated

158/259 33/236

61 14

Therapy Treated with steroids No steroid therapy

103 208

33 67

17 9

5 3

Negative Total

1 TU 10 TU 250 TU 1-250 TU

Cause of Death Due to sarcoidosis Other causes

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lesions have prime importance in diagnosis, prognosis, and management. In the diagnostic hierarchy of sarcoidosis, the presence of symmetrically enlarged hilar nodes holds a key position. Whether the dissemination of granulomas involves the lung parenchyma, the eyes, the salivary and lacrimal glands, the liver, spleen, skin, or central nervous system, the presence of hilar adenopathy as well alerts one immediately to the possibility of underlying sarcoidosis and sets one on the road toward obtaining confirmatory tissue diagnosis by Kveim test or organ biopsy. Because of the continued availability of a validated Kveim test suspension, major diagnostic reliance was placed on the intracutaneous Kveim reaction in this series. More recently, microscopic examination of a Kveim site after six weeks has constituted the standard means of verifying the diagnosis. 13 Stages of Intrathoracic Sarcoidosis Several classifications of intrathoracic sarcoidosis are currently in use. Almost all systems divide the cases into three stages depending in the main, upon the extent of involvement revealed by a chest radiograph and, to a lesser degree, upon the chronology of involvement. The earliest, Stage 1, characterized by bilateral hilar adenopathy with or without paratracheal node enlargement, comprised the largest group of the patients in the present series, numbering 133. In Stage 2, in which pulmonary mottling is combined with hilar adenopathy and which usually follows Stage 1 within one year or less, included 108 patients. In Stage 3, comprising 44 patients, pulmonary mottling persisted but the hilar node enlargement underwent shrinkage. This advanced stage is usually reached after one or more years following the first appearance of hilar adenopathy. In patients presenting in this stage, pulmonary lesions often progress to irreversible fibrosis, bulla formation and cor pulmonale. Finally, there were 26 patients who presented with multisystemed extrathoracic sarcoidosis but whose chest x-ray had already cleared and was normal. Paradoxically, a normal chest x-ray pattern almost always signifies a relatively late stage of sarcoidosis. Whatever hilar node or pulmonary involvement originally present has undergone complete resolution, while the active granulomatous foci in the extrathoracic organs remain either chronically in a florid state or cause symptoms through disturbance in organ functions following upon hyalinized scarring. Examples of this were the findings in some patients of hypersplenism, of secondary glaucoma resulting from chronic uveitis, or of nephrocalcinosis after prolonged hypercalciuria, each of which was on occasion associated with a normal chest x-ray pattern. STAGE 1. HILAR ADENOPATHY. Because the hilar nodes are the seat of the earliest detectable localization of sarcoidosis, it has been suggested that the unknown etiologic agent or agents may first be inhaled into the lungs and then drained into the mediastinal nodes. It would appear from autopsy studies 14 that the retroperitoneal lymph nodes, on the other hand, are not nearly so commonly involved with granuloma in sarcoidosis. Bilateral hilar adenopathy at the outset was noted in 133 patients in this series, or 43 per cent (Fig. 2).

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It has been speculated that all clinical sarcoidosis begins with silent hilar adenopathy along with radiographic ally undetectable granulomas within the lung parenchyma. No stage of sarcoidosis preceding hilar adenopathy is known. Characteristically in sarcoidosis, the bronchopulmonary nodes in the right hilar area tend to stand away from the right border of the heart more than they do in enlargement caused by lymphomatous or metastatic neoplastic nodal involvement. In the latter conditions, the shadow of the nodes tends to fuse with the right cardiac border. The right paratracheal chain of nodes also exhibits frequent enlargement in early sarcoidosis. 15 Hilar node enlargement is the hallmark of the subacute phase of sarcoidosis. Symptoms are minimal. Occasionally a troublesome cough or a vague substernal discomfort may be experienced. A few patients with hilar adenopathy complain that they cannot take a satisfactorily full breath. If extrathoracic lesions more characteristic of the chronic stage are present, e.g., cutaneous lesions, one usually finds, if an old chest radiograph becomes available, that the hilar adenopathy has been present for some years. About 10 per cent of the cases with hilar adenopathy detected at presentation are of this chronic variety. Lung function studies show few abnormalities, but in some patients a mild deficit in the diffusing capacity may be demonstrated. STAGE 2. HILAR ADENOPATHY ASSOCIATED WITH LUNG MOTTLING. Hilar adenopathy plus parenchymal mottling of the lungs was noted in 108 patients or 35 per cent of the patients. Parenchymal mottling took the form of localized or disseminated fine miliary and occasionally coarse miliary nodulations in both lung fields (Fig. 3), or it assumed a fluffy, cotton-wool appearance (Fig. 4), sometimes with margins sharply circumscribed. The miliary forms of pulmonary infiltration occurred

Fig. 2

Fig. 3

Figure 2. Bilateral hilar and right paratracheal adenopathy without parenchymal densities (Stage 1). Figure 3. Soft cotton-wool infiltrations in both lung fields with persistent hilar and paratracheal adenopathy (Stage 2).

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LOUIS SILTZBACH

Fig. 4

Fig. 5

Figure 4. Diffuse reticulation in both lung fields with interspersed coarse nodulation. No discrete adenopathy discernible (Stage 3). Figure 5. Dense fibrosis with giant bullae in right upper lobe and downward displacement of sclerosed right lung root shadow. Fibrosis of left upper lobe with upward retraction of left lung root shadow. Tenting of domes of the diaphragm. (Stage 3 , late.)

within one year or less after sarcoidosis was detected, but sometimes the fine and coarse nodulations occurred during the second year or even later. The hilar node enlargement persisted from the earlier period. Often, however, the nodes regressed while the miliary nodulation increased, leading rapidly to Stage 3. Among patients in Stage 2 whose pulmonary mottling took the form of fluffy, cotton-wool infiltrates, it was not possible to obtain any chest radiographs of a preceding period showing hilar adenopathy alone. Either the hilar node enlargement and the infiltrates were both present earlier or a completely normal film preceded the onset of the combined nodal and pulmonary lesions. Among the 133 patients who presented with nodal enlargement without pulmonary parenchymal involvement, none subsequently showed these cotton-wool infiltrates. One must conclude that if a prior stage of hilar adenopathy alone existed for these patients with confluent densities, that stage must have been of singularly short duration. Patients with miliary nodulation accompanied by enlarged hilar nodes usually present few or no respiratory symptoms. In exceptional instances, however, when miliary nodulation is particularly dense and produces almost a ground-glass appearance on chest radiography, the patient may display evidence of an acute alveolar-capillary block with tachypnea and cyanosis appearing within a matter of weeks after the onset. Worth mentioning in the differential diagnosis of miliary nodulation in pulmonary sarcoidosis are miliary tuberculosis, pneumoconiosis, beryllium disease, lymphangitic carcinoma, idiopathic hemosiderosis,

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495

and alveolar microlithiasis. In none of these mimicking conditions is the hilar adenopathy likely to be as prominent as it is in pulmonary sarcoidosis. To be sure, often in sarcoidosis the hilar adenopathy may be obscured by an overlying confluence of nodular densitites; then only with the aid of planographic roentgen studies can one clearly recognize the nodal component. In the presence of cotton-wool, fluffy infiltrations, metastatic neoplasms, exudative pulmonary tuberculosis, eosinophilic pneumonia and nonspecific bronchopneumonia must also be held in mind. On lung biopsy in pulmonary sarcoidosis, these fluffy lesions are found to consist of innumerable and densely packed, discrete and confluent epithelioid cell granulomas located in the septal walls, often compressing alveolar spaces. Symptoms in Stage 2 are variable and they include fever, weight loss, easy fatigue, and dyspnea on exertion. Other symptoms referable to extrathoracic involvement may also be present. Even at this stage, however, many patients remain relatively asymptomatic and the disparity between the extensive pulmonary involvement visible on the chest x-ray and the absence of symptoms may be just as striking as it is in some patients with advanced silicosis or pulmonary tuberculosis. Lung function studies may show a reduction of vital capacity, diminished lung compliance, an increase in both dead space ventilation and venous admixture, and a significant reduction of the diffusing capacity. On the other hand, maximum breathing capacity is well maintained. STAGE

3.

PULMONARY MOTTLING WITHOUT HILAR ADENOPATHY.

In 44 patients or 14 per cent, the hilar adenopathy had waned but pulmonary mottling persisted, usually in the form of generalized or localized, coarse or fine reticulation intermixed with nodular densities measuring 1 to 5 mm. in diameter. In some instances confluence of the mottled areas was noted. Later, usually over a two- to seven-year period, dense fibrosis with retraction upward of the densely hyalinized lung roots occurred (Fig. 5). Bulla formation, some of the bullae reaching giant size, was present and, on occasion, soft infiltrations of a complicating nonspecific pneumonia were also seen. Gradual enlargement of the right ventricle foreshadowed a fatal outcome. Cough and dyspnea were more common and symptoms stemming from chronic ocular and cutaneous involvement were now more prominent. The changes in lung functions described for patients in Stage 2 were even more pronounced in this stage. In the terminal stages of pulmonary insufficiency, ventilatory impairment occasionally supervened with alveolar hypoventilation, hypercapnea and respiratory acidosis. These abnormalities are ordinarily not encountered in diffusely fibrosing interstitial pulmonary disease. Dyspnea was fairly often disabling at this stage. Only a small number of patients in this series exhibited pulmonary insufficiency at the time of diagnosis. In the stage of lung mottling without hilar adenopathy, the chest x-ray pattern can easily be confused with diffuse idiopathic pulmonary fibrosis, scleroderma, rheumatoid lung, pneumoconiosis, congestive

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heart failure, and lymphangitic carcinoma. With bulla formation, advanced bullous emphysema may be simulated closely. Not infrequently the streaks and nodules are confined to one or both upper lobes and these have been designated by us as upper lobe sarcoidosis.1 6 We have observed a group of patients in whom the diagnosis of pulmonary tuberculosis was suggested by a radiologist because the roentgen patterns so closely simulated those of upper lobe tuberculosis. The lesions of sarcoidosis located in the upper lobes represent residual lesions of a generalized pulmonary seeding with granulomas which persist after resolution of shadows in the lower lung fields. Upper lobe lesions may also evolve by a gradual upward retraction through fibrosis of middle or even lower lung field granulomatous infiltrations, a migration which may take place over a number of years. In such cases, small lucencies within the densely fibrotic upper lung fields may also be noted and may even be accompanied by deviation of the trachea to one side adding to the difficulties of differentiating between pulmonary tuberculosis and upper lobe sarcoidosis. Further diagnostic investigations usually lead to a clearing up of the confusion between these two conditions.

First Histological Confirmation of Diagnosis In 165 patients, one or more organ biopsy specimens revealed compatible noncaseating epithelioid tubercles, with or without fibrinoid necrosis. In the remaining 146 patients, a microscopically positive Kveim test provided the histological corroboration of the diagnosis. Biopsies of peripheral lymph nodes, skin, scalene fat pad, liver, or bronchial wall together supplied the histological support for the diagnosis in 87 per cent of patients. Open lung biopsies had to be employed in only 5 per cent of the patients. More recently, biopsies of mediastinal nodes by mediastinoscopy, bronchoscopically removed lung tissue, and so-called blind biopsies of lacrimal gland, bronchial wall, and palatal mucosal biopsies have also proved useful. Nevertheless, at present, most reliance is placed upon the Kveim reaction, as stated. Extrathoracic Organ Involvement As a rule, generalized lymphadenopathy occurs relatively late in the course of subacute sarcoidosis, months or even years after the discovery of hilar adenopathy. Peripheral lymphadenopathy was demonstrable in 116 patients or 37 per cent, at some time during the course of the illness. Hepatosplenomegaly, which occurred in 18 to 20 per cent of patients, also usually appeared late in the subacute stage and persisted into the chronic stage. An even longer delayed appearance characterized cutaneous lesions (other than erythema nodosum), bone cysts, kidney damage from chronic hypercalcemia, chronic uveitis and some manifestations of involvement of the central nervous systemY On the other hand, acute uveitis, parotid and lacrimal gland enlargement, and joint and muscle involvement all tended to follow within weeks or months of the recognition of hilar adenopathy.

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Test Results KVEIM TEST. The intracutaneous Kveim test employing validated test suspensions was microscopically positive in 285 or 92 per cent of the patients. Among the 165 patients with organ biopsy verification, 84 per cent exhibited positive Kveim reactions. 18 TUBERCULIN TEST. The tuberculin test was negative to all strengths between 1 and 250 TU in 63 per cent and positive in 37 per cent. But 26 per cent of the 37 per cent who responded did so only to 250 TU. This demonstrates the relative tuberculin insensitivity of the group as a whole. A similar insensitivity to tuberculin and other delayed hypersensitivity type antigens has been documented in many other series of patients with sarcoidosis. It must not be overlooked, however, that the insensitivity in sarcoidosis is only a relative and not an absolute one; nor does the insensitivity appear to be as profound as it is in the malignant lymphomatous diseases. 19 BLOOD TESTS. Hyperglobulinemia with serum globulins elevated above 3.5 gm. per 100 ml. mostly with elevation of the gamma globulin fraction, was encountered in 61 per cent of patients at some time during the course of observation, most commonly in the chronic stage. Serum calcium levels of 11.5 mg. per 100 ml. or higher were observed in 14 per cent of the patients in this series. CORTICOSTEROID THERAPY Most patients with sarcoidosis require no therapy because symptoms are seldom disabling and the proportion in whom lesions improve spontaneously is high. For this reason, it is prudent to observe the patient with sarcoidosis for three to six months to assess the trend of the disease process before deciding to treat. When granulomas imperil function of a vital organ, therapy is best begun promptly. In this series, 103 patients or one-third of the entire group were treated with one or more courses of corticosteroid therapy. Prednisone, prednisolone, and dexamethasone were most commonly used. In patients with fresh and extensive granulomatous lesions, corticosteroids and ACTH suppressed disabling symptoms. The hormones tided a patient over hazardous episodes, holding the granulomas in check until a natural remission of the disease set in. Hormonal treatment was not curative and the relapse rate was high but maintenance therapy succeeded in enabling a patient to return to his daily activities. This restorative action may be regarded as one of the outstanding accomplishments of corticosteroid therapy in sarcoidosis. The healing of granulomatous deposits under corticosteroid therapy was histologic ally similar to the healing which the lesions underwent spontaneously. But, with the hormones, hyalinization and scarring were accelerated, occurring within days and weeks rather than in months and years. There is no evidence available which suggests that residual SCarring is more extensive with hormonal therapy than it is in spontaneous healing. The hormones do effect a suppression of new granu-

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loma formation and, theoretically, the treated patient should have less scarring to contend with when a natural remission sets in than he might when the granulomas are allowed to multiply unhindered. The nonspecific anti-inflammatory capacities of the corticosteroids also help control superimposed nongranulomatous inflammatory processes with relief of such symptoms as unremitting cough or dyspnea. Indications for Corticosteroid Therapy The indications for therapy are divided into two categories: absolute indications for prompt treatment of lesions which may permanently imperil vital organ function (approximately 10 per cent of all patients); and relative indications, for patients in whom a preliminary period of assessment yields a clear-cut decision with respect to the need for therapy (20 per cent of all patients). Localizations which were promptly treated were intrinsic ocular disease, diffuse pulmonary lesions with alveolar-capillary block, severe central nervous system lesions, myocardiallesions, hypersplenism, and persistent hypercaicemia, especially with renal damage. Localizations which required therapy with relative urgency included progressive and/or symptomatic pulmonary lesions, disfiguring cutaneous lesions, lymph node and salivary gland lesions, nasal, laryngeal, and bronchial mucosal lesions, constitutional symptoms and joint involvement, and persistent facial palsy. It was not found necessary to treat two-thirds of the patients including those exhibiting hilar node enlargement, localized pulmonary involvement undergoing regression, erythema nodosum, except for instances associated with persistent and disabling arthralgia, minor superficial lymph node enlargement, asymptomatic hepatosplenomegaly, and isolated bone cysts. Continuous observation was practiced in patients with asymptomatic miliary seeding of the lungs, particularly if only minor lung function abnormalities are present. For patients with widespread flocculent shadows occupying major portions of both lungs, hormonal therapy was thought advisable even in the face of minimal symptoms. Pulmonary insufficiency appeared to follow more frequently in patients presenting with this chest x-ray appearance than it did with fine miliary nodulation but even massive flocculent infiltration at times disappeared spontaneously after some months. Dosage of Corticosteroids and Duration of Treatment The initial daily dose employed for suppression of the manifestations of sarcoidosis being treated was 20 to 30 mg. of prednisone or prednisolone or 3.0 to 4.5 mg. of dexamethasone given in a single or divided doses. For maintenance therapy, the dose of prednisone and prednisolone was 7.5 to 10 mg. and for dexamethasone, 0.5 to 1.5 mg. On the average, a course of therapy required six to 9 months but patients with extensively disseminated lesions known to be progressive required therapy of one year or longer. Terminating the course was determined by trial and error. When maximum benefit had endured for three or more months, the drug was tapered over a two- to eight-week period. ACTH was not given during the withdrawal period. If disabling

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symptoms recuned and did not subside within a month, corticosteroid treatment was resumed and a later attempt to discontinue therapy was made. Side Effects and Complications of Corticosteroid Therapy Some rounding of the face and mild hirsutism occuned but were not pronounced. A single instance each of hypertension, diabetes, and perforated duodenal ulcer occuned among the 103 treated patients. Two patients became ill with active pulmonary tuberculosis under therapy. This was the same frequency as was encountered among the untreated group, that is, four cases among approximately 200 patients. Isoniazid in doses of 300 mg. daily was administered as prophylaxis during corticosteroid therapy to those treated patients who exhibited positive tuberculin reactions. Isoniazid was also given to the treated patients with extensive and chronic pulmonary infiltrations and scarring even when tuberculin sensitivity was absent. A negative tuberculin test in patients with sarcoidosis does not necessarily imply that the patient may not harbor encapsulated tuberculous foci. The infrequency of complications in this series of corticosteroidtreated patients is probably explained by the relatively low dose of hormones used. In other series of patients, in whom considerably higher dosage of corticosteroids has been employed, the frequency of side effects and complications has also been higher. Results of Therapy The response to corticosteroids at various sites of involvement is listed in Table 3. Fresh lesions proved to be more responsive than older ones. Even patients with late pulmonary fibrosis occasionally obtained symptomatic relief. Fever, weight loss, weakness, cough, dyspnea, blurred vision, hypercalcemia, and hyperglobulinemia were suppressed or returned to normal levels. As a rule, improvement or clearing occuned in lung lesions, mediastinal and peripheral lymph nodes, ocular lesions, and cutaneous lesions. Table 3. Response to Prednisone-Prednisolone and Dexamethasone Therapy (62 Patients)

SITE

NUMBER PATIENTS

IMPROVED UNDER THERAPY

RELAPSED

Lung Mediastinal lymph nodes Peripheral lymph nodes Fever, weight loss Skin Eyes Salivary and lacrimal glands Central nervous system Hypercalcemic kidney

41 44 25 23 21 15 15 3 2

28 28 17 23 16 13 13 3 2

12 5 1 4 10 5 0 0 1

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When the superficial or mediastinal lymph nodes disappeared, there was little tendency for them to recur. In patients in whom widespread pulmonary fibrosis had not yet taken place, there was rapid radiographic improvement with a significant increase in lung volumes and a return to more normal levels of dead space ventilation and venous admixture. The lowered diffusing capacity and pulmonary compliance were not so promptly restored. These defects persisted long after radiographic clearing or improvement of lung fields had taken place. An increase in vital capacity was the simplest measure of the beneficial effects of corticosteroid therapy. Half the patients with improvement of pulmonary lesions relapsed after treatment was halted, but in most patients the relapses were symptomatic ally mild and were left untreated with eventual improvement taking place in the following weeks and months. There were five patients with ocular relapse and all required prompt re-treatment because of the danger of later secondary glaucoma. Unsightly chronic cutaneous lesions responded regularly but they almost always relapsed after the hormones were stopped. Many patients with cutaneous lesions, especially when they were located about the face, preferred to remain indefinitely on maintenance low-dosage corticosteroid therapy rather than endure gross disfigurement. In many instances of recurring cutaneous involvement, chloroquine in doses of 250 to 500 mg. daily was found to be just as effective as corticosteroid therapy, but ocular side effects of this drug can be permanently disabling, and even with close supervision by an ophthalmologist irreversible retinopathy has been reported. No retinal damage was experienced by 43 patients treated with this drug for a mean course of eight months. 20 With corticosteroids, most relapses occur within two months of discontinuation of therapy, although recurrences may sometimes appear after six months.

PROGNOSIS Overall, the outcome of the illness in these 311 patients with sarcoidosis was favorable. 21 During a span of observation of 1 to 20 years (mean duration of follow-up, 5.0 years), one-third of the patients made a complete recovery with return to a clear chest x-ray and without any clinically evident residua. An additional 30 per cent of patients showed improvement and together these two groups of patients with favorable outcome amounted to 64 per cent. In the less favorable categories were patients whose status remained unchanged (20 per cent), while 8 per cent lost ground and were definitely worse and 8 per cent were dead, most deaths resulting from sarcoidosis or its complications. The death rate was 2112 times the predicted rate for all causes in the general population of similar makeup- a rather significant excess of deaths attributable to sarcoidosis. These findings indicate that sarcoidosis is by no means entirely benign.

Prognosis Related to Initial Chest X-ray Film In 110 patients with hilar adenopathy and no radiographic evidence of parenchymal densities, 54 per cent eventually showed complete

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clearing, half of them within the first year. In the other half, with a few exceptions, clearing was noted in the second to the fifth year. In one patient, the hilar nodes did not disappear until the sixteenth year of observation. Patients in this and in subsequently mentioned categories were all observed for a minimum of one year. Substantial shrinkage of hilar nodes occurred in 19 per cent and in an additional 17 per cent, no radiographic changes occurred under observation. In 7 per cent, the condition grew worse with the appearance of pulmonary infiltrations which persisted or with re-enlargement of hilar nodes that had partially shrunken. When hilar nodes cleared entrrely, they rarely recurred. Three patients presenting with hilar nodes died within 1 to 20 years, all three of causes other than sarcoidosis. When, in the presence of hilar adenopathy, spread to the lungs had already occurred at the time of recognition, the outlook was less favorable than in patients with hilar adenopathy alone. Among 94 patients with combined nodal and pulmonary shadows, 31 per cent eventually exhibited complete clearing. The clearing occurred within two years in two-thirds of these patients. Once spontaneous clearing of lung lesions occurred, relapse with reappearance of pulmonary shadows was rare. Only two patients with complete spontaneous clearing showed relapse with reappearance of miliary nodulation three and seven years after clearing. In addition, combined nodal and pulmonary shadows cleared partially in 37 per cent of patients showing them, while in 13 per cent they grew worse. Twelve patients died, ten of the 12 deaths being caused by sarcoidosis. Least favorable was the outcome in the 40 patients who presented with pulmonary mottling and no hilar adenopathy. Often there was irreversible fibrosis and bulla formation. A return to a normal chest x-ray occurred only four times, that, is in 10 per cent, but some degree of improvement was noted in an additional 52 per cent. Four other patients with mottling grew worse and eight patients or 20 per cent died, seven of the eight deaths being caused by sarcoidosis. The high mortality among patients presenting with pulmonary mottling alone on chest x-ray stands in contrast to the mortality of patients with hilar adenopathy alone, a difference which is statistically significant at the 1 per cent level. Overall, patients whose intrathoracic lesions cleared within the first year did extremely well, rarely experiencing difficulties in later years. On the other hand, those whose x-rays showed worsening in the first year stood the poorest chance of escaping some degree of incapacity and, in some instances, death. Several factors besides the appearance of the chest x-ray at presentation had prognostic weight. A poorer outcome was experienced by patients with chronic lung lesions of two or more years' duration, by those having three or more systems involved, as well as by those whose lesions required corticosteroid therapy for their control. On the other hand, sex, age, and race of the patient and the presence of ocular and cutaneous involvement appeared to have no clear-cut relation to the eventual outcome in this series of patients.

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CONCLUSIONS The world-wide distribution of sarcoidosis has been pointed up by a recently completed international study of intracutaneous Kveim reactivity employing a single standardized test suspension among approximately 2400 subjects in 37 countries around the world. 22 • 2:1 This study has helped confirm the identity of sarcoidosis as a single disorder regardless of the geographic area in which it is discovered. The histological, histochemical, immunofluorescent, and ultrastructural features of the epithelioid granuloma induced at the intradermal site of a positive Kveim reaction are indistinguishable from the granulomas of sarcoidosis itself.7 Elucidation of the pathogenesis of the Kveim reaction may throw light on the nature of sarcoidosis, a puzzle which has been with us now for almost a full century. REFERENCES 1. International Conference on Sarcoidosis. Am. Rev. Resp. Dis. 84: 171, 1960. 2. Bauer, H. J., and Wijkstroem, S.: Sarcoidosis prevalence in Sweden. Acta med. scandinav. 176(Supp 425):112,1964. 3. Alsbirk, P. H.: Sarcoidosis prevalence in Denmark. Idem, 106. 4. Horwitz, 0.: Geographic epidemiology of sarcoidosis in Denmark. Am. Rev. Resp. Dis. 84:135,1961. 5. Haegerstrand, I. and Linell, F.: Prevalence of sarcoidosis in the autopsy material from a Swedish town. Acta med. scandinav. 176(Supp 425): 171, 1964. 6. Siltzbach, L. E., and Ehrlich, J. C.: The Nickerson-Kveim reaction in sarcoidosis. Am. J. Med. 16:790, 1954. 7. Siltzbach, L. E.: Significance and specificity of the Kveim reaction. Acta med. scandinav. 176(Supp 425):74,1964. 8. Sutherland, I., Mitchell, D. N., and Hart, P. D.: Incidence of intrathoracic sarcoidosis among young adults participating in a trial of tuberculous vaccines. Brit. M. J. 5460: 497, 1965. 9. Lofgren, S., and Lundback, H.: The bilateral hilar lymphoma syndrome. A study of the relation to age and sex in 212 cases. Acta med. scandinav. 142:259, 1952. 10. James, D. G.: Clinical concept of sarcoidosis. Am. Rev. Resp. Dis. 84(Supp):14, 1961. 11. Siltzbach, L. E.: Effects of cortisone in sarcoidosis. A study of thirteen patients. Am. J. Med. 12:139, 1952. 12. Sones, M., and Israel, H. L.: Course and prognosis of sarcoidosis. Am. Rev. Resp. Dis. 84(Supp):60, 1961. 13. Siltzbach, L. E.: The Kveim test in sarcoidosis-A study in 750 patients. J.A.M.A. 178: 476, 1961. 14. Iwai, K., and Oka, H.: Report of ten autopsy cases in Japan. Am. Rev. Resp. Dis. 90:612, 1964. 15. Siltzbach, L. E.: Pulmonary sarcoidosis. Am. J. Surg. 89:556, 1955. 16. Teirstein, A. S., and Siltzbach, L. E.: Upper lobe sarcoidosis simulating pulmonary tuberculosis (in preparation). 17. Silverstein, A., Feuer, M. M., and Siltzbach, L. E.: Neurologic sarcoidosis-A study of 18 cases. Arch. Neurol. 12:1, 1965. 18. Siltzbach, L. E.: Current status of the Nickerson-Kveim reaction. Am. Rev. Resp. Dis. 84:89, 1961. 19. Chase, M. W.: Delayed-type hypersensitivity and the immunology of Hodgkin's disease, with a parallel examination of sarcoidosis. Cancer Res. 26: 1097, 1966. 20. Siltzbach, L. E. and Teirstein, A. S.: Chloroquine therapy in 43 patients with intrathoracic and cutaneous sarcoidosis. Acta med. scandinav. 176(Supp 425):230,1964. 21. Siltzbach, L. E., Berger, H. W., and Teirstein, A. S.: Prognosis in sarcoidosis-A study of 311 cases (in preparation). 22. Siltzbach, L. E.: An international Kveim test study. Acta med. scandinav. 176(Supp 425): 178,1964. 23. Siltzbach, L. E.: An international Kveim test study-final report. Proc. Fourth International Conference on Sarcoidosis, Paris, September, 1966 (to be published). The Mount Sinai School of Medicine Fifth Avenue at 100th Street New York, N.Y. 10029