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Sarcoidosis in children
THE JOURNAL OF
PEDIATRICS OCTOBER
1968
Volume 73
Number 4
SPECIAL ARTICLE
Sarcoidosis in children With special emphasis on the natural history and treatment
Patrick L. Jasper, M.D., and Floyd W. Denny, M.D. ~ CHAPEL
HILL,
N.
G.
S A R C O I D O S l S is a chronic, multisystem disease of unknown etiology that has been reported infrequently in children. In principal reviews of childhood sarcoidosis only 199 cases have been documented in patients 15 years of age or younger, a relatively small number of cases compared with the frequency witlx which the disease has been reported in adults. The data from several series suggest that sarcoidosis in children is a benign disease generally subject to spontaneous remission without subsequent morbidity. However, documentation of the natural history and effect of corticosteroid therapy in children is limited. T h e first large group of children with sarcoidosis, a series of 12 patients diagnosed at From the Department o/Pediatrics, University o[ North Carolina School of Medicine. Supported in part by The United Medical Research Foundation Grant No. 324-UNI-I (255). eAddress for reprints: Department of Pediatrics, University of North Carohna School o[ Medicine, Chapel Hill, N. C.
Duke Hospital, Durham, North Carolina, was reported in 1948 by Cone? All had multiple system involvement and were treated conservatively. Although follow-up was not optimal, the author described the disease as relatively benign except for residual ocular lesions. Sarcoidosis in children was not comprehensively described until 1956 when McGovern and Merritt 2 reviewed 104 cases under 15 years of age (including Cone's group) in the world literature. To this total they added 9 cases which were diagnosed in Washington, D. C. Most of the patients they encountered in the literature were single case reports without data on follow-up, making it difficult to interpret the course of the disease. Less than half (49) of the cases were from the United States. Forty-nine per cent of the patients from the United States were Caucasian; the remainder were Negro. The combined data from the patients reviewed provided a basis for characterizing childhood Vol. 73, No. 4, pp. 499~512
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Table I. Children with sarcoidosis reported since the world review by M c G o v e r n and Merritt s
Author
KendlgS, 4 Beier and Lahey5 Mandi 6
No.
Per cent in 9 to 15 year age range
Method of selection
Geographical origin
13
Hospital study-
U. S. (Virginia)
10 Negro and 3 Caucasian
92
8
Hospital study
U. S. (Utah, Idaho)
Caucasian
63
X-ray survey
Hungary
Caucasian
93
o[ patients
14
Race
Niitu and associatesr
16
X-ray survey
Japan
Japanese
Unknown
Walter s
17
Hospital study
Germany
Caucasian
100
Siltzbach and Greenberg4
18
Hospital study
U. S. (New York) 12 Negro and 6 Caucasian
sarcoidosis regarding age, sex and race distribution, and clinical manifestations. A total of 86 cases of sarcoidosis in children has been documented in 6 reports since M c G o v e r n and Merritt's 2 world review. These are shown in Table I. I n the reviews of M a n d i ~ and Niitu a n d associates, ~ the patients were generally asymptomatic and did not have widespread organ involvement. This is in contrast to the more severe clinical manifestations of the patients from the other series. Beier and Lahey's s cases were unusual because all were from an area of the United States where the incidence of sarcoidosis is very low, all were Caucasian, and over one third were under 9 years of age. D a t a on the course of the disease and response to treatment were indicated in 3 of the reportsS, c, s T h e incidence of remission with either conservative m a n a g e m e n t or corticosteroid therapy was nearly equal in Beier and Lahey's 5 patients and in M a n d i ' s ~ patients. I n Waiter's group, s 7 of 11 patients who were treated conservatively were unchanged and one h a d progression of disease; 5 of 6 patients improved while on corticosteroid therapy. Because the epidemlology, natural history, and effect of corticosteroid therapy in childhood sarcoidosis are not well defined, the cases diagnosed at North Carolina Memorial
100
Hospital were reviewed and form the basis for this report. This group of 25 patients comprises the largest number of cases of sarcoidosis in childhood reported from a single institution~; they will be compared with data available from the world group reported by M c G o v e r n and Merritt ~ and from subsequent series.t Specific attention will be paid to the spectrum of signs and symptoms, extent of organ involvement, frequency of abnormal laboratory data, and response to conservative m a n a g e m e n t as well as to corticosteroid therapy. PATIENT
MATERIAL
T h e data from the 25 patients in this review were obtained from the records of the pediatric service of North Carolina Memorial Hospital from 1954 to early 1968. All but one of the patients were admitted to the hospital for their initial diagnostic evaluation. T h e diagnostic criteria of sarcoidosis as outlined by the National Research Council were used for the selection of patients. 9 All patients had tissue biopsies and in 22 patients these were compatible with the diagnosis of sarcoidosis. Although the remaining * R e f e r r e d to in the " N o r t h C a r o l i n a " cases. ~Referred
"reported"
to in cases.
the
remainder
of
the
paper
as
the
remainder
of
the
paper
as
the
Volume 73 Number 4
Sarcoidosis in children
5 0 1
8 or) P
7
Z
UJ
6
I.l_ 0 0! I.O m Z
5 4-
3 2I I
5
6
I
"g
I
I
8
9 AGE
I0 IN
II
12
13
14
15
YEARS
Fig. 1. Age at the time of diagnosis of ?.5 children with sarcoidosis from North Carolina Memorial Hospital.
3 patients had normal tissues on biopsy, they are included in the series because their clinical courses and other laboratory findings were consistent with the diagnosis of sarcoidosis. O n e patient died in the hospital after diagnosis; one patient did not return for follow-up. I n the remaining group, 13 patients were observed for an average of 3.t years before being lost to follow-up. T e n patients are currently under observation and have been followed for an average of 2.4 years. AGE, SEX, AND RACE DISTRIBUTION
Sarcoidosis has been described in all age groups and most frequently occurs in adults between the ages of 20 and 40 years. While it can occur rarely in children less than one year of age, t~ it usuMIy is encountered in early to mid-adolescence. As depicted in Fig. 1, all the patients in the N o r t h Carolina series except one were 9 to 15 years old when a diagnosis was established; the average age was 13 years. This is consistent with the age of the reported patients where 82 per cent were between 9 and 15 years of age at the time of diagnosis. T h e r e would appear to be no male or female predominance in childhood sarcoidosls.
As shown on Table I I , i4 patients in the North Carolina series were male and 11 were female. This relatively equal distribution between sexes was found in reported series also where 46 per cent of patients were male and 54 per cent were female. I n general, race distribution a m o n g children with sarcoidosis varies wittl geographical location. I n the N o r t h Carolina series, as illustrated in Table I I , 18 patients were Negro, 5 were Caucasian, and 2 were Indian. This predominance of Negro children is shared in some series 1' ~ but is in contrast with the total reported group where 61 per cent were Caucasian, 30 per cent were Negro, and 9 per cent were of other races. In the United States, where the ratio of Negro to Caucasian adults with sarcoidosis varied between 3 : 2 and 26:1, ~3-~6 the distribution a m o n g U. S. children was relatively equal; 58 per cent were Negro and 42 per cent were Caucasian. GEOGRAPHICAL
DISTRIBUTION
T h e distribution of sarcoidosis is worldwide, but it has been reported most frequently in Scandinavia and in the southeastern United States. T h e increased incidence in certain geographical areas is unexplained, although attempts have been made
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The Journal o[ Pediatrics October 1968
Table II. Race and sex o;f 25 children with sarcoidosis from North Carolina Memorial Hospital
Race Negro Caucasian Indian Total
I Male 12 2 0 14
I Female t 6 3 2 I1
Total 18 5 2 25
to correlate it with forest and plant products.17, is As shown in Fig. 2, patients in this series did not cluster in specific locations but were scattered widely in middle and eastern North Carolina. When the cases of Con@ Kendig, s and McGovern and Merritt 2 are added to the present series, 27 per cent of the total number of children reported with sarcoidosis are located in the southeastern United States. CLINICAL MANIFESTATIONS The most striking feature of childhood sarcoidosis is the multisystem involvement, which results in great variability of clinical manifestations. Although the signs and symptoms depend on the organs involved, these 2 topics are reported separately in order to simplify the presentation. Signs and symptoms. The signs and symptoms of patients in the North Carolina series are illustrated in Fig. 3. There was no pattern specific for sarcoidosis. The presenting complaints were variable also and had been present for an average of 7 months before a diagnosis was established. Only 2 patients were asymptomatic before diagnosis; both had abnormal findings on routine chest x-ray during a school examination. Weight loss was the most ;frequent sign and occurred in 68 per cent of patients. Forty-eight pet" cent of patients had a history of cough and 44 per cent a history of fever. A myriad of other symptoms was present, but occurred less frequently. It is noteworthy that chest pain, an uncommon symptom in children, occurred in 20 per cent of patients. Fig. 2 also compares the frequency of signs and symptoms of the North Carolina
Table I I I . Number of organs involved of 25 children with sarcoidosis from North Carolina Memorial Hospital
No. o[ organs involved
I
No. o[ patients
1
2
2 3 4
4 6 5
5 6
2 3
7
1
8
2
cases with that reported in the literature. In all categories the incidence in reported series was lower than that in the North Carolina series. M a n y of the patients had the same array of symptoms as our patients did, but specific data on symptomology were not always indicated in other reports. Organ and system involvement. Involvement of all majo.r organs and tissues has been described and m a n y m a y be involved simultaneously. I n the North Carolina series the criteria of organ involvement were based on clinical, radiographic, electrocardiographic, and pathologic data. The wide spectrum of this disease is emphasized by the presence of multisystem involvement in 23 o.f 25 patients. As shown in Table I I I , only 2 patients had disease of one organ; the majority of patients had 3 or more organs involved; 2 patients had involvement of 8 organs. The frequency of specific organ and system involvement is illustrated in Fig. 4. AII patients had radiographic evidence of pulmonary parenchymal a n d / o r hilar node involvement of varying degrees. The most severe was in one patient who presented with extensive pulmonary disease and an associated pneumothorax. Eighteen patients had either localized or generalized peripheral lymph node enlargement. Hepatomegaly occurred in 14 patients. Twelve patients had ocular sarcoidosis, all with involvement of the anterior uveal tract. One of the patients with ocular disease was blind at the time of diagnosis. Ten patients had splenomegaly
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Sarcoidosis in children
503
CAROLINA MEMORIAL HOSPITAL
Fig. 2. Geographical origin of 25 children with sarcoidosis diagnosed at North Carolina Memorial Hospital. and 8 had cutaneous sarcoidosis. Parotid gland involvement occurred in 6 patients and was manifested by facial palsy in 2, intracerebral invasion in one, and involvement of the recurrent laryngeal nerve in the other. Cardiac disease was found in 2 patients and was evidenced by conduction defects by electrocardiography. Eleven other patients had electrocardiograms performed and all were normal. Striated muscle sarcoidosis was seen in 2 patients, producing weakness in one patient and pseudohypertrophy in the other. Renal, pituitary, and bone involvement occurred in the same patient and was proved at necropsy. This patient had diabetes insipidus and amenorrhea with no urinary tract or skeletal symptoms. Twenty-one patients had x-rays of the hands and all were normal; intravenous pyelograms were performed in 8 patients and all were normal. One patient had hoarseness; a nodule on the false vocal cords was not biopsied but was thought to be sarcoid in nature. None of the North Carolina patients had joint or gastrointestinal involvement. The degree of organ involvement was more widespread in the North Carolina series than in reported series, with a higher percentage of patients having intrathoracic, lymph node, liver, spleen, and nervous system involvement. In only 2 organ systems, bone and skin, was sarcoidosis found more frequently in reported patients. Involvement
of striated muscle, the pituitary gland, and the larynx which occurred in the North Carolina patients was not reported by others. DIAGNOSTIC
PROCEDURES
The diagnosis of sarcoidosis is chiefly one of exclusion of other granulomatous diseases and should be based on clinical and laboratory data which are supported by compatible biopsy material. Biopsies. Although there is no histological picture pathognomonic for sarcoidosis, the characteristic lesion is remarkably uniform and m a y be seen in any tissue in the body. It is a well-outlined follicle composed chiefly of epithelioid and giant cells, usually surrounded by lymphocytes, with no caseation. Inclusion bodies m a y be seen in the giant cells but are not specific for sarcoidosis. As illustrated in Table IV, a total of 35 biopsies was performed on the patients in the North Carolina series. Peripheral lymph nodes and skin were the most accessible and productive areas for biopsy. Striated muscle sarcoid, which is rare in children, was found in 2 patients. Biopsies from 22 (88 per cent) patients were compatible with the diagnosis of sarcoidosis. In the 3 other patients biopsies revealed normal tissues, but the clinical and laboratory findings were compatible with a diagnosis of sarcoidosis. Appropriate cultures and special staining of biopsy material were used to rule out other chronic
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Jasper and Denny
The Journal of Pediatrics October 1968
WEIGHT LOSS
COUGH
FEVER
ABDOMINAL PAIN
OCULAR PAIN
ANOREXIA
DYSPNEA CHEST PAIN PAIN IN EXTREMITIES
HEADACHE PAROTID SWELLING DECREASED VISION NAUSEA & VOMITING EASY FATIGABI LITY NORTH CAROLINA CASES ENLARGED NODES NOCTURIA HOARSENESS SKIN RASH
]
REPORTED CASES
m m l 20
30
40
0
60
70
8
90
l O0
PERCENT OF PATIENTS
Fig. 3. Frequency of signs and symptoms of 25 children with sarcoidosis from North Carolina Memorial Hospital and in children with sarcoidosis reported in the literature. The denominator for reported cases was restricted to patients in those series in which symptomatology was indicated. 2, 5, 6 granulomatous diseases. Nineteen patients had negative stains of biopsy material for acid-fast and fungaI organisms; I0 of these had negative cultures, while the remainder were not cultured. In the reported series 79 per cent of patients biopsied had a histological diagnosis compatible with sarcoidosis. L y m p h nodes were the primary source for biopsy, although in a few cases skin and liver biopsies were used to substantiate the diagnosis.
Kvehn and ether intradermal skin tests. Another method for corroborating the diagnosis of sarcoidosis is by the Kveim test. This test is performed by injecting intracutaneously a suspension 6f sarcoid tissue in an attempt to evoke a specific skin reaction. When positive, a papul e or nodule forms in 4 to 6 weeks which is indistinguishable histologically from the granuloma of sarcoidosis itself? ~ Since the antigen is a variable and unstandardized product, inconsistencies m a y
Volume 73 Number 4
Sarcoidosis in children
5 05
LUNGS- HILAR NODES
LUNGS-PARENCHYMA
LYMPH NODES-GENERAL LYMPH NODES-LOCAL LIVER
EYE
SPLEEN
SKIN
PAROTID
NERVOUS SYSTEM HEART STRIATED MUSCLE KIDNEY LARYNX
ENDOCRINE
=
B
NORTH CAROLINA CASES
[]REPORTED
CASES
BONE I0
20
I 50
l 40
I 50
i 60
I 70
I SO
I 90
I00
PERCENT OF PATIENTS
Fig. 4. Frequency of organ and system involvement of 25 children with sarcoidosis from North Carolina Memorial Hospital and in children with sarcoidosis reported in the literature. The denominator for reported cases was restricted to patients in those series in which organ and system involvement was indicated. 2-s
occur. I n the present series 8 patients who h a d biopsy-compatible sarcoid h a d K v e i m tests, b u t only 2 were positive. T h e tests were done over a period of several years and it is not k n o w n how the test m a t e r i a l was prep a r e d . I n the r e p o r t e d cases of childhood sarcoidosis the K v e i m test was p e r f o r m e d in 23 patients a n d 19 were positive. Histoplasmin, blastomycin, and coccidioidin skin tests were p e r f o r m e d on 21 patients a n d all were negative. T w o of 94 p a -
tients h a d positive tuberculin skin tests, b u t both h a d negative acid-fast cultures or stains of biopsy material. I n the literature, 14 of 86 patients (16 per cent) h a d a positive tuberculin skin test. Miscellaneous l a b o r a t o r y data. A n associated increased incidence of eosinophilia, ~~ hyperglobulinemia, 21 and h y p e r c a l c e m i a 22 has been r e p o r t e d in sarcoidosis. T h e reasons for the increase in eosinophils a n d serum proteins are unknown; the excess p r o t e i n corn-
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Jasper and Denny
The Journal of Pediatrics October 1968
ponents have been d e m o n s t r a t e d to be increases in alpha, beta, and g a m m a globulins?3, 24 T h e cause of the h y p e r c a l c e m i a has been shown to be a hypersensitivity to vitamin D. 2~ As shown in Fig. 5, in the N o r t h C a r o l i n a series serum calcium of 11 mg. p e r cent or
g r e a t e r occurred in 52 p e r cent of patients, 80 p e r cent o.f patients h a d total proteins of 8 Gin. p e r cent or greater, a n d 52 p e r cent h a d an eosinophilia of 6 p e r cent or greater. T h e s e l a b o r a t o r y findings were observed in a h i g h e r p e r c e n t a g e of patients t h a n in those reported, despite the use of higher values for defining h y p e r p r o t e i n e m i a and eosinophilia. Anemia, leukopenia, a n d a b n o r m a l liver function tests were not observed in this series, b u t these abnormalities did occur in a small p e r c e n t a g e of r e p o r t e d patients. O n e of the N o r t h C a r o l i n a patients h a d an abn o r m a l urinalysis a n d an elevated blood u r e a nitrogen t h o u g h t to be s e c o n d a r y to h y p e r calcemia. I n the N o r t h C a r o l i n a series 11 patients h a d p u l m o n a r y v e n t i l a t o r y studies per-
T a b l e I V . Biopsy results in 25 children with sarcoidosis from N o r t h C a r o l i n a M e m o r i a l Hospital
Site
Biopsy I
Lymph node Skin Striated muscle Liver
Positive [ %
No.
No.
23 8 2'
19 8 2
83 100 100
2
0
0
HYPERCALCEMIA
m
NORTH CAROLINA CASES
~
REPORTED CASES
HYPERPROTEI N EMIA
EOSINOPHI LIA
IO
20
30
40
50
I 60
PERCENT
OF
PATIENTS
I 70
I 80
90
I00
Fig. 5. Frequency of common laboratory abnormalities of 25 children with sarcoidosis reported in the literature. The denominator for reported cases was restricted to patients in those series in which these laboratory abnormalities were indicated, a-5
Volume 73 Number 4
formed; 6 were abnormal initially and in the follow-up period 3 of these patients had repeat studies, with 2 showing improvement and one being unchanged. In reported series of pediatric patients no data on pulmonary function studies were cited. NATURAL HISTORY AND EFFECT OF C O R T I C O S T E R O I D THERAPY
The natural history of childhood sarcoidosis is difficult to define because of the rarity of the disease, its chronicity, and spectrum of organ involvement. I n adults it is commonplace for spontaneous remission to occur. In children, where there are only brief recordings of long term follow-up in reported series, the remission rate is unknown and there are no data available on the mortality rate. Similarily, data on the response to corticosteroid therapy in children are sparse. Where large groups of adults have been treated with corticosteroids without associated controls, the effectiveness has been inconsistent.2s, 27 With these factors in mind, an effort was made to determine the course of this disease in the North Carolina patients. D a t a were collected from those patients who were followed with or without corticosteroid therapy for at least one year. Six patients were followed for less than one year, providing inadequate information for interpretation of their course. One patient, who had intracerebral sarcoidosis, died several days after craniotomy. Of the remaining 18 patients, all were followed for one year or more; 8 were treated symptomatically and 10 were treated with corticosteroids. Natural history. The clinical data from the 8 patients who were not treated with corticosteroids are presented in Table V. This group was followed for an average of 3.5 years with a range of 1.2 to 5 years. Signs and symptoms were variable and suggested no special pattern. As shown in Table V, patients tended to develop new findings during follow-up which were not present before or at diagnosis. The degree of organ involvement generally remained unchanged, although one patient had progressive, destructive pulmonary disease. In only one patient
Sarcoidosis in children
50 7
was there a spontaneous remission. Since comparable data are not available in the literature, it is difficult to compare our patients with those of reported series. It appears, however, that the disease characterized in the North Carolina series does not fit a picture of a benign, self-limiting process. The mortality rate of childhood sarcoidosis is probably low and would be related to the type and degree of organ involvement. As far as can be determined, 21 patients in North Carolina series are presently alive; the other 3 patients have moved from the state and their whereabouts are unknown. In reported series no mention was made of death attributed to sarcoidosis. Corticosteroid therapy. In the North Carolina series data were available on 10 patients who were treated with corticosteroids (Table V I ) . T h e criterion for instituting corticosteroid therapy in all cases was the presence of ocular involvement. As in the untreated patients, signs and symptoms were variable. However, the disease was generally more severe in the treated group as indicated by the wider spectrum of organ involvement. All patients had hilar node a n d / or pulmonary involvement, in addition to ocular involvement. M a n y had lymphadenopathy, hepatosplenomegaly, and skin involvement. Patients in this group were followed for an average of 4 years with a range of 1 to 8 years. They were treated for an average of 2.1 years, usually with prednisone in varying doses. Five patients were followed for an average of 2.8 years after corticosteroid therapy. Three patients are still on corticosteroids and 2 were lost to follow-up while on therapy. Manifestations present before or at the initiation of therapy generally disappeared or diminished during steroid administration and rarely developed or recurred after treatment. In most cases organ involvement resolved or was diminished in severity. In only 2 patients was pulmonai;z parenchymal disease unchanged; hilar node disease was unchanged in 2 other patients. Lymphadenopathy disappeared in half the patients and decreased in the other half.
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Jasper and D e n n y
7"he Journal of Pediatrics October 1968
Table V. N a t u r a l history of sarcoidosis in 8 children from N o r t h Carolina Memorial Hospital who were followed for one year or more
Abnormality Signs and symptoms Weight loss Cough Fever Anorexia Enlarged lymph nodes Chest pain Dyspnea Abdominal pain Ocular pain Easy fatigability Headache
No. of patients with abnormality before or at diagnosis
No. of patients with abnormality during follow-up Persisting from Developing after initial observation initial observation
3 3 3 3 3 2 2 2 1 1 1
0 1 1 0 0 I 1 0 1 1 0
3 1 0 0 0 1 0 0 1 1 0
Organ involvement Lungs--hilar nodes Lungs--parenchyma Lymph nodes--general Lymph nodes~local Liver Eye Spleen Parotid Nervous system Skin
7 6 5 2 2 1 1 1 1 0
4 4 1 2 0 0 0 0 0 0
1 2 1 0 0 0 1 0 0 2
Laboratory findings Hypercaleemia Hyperproteinemia Eosinophilia
3 4 2
2 3 1
1 1 2
O c u l a r involvement cleared in 5 patients and regressed to a chronic, mild, smoldering state in the other 5. Hepatosplenomegaly disappeared in all patients but did appear in 3 other patients during or after therapy. Cutaneous and parotid involvement were also effectively cleared with corticosteroids. No effect was noted in one patient w h o had vocal cord, striated muscle, and cardiac disease simultaneously. Hypercalcemia, hyperproteinemia, and eosinophilia disappeared in most patients while on therapy. Only one patient who initially had abnormal p u l m o n a r y ventilatory studies had a repeat study during treatment and this showed improved function. I n reported series only 10 patients were treated with corticosteroids and 8 of these showed improvement on therapy. Criteria
for therapy were variable and the period of follow-up was not indicated in most cases. COMMENTS
T h e syndrome of sarcoidosis is difficult to define because the etiology and pathogenesis are unknown. T h e relative infrequency of the disease in the first 2 decades of life adds to the diffictilty of characterizing the disease in children. Although an increasing n u m b e r of childhood cases has been reported in recent years, m a n y questions are unanswered. An effort was made in this report not only to summarize the clinical and laboratory manifestations of childhood sarcoidosls, but to d o c u m e n t the natural history and effect of corticosteroid therapy in children f r o m N o r t h Carolina Memorial Hospital. I n general the patients in the N o r t h Car-
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Sarcoidosis in children
509
T a b l e V I . Effect of corticosteroid t h e r a p y in 10 children with sarcoidosis f r o m N o r t h C a r o l i n a M e m o r i a l H o s p i t a l who were followed for one y e a r or m o r e No. o[ patients with abnormality Abnormality
Present be[ore or at time o[ treatment
Cured or diminished during treatment
Developing or recurring alter treatment
8 6 5 5 5 5 3 3 2 2 2 2 2
8 6 5 5 5 5 3 3 2 2 1 2 2
0 0 0 0 0 0 0 1 1 0 0 0 0
9 9 5 1 10 6 5 5 4 2 1 1
7 7 5 1 10 6 5 4 4 1 0 0
0 0 1 1 0 1 2 0 1 0 1 1
5 6 5
5 5 4
2 1 0
Signs and symptoms
Weight loss Fever Anorexia Ocular pain Abdominal pain Cough Parotid swelling Pain in extremities Chest pain Easy fatigability Dyspnea Headache Hoarseness Organ involvement
Lungs hilar nodes Lungs--parenchyma Lymph nodes--general Lymph nodes--local Eye Liver Spleen Skin Parotid Ear, nose, throat Striated muscle Heart Laboratory findings
Hypercalcemia Hyperproteinemia Eosinophilia
olina series were m o r e severely affected t h a n those r e p o r t e d in the literature, a l t h o u g h there were m a n y c o m m o n features. T h e age, sex, a n d r a c e distribution of t h e N o r t h C a r olina patients was n o t u n u s u a l a n d was similar to t h a t of o t h e r r e p o r t e d patients. A nonspecific s p e c t r u m of signs a n d symptoms was evident in our patients, as well as in patients of r e p o r t e d series. T h e t y p e of organs involved was generally t h e same in b o t h groups; however, the f r e q u e n c y of m u l t i p l e organ involvement in t h e N o r t h C a r o l i n a patients exceeded t h a t of r e p o r t e d cases. T h e r e were no unusual l a b o r a t o r y findings in this series. T h e classical abnormalities of h y p e r c a l c e m i a , h y p e r p r o t e i n e m i a , a n d eosinophilia w e r e frequently helpful in s u p p o r t i n g
the diagnosis in the N o r t h C a r o l i n a patients a n d in those r e p o r t e d in the literature. T h e etiology of sarcoidosis remains obscure despite extensive investigations of bacteria, 2s viruses, 29 fungi, 3~ parasites, sl atypical m y c o b a c t e r i a , s2 foreign bodies, 17, 3s a n d imm u n e mechanisms 34, s0 as possible causes. N e i t h e r h a v e substantial clues to the etiology been found in epidemiological surveys? 5 D u r ing the initial evaluation o;f the N o r t h C a r olina patients no special a t t e m p t s were m a d e to d e t e r m i n e an etiology, a l t h o u g h similar chronic g r a n u l o m a t o u s diseases were ruled out b y skin tests a n d a p p r o p r i a t e cultures of biopsy material. I n retrospective analysis, patients h a d no characteristics in c o m m o n t h a t would suggest an etiological mechanism.
5 10
Jasper and Denny
T h e natural history of sarcoidosis in children is unknown. Most of the information concerning the course of the disease is based on data from adults which m a y not be applicable to children. Siltzbach 86 and James a7 prefer to classify adults into 2 groups, those with subacute and those with chronic disease. In the former group of patients, the onset is usually abrupt, duration of the illness has been less than 2 years, organ involvement is not widespread, the lesions are usually transient, and the prognosis is good. In the chronic group, the onset is insidious with the disease having been present for longer than 2 years, organ involvement is more widespread, and the prognosis is poor. It would be difficult to apply this classification to children. Based on the data from the 8 patients in this series who were followed without treatment, all but one would be considered in the chronic state. A longer period of follow-up would be necessary to establish guidelines in children. T h e treatment of sarcoidosis has been the subject of numerous reports with m a n y different agents being used. There now is general agreement that corticosteroids are the drugs of choice. The criteria for therapy with corticosteroids have been outlined 8s and include treating patients with active ocular disease, persistent hypercalcemia, central nervous system or myocardial involvement, disfiguring skin lesions, and progressive pulmonary disease as evidenced by increasing symptoms or roentgenographic findings or impaired or deteriorating pulmonary function. T h e latter is a particularly objective way of deciding when the patient with sarcoidosis should be treated. It is well known that the roentgenographic appearance of the pulmonary lesions frequently may not reflect serious functional defects. Adults with only hilar lymph node or pulmonary parenchymal involvement have been shown to have impaired pulmonary function, which on followup exalnination worsened despite evidence of clearing of the lesions on roentgenograms. ~9, 4o Data on pulmonary function studies in children with sarcoidosis are lacking. With the high incidence of pulmonary involve-
The Journal o[ Pediatrics October 1968
ment in childhood, it would seem appropriate that frequent evaluations of pulmonary function should be done. I n the individual patient other reasons for treatment with eorticosteroids m a y arise which are not included in these criteria. Although this was a retrospective study and there were no control patients, the data suggest that corticosteroids were effective in alleviating symptoms and in resolving or decreasing the severity of organ involvement. It was uncommon for symptoms or lesions to recur. This favorable response in young patients whose lesions were relatively new is in keeping with Siltzbach's 41 suggestion that the fresher lesions of sarcoidosis are those most likely to respond to steroid therapy. Whether or not the treatment affects the outcome of the disease is unanswered by these data. During the observation period it was uncommon for lesions to reappear clinically, but it is obvious that these patients will need to be followed for a longer period. Ideally, controlled series of patients observed for a protracted time are necessary for a more valid evaluation of the efficacy of steroid therapy. SUMMARY
Twenty-five cases of childhood sarcoidosis were diagnosed at North Carolina Memorial Hospital between 1954 and early 1968. Biopsies from 92 cases were compatible with the diagnosis of sarcoidosis; the other 3 cases had negative biopsies but their clinical courses were consistent with a POsitive diagnosis. Other chronic granulomatous diseases were ruled out by skin tests, appropriate cultures, special staining of biopsy material, and clinical course of the patients. The age, sex, and race distribution of the North Carolina patients was similar to that in other reported series. In the North Carolina series, the average age at diagnosis was 13 years, the male to female ratio was almost equal, and the Negro race predominated. Cases were scattered in the hospital's referral area in middle and eastern North Carolina and did not suggest any special epidemiological pattern. Weight loss, cough, and fever were the most frequent of an
Volume 73 Number 4
otherwise v a r i a b l e p a t t e r n of signs a n d symptoms. T h e f r e q u e n c y of signs a n d s y m p t o m s was h i g h e r t h a n in r e p o r t e d series w h e r e specific d a t a on s y m p t o m a t o l o g y were not always indicated. I n the N o r t h C a r o l i n a series there was multisystem involvement in 23 of 25 patients. All p a t i e n t s h a d p u l m o n a r y p a r e n c h y m a l a n d / o r h i l a r n o d e involvement a n d 12 patients h a d o c u l a r disease. L u n g , l y m p h node, eye, liver, spleen, p a r o t i d gland, nervous system, heart, a n d striated muscle involvement o c c u r r e d m o r e c o m m o n l y in the N o r t h C a r o l i n a patients t h a n in o t h e r rep o r t e d cases. H y p e r c a l c e m i a , h y p e r p r o t e i n emia, a n d eosinophilia w e r e the most persistent a b n o r m a l r o u t i n e l a b o r a t o r y findings a n d were observed in a h i g h e r p e r c e n t a g e of the N o r t h C a r o l i n a p a t i e n t s t h a n in r e p o r t e d cases. Eleven patients h a d p u l m o n a r y ventil a t o r y studies p e r f o r m e d a n d 6 w e r e abnormal. O f the 18 patients w h o were followed for one y e a r o r more, 10 were t r e a t e d with corticosteroids a n d 8 were t r e a t e d s y m p t o m a t i cally w i t h o u t corticosteroid t h e r a p y . I n the n o n s t e r o i d - t r e a t e d group, symptoms were v a r i a b l e a n d new ones t e n d e d to a p p e a r d u r i n g follow-up. T h e degree of o r g a n involvement at the onset in this g r o u p generally r e m a i n e d u n c h a n g e d b u t in some p a tients t h e r e was progression to o t h e r organs. I n the c o r t i c o s t e r o i d - t r e a t e d group, in w h i c h all patients h a d o c u l a r involvement a n d the disease was generally m o r e severe, s y m p t o m s resolved within a few months. I n most cases o r g a n involvement resolved or was diminished in severity. I t was u n c o m m o n for the disease to r e c u r after corticosteroids were discontinued. C o m p a r a t i v e d a t a f r o m the lite r a t u r e on t h e n a t u r a l history a n d effect of corticosteroid t h e r a p y a r e n o t available. I n m i d d l e a n d eastern N o r t h C a r o l i n a sarcoidosis in children w o u l d a p p e a r to be m o r e c o m m o n t h a n previously suspected. T h e multiplicity of system i n v o l v e m e n t a n d t h e sev e r i t y of t h e disease were evident in these patients. A l t h o u g h longer periods of observ a t i o n a r e necessary a n d controlled studies need to be p e r f o r m e d for a b e t t e r e v a l u a t i o n of this disease, the d a t a presented here sug-
Sarcoidosis in children
5 11
gest t h a t corticosteroids are beneficial in alleviating s y m p t o m s a n d in resolving or decreasing t h e severity or o r g a n involvement. We wish to thank Drs. Wallace A. Clyde, Jr., Gerald W. Fernald, W. Paul Glezen, and Richard P. Lipman for review of the manuscript and Mrs, Sherri Davis for its preparation. REFERENCES
1. Cone, R. B.: A review of Boeck's sarcoid with analysis of 12 cases in children, J. PEDIAT. 32: 629, 1948. 2. McGovern, J. P., and Merritt, D. M.: Sarcoidosis in childhood, Advances Pediat. 8" 97, 1956. 3. Kendig, E. L., Jr.: Sarcoidosis among children, J. PEDIAT. 61: 269, 1962. 4. Kendig, E. L., Jr.: Sarcoidosis, in Kendig, E. L., Jr., editor: Disorders of the respiratory tract in children, ed. 1, Philadelphia, 1967, W. B. Saunders Company. 5. Beier, F. R., and Lahey, M. E.: Sarcoidosis among children in Utah and Idaho, J. PEDIAT. 65: 350, 1964. 6. Mahdi, L.: Thoracic sarcoidosis in childhood, Acta tuberc, scandinav. 45: 256, 1964. 7. Niitu, Y., Watanabe, M., Swetake, T., Handla, T,, Munakata, K , and Shiroishi, K.: Sixteen cases of intrathoracic sarcoidosis found among school children in Sendal in mass x-ray surveys of the chest, Res. Rep. Res. Inst. Tuberc. Lepr. & Cancer 12: 99, 1965. 8. Walter, H. H.: Zum bilde des lungen-Boeck bei kindern und jungenlichen, Tuberkulosearzt 14: 828, 1966. 9. Cummings, M. M., and Dunner, E.: Pulmonary sarcoidosis, M. Clin. North America 43: 169, 1959. 10. Polland, R.: Multiples benlgnes Sarkoid bei linem Sangling, Dermal. Ztschr. 61: 360, 1931. 11. Naumann, O.: Kasuistischer Beitrag zur Kenntis der Schaumannschen "benign granulomatose" (Morbus Besnier-Boeck-Shaumann), Ztschr. Kinderh. 60: 1, 1938. 12. Leidi, F.: Contributo allo studio dei sarcoidi cutanii di Boeck, Gior. ital. dermat, e sif. 69: 875, 1928. 13. Maycock, R. L., Bertrand, P., Morrison, C. E., and Scott, J. H.: Manifestations of sarcoidosis, Am. J. Med. 35: 67, 1963. 14. Gentry, J. T., Nitowsky, H. M., and Michael, M., Jr.: Studies on the epidemlology of sareoidosis in the United States: The relationship to soil area and to urban-rural residence, J. Clin. Invest. 34: 1839, 1955. 15. Cummings, M. M., Dunner, E., Schmidt, R. H., Jr., and Barnwell, J. B.: Concepts of epidemiology of sarcoidosis, Postgrad. Med. 19: 437, 1956. 16. Sarcoidosis, Statist. Navy Med. 13: 3, 1957. 17. Cummings, M. M., and Hudgins, P. C.:
5 12
18.
19. 20. 21. 22.
23. 24.
25.
26.
27. 28. 29.
Jasper and Denny
Chemical constituents of pine pollen and their possible relationship to sarcoldosis, Am. J. M. Sc. 236: 311, 1958. Kendig, E. L., Jr., Peacock, R. L., and Ryburn, S.: Sarcoidosis: Report of three siblings under fifteen years of age, New England J. Med. 260: 962, 1959. Siltzbaeh, L. E.: Significance and specificity of the Kviem reaction, Acta reed. scandinav. Suppl. 425 176: 74, 1964. Longcope, W. T., and Pierson, J. W.: Boeck's sarcoid (sarcoidosis), Bull. Johns Hopkins Hosp. 60: 223, 1937. Salvesen, H. A.: The sarcoid of Boeck, a disease of importance in internal medicine, Acta med. scandinav. 86: 127, 1935. I-Iarrell,~ G. T., and Fischer, S.: Blood chemical changes in Boeck's sarcoid with particular reference to protein, calcium and phosphatase values, J. Clin. Invest. 18" 687, 1939. Levitt, N.: The clinical application of paper electrophoresis in sarcoidosis; a preliminary report, Dis. Chest 36: 243, 1959. McCuiston, C. F., and Hudgins, P. C.: Serum electrophoresis in sarcoidosis, tuberculosis, and disease due to unclassified myeobacteria, Am. Rev. Resp. Dis. 82: 59, 1960. Anderson, J., Dent, C. E., Harper, C., and Philpott, G. R.: Effect of cortisone on calcium metabolism in sarcoidosis with hypercalacemia; possible antagonistic actions of cortisone and vitamin D, Lancet 2: 720, 1954. Stone, D. J., Schwartz, A., Feltman, J. A., and Loveloek, F. J.: Pulmonary function in sarcoidosis and results with cortisone therapy, Am. J. Med. 15: 468, 1953. Stone, D. J., and Schwartz, A.: A long-term study of sareoid and its modification by steroid therapy, Am. J. Med. 41: 528, 1966. Rostenberg, A., Jr.: Etiologic and immunologic concepts regarding sarcoidosis, Arch. Dermat. & Syph. 64: 385, 1951. Lundback, H., and Lofgren, S.: Attempts at isolation of virus strains from cases of sar-
The Journal o[ Pediatrics October 1968
30.
31. 32.
33. 34. 35. 36. 37. 38. 39.
40.
41.
coidosis and malignant lymphoma, Acta med. scandinav. 143: 98, 1952. Israel, H. L., DeLamater, E., Sones, M., Willis, W. D., and Mirmelstein, A.: Chronic disseminated histoplasmosis; an investigation of its relationship to sarcoidosls, Am. J. Med. 12: 252, 1952. Dupont, A.: Leishmaniose cutaee a structure histologique de sarcoide de Boeck, Bull. Soc. fran~, dermat, et syph. 41: 1291, 1934. Mankiewicz, E.: The relationship of sarcoidosis to anonymous bacteria, Proceedings of the Third International Conference on Sarcoidosis, Aeta reed. scandinav. Suppl. 425 176: 68, 1964. German, W. M.: Lupoid-sarcoid inducted by foreign body (silica), Am. J. Clin. Path. 10: 245, 1940. Sones, M., and Israel, H. L.: Altered immunologic reactions in sarcoidosis, Ann. Int. Med. 40: 260, 1954. Buckley, C. E., III, Nagaya, H., and Sieker, H. O.: Altered immunologic activity in sareoidosis, Ann. Int. Med. 64: 508, 1966. Siltzbach, L. E . : Current thoughts on the epidemiology and etiology of sarcoidosis, Am. J. Med. 39: 361, 1965. James, D. G.: Clinical concept of sarcoidosis, Am. Rev. Resp. Dis. part 2 84: 14, 1961. Israel, H. L.: Proceedings of the International Conference on Sarcoidosis, Am. Rev. Resp. Dis. part 2 84: 171, 1961. Sharma, O. P., Colp, C. C., and Williams, M. H., Jr.: Pulmonary function studies in patients with bilateral hilar nodes due to sarcoidosis, Arch. Int. Med. 117: 436, 1966. Bousky, S. F., Kurtzman, R. S., Martin, N. D., and Lewis, B. M.: The course of pulmonary function in sarcoidosis, Ann. Int. Med. 62: 939, 1965. Siltzbach, L. E.: Sarcoidosis: Clinical features and management, M. Clin. North America 51: 483, 1967.
PEDIATRICS OCTOBER
1968
Volume 73
Number 4
SPECIAL ARTICLE
Sarcoidosis in children With special emphasis on the natural history and treatment
Patrick L. Jasper, M.D., and Floyd W. Denny, M.D. ~ CHAPEL
HILL,
N.
G.
S A R C O I D O S l S is a chronic, multisystem disease of unknown etiology that has been reported infrequently in children. In principal reviews of childhood sarcoidosis only 199 cases have been documented in patients 15 years of age or younger, a relatively small number of cases compared with the frequency witlx which the disease has been reported in adults. The data from several series suggest that sarcoidosis in children is a benign disease generally subject to spontaneous remission without subsequent morbidity. However, documentation of the natural history and effect of corticosteroid therapy in children is limited. T h e first large group of children with sarcoidosis, a series of 12 patients diagnosed at From the Department o/Pediatrics, University o[ North Carolina School of Medicine. Supported in part by The United Medical Research Foundation Grant No. 324-UNI-I (255). eAddress for reprints: Department of Pediatrics, University of North Carohna School o[ Medicine, Chapel Hill, N. C.
Duke Hospital, Durham, North Carolina, was reported in 1948 by Cone? All had multiple system involvement and were treated conservatively. Although follow-up was not optimal, the author described the disease as relatively benign except for residual ocular lesions. Sarcoidosis in children was not comprehensively described until 1956 when McGovern and Merritt 2 reviewed 104 cases under 15 years of age (including Cone's group) in the world literature. To this total they added 9 cases which were diagnosed in Washington, D. C. Most of the patients they encountered in the literature were single case reports without data on follow-up, making it difficult to interpret the course of the disease. Less than half (49) of the cases were from the United States. Forty-nine per cent of the patients from the United States were Caucasian; the remainder were Negro. The combined data from the patients reviewed provided a basis for characterizing childhood Vol. 73, No. 4, pp. 499~512
500
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The Journal o[ Pediatrics October 1968
Table I. Children with sarcoidosis reported since the world review by M c G o v e r n and Merritt s
Author
KendlgS, 4 Beier and Lahey5 Mandi 6
No.
Per cent in 9 to 15 year age range
Method of selection
Geographical origin
13
Hospital study-
U. S. (Virginia)
10 Negro and 3 Caucasian
92
8
Hospital study
U. S. (Utah, Idaho)
Caucasian
63
X-ray survey
Hungary
Caucasian
93
o[ patients
14
Race
Niitu and associatesr
16
X-ray survey
Japan
Japanese
Unknown
Walter s
17
Hospital study
Germany
Caucasian
100
Siltzbach and Greenberg4
18
Hospital study
U. S. (New York) 12 Negro and 6 Caucasian
sarcoidosis regarding age, sex and race distribution, and clinical manifestations. A total of 86 cases of sarcoidosis in children has been documented in 6 reports since M c G o v e r n and Merritt's 2 world review. These are shown in Table I. I n the reviews of M a n d i ~ and Niitu a n d associates, ~ the patients were generally asymptomatic and did not have widespread organ involvement. This is in contrast to the more severe clinical manifestations of the patients from the other series. Beier and Lahey's s cases were unusual because all were from an area of the United States where the incidence of sarcoidosis is very low, all were Caucasian, and over one third were under 9 years of age. D a t a on the course of the disease and response to treatment were indicated in 3 of the reportsS, c, s T h e incidence of remission with either conservative m a n a g e m e n t or corticosteroid therapy was nearly equal in Beier and Lahey's 5 patients and in M a n d i ' s ~ patients. I n Waiter's group, s 7 of 11 patients who were treated conservatively were unchanged and one h a d progression of disease; 5 of 6 patients improved while on corticosteroid therapy. Because the epidemlology, natural history, and effect of corticosteroid therapy in childhood sarcoidosis are not well defined, the cases diagnosed at North Carolina Memorial
100
Hospital were reviewed and form the basis for this report. This group of 25 patients comprises the largest number of cases of sarcoidosis in childhood reported from a single institution~; they will be compared with data available from the world group reported by M c G o v e r n and Merritt ~ and from subsequent series.t Specific attention will be paid to the spectrum of signs and symptoms, extent of organ involvement, frequency of abnormal laboratory data, and response to conservative m a n a g e m e n t as well as to corticosteroid therapy. PATIENT
MATERIAL
T h e data from the 25 patients in this review were obtained from the records of the pediatric service of North Carolina Memorial Hospital from 1954 to early 1968. All but one of the patients were admitted to the hospital for their initial diagnostic evaluation. T h e diagnostic criteria of sarcoidosis as outlined by the National Research Council were used for the selection of patients. 9 All patients had tissue biopsies and in 22 patients these were compatible with the diagnosis of sarcoidosis. Although the remaining * R e f e r r e d to in the " N o r t h C a r o l i n a " cases. ~Referred
"reported"
to in cases.
the
remainder
of
the
paper
as
the
remainder
of
the
paper
as
the
Volume 73 Number 4
Sarcoidosis in children
5 0 1
8 or) P
7
Z
UJ
6
I.l_ 0 0! I.O m Z
5 4-
3 2I I
5
6
I
"g
I
I
8
9 AGE
I0 IN
II
12
13
14
15
YEARS
Fig. 1. Age at the time of diagnosis of ?.5 children with sarcoidosis from North Carolina Memorial Hospital.
3 patients had normal tissues on biopsy, they are included in the series because their clinical courses and other laboratory findings were consistent with the diagnosis of sarcoidosis. O n e patient died in the hospital after diagnosis; one patient did not return for follow-up. I n the remaining group, 13 patients were observed for an average of 3.t years before being lost to follow-up. T e n patients are currently under observation and have been followed for an average of 2.4 years. AGE, SEX, AND RACE DISTRIBUTION
Sarcoidosis has been described in all age groups and most frequently occurs in adults between the ages of 20 and 40 years. While it can occur rarely in children less than one year of age, t~ it usuMIy is encountered in early to mid-adolescence. As depicted in Fig. 1, all the patients in the N o r t h Carolina series except one were 9 to 15 years old when a diagnosis was established; the average age was 13 years. This is consistent with the age of the reported patients where 82 per cent were between 9 and 15 years of age at the time of diagnosis. T h e r e would appear to be no male or female predominance in childhood sarcoidosls.
As shown on Table I I , i4 patients in the North Carolina series were male and 11 were female. This relatively equal distribution between sexes was found in reported series also where 46 per cent of patients were male and 54 per cent were female. I n general, race distribution a m o n g children with sarcoidosis varies wittl geographical location. I n the N o r t h Carolina series, as illustrated in Table I I , 18 patients were Negro, 5 were Caucasian, and 2 were Indian. This predominance of Negro children is shared in some series 1' ~ but is in contrast with the total reported group where 61 per cent were Caucasian, 30 per cent were Negro, and 9 per cent were of other races. In the United States, where the ratio of Negro to Caucasian adults with sarcoidosis varied between 3 : 2 and 26:1, ~3-~6 the distribution a m o n g U. S. children was relatively equal; 58 per cent were Negro and 42 per cent were Caucasian. GEOGRAPHICAL
DISTRIBUTION
T h e distribution of sarcoidosis is worldwide, but it has been reported most frequently in Scandinavia and in the southeastern United States. T h e increased incidence in certain geographical areas is unexplained, although attempts have been made
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The Journal o[ Pediatrics October 1968
Table II. Race and sex o;f 25 children with sarcoidosis from North Carolina Memorial Hospital
Race Negro Caucasian Indian Total
I Male 12 2 0 14
I Female t 6 3 2 I1
Total 18 5 2 25
to correlate it with forest and plant products.17, is As shown in Fig. 2, patients in this series did not cluster in specific locations but were scattered widely in middle and eastern North Carolina. When the cases of Con@ Kendig, s and McGovern and Merritt 2 are added to the present series, 27 per cent of the total number of children reported with sarcoidosis are located in the southeastern United States. CLINICAL MANIFESTATIONS The most striking feature of childhood sarcoidosis is the multisystem involvement, which results in great variability of clinical manifestations. Although the signs and symptoms depend on the organs involved, these 2 topics are reported separately in order to simplify the presentation. Signs and symptoms. The signs and symptoms of patients in the North Carolina series are illustrated in Fig. 3. There was no pattern specific for sarcoidosis. The presenting complaints were variable also and had been present for an average of 7 months before a diagnosis was established. Only 2 patients were asymptomatic before diagnosis; both had abnormal findings on routine chest x-ray during a school examination. Weight loss was the most ;frequent sign and occurred in 68 per cent of patients. Forty-eight pet" cent of patients had a history of cough and 44 per cent a history of fever. A myriad of other symptoms was present, but occurred less frequently. It is noteworthy that chest pain, an uncommon symptom in children, occurred in 20 per cent of patients. Fig. 2 also compares the frequency of signs and symptoms of the North Carolina
Table I I I . Number of organs involved of 25 children with sarcoidosis from North Carolina Memorial Hospital
No. o[ organs involved
I
No. o[ patients
1
2
2 3 4
4 6 5
5 6
2 3
7
1
8
2
cases with that reported in the literature. In all categories the incidence in reported series was lower than that in the North Carolina series. M a n y of the patients had the same array of symptoms as our patients did, but specific data on symptomology were not always indicated in other reports. Organ and system involvement. Involvement of all majo.r organs and tissues has been described and m a n y m a y be involved simultaneously. I n the North Carolina series the criteria of organ involvement were based on clinical, radiographic, electrocardiographic, and pathologic data. The wide spectrum of this disease is emphasized by the presence of multisystem involvement in 23 o.f 25 patients. As shown in Table I I I , only 2 patients had disease of one organ; the majority of patients had 3 or more organs involved; 2 patients had involvement of 8 organs. The frequency of specific organ and system involvement is illustrated in Fig. 4. AII patients had radiographic evidence of pulmonary parenchymal a n d / o r hilar node involvement of varying degrees. The most severe was in one patient who presented with extensive pulmonary disease and an associated pneumothorax. Eighteen patients had either localized or generalized peripheral lymph node enlargement. Hepatomegaly occurred in 14 patients. Twelve patients had ocular sarcoidosis, all with involvement of the anterior uveal tract. One of the patients with ocular disease was blind at the time of diagnosis. Ten patients had splenomegaly
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Sarcoidosis in children
503
CAROLINA MEMORIAL HOSPITAL
Fig. 2. Geographical origin of 25 children with sarcoidosis diagnosed at North Carolina Memorial Hospital. and 8 had cutaneous sarcoidosis. Parotid gland involvement occurred in 6 patients and was manifested by facial palsy in 2, intracerebral invasion in one, and involvement of the recurrent laryngeal nerve in the other. Cardiac disease was found in 2 patients and was evidenced by conduction defects by electrocardiography. Eleven other patients had electrocardiograms performed and all were normal. Striated muscle sarcoidosis was seen in 2 patients, producing weakness in one patient and pseudohypertrophy in the other. Renal, pituitary, and bone involvement occurred in the same patient and was proved at necropsy. This patient had diabetes insipidus and amenorrhea with no urinary tract or skeletal symptoms. Twenty-one patients had x-rays of the hands and all were normal; intravenous pyelograms were performed in 8 patients and all were normal. One patient had hoarseness; a nodule on the false vocal cords was not biopsied but was thought to be sarcoid in nature. None of the North Carolina patients had joint or gastrointestinal involvement. The degree of organ involvement was more widespread in the North Carolina series than in reported series, with a higher percentage of patients having intrathoracic, lymph node, liver, spleen, and nervous system involvement. In only 2 organ systems, bone and skin, was sarcoidosis found more frequently in reported patients. Involvement
of striated muscle, the pituitary gland, and the larynx which occurred in the North Carolina patients was not reported by others. DIAGNOSTIC
PROCEDURES
The diagnosis of sarcoidosis is chiefly one of exclusion of other granulomatous diseases and should be based on clinical and laboratory data which are supported by compatible biopsy material. Biopsies. Although there is no histological picture pathognomonic for sarcoidosis, the characteristic lesion is remarkably uniform and m a y be seen in any tissue in the body. It is a well-outlined follicle composed chiefly of epithelioid and giant cells, usually surrounded by lymphocytes, with no caseation. Inclusion bodies m a y be seen in the giant cells but are not specific for sarcoidosis. As illustrated in Table IV, a total of 35 biopsies was performed on the patients in the North Carolina series. Peripheral lymph nodes and skin were the most accessible and productive areas for biopsy. Striated muscle sarcoid, which is rare in children, was found in 2 patients. Biopsies from 22 (88 per cent) patients were compatible with the diagnosis of sarcoidosis. In the 3 other patients biopsies revealed normal tissues, but the clinical and laboratory findings were compatible with a diagnosis of sarcoidosis. Appropriate cultures and special staining of biopsy material were used to rule out other chronic
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Jasper and Denny
The Journal of Pediatrics October 1968
WEIGHT LOSS
COUGH
FEVER
ABDOMINAL PAIN
OCULAR PAIN
ANOREXIA
DYSPNEA CHEST PAIN PAIN IN EXTREMITIES
HEADACHE PAROTID SWELLING DECREASED VISION NAUSEA & VOMITING EASY FATIGABI LITY NORTH CAROLINA CASES ENLARGED NODES NOCTURIA HOARSENESS SKIN RASH
]
REPORTED CASES
m m l 20
30
40
0
60
70
8
90
l O0
PERCENT OF PATIENTS
Fig. 3. Frequency of signs and symptoms of 25 children with sarcoidosis from North Carolina Memorial Hospital and in children with sarcoidosis reported in the literature. The denominator for reported cases was restricted to patients in those series in which symptomatology was indicated. 2, 5, 6 granulomatous diseases. Nineteen patients had negative stains of biopsy material for acid-fast and fungaI organisms; I0 of these had negative cultures, while the remainder were not cultured. In the reported series 79 per cent of patients biopsied had a histological diagnosis compatible with sarcoidosis. L y m p h nodes were the primary source for biopsy, although in a few cases skin and liver biopsies were used to substantiate the diagnosis.
Kvehn and ether intradermal skin tests. Another method for corroborating the diagnosis of sarcoidosis is by the Kveim test. This test is performed by injecting intracutaneously a suspension 6f sarcoid tissue in an attempt to evoke a specific skin reaction. When positive, a papul e or nodule forms in 4 to 6 weeks which is indistinguishable histologically from the granuloma of sarcoidosis itself? ~ Since the antigen is a variable and unstandardized product, inconsistencies m a y
Volume 73 Number 4
Sarcoidosis in children
5 05
LUNGS- HILAR NODES
LUNGS-PARENCHYMA
LYMPH NODES-GENERAL LYMPH NODES-LOCAL LIVER
EYE
SPLEEN
SKIN
PAROTID
NERVOUS SYSTEM HEART STRIATED MUSCLE KIDNEY LARYNX
ENDOCRINE
=
B
NORTH CAROLINA CASES
[]REPORTED
CASES
BONE I0
20
I 50
l 40
I 50
i 60
I 70
I SO
I 90
I00
PERCENT OF PATIENTS
Fig. 4. Frequency of organ and system involvement of 25 children with sarcoidosis from North Carolina Memorial Hospital and in children with sarcoidosis reported in the literature. The denominator for reported cases was restricted to patients in those series in which organ and system involvement was indicated. 2-s
occur. I n the present series 8 patients who h a d biopsy-compatible sarcoid h a d K v e i m tests, b u t only 2 were positive. T h e tests were done over a period of several years and it is not k n o w n how the test m a t e r i a l was prep a r e d . I n the r e p o r t e d cases of childhood sarcoidosis the K v e i m test was p e r f o r m e d in 23 patients a n d 19 were positive. Histoplasmin, blastomycin, and coccidioidin skin tests were p e r f o r m e d on 21 patients a n d all were negative. T w o of 94 p a -
tients h a d positive tuberculin skin tests, b u t both h a d negative acid-fast cultures or stains of biopsy material. I n the literature, 14 of 86 patients (16 per cent) h a d a positive tuberculin skin test. Miscellaneous l a b o r a t o r y data. A n associated increased incidence of eosinophilia, ~~ hyperglobulinemia, 21 and h y p e r c a l c e m i a 22 has been r e p o r t e d in sarcoidosis. T h e reasons for the increase in eosinophils a n d serum proteins are unknown; the excess p r o t e i n corn-
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Jasper and Denny
The Journal of Pediatrics October 1968
ponents have been d e m o n s t r a t e d to be increases in alpha, beta, and g a m m a globulins?3, 24 T h e cause of the h y p e r c a l c e m i a has been shown to be a hypersensitivity to vitamin D. 2~ As shown in Fig. 5, in the N o r t h C a r o l i n a series serum calcium of 11 mg. p e r cent or
g r e a t e r occurred in 52 p e r cent of patients, 80 p e r cent o.f patients h a d total proteins of 8 Gin. p e r cent or greater, a n d 52 p e r cent h a d an eosinophilia of 6 p e r cent or greater. T h e s e l a b o r a t o r y findings were observed in a h i g h e r p e r c e n t a g e of patients t h a n in those reported, despite the use of higher values for defining h y p e r p r o t e i n e m i a and eosinophilia. Anemia, leukopenia, a n d a b n o r m a l liver function tests were not observed in this series, b u t these abnormalities did occur in a small p e r c e n t a g e of r e p o r t e d patients. O n e of the N o r t h C a r o l i n a patients h a d an abn o r m a l urinalysis a n d an elevated blood u r e a nitrogen t h o u g h t to be s e c o n d a r y to h y p e r calcemia. I n the N o r t h C a r o l i n a series 11 patients h a d p u l m o n a r y v e n t i l a t o r y studies per-
T a b l e I V . Biopsy results in 25 children with sarcoidosis from N o r t h C a r o l i n a M e m o r i a l Hospital
Site
Biopsy I
Lymph node Skin Striated muscle Liver
Positive [ %
No.
No.
23 8 2'
19 8 2
83 100 100
2
0
0
HYPERCALCEMIA
m
NORTH CAROLINA CASES
~
REPORTED CASES
HYPERPROTEI N EMIA
EOSINOPHI LIA
IO
20
30
40
50
I 60
PERCENT
OF
PATIENTS
I 70
I 80
90
I00
Fig. 5. Frequency of common laboratory abnormalities of 25 children with sarcoidosis reported in the literature. The denominator for reported cases was restricted to patients in those series in which these laboratory abnormalities were indicated, a-5
Volume 73 Number 4
formed; 6 were abnormal initially and in the follow-up period 3 of these patients had repeat studies, with 2 showing improvement and one being unchanged. In reported series of pediatric patients no data on pulmonary function studies were cited. NATURAL HISTORY AND EFFECT OF C O R T I C O S T E R O I D THERAPY
The natural history of childhood sarcoidosis is difficult to define because of the rarity of the disease, its chronicity, and spectrum of organ involvement. I n adults it is commonplace for spontaneous remission to occur. In children, where there are only brief recordings of long term follow-up in reported series, the remission rate is unknown and there are no data available on the mortality rate. Similarily, data on the response to corticosteroid therapy in children are sparse. Where large groups of adults have been treated with corticosteroids without associated controls, the effectiveness has been inconsistent.2s, 27 With these factors in mind, an effort was made to determine the course of this disease in the North Carolina patients. D a t a were collected from those patients who were followed with or without corticosteroid therapy for at least one year. Six patients were followed for less than one year, providing inadequate information for interpretation of their course. One patient, who had intracerebral sarcoidosis, died several days after craniotomy. Of the remaining 18 patients, all were followed for one year or more; 8 were treated symptomatically and 10 were treated with corticosteroids. Natural history. The clinical data from the 8 patients who were not treated with corticosteroids are presented in Table V. This group was followed for an average of 3.5 years with a range of 1.2 to 5 years. Signs and symptoms were variable and suggested no special pattern. As shown in Table V, patients tended to develop new findings during follow-up which were not present before or at diagnosis. The degree of organ involvement generally remained unchanged, although one patient had progressive, destructive pulmonary disease. In only one patient
Sarcoidosis in children
50 7
was there a spontaneous remission. Since comparable data are not available in the literature, it is difficult to compare our patients with those of reported series. It appears, however, that the disease characterized in the North Carolina series does not fit a picture of a benign, self-limiting process. The mortality rate of childhood sarcoidosis is probably low and would be related to the type and degree of organ involvement. As far as can be determined, 21 patients in North Carolina series are presently alive; the other 3 patients have moved from the state and their whereabouts are unknown. In reported series no mention was made of death attributed to sarcoidosis. Corticosteroid therapy. In the North Carolina series data were available on 10 patients who were treated with corticosteroids (Table V I ) . T h e criterion for instituting corticosteroid therapy in all cases was the presence of ocular involvement. As in the untreated patients, signs and symptoms were variable. However, the disease was generally more severe in the treated group as indicated by the wider spectrum of organ involvement. All patients had hilar node a n d / or pulmonary involvement, in addition to ocular involvement. M a n y had lymphadenopathy, hepatosplenomegaly, and skin involvement. Patients in this group were followed for an average of 4 years with a range of 1 to 8 years. They were treated for an average of 2.1 years, usually with prednisone in varying doses. Five patients were followed for an average of 2.8 years after corticosteroid therapy. Three patients are still on corticosteroids and 2 were lost to follow-up while on therapy. Manifestations present before or at the initiation of therapy generally disappeared or diminished during steroid administration and rarely developed or recurred after treatment. In most cases organ involvement resolved or was diminished in severity. In only 2 patients was pulmonai;z parenchymal disease unchanged; hilar node disease was unchanged in 2 other patients. Lymphadenopathy disappeared in half the patients and decreased in the other half.
508
Jasper and D e n n y
7"he Journal of Pediatrics October 1968
Table V. N a t u r a l history of sarcoidosis in 8 children from N o r t h Carolina Memorial Hospital who were followed for one year or more
Abnormality Signs and symptoms Weight loss Cough Fever Anorexia Enlarged lymph nodes Chest pain Dyspnea Abdominal pain Ocular pain Easy fatigability Headache
No. of patients with abnormality before or at diagnosis
No. of patients with abnormality during follow-up Persisting from Developing after initial observation initial observation
3 3 3 3 3 2 2 2 1 1 1
0 1 1 0 0 I 1 0 1 1 0
3 1 0 0 0 1 0 0 1 1 0
Organ involvement Lungs--hilar nodes Lungs--parenchyma Lymph nodes--general Lymph nodes~local Liver Eye Spleen Parotid Nervous system Skin
7 6 5 2 2 1 1 1 1 0
4 4 1 2 0 0 0 0 0 0
1 2 1 0 0 0 1 0 0 2
Laboratory findings Hypercaleemia Hyperproteinemia Eosinophilia
3 4 2
2 3 1
1 1 2
O c u l a r involvement cleared in 5 patients and regressed to a chronic, mild, smoldering state in the other 5. Hepatosplenomegaly disappeared in all patients but did appear in 3 other patients during or after therapy. Cutaneous and parotid involvement were also effectively cleared with corticosteroids. No effect was noted in one patient w h o had vocal cord, striated muscle, and cardiac disease simultaneously. Hypercalcemia, hyperproteinemia, and eosinophilia disappeared in most patients while on therapy. Only one patient who initially had abnormal p u l m o n a r y ventilatory studies had a repeat study during treatment and this showed improved function. I n reported series only 10 patients were treated with corticosteroids and 8 of these showed improvement on therapy. Criteria
for therapy were variable and the period of follow-up was not indicated in most cases. COMMENTS
T h e syndrome of sarcoidosis is difficult to define because the etiology and pathogenesis are unknown. T h e relative infrequency of the disease in the first 2 decades of life adds to the diffictilty of characterizing the disease in children. Although an increasing n u m b e r of childhood cases has been reported in recent years, m a n y questions are unanswered. An effort was made in this report not only to summarize the clinical and laboratory manifestations of childhood sarcoidosls, but to d o c u m e n t the natural history and effect of corticosteroid therapy in children f r o m N o r t h Carolina Memorial Hospital. I n general the patients in the N o r t h Car-
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Sarcoidosis in children
509
T a b l e V I . Effect of corticosteroid t h e r a p y in 10 children with sarcoidosis f r o m N o r t h C a r o l i n a M e m o r i a l H o s p i t a l who were followed for one y e a r or m o r e No. o[ patients with abnormality Abnormality
Present be[ore or at time o[ treatment
Cured or diminished during treatment
Developing or recurring alter treatment
8 6 5 5 5 5 3 3 2 2 2 2 2
8 6 5 5 5 5 3 3 2 2 1 2 2
0 0 0 0 0 0 0 1 1 0 0 0 0
9 9 5 1 10 6 5 5 4 2 1 1
7 7 5 1 10 6 5 4 4 1 0 0
0 0 1 1 0 1 2 0 1 0 1 1
5 6 5
5 5 4
2 1 0
Signs and symptoms
Weight loss Fever Anorexia Ocular pain Abdominal pain Cough Parotid swelling Pain in extremities Chest pain Easy fatigability Dyspnea Headache Hoarseness Organ involvement
Lungs hilar nodes Lungs--parenchyma Lymph nodes--general Lymph nodes--local Eye Liver Spleen Skin Parotid Ear, nose, throat Striated muscle Heart Laboratory findings
Hypercalcemia Hyperproteinemia Eosinophilia
olina series were m o r e severely affected t h a n those r e p o r t e d in the literature, a l t h o u g h there were m a n y c o m m o n features. T h e age, sex, a n d r a c e distribution of t h e N o r t h C a r olina patients was n o t u n u s u a l a n d was similar to t h a t of o t h e r r e p o r t e d patients. A nonspecific s p e c t r u m of signs a n d symptoms was evident in our patients, as well as in patients of r e p o r t e d series. T h e t y p e of organs involved was generally t h e same in b o t h groups; however, the f r e q u e n c y of m u l t i p l e organ involvement in t h e N o r t h C a r o l i n a patients exceeded t h a t of r e p o r t e d cases. T h e r e were no unusual l a b o r a t o r y findings in this series. T h e classical abnormalities of h y p e r c a l c e m i a , h y p e r p r o t e i n e m i a , a n d eosinophilia w e r e frequently helpful in s u p p o r t i n g
the diagnosis in the N o r t h C a r o l i n a patients a n d in those r e p o r t e d in the literature. T h e etiology of sarcoidosis remains obscure despite extensive investigations of bacteria, 2s viruses, 29 fungi, 3~ parasites, sl atypical m y c o b a c t e r i a , s2 foreign bodies, 17, 3s a n d imm u n e mechanisms 34, s0 as possible causes. N e i t h e r h a v e substantial clues to the etiology been found in epidemiological surveys? 5 D u r ing the initial evaluation o;f the N o r t h C a r olina patients no special a t t e m p t s were m a d e to d e t e r m i n e an etiology, a l t h o u g h similar chronic g r a n u l o m a t o u s diseases were ruled out b y skin tests a n d a p p r o p r i a t e cultures of biopsy material. I n retrospective analysis, patients h a d no characteristics in c o m m o n t h a t would suggest an etiological mechanism.
5 10
Jasper and Denny
T h e natural history of sarcoidosis in children is unknown. Most of the information concerning the course of the disease is based on data from adults which m a y not be applicable to children. Siltzbach 86 and James a7 prefer to classify adults into 2 groups, those with subacute and those with chronic disease. In the former group of patients, the onset is usually abrupt, duration of the illness has been less than 2 years, organ involvement is not widespread, the lesions are usually transient, and the prognosis is good. In the chronic group, the onset is insidious with the disease having been present for longer than 2 years, organ involvement is more widespread, and the prognosis is poor. It would be difficult to apply this classification to children. Based on the data from the 8 patients in this series who were followed without treatment, all but one would be considered in the chronic state. A longer period of follow-up would be necessary to establish guidelines in children. T h e treatment of sarcoidosis has been the subject of numerous reports with m a n y different agents being used. There now is general agreement that corticosteroids are the drugs of choice. The criteria for therapy with corticosteroids have been outlined 8s and include treating patients with active ocular disease, persistent hypercalcemia, central nervous system or myocardial involvement, disfiguring skin lesions, and progressive pulmonary disease as evidenced by increasing symptoms or roentgenographic findings or impaired or deteriorating pulmonary function. T h e latter is a particularly objective way of deciding when the patient with sarcoidosis should be treated. It is well known that the roentgenographic appearance of the pulmonary lesions frequently may not reflect serious functional defects. Adults with only hilar lymph node or pulmonary parenchymal involvement have been shown to have impaired pulmonary function, which on followup exalnination worsened despite evidence of clearing of the lesions on roentgenograms. ~9, 4o Data on pulmonary function studies in children with sarcoidosis are lacking. With the high incidence of pulmonary involve-
The Journal o[ Pediatrics October 1968
ment in childhood, it would seem appropriate that frequent evaluations of pulmonary function should be done. I n the individual patient other reasons for treatment with eorticosteroids m a y arise which are not included in these criteria. Although this was a retrospective study and there were no control patients, the data suggest that corticosteroids were effective in alleviating symptoms and in resolving or decreasing the severity of organ involvement. It was uncommon for symptoms or lesions to recur. This favorable response in young patients whose lesions were relatively new is in keeping with Siltzbach's 41 suggestion that the fresher lesions of sarcoidosis are those most likely to respond to steroid therapy. Whether or not the treatment affects the outcome of the disease is unanswered by these data. During the observation period it was uncommon for lesions to reappear clinically, but it is obvious that these patients will need to be followed for a longer period. Ideally, controlled series of patients observed for a protracted time are necessary for a more valid evaluation of the efficacy of steroid therapy. SUMMARY
Twenty-five cases of childhood sarcoidosis were diagnosed at North Carolina Memorial Hospital between 1954 and early 1968. Biopsies from 92 cases were compatible with the diagnosis of sarcoidosis; the other 3 cases had negative biopsies but their clinical courses were consistent with a POsitive diagnosis. Other chronic granulomatous diseases were ruled out by skin tests, appropriate cultures, special staining of biopsy material, and clinical course of the patients. The age, sex, and race distribution of the North Carolina patients was similar to that in other reported series. In the North Carolina series, the average age at diagnosis was 13 years, the male to female ratio was almost equal, and the Negro race predominated. Cases were scattered in the hospital's referral area in middle and eastern North Carolina and did not suggest any special epidemiological pattern. Weight loss, cough, and fever were the most frequent of an
Volume 73 Number 4
otherwise v a r i a b l e p a t t e r n of signs a n d symptoms. T h e f r e q u e n c y of signs a n d s y m p t o m s was h i g h e r t h a n in r e p o r t e d series w h e r e specific d a t a on s y m p t o m a t o l o g y were not always indicated. I n the N o r t h C a r o l i n a series there was multisystem involvement in 23 of 25 patients. All p a t i e n t s h a d p u l m o n a r y p a r e n c h y m a l a n d / o r h i l a r n o d e involvement a n d 12 patients h a d o c u l a r disease. L u n g , l y m p h node, eye, liver, spleen, p a r o t i d gland, nervous system, heart, a n d striated muscle involvement o c c u r r e d m o r e c o m m o n l y in the N o r t h C a r o l i n a patients t h a n in o t h e r rep o r t e d cases. H y p e r c a l c e m i a , h y p e r p r o t e i n emia, a n d eosinophilia w e r e the most persistent a b n o r m a l r o u t i n e l a b o r a t o r y findings a n d were observed in a h i g h e r p e r c e n t a g e of the N o r t h C a r o l i n a p a t i e n t s t h a n in r e p o r t e d cases. Eleven patients h a d p u l m o n a r y ventil a t o r y studies p e r f o r m e d a n d 6 w e r e abnormal. O f the 18 patients w h o were followed for one y e a r o r more, 10 were t r e a t e d with corticosteroids a n d 8 were t r e a t e d s y m p t o m a t i cally w i t h o u t corticosteroid t h e r a p y . I n the n o n s t e r o i d - t r e a t e d group, symptoms were v a r i a b l e a n d new ones t e n d e d to a p p e a r d u r i n g follow-up. T h e degree of o r g a n involvement at the onset in this g r o u p generally r e m a i n e d u n c h a n g e d b u t in some p a tients t h e r e was progression to o t h e r organs. I n the c o r t i c o s t e r o i d - t r e a t e d group, in w h i c h all patients h a d o c u l a r involvement a n d the disease was generally m o r e severe, s y m p t o m s resolved within a few months. I n most cases o r g a n involvement resolved or was diminished in severity. I t was u n c o m m o n for the disease to r e c u r after corticosteroids were discontinued. C o m p a r a t i v e d a t a f r o m the lite r a t u r e on t h e n a t u r a l history a n d effect of corticosteroid t h e r a p y a r e n o t available. I n m i d d l e a n d eastern N o r t h C a r o l i n a sarcoidosis in children w o u l d a p p e a r to be m o r e c o m m o n t h a n previously suspected. T h e multiplicity of system i n v o l v e m e n t a n d t h e sev e r i t y of t h e disease were evident in these patients. A l t h o u g h longer periods of observ a t i o n a r e necessary a n d controlled studies need to be p e r f o r m e d for a b e t t e r e v a l u a t i o n of this disease, the d a t a presented here sug-
Sarcoidosis in children
5 11
gest t h a t corticosteroids are beneficial in alleviating s y m p t o m s a n d in resolving or decreasing t h e severity or o r g a n involvement. We wish to thank Drs. Wallace A. Clyde, Jr., Gerald W. Fernald, W. Paul Glezen, and Richard P. Lipman for review of the manuscript and Mrs, Sherri Davis for its preparation. REFERENCES
1. Cone, R. B.: A review of Boeck's sarcoid with analysis of 12 cases in children, J. PEDIAT. 32: 629, 1948. 2. McGovern, J. P., and Merritt, D. M.: Sarcoidosis in childhood, Advances Pediat. 8" 97, 1956. 3. Kendig, E. L., Jr.: Sarcoidosis among children, J. PEDIAT. 61: 269, 1962. 4. Kendig, E. L., Jr.: Sarcoidosis, in Kendig, E. L., Jr., editor: Disorders of the respiratory tract in children, ed. 1, Philadelphia, 1967, W. B. Saunders Company. 5. Beier, F. R., and Lahey, M. E.: Sarcoidosis among children in Utah and Idaho, J. PEDIAT. 65: 350, 1964. 6. Mahdi, L.: Thoracic sarcoidosis in childhood, Acta tuberc, scandinav. 45: 256, 1964. 7. Niitu, Y., Watanabe, M., Swetake, T., Handla, T,, Munakata, K , and Shiroishi, K.: Sixteen cases of intrathoracic sarcoidosis found among school children in Sendal in mass x-ray surveys of the chest, Res. Rep. Res. Inst. Tuberc. Lepr. & Cancer 12: 99, 1965. 8. Walter, H. H.: Zum bilde des lungen-Boeck bei kindern und jungenlichen, Tuberkulosearzt 14: 828, 1966. 9. Cummings, M. M., and Dunner, E.: Pulmonary sarcoidosis, M. Clin. North America 43: 169, 1959. 10. Polland, R.: Multiples benlgnes Sarkoid bei linem Sangling, Dermal. Ztschr. 61: 360, 1931. 11. Naumann, O.: Kasuistischer Beitrag zur Kenntis der Schaumannschen "benign granulomatose" (Morbus Besnier-Boeck-Shaumann), Ztschr. Kinderh. 60: 1, 1938. 12. Leidi, F.: Contributo allo studio dei sarcoidi cutanii di Boeck, Gior. ital. dermat, e sif. 69: 875, 1928. 13. Maycock, R. L., Bertrand, P., Morrison, C. E., and Scott, J. H.: Manifestations of sarcoidosis, Am. J. Med. 35: 67, 1963. 14. Gentry, J. T., Nitowsky, H. M., and Michael, M., Jr.: Studies on the epidemlology of sareoidosis in the United States: The relationship to soil area and to urban-rural residence, J. Clin. Invest. 34: 1839, 1955. 15. Cummings, M. M., Dunner, E., Schmidt, R. H., Jr., and Barnwell, J. B.: Concepts of epidemiology of sarcoidosis, Postgrad. Med. 19: 437, 1956. 16. Sarcoidosis, Statist. Navy Med. 13: 3, 1957. 17. Cummings, M. M., and Hudgins, P. C.:
5 12
18.
19. 20. 21. 22.
23. 24.
25.
26.
27. 28. 29.
Jasper and Denny
Chemical constituents of pine pollen and their possible relationship to sarcoldosis, Am. J. M. Sc. 236: 311, 1958. Kendig, E. L., Jr., Peacock, R. L., and Ryburn, S.: Sarcoidosis: Report of three siblings under fifteen years of age, New England J. Med. 260: 962, 1959. Siltzbaeh, L. E.: Significance and specificity of the Kviem reaction, Acta reed. scandinav. Suppl. 425 176: 74, 1964. Longcope, W. T., and Pierson, J. W.: Boeck's sarcoid (sarcoidosis), Bull. Johns Hopkins Hosp. 60: 223, 1937. Salvesen, H. A.: The sarcoid of Boeck, a disease of importance in internal medicine, Acta med. scandinav. 86: 127, 1935. I-Iarrell,~ G. T., and Fischer, S.: Blood chemical changes in Boeck's sarcoid with particular reference to protein, calcium and phosphatase values, J. Clin. Invest. 18" 687, 1939. Levitt, N.: The clinical application of paper electrophoresis in sarcoidosis; a preliminary report, Dis. Chest 36: 243, 1959. McCuiston, C. F., and Hudgins, P. C.: Serum electrophoresis in sarcoidosis, tuberculosis, and disease due to unclassified myeobacteria, Am. Rev. Resp. Dis. 82: 59, 1960. Anderson, J., Dent, C. E., Harper, C., and Philpott, G. R.: Effect of cortisone on calcium metabolism in sarcoidosis with hypercalacemia; possible antagonistic actions of cortisone and vitamin D, Lancet 2: 720, 1954. Stone, D. J., Schwartz, A., Feltman, J. A., and Loveloek, F. J.: Pulmonary function in sarcoidosis and results with cortisone therapy, Am. J. Med. 15: 468, 1953. Stone, D. J., and Schwartz, A.: A long-term study of sareoid and its modification by steroid therapy, Am. J. Med. 41: 528, 1966. Rostenberg, A., Jr.: Etiologic and immunologic concepts regarding sarcoidosis, Arch. Dermat. & Syph. 64: 385, 1951. Lundback, H., and Lofgren, S.: Attempts at isolation of virus strains from cases of sar-
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30.
31. 32.
33. 34. 35. 36. 37. 38. 39.
40.
41.
coidosis and malignant lymphoma, Acta med. scandinav. 143: 98, 1952. Israel, H. L., DeLamater, E., Sones, M., Willis, W. D., and Mirmelstein, A.: Chronic disseminated histoplasmosis; an investigation of its relationship to sarcoidosls, Am. J. Med. 12: 252, 1952. Dupont, A.: Leishmaniose cutaee a structure histologique de sarcoide de Boeck, Bull. Soc. fran~, dermat, et syph. 41: 1291, 1934. Mankiewicz, E.: The relationship of sarcoidosis to anonymous bacteria, Proceedings of the Third International Conference on Sarcoidosis, Aeta reed. scandinav. Suppl. 425 176: 68, 1964. German, W. M.: Lupoid-sarcoid inducted by foreign body (silica), Am. J. Clin. Path. 10: 245, 1940. Sones, M., and Israel, H. L.: Altered immunologic reactions in sarcoidosis, Ann. Int. Med. 40: 260, 1954. Buckley, C. E., III, Nagaya, H., and Sieker, H. O.: Altered immunologic activity in sareoidosis, Ann. Int. Med. 64: 508, 1966. Siltzbach, L. E . : Current thoughts on the epidemiology and etiology of sarcoidosis, Am. J. Med. 39: 361, 1965. James, D. G.: Clinical concept of sarcoidosis, Am. Rev. Resp. Dis. part 2 84: 14, 1961. Israel, H. L.: Proceedings of the International Conference on Sarcoidosis, Am. Rev. Resp. Dis. part 2 84: 171, 1961. Sharma, O. P., Colp, C. C., and Williams, M. H., Jr.: Pulmonary function studies in patients with bilateral hilar nodes due to sarcoidosis, Arch. Int. Med. 117: 436, 1966. Bousky, S. F., Kurtzman, R. S., Martin, N. D., and Lewis, B. M.: The course of pulmonary function in sarcoidosis, Ann. Int. Med. 62: 939, 1965. Siltzbach, L. E.: Sarcoidosis: Clinical features and management, M. Clin. North America 51: 483, 1967.