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Sarcoidosis among children
MEDICAL
PROGRESS
Xarcoiclosis among cbildren A review
Sarcoidosis, a disease o[ unknown etiology and pathogenesis, is relatively rare in children. I n the two series among children in the United States, all cases were in Negroes, and practically all were in the preadolescent or adolescent age group. Hilar lymph node enlargement was practically always present, ocular lesions were [requently present, and serious ones were not unusual. A m o n g the most [requent significant laboratory findings in sarcoidosis among children are hyperglobuIinemia, eosinophitia, leukopenia, hypercalcemia, hypercalciuria, and elevated alkaline phosphatase. Corticosteroids and corticotrophin are the only agents presently available which can suppress the acute mani[estations o[ sarcoidosis.
E d w i n L. K e n d i g , Jr., M . D . ~ R I G H M O N D , VA,
S A R 13 O I D O S I S a p p e a r s to be relatively r a r e a m o n g children. M c G o v e r n a n d M e r ritt 2 reviewed the world l i t e r a t u r e u p until F e b r u a r y , 1953, a n d were able to d o c u m e n t only 104 cases in children u n d e r 15 years of age; to these they a d d e d 9 others, all diagnosed in W a s h i n g t o n hospitals. As far as we can d e t e r m i n e , there have been only
scattered cases of sarcoidosis in children r e p o r t e d since t h a t time 2-4 except for our own series, a, 6 Since the cases of M c G o v e r n a n d M e r r i t t a n d o u r own a p p e a r to be the only series a m o n g c h i l d r e n recently reported, these will be the object of frequent reference in the ensuing discussion a n d will be designated as the W o r l d G r o u p (104 cases f r o m l i t e r a t u r e ) , the W a s h i n g t o n Series ( M c G o v e r n a n d M e r r i t t ) , a n d the R i c h m o n d Series ( K e n d i g a n d W i l e y ) . I t is, of course, conceded t h a t there are u n d o u b t e d l y a n u m b e r o f other cases t h a t have been rec-
From the Department o[ Pediatrics and the Child Chest Clinic Medical College o[ Virginia, Richmond, Va. ~Address, 3603 Grove Avenue, Richmond 21, Va.
269
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Kendig
ognized in children, b u t the disease m u s t be considered relatively r a r e in this age group. T h e criteria for diagnosis of sarcoidosis as o u t l i n e d b y a s u b c o m m i t e e of the N a t i o n a l R e s e a r c h Council in 1948 a n d redefined in October, 1956, are as follows: 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,z The intracutaneous tuberculin test is frequently negative, but a positive test does not controvert the diagnosis. Hyperglobulinemia and leucopenia are common and hypercalcemia, hypercalciurla, elevated alkaline phosphatase, and eosinophilia are variable but sometimes significant features of sarcoidosis. 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.
August 1962
finding of this survey was the h i g h incidence of p r e s u m p t i v e a s y m p t o m a t i c sarcoidosis, is AGE INCIDENCE Sarcoidosis m a y occur at a n y age, b u t it is e n c o u n t e r e d m o r e f r e q u e n t l y in adults between 20 a n d 40 years of age. W h i l e the case of the youngest p a t i e n t reported, p r o v e d b y biopsy, was in a 2 - m o n t h - o l d infant, 16 most childhood cases r e p o r t e d have occurred in the p r e a d o l e s c e n t or adolescent age group. Of the g r o u p d o c u m e n t e d from the world l i t e r a t u r e b y M c G o v e r n a n d M e r r i t t , 73.5 per cent were b e t w e e n t h e age of 9 a n d 15 years; eight of their 9 a n d all of our 7 cases fell into the same age group. I t m u s t be noted, however, t h a t the m i l d or insidious onset of the disease m a y have caused delay in recognition. RACE
T h e racial incidence of sarcoidosis varies considerably. I n Europe, a n d p a r t i c u l a r l y in Scandinavia, w h e r e t h e N e g r o p o p u l a t i o n is low, the disease occurs m o r e often in the white race. I n the U n i t e d States, on the other hand, sarcoidosis occurs m o r e comm o n l y a m o n g Negroes. I n 3 r a d i o g r a p h i c surveys of the U n i t e d States A r m e d Forces, 1~-19 Negroes with sarcoidosis o u t n u m b e r e d white personnel w i t h the disease b y a r a t i o v a r y i n g f r o m 7:1 to 26:1. C u m m i n g s z8 rep o r t e d the hospitalization r a t e for white a n d
HISTORY
T h e disease was first described in Engl a n d b y H u t c h i n s o n s in 1875. Besnier 9 in 1889, Boeck ~~ in 1899, a n d S c h a u m a n n 11 in 1917 m a d e contributions clarifying c e r t a i n clinical a n d p a t h o l o g i c features, a n d H e e r fordt, z2 a n d m o r e recently, G a r l a n d a n d T h o m p s o n 13 a n d L o n g c o p e a n d Pierson 1~ have c o n t r i b u t e d f u r t h e r to the description of the disease. A significant a d v a n c e in the k n o w l e d g e of sarcoidosis was a t t a i n e d a b o u t the time of W o r l d W a r I I w h e n mass r a d i o g r a p h y was i n t r o d u c e d in m a n y countries in an effort to d e t e c t tuberculosis, This m e t h o d was used first in the A r m e d Forces a n d l a t e r in the general p o p u l a t i o n . A n u n e x p e c t e d
T a b l e I. C o m p a r i s o n of organs affected in the r e p o r t e d W o r l d G r o u p , W a s h i n g t o n Series ( M c G o v e r n a n d M e r r i t t ) , a n d R i c h m o n d Series
ington Series (9)
Richmond Series (7)
54
8
7
32 51 51 30 28 24 13
6 6 4 3 0 1 3
4 2 4 1 0 2 2
W~sh
Reported World Group (lo4) Lungs (parenchymahilar nodes) Peripheral lymphadenopathy Skin Eyes Bones Uveoparotid fever Spleen Liver
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Negro World W a r I I veterans with sarcoidosis to be 3.3 and 40.1 per 100,000, respectively. Although Siltzbach 15 has noted that this susceptibility of the American Negro is not shared by the Negroes of Central Africa, where the disease is apparently unknown, 2~ he also pointed out that cases of sarcoidosis are beginning to be reported in numbers among natives of North and South Africa. However, he suggests that the latter finding is the result of better facilities now available there for the detection of sarcoidosis. Among children for whom race was stated in the world literature, 27.6 per cent were Negro, but all 9 Washington patients and the 7 children in the Richmond Series were Negroes. SEX
DISTRIBUTION
It is generally agreed that both sexes appear to be affected with equal frequency, and in the Richmond Series there were 4 females and 3 males. In the Washington Series, however, there were 6 females and only 3 males. HEREDITY
There appears to be little evidence that heredity is in any way connected with either the incidence of the disease or predisposition toward it. Such reports as that of 3 cases among siblings under 15 years of age 21 are probably not an indication of hereditary involvement. GEOGRAPHIC
DISTRIBUTION
Sarcoidosis has been observed throughout much of the world. The highest national rate for the disease has been reported in Sweden: the prevalence in the Armed Forces, in the general population, and in Stockholm was reported to be above 40 per 100,000 population 22"24 and one rural county, Jaemtlands, had a rate of 140 per 100,000. 2a In the United States, reports by Michael, 2~ Gentry, a7 and Cummings, ~s on the study of the birthplace and residence of persons in the Armed Forces with sarcoidosis indicate
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areas with high attack rates of sarcoidosis in the South Atlantic and Gulf states with endemic areas in New England and the Midwest. ETIOLOGY
AND
PATHOGENESIS
Jacques 2~ and Longcope 27 have reviewed the concepts of the cause of sarcoidosis. M a n y theories have been advanced, including a causal relationship with leprosy, syphilis, brucellosis and infections due to viruses, fungi, protozoa and helminths, and the possibility that sarcoidosis m a y be a syndrome caused by a number of etiologic agents. Tuberculosis, one of the diseases earlier considered as a possible causative agent, has again been recently championed by Scadding? s The similarity of sarcoidosis to berylliosis and to histoplasmosis has been described.2~, a0 Refvem,al analyzing tissue obtained from patients with sarcoidosis, suggested that calcareous spar found in certain soil types m a y be a possible etiologic agent and also demonstrated that particles of quartz and other foreign bodies may provoke localized sarcoid formation. Cummings zs has recently noted that forest products or even diseases of plant life appear to be related in some way to sarcoidosis, and the idea has been advanced that pine pollen m a y be involved in the causation? 2 The discovery of a small area in Virginia where the incidence of sarcoidosis appears to be extremely high (50 presumptive cases of sareoidosis in a county of 38,000 population) has suggested another possible factor. 21 This area is predominantly rural, with pine forests and sandy soil, and the chief crop is peanuts. Among the patients with sarcoidosis, no history of contact with a known infectious agent or unusual dietary regimen can be elicited. However, it is said that practically all the persons in this locality known to be affected have worked with peanuts, either in the fields or in factories, and the possibility that in this particular area the causative agent is either disseminated from the dust from peanut shells or is activated by it must be considered.
2 7 2 Kendig
CLINICAL MANIFESTATIONS ORGAN INVOLVEMENT
August 1962
AND
Lesions have been found in practically every tissue a n d o r g a n of the body. Since symptoms are due p r i m a r i l y to local tissue infiltration a n d i n j u r y by pressure a n d disp l a c e m e n t by sarcoid lesions, the clinical manifestations depend largely on the organ or system involved. A n illustrative case is as follows:* J. L., a 13-year-old Negro, was admitted t o Dooley Hospital on December 20, I955. Four months previously he had complained of pain and decreasing vision in the left eye. Small nodules appeared on the face and eyelids. A short time later, he began to have exertional dyspnea. A sister was admitted to the hospital at the same time with similar symptoms. Positive findings on physical examination ineluded extensive scarring (burn) over the arms, legs, and face, with moderate keloid formation and small yellowish noduIes, 1 to 2 mm. in diameter, over the lower eyelids, nose, upper lip, palms of the hands and soles of the feet. There was minimal posterior synechia formation in the right eye, and multiple posterior synechiae of the left, prohibiting reaction of the pupil. In the left eye, there was a dense, brownish-white opacity over the lower half of the cornea and mild lenticular opacity. Vision in the left eye was limited to gross hand movements. There were fine, moist inspiratory r~les at both lung bases. The liver edge, which was smooth and non-tender, was 4 cm. below the right costal margin. The spleen extended down to the iliae crest and medially to the midline. There was generalized lymphadenopathy. The temperature was 100.2~ F., the pulse, 90, a n d the respirations 20. The blood pressure was 112/80. Examination of the blood showed a hemoglobin of 11.8 grams per i00 ml. and a white cell count of 2,350 [per cubic millimeter], with 37 per cent neutrophils, 15 per cent eosinophils, 3 per cent basophils and 45 per cent lymphocytes. A serologic test for syphilis was nonreactive. The erythrocyte sedimentation rate was 38 mm. per hour. Sickle-cell preparations were negative. The total serum protein was 9 Gm., the albumin 3.2 grams, and the globulin 5.8 grams per 100 ml. The serum calcium was 12.8 mg. and the phosphorus 4.5 rag. per 100 ml., and the alkaIine phosphatase 9 Bodansky units. Liver function tests gave normal findings. Urinalysis was negative. An old tuberculin test [O.T.] (0.2 mg.) was negative, as were histoplasmin and coccidioidin skin tests. A roentgenogram of the chest showed marked *From The New England Journal of Medicine260: 962, 1959.
hilar lymphadenopathy, with diffuse infiltration into both lung fields. X-ray studies of the bones were negative. Lymph-node biopsy disclosed lesions typical of sarcoidosis, with tuberculoid bodies without caseous necrosis and with multinucleated giant cells. Refractile bodies were also present. As noted earlier, sarcoidosis most comm o n l y involves l y m p h nodes, lungs, skin, eyes, liver, spleen, a n d p h a l a n g e a l bones. Lungs. Symptoms referable to the chest are usually mild a n d often consist of a dry, hacking cough, with or w i t h o u t mild to moderate dyspnea. This is p a r t i c u l a r l y true in children. Gendel, Young, a n d Greiner 83 have classified the p u l m o n a r y lesions of sarcoidosis seen on r o e n t g e n o g r a m as follows: ( 1 ) early bilateral hilar l y m p h node enlargem e n t without detectable l u n g changes; (2) bilateral hilar node e n l a r g e m e n t with strandlike infiltration e x t e n d i n g from the hilar regions into both lung fields, and small n o d u l a r beading a n d diffuse m o t t l i n g sometimes occurring along the strands; (3) later, diffuse p u l m o n a r y infiltration consisting of p a t c h y coalescent densities; (4) finally, a stage of fibrosis a n d secondary emphysema with f o r m a t i o n of bullae. T h e most c o m m o n roentgenographic finding in children is that of bilateral hilar
Fig. 1. Bilateral hilar adenopathy. (From Kendig, Peacock, and Ryburn: New England J. Med. 260, 962, 1959.)
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Fig. 2. Bilateral hilar adenopathy and pulmonary infiltration.
lymph node enlargement, with or without detectable lung changes (Figs. 1 and 2). Cummings and colleagues 18 noted involvement of the lung a n d / o r hilar lymph nodes in 96 per cent of adult cases, while only 54 (52 per cent) of the 104 world cases in children were so affected; nevertheless, this 52 per cent constituted the most common finding in that series. Such involvement was noted in 8 of 9 cases in the Washington group and in all 7 cases in the Richmond group (Table I). Lymphatics. Peripheral lymphadenopathy is a common feature of sarcoidosis. The typical histologic picture is that of epithelioid cell tubercles, showing little or no necrosis (Fig. 3). The nodes are discrete, painless, and freely movable. A m o n g the reported world cases in children, there was generalized lymphadenopathy in 32 of 104 cases with an additional 16 cases of isolated or localized node involvement, a total of 46 per cent. Peripheral lymphadenopathy occurred in 6 of the 9 Washington and 4 of the 7 Richmond cases, respectively. Skin. According to Longcope and Freiman, 34 skin lesions m a y appear in 3 different forms : ( 1 ) small discrete, slightly elevated nodules; (2) large conglomerate masses,
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slightly elevated and involving subcutaneous tissues; (3) large flat placques covering considerable areas of skin over the trunk or extremities, These lesions m a y vary in color from waxy, depigmented areas to a reddish blue or violacious hue. In size, they vary from a few millimeters to more than a centimeter in diameter. The lesions are more often seen on the face, but m a y occur elsewhere. Although Cummings is reported the incidence of skin lesions in a series of adults to be only 15 per cent, such lesions appear to be much more common in children. Of the 104 reported world Cases, skin lesions were present in 51, and there was involvement of the skin in 6 of the Washington group and 2 of the Richmond patients. Eyes. T h e ocular lesions have been described by a number of investigators25-42 U v e l t i s and iritis constitute the most frequently observed lesions, but keratitis, retinitis, glaucoma, and involvement of the eyelids and lacrimal glands m a y also occur. Involvement of the eye with resultant partial or total blindness is one of the most feared lesions of sarcoidosis. Although examination of the world literature suggests that eye lesions in children are not usually severe, survey of the Washington and Richmond Series, in which eye involvement was noted in 4 of 9 and 4 of 7 cases, respectively, appears to refute this conception; such involvement in 1 of the Washington patients and 2 of the Richmond group resulted in p a r t i a l blindness. Uveoparotid fever. This syndrome consisting of ocular disturbances, parotid gland swelling, and frequent facial palsy, was first described by Heerfordt 12 in 1909. Uveitis is always present a t some time in the course of this syndrome? 4, ~8 Usually, low-grade fever, malaise, and gastrointestinal symptoms precede the eye involvement. The World Group includes 28 cases (27 per cent), but there were no cases in either the Washington or Richmond Series. Bones. Osseous lesions are usually demonstrable as areas of decreased density and, often, as "punched out" areas in the met-
2 7 4 Kendig
acarpals, metatarsals, and distal phalanges. These may be either single or multiple. Early changes, not recognizable on roentgenogram, have been revealed by marrow puncture.43, 44 The incidence of osseous lesions in adults has been variously stated as 2 to 29 per cent45-5~ among children, there was an incidence of 29 per cent in the World Group, while 3 of the 9 Washington cases and only 1 of the 7 in the Richmond group had such involvement. Dunner 5~ has suggested that bone lesions may not be as common as previously suspected. Liver. Although hepatic involvement is frequently seen at necropsy, a4, 51 clinical evidence of liver disease is not often apparent. Liver enlargement is the usual finding, and impairment of function is relatively uncommon unless serum protein changes are an indication of liver pathology. In the world cases, liver involvement was noted 13 times. In the Washington Series there were 3 cases, and in the Richmond Series there were 2 children with enlarged liver. Spleen. While splenic involvement has been demonstrated by needle biopsy, ~2 enlargement is practically the only clinical finding noted. The spleen was palpable in 24 of the world cases, 1 of the Washington, and 2 of the Richmond group. Kidney. Kogut and Neumann 4 have recently reviewed renal involvement in sarcoidosis and reported a case of their own. These authors point out that there have been less than 10 reported cases in children; nevertheless, this would appear to place the kidney as a not uncommon site of sarcoid involvement in this age group, Renal involvement has been ascribed to one or more of the following processes: (1) sarcoid granulomas infiltrating the renal parenchyma s~, 5s; (9) glomerulitis with basement membrane changesS~; and, (3) hypercalcemia with or without nephrolithiasis and nephrocalcinosis. 4, 34, 54-G7 Abnormal urinary findings may include proteinuria, pyuria, hematuria, granular casts, and calciuria. Heart. Sarcoid lesions in the myocardium have been found ~t necropsy in a number of cases?4, 51, ~8-70 In the 104 world cases there
August 1962
Fig. 3. The architecture of the node is distorted by numerous solid masses of epithelioid cells with occasional giant cells. The masses are surrounded by lymphocytes. No necrosis or caseation is apparent. Lymphoid follicles are almost absent. (From Kendig, Peacock, and Ryburn: New England J. Med. 260, 962, 1959.) was associated cardiac involvement in 4 instances, and 2 patients in the Washington Series had roentgenographic evidence of cardiac enlargement; there was no evidence of cardiac involvement in the Richmond group. Cardiac change may be secondary to extensive pulmonary sarcoldosls or may be the result of conduction aberration caused by sarcoid lesions. Nervous system. Although central nervous system involvement has been reported in adults,50, 71-78 the most commonly noted neurologic involvement in childhood seems to be paralysis of the facial nerve. In the 104 world cases there were 4 instances of facial nerve palsy. Neurologic symptoms apparently result when sarcoid lesions cause local interruption of function. Endocrine glands. A definite relationship can be demonstrated with the pituitary gland. TM Diabetes insipidus has been reported in adults, 7'~, 76 and 2 of the children in the world group had some evidence of such involvement. One of the Washington patients had polydipsia and polyuria, but none of the Richmond patients were so involved. It will be noted, then, that cases in the two American series among children (Washington and Richmond) ~losely parallel each
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Number 2
other and differ considerably from that culled from the world literature. All cases in both the former groups were Negroes, and practically all were in the older age group. Hilar lymph node involvement was almost always present, the syndrome of uveoparotid fever did not occur, eye lesions were frequently present, and eye lesions of the serious nature were noted in 3 instances, 1 in the Washington Series and 2 in the Richmond Series. It m a y be concluded, therefore, that the clinical picture of sarcoidosis among children in the United States follows the pattern outlined in these 2 studies.
LABORATORY STUDIES There are no detailed reports of laboratory findings in the 104 world cases or in those of the Washington Series. Among the most frequent significant laboratory changes in sarcoidosis are hyperglobulinemia, leukopenia, hypercalcemia, hypercalciuria, elevated alkaline phosphatase, and eosinophilia. Hyperglobulinemia. Salveson 7r was the first to point out that the serum protein concentration may be abnormally high in cases of sarcoidosis. I t has since been established that this hyperproteinemia is due to an absolute increase in serum globulin, so that the albumin-globulin ratio is frequently reversed. T h e Richmond Series showed hyperglobulinemia in 6 of 7 cases. Serum calcium. Hypercalcemia occurs in about 20 to 45 per cent of adult patients, a~, 7s Serum calcium above 11 mg. per 100 ml. of serum was noted in 2 of the 5 tested Richmond patients. Serum alkaline phosphatase. Although Cummings TM reported the value of serum alkaline phosphatase above 5 Bodansky units in 6 of 20 adult cases, only 1 of the 5 tested Richmond cases showed such an increase. Leukopenia. This finding occurred in 2 of the 7 Richmond patients. In an adult series, *~ leukopenia was found in one fourth of the cases, but was more common among the Negroes.
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Eosinophilia. Next to hyperglobulinemia, the most consistent laboratory finding among the Richmond patients was eosinophilia (above 4 per cent). This occurred in 4 of 7 cases, and in 2 instances there was eosinophilia above 7 per cent. This finding also occurs in adults, although apparently to a lesser degree. Other laboratory data. Elevation of the erythrocyte sedimentation rate will naturally be expected during the acute phase of the disease. Abnormal urinary findings will be present in those instances where there is renal involvement, among which m a y be hematuria, pyuria, proteinuria, granular casts, and hypercalciuria. OTHER DIAGNOSTIC PROCEDURES The Kveim test. This test represents an attempt to elicit a specific skin reaction by the intracutaneous injection of emulsified sarcoid tissue into patients with suspected sarcoidosis. Methods for preparing Kveim suspension have not changed since Williams and Nickerson, z9 Kveim, s~ and Danbolt, 81 first published their work about 20 years ago. Siltzbach s2 described this method in which tissue of a sarcoidal lymph node or spleen meeting certain specifications is ground in a mortar with sterile saline solution to make a 10 per cent suspension. The heavier particles are allowed to settle out and are then discarded. T h e cloudy suspension obtained is then heated to 56 ~ C. for 1 hour, on 2 successive days. It is tested for sterility, preservatives added, and is then ready for use. The intracutaneous test is performed in the manner of a Mantoux test, with the use of 0.15 to 0.2 ml. per injection. Any nodule which appears at the injection site, no matter how small, is biopsed after 28 days. Whiie it is Siltzbach's contention that 3 out of 4 patients with sarcoidosis will respond with a positive Kveim test, scarcity of effective Kveim test material limits the usefulness of the test at this time. Lymph node biopsy. Biopsy of a lymph node, demonstrating an epithelioid cell tubercle, with little or no necrosis, is an essential
2 76
Kendig
in diagnosis. E i g h t of the 9 W a s h i n g t o n cases a n d all the R i c h m o n d g r o u p met this requirement. A n enlarged p e r i p h e r a l node is most suitable for biopsy, b u t if none is present, biopsy of the scalene f a t p a d is most likely to reveal a lesion c o m p a t i b l e w i t h sarcoidosis. Muscle biopsy is also sometimes helpful. O t h e r tests. T h e t u b e r c u l i n test, histoplasmin skin test, a n d the coccidioidin skin test should be p e r f o r m e d on each p a t i e n t with suspected sarcoidosis. W h i l e a positive reaction with one of these antigens does n o t necessarily c o n t r o v e r t the diagnosis, it m a y be an i n d i c a t i o n t h a t the infection is m e r e l y one which simulates sarcoidosis. PROGNOSIS
Sones a n d Israel; s~ in a review of m o r e t h a n 200 a d u l t patients in P h i l a d e l p h i a , h a v e a t t e m p t e d to d e t e r m i n e the prognosis of sarcoidosis. T h e y state t h a t sarcoidosis, as observed by them, was neither as benign as some reports, s4, s4-s6 nor as m a l i g n a n t as others, s~-9~ Sones a n d Israel f o u n d survival rates, c a l c u l a t e d by the life table method, to be 88.8 per cent after 5 years of observation a n d 84.8 p e r cent after 10 years' observation, i n d i c a t i n g considerable d i m i n u t i o n of survival as the result of sarcoidosis. TREATMENT Corticosteroids a n d corticotrophin are the only agents available a t present which can suppress the acute manifestations of sarcoidosisY ~ These agents are used only d u r i n g the acute a n d d a n g e r o u s episodes. T h e initial daily dose of prednisone or prednisolone in adults is 20 to 30 mg. a n d after a few weeks the dose is g r a d u a l l y reduced. I n children, the dose of prednisone o r p r e d nisolone is 1 rag. p e r k i l o g r a m of b o d y weight, with g r a d u a l reduction as n o t e d above. Siltzbach has r e p o r t e d the f r e q u e n t occurrence of t e m p o r a r y relapse following disc o n t i n u a t i o n of corticosteroid t h e r a p y , b u t has n o t e d t h a t i m p r o v e m e n t usually follows even ~f t r e a t m e n t is not resumed.
August 1962
REFERENCES
1. McGovern, J. P., and Merritt, D. M.: Sarcoidosis in childkood, Advances in Pediatrics 8: 97, 1956. 2. Andersen, H.: Sarcoidosis (Boeck) in a child treated with cortisone and ACTH, Acta paediat. 45: 343, 1956. 3. Weekly Case Conference: Sarcoidosis, Clin. Proc. Child. Hosp. 12: 253, 1956. 4. Kogut, M. D., and Neumann, L. L.: Renal involvement in Boeck's sarcoidosis, Pediatrics 28: 410, 1961. 5. Kendig, E. L., Jr.: Sarcoidosis in children, Am. Rev. Resp. Dis. 84: 49, 1961. 6. Kendig, E. L., Jr., and Wiley, E. J., Jr.: Sarcoidosis in children, Postgrad. M. J. 37: 590, 1961. 7. Cummings, M. M., and Dunner, E.: Pulmonary sarcoidosis, M. Clin. North Am. 43: 163, 1959. 8. Hutchinson, J.: Cases of mortimer's malady (lupus vulgaris multiplex non-ulcerans et non-serpiginosus), Arch. Surg. (London) 9" 307, 1898. 9. Besnier, E.: Lupus pernio de Ia face, synovitis fongeuses (scrofulotubereuleuses) symgtriques des extremit~s sup~rieures, Ann. dermat, et syph. 10: 333, 1889. 10. Boeck, C.: Multiple benign sarkoid of skin, J. Cutan. Dis. incl. Syph. 17: 543, 1899. 11. Schaumann, J.: t~tude sur le lupus pernio et ses rapports avec les sarcoides et la tubereulose, Ann. dermat, et syph, 6 (fifth series): 357, 1916-1917. 12. tIeerfordt, C. F,: Ueber eine "Febris uveoparotidea subchronica" an der glandula parotis und der uvea des auges lokalisiert und haiifig mit Paresen cerebrospinalen nerven kompliziert, Arch. f. Ophth. 70" 254, 1909. 13. Garland, H. C., and Thompson, J. C.: Uveoparotid tuberculosis (febris uveo-parotidea of Heerfordt), Quart. J. Med. 2: 157, 1933. 14. Longcope, W. T., and Pierson, J. W.: Boeek's sarcoid (sarcoidosis), Bull. Johns Hopkins Hosp. 60" 223, 1937. 15. Siltzbach, L. E.: Sarcoidosis: prevalence and diagnosis, Seminar Internat. 9: 2, 1960. I6. Polland, R.: Multiple Benignes Sarkold bei einem sS_ugling, Dermat. Ztschr. 61: 360, 1931. 17. Gentry, J, T., Nitowsky, H. M., and Michael, M., Jr.: Studies on the epidemiology of sarcoidosis in the United States; the relationship to soil areas and to urban-rural residence, J. Clin. Invest. 34: 1839, 1955. 18. Cummings, M. M., Dunner, E., Schmidt, R. H., Jr., and Barnwell, J. B.: Concepts of epidemiology of sarcoidosis, Postgrad. Med. 19: 437, 1956. 19. Sareoidosis, Statistics of Navy Med. 13" 3, 1957. 20. Chapman, J. S.: Notes on the secondary factors involved in the etiology of sarcoidosis, Am. Rev. Tuberc. 7I: 459, I955. 21. Kendig, E. L., Jr., Peacock, R. L., and ll.yburn, S.': Sarcoidosis: report of three
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22. 23. 24.
25.
26. 27. 2B. 29. 30.
31. 32.
33. 34.
35.
36. 37. 38. 39. 40. 41.
Sarcoidosis a m o n g children
Number 2
siblings under fifteen years of age, New England J. Med. 260: 962, 1959. Walgren, S.: Pulmonary sarcoidosis detected by photofluorographic surveys in Sweden, 1950-1957, Nord. med. 60: 1194, 1958. Wegelius, C., and Wijkstroem, S.: Mass radiography in Sweden, Nor& med. 60:1191, 1958. Bauer, H. J., and Gentz, C.: The results of mass x-ray examination in Stockholm City during the years 1949-1951, Acta tuberc. scandinav. 29: 22, 1953. Michael, M., Jr., Cole, R. M., Beeson, P. B., and Olson, B. J.: Sareoidosis: preliminary report on a study of 350 cases with special reference to epidemiology, Am. Rev. Tuberc. 62: 403, 1950. Jacques, W. E.: Sarcoidosis: a review and a proposed etiologic concept, Arch. Path. 53: 558, 1952. Longcope, W. T.: Sarcoidosis, Veterans Admln. Teeh. Bull. TB-73: 1, 1951. Scadding, J. G.: Mycobacterium tuberculosis and the etiology of sarcoidosis, Brit. M. J. 2: 16, 1960. Higgin, H. L.: Pulmonary sarcoidosls, Connecticut M. J. 11: 330, 1947. Fisher, A. M.: In discussion on Fisher, A. M.: Some clinical and pathological features observed in sarcoidosis, Tr. Am. Clin. Climat. A. 59: 73, 1947. Refvem, O.: Pathogenesis of Boeck's disease (sarcoidosls), Acta reed. seandinav. 119: ,(Suppl. 294) 1, 1954. Cummings, M. M., and Hudgins, P. C.: Chemical constituents of pine pollen and their possible relation to sarcoidosls, Am. J. M. Sciences 236: 311, 1958_ Gendel, B. R., Young, J. M., and Greiner, D..1.: Sarcoidosls: a review with twenty-four additional cases, Am. J. Med. 12: 205, 1952. Longcope, W. T., and Freiman, D. G.: A study of sareoidosis based on a combined investigation of 160 cases including 30 autopsies from the Johns Hopkins Hospital and Massachusetts General Hospital, Medicine 31: 1, 1952. Pautrier, L. M.: Le Syndrome de Heerfordt des Ophthalmologlstes n'est qu'une forme particuller~ de la maladie de Besnier-BoeckSchaumann, Ann. dermat, et Syph. 9: 161, 1938. King, M. J.: Ocular lesions of Boeck's sareoid, Tr. Am. Ophth. Soe. 37: 422, 1939. Osterberg, G.: Iritis Boeck (sarkoid of Boeek in iris), Brit. J. Ophth. 23: 145, 1939. Walsh, F. B.: Ocular importance of sarcoid: its relation to uveo-parotid fever, Arch. Ophth. 21: 421, 1939. Lindau, A., and L6wegren, A.: Benign lymphogranuloma (Schaumann's disease) and the eye, Acta. reed. scandinav. 105: 242, 1940. Dunn, A. G., and Anderson, G. H.: Ocular manifestations of Boeck's sarcoid: report of four cases, Wisconsin M. J. 50: 279, 1951. Maekensen, G.: Vergnderungen am Augenhln-
42. 43.
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45. 46. 47.
48.
49. 50.
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52. 53.
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tergrund bei Besnier-Boeek-Schaumannscher Erkrankung, Klin. Monatsbl. Augenh. 121: 51, 1952. James, D. G.: Ocular sarcoidosis, Am. J. Med. 26: 331, 1959. Dressier, M.: l~ber einem Fall von Splenomegalie durch Sternalpunktion als Boecksche Krankheit verifiziert, Kiln. Wchnschr. 2: 1467, 1938. Kennedy, A. C.: Boeck's sarcoid: report of a case with lesions detected in material obtained by sternal puncture, Glasgow M. J. 31: 10, 1950. Pautrier, L.-M.: Une Nouvelle Grande R6ticulo-endoth61iose: Maladie de Besnier-BoeckSehaumann, Paris, 1940, Masson & Cie. Katz, S., Coke, C. P., and Reed, H. S.: Sareoidosis, New England J. Med. 229: 498, 1943. Reisner, D.: Boeck's sarcoid and systemic sarcoidosis (Besnier-Boeck-Sehaumann disease): study of 35 cases, Am. Rev. Tuberc. 49: 289, 1944. MeCort, S. S., Wood, R. H., Hamilton, J. B.. and Erlich, D. E.: Sarcoidosis: clinical and roentgenologic study of 28 proved cases, Arch. Int. Med. 130- 293, 1947. Holt, F', and Owens, W. I.: The osseous lesions, Radiology 53" 11, 1949. Dunner, E., Cummings, M. M., Williams, J. H., Jr., Schmidt, R. H., and Barnwell, J. B.: A new look at sarcoidosis, a review of clinical records of 160 patients with a diagnosis of sarcoidosis, Southern M. J. 50: 1141, 1957. Ricker, W., and Clark, M.: Sarcoidosis: a clinieopathologic review of 300 cases, including 22 autopsies, Am. J. Clin. Path. 19" 725, 1949. Block, M.: Sarcoid diagnosed by needle biopsy of the spleen: report of a case, J. A. M. A. 149: 748, 1952. Berger, K. W., and Relman, A. S.: Renal impairment due to sarcoid infiltration of the kidney:' report of a case proved by renal biopsies before and after treatment with cortisone, New England J. Med. 252" 44, 1955. Dent, C. E., Flynn, F. V., and Nabarro, J. D. N.: Hypercalcemia and impairment of renal function in generalized sarcoidosis, Brit. M. J. 2: 808, 1953. Klatskin, G., and Gordon, M.: Renal complications of sarcoidosis and their relationship to hypercalcemia: with a report of two cases simulating hyperparathyroidism, Am. J. Med. 15: 484, 1953. Anderson, J., Dent, C. E., Harper, C., and Philpot, G. R.: Effect of cortisone on calcium metabolism in sarcoidosis with hypercalcemia; possible antagonistic action of cortisone and vitamin D, Lancet 2: 720, 1954. Hennenaan, P. H., Carroll, E. L., and Dempsey, E. F.: The mechanism responsible for hypercalciuria in sarcoid, J. Clin. Invest. 33: 941, 1954. Davidson, C. N., et al: Nephrocalcinosis associated with sarcoidosis: a presentation
278
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62. 63. 64.
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and discussion of seven cases, Radiology 62: 203, 1954. I.ienneman, P. H., et al: The cause of hypercalciuria in sarcoid and its treatment with cortisone and sodium phytate, J. Clin. Invest. 35: 1229, 1956. Seholz, D. A., and Keatlng, F. R., Jr.: Renal insufficiency, renal calculi and nephroealcinosis in sarcoidosis, Am. J. Med. 21: 75, 1956. Phillips, R. W., and Fitzpatrick, D. P.: Steroid therapy of hypercalcemia and renal insufficiency in sarcoidosls, New England J. Med. 254: 1216, 1956. McSwiney, R. R., and MiUs, I. I-I.: I-Iypercalcemia due to sarcoidosis: treatment with cortisone, Lancet 2: 862, 1956. Gleckler, W. J.: Hypercalcemia and renal insufficiency due to sarcoldosis: treatment with cortisone, Ann. Int. Meal. 44: 174, 1956. Scholz, D. A., Power, M. H., and Dearing, W. H.: Metabolic effects of cortisone in a case of sarcoidosis with hypercalcemia and renal insufficiency, Proe. Staff Meet., Mayo Clin. 32: 182, 1957. Scholz, D. A.: Effect of steroid therapy on hypercalcemia and renal insufficiency in sarcoidosis, J. A. M. A. 169: 682, I959. Deller, D. J., Brodzlak, I. A., and PhiIllps, A. D.: Renal failure in hypercalcaemlc sarcoldosls, Brit. M. J. 1: 1278, 1959. Nagle, R.: Hypercalcemla and nephrocalcinosis in sarcoidosis, J. Mt. Sinai Hosp. 28: 268, 1961. Longcope, W. T., and Fisher, A. M.: Involvement of the heart in sarcoldosis, J. Mt. Sinai Hosp. 8: 784, 1942. Johnson, J. B., and Jason, R. H.: Sarcoidosis of the heart: report of a case and review of the literature, Am. Heart J. 27: 246, 1944. Yesner, R., and Silver, M.: Fatal myocardial sarcoidosis, Am. Heart J. 41: 777, 1951. Roos, B.: Cerebral manifestations of lymphogranulomatosis benigna (Sehaumann) and uveoparotid fever (Heerfordt), Acta med. Scandinav. 104: 122, 1940. Essellier, A. F., et al.: Die zentralnervgsen Erscheinungsformen des Morbus BesnierBoeck-Schaumann, Schweiz. med. Wchnschr. 81: 376, 1951. Pennell, W. H.: Boeck's sarcold with involvement of the central nervous system, J. Nerv. & Ment. Dis. 115: 451, 1952.
August 1962
74. Barker, D. H. W.: Benign lymphogranulomatosis with apparent involvement of the anterior pituitary, Brit. J. Dermat. 58: 70, 1946. 75. Boman, A.: Diabetes insipidus vid lymphogranulomatosis benigna, Nor& Med. 47: 675, 1952. 76. Krause, E. J.: Sarcoidosis (Boeck-BesnlerSchaumann disease) as a cause of pituitary syndrome, J. Lab. & Clin. Med. 28: 140, 1942. 77. Salveson, H. A.: Sarcoid of Boeck, a disease of importance to internal medicine; report on four cases, Acta. med. Scandinav. 86: 127, 1935. 78. Israel, H. L., and Sones, M.: Sarcoldosis: clinical observations in 160 cases A. M. A. Arch. Int. Med. 102: 766, 1958. 79. Williams, R. H., and Niekerson, D. A.: Skin reactions in sarcold, Proc. Soc. Exper. Biol. & Med. 33: 403, 1935. 80. Kveim, A.: Preliminary report on new and specific cutaneous reaction in Boeck's sarcoid, Nord. Med. 9: 169, 1941. 81. Danbolt, N.: On the skin test with sarcoid tissue-suspension (Kvelm's reaction), Acta dermat, venereol. 31: 184, 1951. 82. Siltzbach, L. E.: The Kvelm test in sarcoldosis, Am. J. Med. 30: 495, 1961 (editorial). 83. Songs, IV[., and Israel, I'i. L.: Course and prognosis of sarcoidosis, Am. J. Med. 29: 84, 1960. 84. King, D. S.: Sarcoid disease as revealed in chest roentgenograms, Am. J. Roentgenol. 45: 505, 1941. 85. Scaddlng, J. G.: Discussion on sarcoidosis, Proc. Roy. Soc. Med. 49: 799, 1956. 86. James, D. G. (Quoted inS2). 87. Reisner, D.: Boeck's sarcoid and systemic sarcoidosis, Am. Rev. Tuberc. 49: 437, 1944. 88. Riley, E. A.: Boeck's sarcoid, Am. Rev. Tuberc. 62: 231, 1950. 89. Nitter, L.: Changes in the chest roentgenogram in Boeck's sarcoid of the lungs, Acta Radiol. (suppl. 105) 1, 1953. 90. Gilg, I.: Kliniske undersogelser over Boeck's Sarcoid (Sarcoidose): behandling og forlob, Ugeskr. laeger 18: 46, 1956. 91. Siltzbach, L. E.: Effect of Cortisone in Sarcoidosis, Am. J. Med. 12: 139, 1952.
PROGRESS
Xarcoiclosis among cbildren A review
Sarcoidosis, a disease o[ unknown etiology and pathogenesis, is relatively rare in children. I n the two series among children in the United States, all cases were in Negroes, and practically all were in the preadolescent or adolescent age group. Hilar lymph node enlargement was practically always present, ocular lesions were [requently present, and serious ones were not unusual. A m o n g the most [requent significant laboratory findings in sarcoidosis among children are hyperglobuIinemia, eosinophitia, leukopenia, hypercalcemia, hypercalciuria, and elevated alkaline phosphatase. Corticosteroids and corticotrophin are the only agents presently available which can suppress the acute mani[estations o[ sarcoidosis.
E d w i n L. K e n d i g , Jr., M . D . ~ R I G H M O N D , VA,
S A R 13 O I D O S I S a p p e a r s to be relatively r a r e a m o n g children. M c G o v e r n a n d M e r ritt 2 reviewed the world l i t e r a t u r e u p until F e b r u a r y , 1953, a n d were able to d o c u m e n t only 104 cases in children u n d e r 15 years of age; to these they a d d e d 9 others, all diagnosed in W a s h i n g t o n hospitals. As far as we can d e t e r m i n e , there have been only
scattered cases of sarcoidosis in children r e p o r t e d since t h a t time 2-4 except for our own series, a, 6 Since the cases of M c G o v e r n a n d M e r r i t t a n d o u r own a p p e a r to be the only series a m o n g c h i l d r e n recently reported, these will be the object of frequent reference in the ensuing discussion a n d will be designated as the W o r l d G r o u p (104 cases f r o m l i t e r a t u r e ) , the W a s h i n g t o n Series ( M c G o v e r n a n d M e r r i t t ) , a n d the R i c h m o n d Series ( K e n d i g a n d W i l e y ) . I t is, of course, conceded t h a t there are u n d o u b t e d l y a n u m b e r o f other cases t h a t have been rec-
From the Department o[ Pediatrics and the Child Chest Clinic Medical College o[ Virginia, Richmond, Va. ~Address, 3603 Grove Avenue, Richmond 21, Va.
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ognized in children, b u t the disease m u s t be considered relatively r a r e in this age group. T h e criteria for diagnosis of sarcoidosis as o u t l i n e d b y a s u b c o m m i t e e of the N a t i o n a l R e s e a r c h Council in 1948 a n d redefined in October, 1956, are as follows: 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,z The intracutaneous tuberculin test is frequently negative, but a positive test does not controvert the diagnosis. Hyperglobulinemia and leucopenia are common and hypercalcemia, hypercalciurla, elevated alkaline phosphatase, and eosinophilia are variable but sometimes significant features of sarcoidosis. 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.
August 1962
finding of this survey was the h i g h incidence of p r e s u m p t i v e a s y m p t o m a t i c sarcoidosis, is AGE INCIDENCE Sarcoidosis m a y occur at a n y age, b u t it is e n c o u n t e r e d m o r e f r e q u e n t l y in adults between 20 a n d 40 years of age. W h i l e the case of the youngest p a t i e n t reported, p r o v e d b y biopsy, was in a 2 - m o n t h - o l d infant, 16 most childhood cases r e p o r t e d have occurred in the p r e a d o l e s c e n t or adolescent age group. Of the g r o u p d o c u m e n t e d from the world l i t e r a t u r e b y M c G o v e r n a n d M e r r i t t , 73.5 per cent were b e t w e e n t h e age of 9 a n d 15 years; eight of their 9 a n d all of our 7 cases fell into the same age group. I t m u s t be noted, however, t h a t the m i l d or insidious onset of the disease m a y have caused delay in recognition. RACE
T h e racial incidence of sarcoidosis varies considerably. I n Europe, a n d p a r t i c u l a r l y in Scandinavia, w h e r e t h e N e g r o p o p u l a t i o n is low, the disease occurs m o r e often in the white race. I n the U n i t e d States, on the other hand, sarcoidosis occurs m o r e comm o n l y a m o n g Negroes. I n 3 r a d i o g r a p h i c surveys of the U n i t e d States A r m e d Forces, 1~-19 Negroes with sarcoidosis o u t n u m b e r e d white personnel w i t h the disease b y a r a t i o v a r y i n g f r o m 7:1 to 26:1. C u m m i n g s z8 rep o r t e d the hospitalization r a t e for white a n d
HISTORY
T h e disease was first described in Engl a n d b y H u t c h i n s o n s in 1875. Besnier 9 in 1889, Boeck ~~ in 1899, a n d S c h a u m a n n 11 in 1917 m a d e contributions clarifying c e r t a i n clinical a n d p a t h o l o g i c features, a n d H e e r fordt, z2 a n d m o r e recently, G a r l a n d a n d T h o m p s o n 13 a n d L o n g c o p e a n d Pierson 1~ have c o n t r i b u t e d f u r t h e r to the description of the disease. A significant a d v a n c e in the k n o w l e d g e of sarcoidosis was a t t a i n e d a b o u t the time of W o r l d W a r I I w h e n mass r a d i o g r a p h y was i n t r o d u c e d in m a n y countries in an effort to d e t e c t tuberculosis, This m e t h o d was used first in the A r m e d Forces a n d l a t e r in the general p o p u l a t i o n . A n u n e x p e c t e d
T a b l e I. C o m p a r i s o n of organs affected in the r e p o r t e d W o r l d G r o u p , W a s h i n g t o n Series ( M c G o v e r n a n d M e r r i t t ) , a n d R i c h m o n d Series
ington Series (9)
Richmond Series (7)
54
8
7
32 51 51 30 28 24 13
6 6 4 3 0 1 3
4 2 4 1 0 2 2
W~sh
Reported World Group (lo4) Lungs (parenchymahilar nodes) Peripheral lymphadenopathy Skin Eyes Bones Uveoparotid fever Spleen Liver
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Volume 61
Number 2
Negro World W a r I I veterans with sarcoidosis to be 3.3 and 40.1 per 100,000, respectively. Although Siltzbach 15 has noted that this susceptibility of the American Negro is not shared by the Negroes of Central Africa, where the disease is apparently unknown, 2~ he also pointed out that cases of sarcoidosis are beginning to be reported in numbers among natives of North and South Africa. However, he suggests that the latter finding is the result of better facilities now available there for the detection of sarcoidosis. Among children for whom race was stated in the world literature, 27.6 per cent were Negro, but all 9 Washington patients and the 7 children in the Richmond Series were Negroes. SEX
DISTRIBUTION
It is generally agreed that both sexes appear to be affected with equal frequency, and in the Richmond Series there were 4 females and 3 males. In the Washington Series, however, there were 6 females and only 3 males. HEREDITY
There appears to be little evidence that heredity is in any way connected with either the incidence of the disease or predisposition toward it. Such reports as that of 3 cases among siblings under 15 years of age 21 are probably not an indication of hereditary involvement. GEOGRAPHIC
DISTRIBUTION
Sarcoidosis has been observed throughout much of the world. The highest national rate for the disease has been reported in Sweden: the prevalence in the Armed Forces, in the general population, and in Stockholm was reported to be above 40 per 100,000 population 22"24 and one rural county, Jaemtlands, had a rate of 140 per 100,000. 2a In the United States, reports by Michael, 2~ Gentry, a7 and Cummings, ~s on the study of the birthplace and residence of persons in the Armed Forces with sarcoidosis indicate
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areas with high attack rates of sarcoidosis in the South Atlantic and Gulf states with endemic areas in New England and the Midwest. ETIOLOGY
AND
PATHOGENESIS
Jacques 2~ and Longcope 27 have reviewed the concepts of the cause of sarcoidosis. M a n y theories have been advanced, including a causal relationship with leprosy, syphilis, brucellosis and infections due to viruses, fungi, protozoa and helminths, and the possibility that sarcoidosis m a y be a syndrome caused by a number of etiologic agents. Tuberculosis, one of the diseases earlier considered as a possible causative agent, has again been recently championed by Scadding? s The similarity of sarcoidosis to berylliosis and to histoplasmosis has been described.2~, a0 Refvem,al analyzing tissue obtained from patients with sarcoidosis, suggested that calcareous spar found in certain soil types m a y be a possible etiologic agent and also demonstrated that particles of quartz and other foreign bodies may provoke localized sarcoid formation. Cummings zs has recently noted that forest products or even diseases of plant life appear to be related in some way to sarcoidosis, and the idea has been advanced that pine pollen m a y be involved in the causation? 2 The discovery of a small area in Virginia where the incidence of sarcoidosis appears to be extremely high (50 presumptive cases of sareoidosis in a county of 38,000 population) has suggested another possible factor. 21 This area is predominantly rural, with pine forests and sandy soil, and the chief crop is peanuts. Among the patients with sarcoidosis, no history of contact with a known infectious agent or unusual dietary regimen can be elicited. However, it is said that practically all the persons in this locality known to be affected have worked with peanuts, either in the fields or in factories, and the possibility that in this particular area the causative agent is either disseminated from the dust from peanut shells or is activated by it must be considered.
2 7 2 Kendig
CLINICAL MANIFESTATIONS ORGAN INVOLVEMENT
August 1962
AND
Lesions have been found in practically every tissue a n d o r g a n of the body. Since symptoms are due p r i m a r i l y to local tissue infiltration a n d i n j u r y by pressure a n d disp l a c e m e n t by sarcoid lesions, the clinical manifestations depend largely on the organ or system involved. A n illustrative case is as follows:* J. L., a 13-year-old Negro, was admitted t o Dooley Hospital on December 20, I955. Four months previously he had complained of pain and decreasing vision in the left eye. Small nodules appeared on the face and eyelids. A short time later, he began to have exertional dyspnea. A sister was admitted to the hospital at the same time with similar symptoms. Positive findings on physical examination ineluded extensive scarring (burn) over the arms, legs, and face, with moderate keloid formation and small yellowish noduIes, 1 to 2 mm. in diameter, over the lower eyelids, nose, upper lip, palms of the hands and soles of the feet. There was minimal posterior synechia formation in the right eye, and multiple posterior synechiae of the left, prohibiting reaction of the pupil. In the left eye, there was a dense, brownish-white opacity over the lower half of the cornea and mild lenticular opacity. Vision in the left eye was limited to gross hand movements. There were fine, moist inspiratory r~les at both lung bases. The liver edge, which was smooth and non-tender, was 4 cm. below the right costal margin. The spleen extended down to the iliae crest and medially to the midline. There was generalized lymphadenopathy. The temperature was 100.2~ F., the pulse, 90, a n d the respirations 20. The blood pressure was 112/80. Examination of the blood showed a hemoglobin of 11.8 grams per i00 ml. and a white cell count of 2,350 [per cubic millimeter], with 37 per cent neutrophils, 15 per cent eosinophils, 3 per cent basophils and 45 per cent lymphocytes. A serologic test for syphilis was nonreactive. The erythrocyte sedimentation rate was 38 mm. per hour. Sickle-cell preparations were negative. The total serum protein was 9 Gm., the albumin 3.2 grams, and the globulin 5.8 grams per 100 ml. The serum calcium was 12.8 mg. and the phosphorus 4.5 rag. per 100 ml., and the alkaIine phosphatase 9 Bodansky units. Liver function tests gave normal findings. Urinalysis was negative. An old tuberculin test [O.T.] (0.2 mg.) was negative, as were histoplasmin and coccidioidin skin tests. A roentgenogram of the chest showed marked *From The New England Journal of Medicine260: 962, 1959.
hilar lymphadenopathy, with diffuse infiltration into both lung fields. X-ray studies of the bones were negative. Lymph-node biopsy disclosed lesions typical of sarcoidosis, with tuberculoid bodies without caseous necrosis and with multinucleated giant cells. Refractile bodies were also present. As noted earlier, sarcoidosis most comm o n l y involves l y m p h nodes, lungs, skin, eyes, liver, spleen, a n d p h a l a n g e a l bones. Lungs. Symptoms referable to the chest are usually mild a n d often consist of a dry, hacking cough, with or w i t h o u t mild to moderate dyspnea. This is p a r t i c u l a r l y true in children. Gendel, Young, a n d Greiner 83 have classified the p u l m o n a r y lesions of sarcoidosis seen on r o e n t g e n o g r a m as follows: ( 1 ) early bilateral hilar l y m p h node enlargem e n t without detectable l u n g changes; (2) bilateral hilar node e n l a r g e m e n t with strandlike infiltration e x t e n d i n g from the hilar regions into both lung fields, and small n o d u l a r beading a n d diffuse m o t t l i n g sometimes occurring along the strands; (3) later, diffuse p u l m o n a r y infiltration consisting of p a t c h y coalescent densities; (4) finally, a stage of fibrosis a n d secondary emphysema with f o r m a t i o n of bullae. T h e most c o m m o n roentgenographic finding in children is that of bilateral hilar
Fig. 1. Bilateral hilar adenopathy. (From Kendig, Peacock, and Ryburn: New England J. Med. 260, 962, 1959.)
Volume 61 Number 2
Fig. 2. Bilateral hilar adenopathy and pulmonary infiltration.
lymph node enlargement, with or without detectable lung changes (Figs. 1 and 2). Cummings and colleagues 18 noted involvement of the lung a n d / o r hilar lymph nodes in 96 per cent of adult cases, while only 54 (52 per cent) of the 104 world cases in children were so affected; nevertheless, this 52 per cent constituted the most common finding in that series. Such involvement was noted in 8 of 9 cases in the Washington group and in all 7 cases in the Richmond group (Table I). Lymphatics. Peripheral lymphadenopathy is a common feature of sarcoidosis. The typical histologic picture is that of epithelioid cell tubercles, showing little or no necrosis (Fig. 3). The nodes are discrete, painless, and freely movable. A m o n g the reported world cases in children, there was generalized lymphadenopathy in 32 of 104 cases with an additional 16 cases of isolated or localized node involvement, a total of 46 per cent. Peripheral lymphadenopathy occurred in 6 of the 9 Washington and 4 of the 7 Richmond cases, respectively. Skin. According to Longcope and Freiman, 34 skin lesions m a y appear in 3 different forms : ( 1 ) small discrete, slightly elevated nodules; (2) large conglomerate masses,
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slightly elevated and involving subcutaneous tissues; (3) large flat placques covering considerable areas of skin over the trunk or extremities, These lesions m a y vary in color from waxy, depigmented areas to a reddish blue or violacious hue. In size, they vary from a few millimeters to more than a centimeter in diameter. The lesions are more often seen on the face, but m a y occur elsewhere. Although Cummings is reported the incidence of skin lesions in a series of adults to be only 15 per cent, such lesions appear to be much more common in children. Of the 104 reported world Cases, skin lesions were present in 51, and there was involvement of the skin in 6 of the Washington group and 2 of the Richmond patients. Eyes. T h e ocular lesions have been described by a number of investigators25-42 U v e l t i s and iritis constitute the most frequently observed lesions, but keratitis, retinitis, glaucoma, and involvement of the eyelids and lacrimal glands m a y also occur. Involvement of the eye with resultant partial or total blindness is one of the most feared lesions of sarcoidosis. Although examination of the world literature suggests that eye lesions in children are not usually severe, survey of the Washington and Richmond Series, in which eye involvement was noted in 4 of 9 and 4 of 7 cases, respectively, appears to refute this conception; such involvement in 1 of the Washington patients and 2 of the Richmond group resulted in p a r t i a l blindness. Uveoparotid fever. This syndrome consisting of ocular disturbances, parotid gland swelling, and frequent facial palsy, was first described by Heerfordt 12 in 1909. Uveitis is always present a t some time in the course of this syndrome? 4, ~8 Usually, low-grade fever, malaise, and gastrointestinal symptoms precede the eye involvement. The World Group includes 28 cases (27 per cent), but there were no cases in either the Washington or Richmond Series. Bones. Osseous lesions are usually demonstrable as areas of decreased density and, often, as "punched out" areas in the met-
2 7 4 Kendig
acarpals, metatarsals, and distal phalanges. These may be either single or multiple. Early changes, not recognizable on roentgenogram, have been revealed by marrow puncture.43, 44 The incidence of osseous lesions in adults has been variously stated as 2 to 29 per cent45-5~ among children, there was an incidence of 29 per cent in the World Group, while 3 of the 9 Washington cases and only 1 of the 7 in the Richmond group had such involvement. Dunner 5~ has suggested that bone lesions may not be as common as previously suspected. Liver. Although hepatic involvement is frequently seen at necropsy, a4, 51 clinical evidence of liver disease is not often apparent. Liver enlargement is the usual finding, and impairment of function is relatively uncommon unless serum protein changes are an indication of liver pathology. In the world cases, liver involvement was noted 13 times. In the Washington Series there were 3 cases, and in the Richmond Series there were 2 children with enlarged liver. Spleen. While splenic involvement has been demonstrated by needle biopsy, ~2 enlargement is practically the only clinical finding noted. The spleen was palpable in 24 of the world cases, 1 of the Washington, and 2 of the Richmond group. Kidney. Kogut and Neumann 4 have recently reviewed renal involvement in sarcoidosis and reported a case of their own. These authors point out that there have been less than 10 reported cases in children; nevertheless, this would appear to place the kidney as a not uncommon site of sarcoid involvement in this age group, Renal involvement has been ascribed to one or more of the following processes: (1) sarcoid granulomas infiltrating the renal parenchyma s~, 5s; (9) glomerulitis with basement membrane changesS~; and, (3) hypercalcemia with or without nephrolithiasis and nephrocalcinosis. 4, 34, 54-G7 Abnormal urinary findings may include proteinuria, pyuria, hematuria, granular casts, and calciuria. Heart. Sarcoid lesions in the myocardium have been found ~t necropsy in a number of cases?4, 51, ~8-70 In the 104 world cases there
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Fig. 3. The architecture of the node is distorted by numerous solid masses of epithelioid cells with occasional giant cells. The masses are surrounded by lymphocytes. No necrosis or caseation is apparent. Lymphoid follicles are almost absent. (From Kendig, Peacock, and Ryburn: New England J. Med. 260, 962, 1959.) was associated cardiac involvement in 4 instances, and 2 patients in the Washington Series had roentgenographic evidence of cardiac enlargement; there was no evidence of cardiac involvement in the Richmond group. Cardiac change may be secondary to extensive pulmonary sarcoldosls or may be the result of conduction aberration caused by sarcoid lesions. Nervous system. Although central nervous system involvement has been reported in adults,50, 71-78 the most commonly noted neurologic involvement in childhood seems to be paralysis of the facial nerve. In the 104 world cases there were 4 instances of facial nerve palsy. Neurologic symptoms apparently result when sarcoid lesions cause local interruption of function. Endocrine glands. A definite relationship can be demonstrated with the pituitary gland. TM Diabetes insipidus has been reported in adults, 7'~, 76 and 2 of the children in the world group had some evidence of such involvement. One of the Washington patients had polydipsia and polyuria, but none of the Richmond patients were so involved. It will be noted, then, that cases in the two American series among children (Washington and Richmond) ~losely parallel each
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other and differ considerably from that culled from the world literature. All cases in both the former groups were Negroes, and practically all were in the older age group. Hilar lymph node involvement was almost always present, the syndrome of uveoparotid fever did not occur, eye lesions were frequently present, and eye lesions of the serious nature were noted in 3 instances, 1 in the Washington Series and 2 in the Richmond Series. It m a y be concluded, therefore, that the clinical picture of sarcoidosis among children in the United States follows the pattern outlined in these 2 studies.
LABORATORY STUDIES There are no detailed reports of laboratory findings in the 104 world cases or in those of the Washington Series. Among the most frequent significant laboratory changes in sarcoidosis are hyperglobulinemia, leukopenia, hypercalcemia, hypercalciuria, elevated alkaline phosphatase, and eosinophilia. Hyperglobulinemia. Salveson 7r was the first to point out that the serum protein concentration may be abnormally high in cases of sarcoidosis. I t has since been established that this hyperproteinemia is due to an absolute increase in serum globulin, so that the albumin-globulin ratio is frequently reversed. T h e Richmond Series showed hyperglobulinemia in 6 of 7 cases. Serum calcium. Hypercalcemia occurs in about 20 to 45 per cent of adult patients, a~, 7s Serum calcium above 11 mg. per 100 ml. of serum was noted in 2 of the 5 tested Richmond patients. Serum alkaline phosphatase. Although Cummings TM reported the value of serum alkaline phosphatase above 5 Bodansky units in 6 of 20 adult cases, only 1 of the 5 tested Richmond cases showed such an increase. Leukopenia. This finding occurred in 2 of the 7 Richmond patients. In an adult series, *~ leukopenia was found in one fourth of the cases, but was more common among the Negroes.
Sarcoidosis among children
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Eosinophilia. Next to hyperglobulinemia, the most consistent laboratory finding among the Richmond patients was eosinophilia (above 4 per cent). This occurred in 4 of 7 cases, and in 2 instances there was eosinophilia above 7 per cent. This finding also occurs in adults, although apparently to a lesser degree. Other laboratory data. Elevation of the erythrocyte sedimentation rate will naturally be expected during the acute phase of the disease. Abnormal urinary findings will be present in those instances where there is renal involvement, among which m a y be hematuria, pyuria, proteinuria, granular casts, and hypercalciuria. OTHER DIAGNOSTIC PROCEDURES The Kveim test. This test represents an attempt to elicit a specific skin reaction by the intracutaneous injection of emulsified sarcoid tissue into patients with suspected sarcoidosis. Methods for preparing Kveim suspension have not changed since Williams and Nickerson, z9 Kveim, s~ and Danbolt, 81 first published their work about 20 years ago. Siltzbach s2 described this method in which tissue of a sarcoidal lymph node or spleen meeting certain specifications is ground in a mortar with sterile saline solution to make a 10 per cent suspension. The heavier particles are allowed to settle out and are then discarded. T h e cloudy suspension obtained is then heated to 56 ~ C. for 1 hour, on 2 successive days. It is tested for sterility, preservatives added, and is then ready for use. The intracutaneous test is performed in the manner of a Mantoux test, with the use of 0.15 to 0.2 ml. per injection. Any nodule which appears at the injection site, no matter how small, is biopsed after 28 days. Whiie it is Siltzbach's contention that 3 out of 4 patients with sarcoidosis will respond with a positive Kveim test, scarcity of effective Kveim test material limits the usefulness of the test at this time. Lymph node biopsy. Biopsy of a lymph node, demonstrating an epithelioid cell tubercle, with little or no necrosis, is an essential
2 76
Kendig
in diagnosis. E i g h t of the 9 W a s h i n g t o n cases a n d all the R i c h m o n d g r o u p met this requirement. A n enlarged p e r i p h e r a l node is most suitable for biopsy, b u t if none is present, biopsy of the scalene f a t p a d is most likely to reveal a lesion c o m p a t i b l e w i t h sarcoidosis. Muscle biopsy is also sometimes helpful. O t h e r tests. T h e t u b e r c u l i n test, histoplasmin skin test, a n d the coccidioidin skin test should be p e r f o r m e d on each p a t i e n t with suspected sarcoidosis. W h i l e a positive reaction with one of these antigens does n o t necessarily c o n t r o v e r t the diagnosis, it m a y be an i n d i c a t i o n t h a t the infection is m e r e l y one which simulates sarcoidosis. PROGNOSIS
Sones a n d Israel; s~ in a review of m o r e t h a n 200 a d u l t patients in P h i l a d e l p h i a , h a v e a t t e m p t e d to d e t e r m i n e the prognosis of sarcoidosis. T h e y state t h a t sarcoidosis, as observed by them, was neither as benign as some reports, s4, s4-s6 nor as m a l i g n a n t as others, s~-9~ Sones a n d Israel f o u n d survival rates, c a l c u l a t e d by the life table method, to be 88.8 per cent after 5 years of observation a n d 84.8 p e r cent after 10 years' observation, i n d i c a t i n g considerable d i m i n u t i o n of survival as the result of sarcoidosis. TREATMENT Corticosteroids a n d corticotrophin are the only agents available a t present which can suppress the acute manifestations of sarcoidosisY ~ These agents are used only d u r i n g the acute a n d d a n g e r o u s episodes. T h e initial daily dose of prednisone or prednisolone in adults is 20 to 30 mg. a n d after a few weeks the dose is g r a d u a l l y reduced. I n children, the dose of prednisone o r p r e d nisolone is 1 rag. p e r k i l o g r a m of b o d y weight, with g r a d u a l reduction as n o t e d above. Siltzbach has r e p o r t e d the f r e q u e n t occurrence of t e m p o r a r y relapse following disc o n t i n u a t i o n of corticosteroid t h e r a p y , b u t has n o t e d t h a t i m p r o v e m e n t usually follows even ~f t r e a t m e n t is not resumed.
August 1962
REFERENCES
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74. Barker, D. H. W.: Benign lymphogranulomatosis with apparent involvement of the anterior pituitary, Brit. J. Dermat. 58: 70, 1946. 75. Boman, A.: Diabetes insipidus vid lymphogranulomatosis benigna, Nor& Med. 47: 675, 1952. 76. Krause, E. J.: Sarcoidosis (Boeck-BesnlerSchaumann disease) as a cause of pituitary syndrome, J. Lab. & Clin. Med. 28: 140, 1942. 77. Salveson, H. A.: Sarcoid of Boeck, a disease of importance to internal medicine; report on four cases, Acta. med. Scandinav. 86: 127, 1935. 78. Israel, H. L., and Sones, M.: Sarcoldosis: clinical observations in 160 cases A. M. A. Arch. Int. Med. 102: 766, 1958. 79. Williams, R. H., and Niekerson, D. A.: Skin reactions in sarcold, Proc. Soc. Exper. Biol. & Med. 33: 403, 1935. 80. Kveim, A.: Preliminary report on new and specific cutaneous reaction in Boeck's sarcoid, Nord. Med. 9: 169, 1941. 81. Danbolt, N.: On the skin test with sarcoid tissue-suspension (Kvelm's reaction), Acta dermat, venereol. 31: 184, 1951. 82. Siltzbach, L. E.: The Kvelm test in sarcoldosis, Am. J. Med. 30: 495, 1961 (editorial). 83. Songs, IV[., and Israel, I'i. L.: Course and prognosis of sarcoidosis, Am. J. Med. 29: 84, 1960. 84. King, D. S.: Sarcoid disease as revealed in chest roentgenograms, Am. J. Roentgenol. 45: 505, 1941. 85. Scaddlng, J. G.: Discussion on sarcoidosis, Proc. Roy. Soc. Med. 49: 799, 1956. 86. James, D. G. (Quoted inS2). 87. Reisner, D.: Boeck's sarcoid and systemic sarcoidosis, Am. Rev. Tuberc. 49: 437, 1944. 88. Riley, E. A.: Boeck's sarcoid, Am. Rev. Tuberc. 62: 231, 1950. 89. Nitter, L.: Changes in the chest roentgenogram in Boeck's sarcoid of the lungs, Acta Radiol. (suppl. 105) 1, 1953. 90. Gilg, I.: Kliniske undersogelser over Boeck's Sarcoid (Sarcoidose): behandling og forlob, Ugeskr. laeger 18: 46, 1956. 91. Siltzbach, L. E.: Effect of Cortisone in Sarcoidosis, Am. J. Med. 12: 139, 1952.