November 1975 The Jo~irnal o f P E D I A T R I C S
709
Articular and cutaneous prodromal manifestations of viral hepatitis The association of arthritis, arthralgia, and various types of skin rashes, as a prodrome to viral hepatitis, although well recognized in adults, has not been well described in children. In an 18-month period, three children presented with this serum sickness-like illness before the onset of evident liver involvement. In one case, the prodromal symptoms occurred four weeks before biochemical or clinical evidence of hepatitis. The S S L I tended to subside with the onset of clinically evident liver disease. Hepatitis B surface antigen (HB~ Ag, Australia antigen) was detected in the sera of two patients, but free antibody to the antigen was not demonstrable in either one, Serum complement levels were low during the prodromal phase and tended to return to normal value at the onset of extensive liver involvement. The diagnosis of viral hepatitis should be considered in children presenting with polyarthritis, polyarthralgia, and a rash (serum sickness-like illness) of uncertain etiology.
Richard A. Segool, M.D., Christine Lejtenyi, M.D., and Lynn M. Taussig, M.D.,* M o n t r e a l , P. Q., C a n a d a
IN 1843, Graves ~ first reported the association of acute polyarthritis a n d / o r urticaria as prodromal symptoms of viral hepatitis. This relationship has been discussed frequently in the adult medical literature in recent years, primarily because of increased interest in the possible immunologic pathogenesis of hepatitis-associated arthritis> 3 Review of the pediatric literature indicates that the association of this "serum sickness-like illness" with hepatitis has not been recognized in children.' In fact, standard textbooks of pediatrics do not mention these prodromal manifestations? 6 In a review of 101 patients with articular symptoms associated with hepatitis, the youngest reported patient was 16 years old. 7 Over an 18-month period, three patients who developed hepatitis presented initially to our pediatric wards
From the Departments of Pediatrics, the Annie and Nathan Steinberg Laboratory of Allergy and Immunology, and the Department of Respiratory Function, The Montreal Children's Hospital, McGill University. Presented in part at the Canadian Pediatric Society Meeting, St. Johns, Newfoundland, August, 1974. *Reprint address: Department of Pediatrics, Arizona Medical Center, Tucson, Ariz. 85724.
with arthritis, arthralgia, and skin rashes. They form the basis for this report which is presented to indicate the association of a SSL! with hepatitis in children; to stress that these prodromal manifestations may occur weeks before clinical or biochemical evidence of hepatitis, and to remind physicians that hepatitis should be considered in the evaluation of patients with arthritis and skin rashes of uncertain etiology. Abbreviations used HB~ Ag: Australia antigen; hepatitis B surface antigen anti-HBj Antibody to HB~ Ag SSLI: serum sickness-like illness
CASE REPORTS Case 1. Patient N. S., a 13-year-old girl, was noted on the day of admission to The Montreal Children's Hospital to have several 1 to 3 cm, erythematous, nodular lesions over the left elbow, which soon spread to the extensor surfaces of the extremities, the scalp, and the skin overlying the spine and iliac crest. The lesions were tender and pruritic. Several hours later she noted onset of pain in both knees, both elbows, and in the left hip. There was no history of recent medications, drug abuse, blood transfusions, exposure to hepatitis, or sexual intercourse. Vital signs were normal and she was afebrile. There was pain
Vol. 87, No. 5, pp. 709-712
7 10
Segool, Lejten),L and Taussig
The Journal of Pediatrics November 1975
Table I. L a b o r a t o r y d a t a a n d clinical c o u r s e s o f 3 p a t i e n t s
Days from onset of illness 0
10
20
30
40
50
Follow-up*
Case 1 SGOT (N = 10-271U) B,C (N = 120-170 m g / d l ) HB~ Ag titcr Arthritis and/or arthralgia Urticaria and/or rash Hepatitis
15 100 1:8
800 91
113 100 1:4
84 1:16
4
14 110 Neg?
P
Case 2 411
SGOT (N = l(/-50mLl/ml) B~C (N = 123-167 mg/dl) HB~ Ag titer Arthritis and/or arthralgia Urticaria and/or rash Hepatitis
108 190
3,900
136 250 Neg
Neg
i
L
tt q
~, (Still present on discharge)
q
Case 3 SGOT (N = 10-27IU) B,C (N = 120-170 mg/dl) HB~ Ag titer Arthritis and/or arthralgia Urticaria and/or rash Hepatitis
223 55 Present:~
2,100 93
660
188 135 Neg
34 118 Neg
-4, ~
w
,.- (Still present on discharge)
*Follow-up: Case 1--15 months after onset: Case 2-did not return for follow-up; Case 3 3 months after onset (SGOT 28 months after onset was 15IU). tNeg = negative. J~Present = in serum as determined by electron microscopy. w and biochemical exacerbation of hepatitis.
on motion of the knees and elbows which were warm, but not red or swollen. There were 0.5 to 4.0 cm nodular red lesions (similar to erythema nodosum) over the extensor surfaces of the forearms and kgees with urticarial lesions over the spine, neck, and scalp. Examination of the abdomen was negative. The thyroid gland was of normal size and consistency but was tender. By the third day of hospitalization, both ankles and the interphalangeal joints of the toes were quite painful, and the metacarpophalangeal and interphalangeal joints of the left hand were swollen, warm, and tender. Hydrotherapy and aspirin brought prompt relief from the joint manifestations. The elbow and hip pain resolved over two days, but she complained o f arthralgia in both knees for ten more days (Table I). The nodular and urticarial rashes disappeared by the third day, and the thyroid gland tenderness also abated. Pertinent laboratory data are listed in Table 1. Numerous laboratory examinations were normal or negative including concentrations ,of serum glutamic oxaloacetic transaminase, alkaline phosphatase, total protein; white blood cell count; T~; mononucleosis spot test; rheumatoid factor; lupus erythematosus preparation; thyroglobulin antibody; antinuclear antibody; antistreptolysin 0 titer; cryoglobulins; electrocardiogram; and urinalysis. Serum was positive for HB~ Ag on the second day of
hospitalization (Table I). The patient was discharged with no articular or cutaneous abnormalities with a diagnosis of "possible collagen disease," The patient returned four weeks after her initial presentation with a 2-day history o f anorexia, nausea, vomiting, scleral icterus, and dark urine. Laboratory measurements of liver function were consistent with the diagnosis of hepatitis (Table I). The patient had an uneventful recovery at home during t h e subsequent month. Fifteen months after initial hospitalization she was clinically well, but serum B1 C concentration remained borderline low and serum concentrations of immunoglobulins G and M remained slightly elevated. Case 2. Patient RI W.; a 13-year-old boy, was previously in good health; onset o f generalized malaise, fatigue, and myalgia was noted 10 days prior to admission. Seven days prior to admission, he became febrile and developed weakness, generalized abdominal pain, arthralgia, and an urticarial rash over the lower extremities. Three days later he had persistent nausea and vomiting with high fever and was admitted to the hospital. He denied use of medication, exposure to hepatitis, or drug abuse. In the hospital, he was lethargic, pale, and nonicteric with a temperature of 103 ~ F. The abdomen was diffusely tender," maximally m the right upper quandrant: The spleen tip was
Volume 87 Number 5
palpable, but there was no hepatomegaly. An urticarial rash was present over all extremities and there was diffuse muscle tenderness. Laboratory values on admission were consistent with a diagnosis of hepatitis (Table I). By the second day of hospitalization there was swelling with warmth and redness of the small joints of the hands. Later the right wrist, right elbow, and both shoulders became similarly involved. Hepatomegaly was initially noted on the second day of hospitalization. Arthritis and the urticarial rash were the main problems during the first 10 days in the hospital; the liver remained slightly enlarged, but the abnormal liver enzyme values improved during this 10-day period. The patient's rash persisted for a total of 14 days from onset, and arthritis lasted for 16 days. Five days following disappearance of the rash and arthritis, clinical and biochemical evidence of exacerbation of hepatitis occurred (Table I). Over the following tWOweeks, gradual improvement occurred clinically and biochemically, and the patient was discharged after 47 days of hospitalization. At the time of discharge, laboratory values of liver function were still abnormal but he refused to return for follow-up evaluation. Pertinent laboratory data are listed in Table I. Other laboratory determinations as performed for Case 1 were also normal or negative in Case 2. Evaluation of serum for HBs Ag liters was negative on the eleventh and thirty-sixth days after his illness. Case 3. Patient S. R., a 16-year-old girl with a history of intravenous drug abuse, was admitted to the hospital because of skin rash and arthritis. Ten days before admission, pruritic maculopapular lesions appeared on the extremities, spread to the trunk and face, and coalesced to form a generalized erythematous rash. Three days later, she developed intermittent pain and swelling of the wrists, elbows, shoulders, metacarpophalangeal joints, ankles, knees, and spine. The pain was severe enough to hinder walking and keep her awake at night. On admission she had tenderness, limitation of movement, and soft tissue swelling of the involved joints, with small effusions of both knees. The cervical, axillary, and inguinal lymph nodes were slightly enlarged. The spleen and liver were palpable and slightly tender. Diffuse erythema was present over the whole body. In the hospital, the erythema faded, and the joint pain and swelling responded rapidly to aspirin therapy. Four days after admission (14 days after onset of illness) she complained of anorexia, vomiting, and malaise, and the diagnosis of hepatitis was made (Table I). The patient subsequently made an uneventful recovery. A blood sample drawn two weeks prior to admission as a routine screening test for drug abuse was negative for HB~ Ag by counterelectrophoresis. Subsequent analysis of this specimen by electron microscopy revealed small amounts of free antigen. Serum at the time of admission also revealed HBs Ag. Three months after recovery from hepatitis, HB~ Ag and anti-HB~ were absent from her serum (Table I). METHODS Immunoglobulins and complement were assayed using Hyland Immuno-Diffusion plates (Hyland Laboratories, Chicago, ILL). HB~ Ag and anti-HB~ were measured by
Arthritis and rash with hepatitis
7 11
cross-over immunoelectrophoresis. ~ Electron microscopic examination of, the serum was performed as previously described by Kelen and associates? Liver function and other laboratory examinations were done by Standard methods. DISCUSSION Arthralgia has been described as a prodromal symptom in both type A and type B virus hepatitis in adults5 Arthritis is more often associated with type B hepatitis. :~ From earlier publications, the incidence of arthralgia or arthritis with hepatitisdn adults (10 to 24%); is considerably greater than in children (1.6%). l~ In a recent review 7 of the literature, 101 cases of hepatitis with articular prodromal symptoms were summarized. The patients ranged in age from 16 to 72 years with equal n u m b e r s of males and females. Fortyfour per cent of the patients had only arthralgia, while the remainder had arthritis. For each group, symmetric distribution of joint symptoms was most common. The predominant joints involved in each group were the small joints of the hands, the shoulders, knees, ankles, and elbows. An urticarial or maculopopular rash, most frequently involving the lower extremities, Was present in 30% of patientswith arthralgia and in 42% of patients with arthritis. The rash commonly appeared concurrently with the joint symptoms. The joint symptoms lasted an average of 20 days (range 5 to 33 days). Disappearance of the SSLI was most often temporally associated with the appearance of jaundice. In 5% of cases, arthritis and j a u n d i c e developed simultaneously; joint abnormalities rarely extended beyond the period of jaundice. The patients described in the present report indicate that the manifestations of the SSLI occurring with viral hepatitis are similar in children as in adults. All three patients demonstrated the previously described 7 clinical, biochemical, and immunologic features of the articularrash-hepatitis association. In each case, the hepatitis either developed after the SSLI or demonstrated a severe exacerbation as the joint and skin involvement abated. There are two main theories explaining the pathogenesis of the prodromal articular lesions in viral hepatitis. The first suggests that the virus is actually present in the joint at the time of the arthritis, producing a direct synovial cytopathic effect. T M 1~ The second proposes an immunologic mechanism similar to that occurring in serum sickness. During the prodromal phase when arthritis a n d / o r rash is present there are high levels of HBs Ag, low levels of antibody to the antigen, and low levels of complement (total CH50 and B1C) in serum and synovial fluid. Hematogenous circulating i m m u n e complexes can form during the phase of antigen excess, and these soluble
7 12
Segool, Lejtenyi, and Taussig
complexes are thought to produce the SSLI. W h e n the icteric phas e begins, serum HB~ Ag levels decrease rapidly, serum anti-HB~ levels increase, ~ ~ 13. 1~ complement levels normalize, and the joint and skin manifestations disappear. In addition to implicating HB~ Ag - antiHBs complexes in the pathogenesis of hepatitis-associated arthritis a n d / o r urticaria, several authors have described immune complexes with HBs Ag in polyarteritis nodosa 1~ and in glomerulonephritis with the nephrotic syndrome, t~ In the patients reported here, concentrations of B1C tended to be low during the period of joint and skin manifestations and increased with the onset or worsening of liver abnormalities. HBs Ag was present and in high concentrations in two of the patients during the SSLI and decreased during the icteric phase. In Case 2, determinations of HBs Ag were consistently negative. The patient had developed clinical hepatitis four days prior to the first determination for HBs Ag. It is possible that HB~ Ag was present but undetectable due to binding with developing antibody. 13 However, the more sensitive test (radioimmunoassay) for HB~ Ag was not employed on his serum. Thus the negative HB~ Ag may be a false laboratory result. Alternatively, this may represent a case o f type A hepatitis?~, l g The occurrence of these three cases over a relatively short period of time suggests that a SSLI with hepatitis may not be very rare in children. Although early reports TM of hepatitis in children did not describe these manifestations, it is unlikely that the incidence of these symptoms is actually increasing. The prevalence of type B hepatitis, however, may he increasing due to increasing drug abuse. Since the skin and joint manifestations may occur weeks before obvious hepatitis, these symptoms may be forgotten by the patient, especially if not specifically asked for at the time of hepatitis. It is impor{ant for physicians to be aware that a prodromal serum sicknesslike disease may occur in children days to weeks before the onset of hepatitis. The authors thank Dr. Sidney Pedvis for referring one of the patients and Dr. Stephen Vas and Mrs. G. Deutsch for doing the electron microscopy and HB~ Ag determinations. REFERENCES
1. Graves R: Clinical lectures on practice of medicine, Dublin, 1843, Fannin & Co, p 937.
The Journal of Pediatrics November 1975
2. Koff RS: Immune complex arthritis in viral hepatitis? N Engl J Med 285:229, 1971. 3. Alpert E, Isselbacher K J, and Schur PH: The pathogenesis of arthritis associated with viral hepatitis. Complement component studies, N Engl J Med 285:185, t971. 4. Schaller J: The liver and arthritis, J. PnDIATR 79:139, 1971. 5. Nelson WE, Vaughan VC, and McKay RJ, editors: Textbook of pediatrics, ed 9, Philadelphia, 1969, WB Saunders Company. 6. Barnett HL, and Einhorn AH, editors: Pediatrics, ed 15, New York, 1972, Appleton-Century-Crofts, Inc. 7. Alarcon GS, and Townes AS: Arthritis in viral hepatitis: report of 2 cases and review of the literature, Hopkins Med J 132:1, 1973. 8. Rightsel WA, Moore MS, and Muirhead EE: Electroprecipitin test for hepatitis-associated antigen and antibody, Am J Clin Pathol 55:249, 1971. 9. Kelen AE, Hathaway AE, and McLeod DA: Rapid detection of Australia SH antigen and antibody by a simple and sensitive technique of immunoelectronmicroscopy, Can J Microbiol 17:993, 1971. 10. Stoia MI: Pathologie hepatobiliaire en relation avec les manifestations rhumatismales, Rhumatologie 14 (2)'49, 1962. 11. Klemola E, and Torma S: Arthralgia and arthritis caused by infectious hepatitis, Ann Med Intern (Fenn) 38:161, 1949. 12. Koff RS: Polyarthritis and viral hepatitis: a report of three cases with this relatively unusual association, and review of literature, Hepatitis Surveillance Report 28:20, 1968, National Center for Disease Control, Atlanta, Ga. 13. Onion DK, Crumpacker CS, and Gilliand BC: Arthritis of hepatitis associated with Australia antigen, Ann Intern Med 75:29, 1971. 14. Extrahepatic manifestations of serum hepatitis (editorial), Lancet 2:805, 1971. 15. Gocke DJ, Hsu K, Morgan C, Bombarcheri S, Christian CL, and Lockshin M: Association between polyarteritis and Australia antigen, Lancet 2:1149, 1970. 16. Combes B, Stastry P, Shorey J, Barrera A, Eigenbrodt EH, Hull AR, and Carter NW: Glomerulonephritis with deposition of Australia antigen-antibody complexes in glomerular basement membrane, Lancet 2:234, 1971. 17. Ginsberg AL, Conrad ME, Bancroft WH, Ling CM, Overby LR: Prevention of endemic HAA positive hepatitis with gamma globulin: use of a single radioimmune assay to detect HAA, N Engl J Med 286:562, 1972. 18. Fernandez R, and McCarty DJ: The arthritis of viral hepatitis, Ann Intern Med 74:207, 1971. 19. Horstmann DM, Havens P, and Deutsch J: Infectious hepatitis in childhood, J PEmATR 30:381, 1947.
709
Articular and cutaneous prodromal manifestations of viral hepatitis The association of arthritis, arthralgia, and various types of skin rashes, as a prodrome to viral hepatitis, although well recognized in adults, has not been well described in children. In an 18-month period, three children presented with this serum sickness-like illness before the onset of evident liver involvement. In one case, the prodromal symptoms occurred four weeks before biochemical or clinical evidence of hepatitis. The S S L I tended to subside with the onset of clinically evident liver disease. Hepatitis B surface antigen (HB~ Ag, Australia antigen) was detected in the sera of two patients, but free antibody to the antigen was not demonstrable in either one, Serum complement levels were low during the prodromal phase and tended to return to normal value at the onset of extensive liver involvement. The diagnosis of viral hepatitis should be considered in children presenting with polyarthritis, polyarthralgia, and a rash (serum sickness-like illness) of uncertain etiology.
Richard A. Segool, M.D., Christine Lejtenyi, M.D., and Lynn M. Taussig, M.D.,* M o n t r e a l , P. Q., C a n a d a
IN 1843, Graves ~ first reported the association of acute polyarthritis a n d / o r urticaria as prodromal symptoms of viral hepatitis. This relationship has been discussed frequently in the adult medical literature in recent years, primarily because of increased interest in the possible immunologic pathogenesis of hepatitis-associated arthritis> 3 Review of the pediatric literature indicates that the association of this "serum sickness-like illness" with hepatitis has not been recognized in children.' In fact, standard textbooks of pediatrics do not mention these prodromal manifestations? 6 In a review of 101 patients with articular symptoms associated with hepatitis, the youngest reported patient was 16 years old. 7 Over an 18-month period, three patients who developed hepatitis presented initially to our pediatric wards
From the Departments of Pediatrics, the Annie and Nathan Steinberg Laboratory of Allergy and Immunology, and the Department of Respiratory Function, The Montreal Children's Hospital, McGill University. Presented in part at the Canadian Pediatric Society Meeting, St. Johns, Newfoundland, August, 1974. *Reprint address: Department of Pediatrics, Arizona Medical Center, Tucson, Ariz. 85724.
with arthritis, arthralgia, and skin rashes. They form the basis for this report which is presented to indicate the association of a SSL! with hepatitis in children; to stress that these prodromal manifestations may occur weeks before clinical or biochemical evidence of hepatitis, and to remind physicians that hepatitis should be considered in the evaluation of patients with arthritis and skin rashes of uncertain etiology. Abbreviations used HB~ Ag: Australia antigen; hepatitis B surface antigen anti-HBj Antibody to HB~ Ag SSLI: serum sickness-like illness
CASE REPORTS Case 1. Patient N. S., a 13-year-old girl, was noted on the day of admission to The Montreal Children's Hospital to have several 1 to 3 cm, erythematous, nodular lesions over the left elbow, which soon spread to the extensor surfaces of the extremities, the scalp, and the skin overlying the spine and iliac crest. The lesions were tender and pruritic. Several hours later she noted onset of pain in both knees, both elbows, and in the left hip. There was no history of recent medications, drug abuse, blood transfusions, exposure to hepatitis, or sexual intercourse. Vital signs were normal and she was afebrile. There was pain
Vol. 87, No. 5, pp. 709-712
7 10
Segool, Lejten),L and Taussig
The Journal of Pediatrics November 1975
Table I. L a b o r a t o r y d a t a a n d clinical c o u r s e s o f 3 p a t i e n t s
Days from onset of illness 0
10
20
30
40
50
Follow-up*
Case 1 SGOT (N = 10-271U) B,C (N = 120-170 m g / d l ) HB~ Ag titcr Arthritis and/or arthralgia Urticaria and/or rash Hepatitis
15 100 1:8
800 91
113 100 1:4
84 1:16
4
14 110 Neg?
P
Case 2 411
SGOT (N = l(/-50mLl/ml) B~C (N = 123-167 mg/dl) HB~ Ag titer Arthritis and/or arthralgia Urticaria and/or rash Hepatitis
108 190
3,900
136 250 Neg
Neg
i
L
tt q
~, (Still present on discharge)
q
Case 3 SGOT (N = 10-27IU) B,C (N = 120-170 mg/dl) HB~ Ag titer Arthritis and/or arthralgia Urticaria and/or rash Hepatitis
223 55 Present:~
2,100 93
660
188 135 Neg
34 118 Neg
-4, ~
w
,.- (Still present on discharge)
*Follow-up: Case 1--15 months after onset: Case 2-did not return for follow-up; Case 3 3 months after onset (SGOT 28 months after onset was 15IU). tNeg = negative. J~Present = in serum as determined by electron microscopy. w and biochemical exacerbation of hepatitis.
on motion of the knees and elbows which were warm, but not red or swollen. There were 0.5 to 4.0 cm nodular red lesions (similar to erythema nodosum) over the extensor surfaces of the forearms and kgees with urticarial lesions over the spine, neck, and scalp. Examination of the abdomen was negative. The thyroid gland was of normal size and consistency but was tender. By the third day of hospitalization, both ankles and the interphalangeal joints of the toes were quite painful, and the metacarpophalangeal and interphalangeal joints of the left hand were swollen, warm, and tender. Hydrotherapy and aspirin brought prompt relief from the joint manifestations. The elbow and hip pain resolved over two days, but she complained o f arthralgia in both knees for ten more days (Table I). The nodular and urticarial rashes disappeared by the third day, and the thyroid gland tenderness also abated. Pertinent laboratory data are listed in Table 1. Numerous laboratory examinations were normal or negative including concentrations ,of serum glutamic oxaloacetic transaminase, alkaline phosphatase, total protein; white blood cell count; T~; mononucleosis spot test; rheumatoid factor; lupus erythematosus preparation; thyroglobulin antibody; antinuclear antibody; antistreptolysin 0 titer; cryoglobulins; electrocardiogram; and urinalysis. Serum was positive for HB~ Ag on the second day of
hospitalization (Table I). The patient was discharged with no articular or cutaneous abnormalities with a diagnosis of "possible collagen disease," The patient returned four weeks after her initial presentation with a 2-day history o f anorexia, nausea, vomiting, scleral icterus, and dark urine. Laboratory measurements of liver function were consistent with the diagnosis of hepatitis (Table I). The patient had an uneventful recovery at home during t h e subsequent month. Fifteen months after initial hospitalization she was clinically well, but serum B1 C concentration remained borderline low and serum concentrations of immunoglobulins G and M remained slightly elevated. Case 2. Patient RI W.; a 13-year-old boy, was previously in good health; onset o f generalized malaise, fatigue, and myalgia was noted 10 days prior to admission. Seven days prior to admission, he became febrile and developed weakness, generalized abdominal pain, arthralgia, and an urticarial rash over the lower extremities. Three days later he had persistent nausea and vomiting with high fever and was admitted to the hospital. He denied use of medication, exposure to hepatitis, or drug abuse. In the hospital, he was lethargic, pale, and nonicteric with a temperature of 103 ~ F. The abdomen was diffusely tender," maximally m the right upper quandrant: The spleen tip was
Volume 87 Number 5
palpable, but there was no hepatomegaly. An urticarial rash was present over all extremities and there was diffuse muscle tenderness. Laboratory values on admission were consistent with a diagnosis of hepatitis (Table I). By the second day of hospitalization there was swelling with warmth and redness of the small joints of the hands. Later the right wrist, right elbow, and both shoulders became similarly involved. Hepatomegaly was initially noted on the second day of hospitalization. Arthritis and the urticarial rash were the main problems during the first 10 days in the hospital; the liver remained slightly enlarged, but the abnormal liver enzyme values improved during this 10-day period. The patient's rash persisted for a total of 14 days from onset, and arthritis lasted for 16 days. Five days following disappearance of the rash and arthritis, clinical and biochemical evidence of exacerbation of hepatitis occurred (Table I). Over the following tWOweeks, gradual improvement occurred clinically and biochemically, and the patient was discharged after 47 days of hospitalization. At the time of discharge, laboratory values of liver function were still abnormal but he refused to return for follow-up evaluation. Pertinent laboratory data are listed in Table I. Other laboratory determinations as performed for Case 1 were also normal or negative in Case 2. Evaluation of serum for HBs Ag liters was negative on the eleventh and thirty-sixth days after his illness. Case 3. Patient S. R., a 16-year-old girl with a history of intravenous drug abuse, was admitted to the hospital because of skin rash and arthritis. Ten days before admission, pruritic maculopapular lesions appeared on the extremities, spread to the trunk and face, and coalesced to form a generalized erythematous rash. Three days later, she developed intermittent pain and swelling of the wrists, elbows, shoulders, metacarpophalangeal joints, ankles, knees, and spine. The pain was severe enough to hinder walking and keep her awake at night. On admission she had tenderness, limitation of movement, and soft tissue swelling of the involved joints, with small effusions of both knees. The cervical, axillary, and inguinal lymph nodes were slightly enlarged. The spleen and liver were palpable and slightly tender. Diffuse erythema was present over the whole body. In the hospital, the erythema faded, and the joint pain and swelling responded rapidly to aspirin therapy. Four days after admission (14 days after onset of illness) she complained of anorexia, vomiting, and malaise, and the diagnosis of hepatitis was made (Table I). The patient subsequently made an uneventful recovery. A blood sample drawn two weeks prior to admission as a routine screening test for drug abuse was negative for HB~ Ag by counterelectrophoresis. Subsequent analysis of this specimen by electron microscopy revealed small amounts of free antigen. Serum at the time of admission also revealed HBs Ag. Three months after recovery from hepatitis, HB~ Ag and anti-HB~ were absent from her serum (Table I). METHODS Immunoglobulins and complement were assayed using Hyland Immuno-Diffusion plates (Hyland Laboratories, Chicago, ILL). HB~ Ag and anti-HB~ were measured by
Arthritis and rash with hepatitis
7 11
cross-over immunoelectrophoresis. ~ Electron microscopic examination of, the serum was performed as previously described by Kelen and associates? Liver function and other laboratory examinations were done by Standard methods. DISCUSSION Arthralgia has been described as a prodromal symptom in both type A and type B virus hepatitis in adults5 Arthritis is more often associated with type B hepatitis. :~ From earlier publications, the incidence of arthralgia or arthritis with hepatitisdn adults (10 to 24%); is considerably greater than in children (1.6%). l~ In a recent review 7 of the literature, 101 cases of hepatitis with articular prodromal symptoms were summarized. The patients ranged in age from 16 to 72 years with equal n u m b e r s of males and females. Fortyfour per cent of the patients had only arthralgia, while the remainder had arthritis. For each group, symmetric distribution of joint symptoms was most common. The predominant joints involved in each group were the small joints of the hands, the shoulders, knees, ankles, and elbows. An urticarial or maculopopular rash, most frequently involving the lower extremities, Was present in 30% of patientswith arthralgia and in 42% of patients with arthritis. The rash commonly appeared concurrently with the joint symptoms. The joint symptoms lasted an average of 20 days (range 5 to 33 days). Disappearance of the SSLI was most often temporally associated with the appearance of jaundice. In 5% of cases, arthritis and j a u n d i c e developed simultaneously; joint abnormalities rarely extended beyond the period of jaundice. The patients described in the present report indicate that the manifestations of the SSLI occurring with viral hepatitis are similar in children as in adults. All three patients demonstrated the previously described 7 clinical, biochemical, and immunologic features of the articularrash-hepatitis association. In each case, the hepatitis either developed after the SSLI or demonstrated a severe exacerbation as the joint and skin involvement abated. There are two main theories explaining the pathogenesis of the prodromal articular lesions in viral hepatitis. The first suggests that the virus is actually present in the joint at the time of the arthritis, producing a direct synovial cytopathic effect. T M 1~ The second proposes an immunologic mechanism similar to that occurring in serum sickness. During the prodromal phase when arthritis a n d / o r rash is present there are high levels of HBs Ag, low levels of antibody to the antigen, and low levels of complement (total CH50 and B1C) in serum and synovial fluid. Hematogenous circulating i m m u n e complexes can form during the phase of antigen excess, and these soluble
7 12
Segool, Lejtenyi, and Taussig
complexes are thought to produce the SSLI. W h e n the icteric phas e begins, serum HB~ Ag levels decrease rapidly, serum anti-HB~ levels increase, ~ ~ 13. 1~ complement levels normalize, and the joint and skin manifestations disappear. In addition to implicating HB~ Ag - antiHBs complexes in the pathogenesis of hepatitis-associated arthritis a n d / o r urticaria, several authors have described immune complexes with HBs Ag in polyarteritis nodosa 1~ and in glomerulonephritis with the nephrotic syndrome, t~ In the patients reported here, concentrations of B1C tended to be low during the period of joint and skin manifestations and increased with the onset or worsening of liver abnormalities. HBs Ag was present and in high concentrations in two of the patients during the SSLI and decreased during the icteric phase. In Case 2, determinations of HBs Ag were consistently negative. The patient had developed clinical hepatitis four days prior to the first determination for HBs Ag. It is possible that HB~ Ag was present but undetectable due to binding with developing antibody. 13 However, the more sensitive test (radioimmunoassay) for HB~ Ag was not employed on his serum. Thus the negative HB~ Ag may be a false laboratory result. Alternatively, this may represent a case o f type A hepatitis?~, l g The occurrence of these three cases over a relatively short period of time suggests that a SSLI with hepatitis may not be very rare in children. Although early reports TM of hepatitis in children did not describe these manifestations, it is unlikely that the incidence of these symptoms is actually increasing. The prevalence of type B hepatitis, however, may he increasing due to increasing drug abuse. Since the skin and joint manifestations may occur weeks before obvious hepatitis, these symptoms may be forgotten by the patient, especially if not specifically asked for at the time of hepatitis. It is impor{ant for physicians to be aware that a prodromal serum sicknesslike disease may occur in children days to weeks before the onset of hepatitis. The authors thank Dr. Sidney Pedvis for referring one of the patients and Dr. Stephen Vas and Mrs. G. Deutsch for doing the electron microscopy and HB~ Ag determinations. REFERENCES
1. Graves R: Clinical lectures on practice of medicine, Dublin, 1843, Fannin & Co, p 937.
The Journal of Pediatrics November 1975
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