Acute Pericarditis Associated With Hepatitis B Infection

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Acute

Pericarditis

Associated

With

Hepatitis

B Infection

RObert Adler, M.D., Masato Takahashi, M.D., and Harry T. Wright, Jr., M.D., MPH.

From the Divisions of General Pediatrics, CaITUO1OgIJ, arid Infectious Diseases Childrens HOspital of Las

Angeles, and the Department of Pediatrics, UnIVeYSIti,J of Southern California SChOOL of Medicine, Los

Angeles

ABSTRACT. Patients infected with hepatitis B have demon-strated a wide spectrum of clinical manifestations other than

hepatitis. Immune complex formation has been proposed as a possible mechanism for such varied disease presentations.

The present report describes a case in which acute

pericarditis is associated with hepatitis B surface

antigen-positive disease. Speculations are made relating the pericar-dial changes to the formation of immune complexes following hepatitis B virus infection. Pediatrics 61:716-719,

1978, pericarditis, encephalopathy, hepatitis B, hepatitLs B

surface antigen, immune complex, inflammatory disease.

Recent reports have shown that a wide

spec-trum of diseases are associated with the hepatitis

B

surface antigen (HBsAg), including

polyarthri-tis,’ glomerulonephritis,2 polyarteritis,3 pleural

effusions,4 and hepatitis. Immune complex forma-lion has been proposed as a possible mechanism for such varied clinical manifestations.5

The present report describes a child with surgical repair of a congenital cardiac defect who

subsequently acquired HBsAg-positive hepatitis

complicated by acute pericarditis and a mild encephalopathy. No similar case has come to our attention and we suggest that these clinical maui-festations may represent another example of

immune-complex disease associated with the

presence of HBsAg.

CASE REPORT

A 7#{189}-year-old Spanish-American girl was found to have an

atrial septal defect in 1970. Surgical repair of the cardiac

defect was performed under cardiopulmonaiy bypass. The pump was primed with whole lood. She did well until 90

days after surgery at which time she developed nausea and malaise. By the 93rd postoperative day she developed jaundice and progressive abdominal distention. On the 102nd

postoperative day she was admitted to another institution,

where physical examination revealed a thin, jaundiced girl with 24 respirations per minute, a heart rate of 108 beats per

minute, a blood pressure of 90/68 mm Hg, and a tempera-ture of 37.2 C. She was noted to have jugular venous distention and decreased breath sounds at both lung bases. Heart tones were distant. There was a gallop sound, and a grade 2/6 systolic ejection murmur was heard along the left sternal border. The liver, palpable 7 cm below the right costal margin, was slightly tender. Initial laboratory exami-nation revealed a normal complete blood cell count. The following laboratory values were increased: SCOT, 700 IU;

SGPT, 550 IU; lactic dehydrogenase, 810 IU; and creatinine phosphokinase, 00 IU Alkaline phosphatase level was 8.0

King Armstrong units. Total bilirubin level was 2.9 mg/dI,

with adirect component of1.5 mg/dl; total protein level was 7.3 mg/dl, with an albumin component of 3.4 mg/dI; prothrombin time was 12.5 seconds with a control of 11.0 seconds. A chest roentgenogram revealed a large cardiac shadow; ECG revealed anonnal sinus rhythm with a rate of 100 beats per minute, a right axis deviation, and generalized low voltage.

The patient was transferred to Childrens Hospital of Los Angeles on the same day for further treatment. An echocar-diogram confirmed a large pericardial effusion. On the 103rd

postoperative day a pericardiocentesis was performed and

550 ml of amber fluid was removecL This was followed by immediate improvement in her status, as indicated

clinical-ly and by chest roentgenogram and echocardiogram (Fig-ure).

During the following week the patient remained asympto-matic, but chest roentgenograms revealed progressive enlargement of the heart. Results ofher liver function studies improved steadily. }lBsAg tested by complement fixation reaction, drawn and tested on the same day, was present

both in the serum at a dilution of 1:8 and in the pericardial

fluid at a dilution of 1:32. Antibody to HBsAg in the serum was negative. Prior to cardiac surgery a serum HBsAg test was negative. No microorganisms were isolated in aerobic or anaerobic cultures of the blood or pericardial fluid. Virus

Received July 18; revision accepted for publication September 27, 1977.

Supported in part by the Children’s Heart Foundation of

Southern California.

ADDRESS FOR REPRINTS: (R.A.) Division of General

Pediatrics, Childrens Hospital of Los Angeles, P.O. Box

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ARTICLES 717

A, Patient’s chest roentgenogram taken shortly after admission revealed markedly enlarged

cardiac silhouette and normal pulmonary vascular markings. B, Following pericardiocentesis, cardiac size was normal. C, M-mode echocardiogram obtained on admission showed large

posterior pericardial effusion. D, After pericardiocentesis, in which 550 ml of fluid was removed, amount of effusion was noted to be much less. AO aorta; LA left atrium; IVS

interven-tricular septum; LVPW left ventricular posterior wall; PE pericardial effusion.

isolation attempts in tissue cultures for coxsackievirus, echo-vinis, adenovirus, and human cytomegalovirus were nega-tive. Microscopic examination of the pericardial fluid

revealed no tumor cells. Tests for antinuclear antibodies and

rheumatoid factors were negative. Complement studies were not performed. The patient’s condition remained stable and she was discharged from the hospital. The patient’s condition was stable for about a week before the symptoms re-curred.

On the 120th day after surgery a repeated pericardiocen-tesis yielded 950 ml of amber fluid. Removal of this fluid was associated with immediate improvement in her cardiorespi-ratory status. The fluid had a leukocyte count of 760/cu mm

with 99% lymphocytes; RBC count, 2,600/cu mm; protein

level, 602 mg/dl; and glucose level, 96 mg/dl. Cultures of

this fluid sustained no bacterial, fungal, or viral growth.

Serological tests of both acute (107th postoperative day) and convalescent (122nd postoperative day) serum samples

revealed no rise in titers for influenza A and B, Q fever,

psittacosis, adenovirus, cytomegalovirus, parainfluenza 1 through 3, and respiratory syncytial virus. A repeated

antinuclear antibody test was negative. Subsequently, signs

of congestive heart failure developed with low cardiac

output. A chest roentgenogram and echocardiogram again indicated accumulation of pericardial fluid. On the 129th

postoperative day she was taken to surgery for creation of a pericardial window and a liver biopsy.

Microscopic examination of the pericardium showed

thickened collagenous connective tissue infiltrated with reactive mesothelial cells, lymphocytes, and plasma cells,

consistent with a chronic nonspecific pericarditis. The liver

biopsy specimen showed some disarray of lobular organiza-tion. A few mononuclear cells in the portal areas without

necrosis were seen. These findings were consistent with a

chronic persistent hepatitis.

Concurrently with the worsening of her cardiac status the patient became increasingly lethargic. This progressed to a

stuporous state in which there were no focal neurological

signs. Serum electrolyte, blood glucose, and serum calcium

levels, and CSF were normal. An EEC suggested a mild

encephalopathy. The patient’s sensorium improved rapidly

during the next three days but a right-sided weakness

became apparent.

The patient’s condition improved remarkably after the

pericardial window was made. One month later her cardiac

status and chest roentgenograms were normal; however, she

still had a mild right hemiparesis.

Two years after her original disease, tests for HBsAg were

negative and she had no clinical manifestation of hepatitic

disease.

DISCUSSION

In recent years, the HBsAg has been found in a variety of disease states other than classic

hepati-tis. Pericardial involvement in hepatitis appears

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to be rare. Eisen and Markovich6 reported a case of massive hemopericardium associated with hepatitis and suggested that the primary problem was the generalized hemorrhagic tendency rather than inflammatory process involving the pericar-dium. A case of pericardial effusion, documented by echocardiogram, associated with hepatitis B infection was reported by Miller and Waggoner.7

No further studies were reported and a follow-up

echocardiogram taken when the liver enzyme

concentrations had decreased showed a decrease in pericardial shadow. Nagaratnam and asso-ciates8 reported four cases of myocarditis asso-ciated with hepatitis with one fatality. At necropsy the patient had 60 ml of yellow pericar-dial fluid. A review of the literature failed to reveal any other reports of pericardial involve-ment associated with hepatitis and no cases in the pediatric age group have come to our attention.

Several reports have implicated myocardial involvement in association with hepatitis,9’1#{176} but necropsy findings in patients who died of hepa-titis have described no pericardial involve-ment.’1”2

The case presented here is unique in that the pericardium was inflamed and the pericardial fluid contained HBsAg in a higher titer than did the serum. It seems reasonable to speculate that the inflammatory changes seen may have been produced by a secondary response to antigen-antibody complexes localized within the pericar-dium or may have resulted directly from virus replicating within the pericardial cells. Another possibility is that the pericarditis and the presence of HBsAg in this patient are purely coincidental.

Inflammatory changes mediated by an immune complex have been described by Dixon et al.’3 and demonstrated by experiments producing serum sickness in animals. In this model, locahiza-tion of antibody-antigen at a site distant from where the antigen and antibody were formed was

associated with inflammatory changes and subse-quent damage to the tissue. Evidence for a similar interaction between antigen and antibody that causes local tissue damage has been represented by the expanded clinical spectrum of hepatitis.’4

A characteristic pattern of immune complex deposition consisting of IgG, C3, and HBsAg has been demonstrated by immunofluorescent studies of a renal biopsy specimen from a patient who

developed glomerulonephritis following serum

hepatitis.” Gocke et al.,3 studying polyarteritis in hepatitis, discovered the existence of an immune complex of HBsAg with antibody and localization of this immune complex along with 1gM and

B,C

in affected blood vessels. This evidence suggests that many of the clinical manifestations of hepa-titis B may be mediated by complexes of HBsAg, antibody to HBsAg, and complement and not a consequence of viral invasion.

Ogra’6 has suggested that hepatitis

B

virus may replicate in various mucosal surfaces. Production of HBsAg within the pericardial cells may account for the greater concentration of HBsAg seen within the pericardial fluid. Although this remains a possibility, production of HBsAg

outside the liver has not been demonstrated and seems unlikely as an explanation for the clinical presentation.

Other explanations for findings in the present case were considered. No evidence was obtained for bacterial, viral, or fungal infecti#{224}n. Tests for

collagen vascular disease were repeatedly nega-live. The prodrome of hepatitis and the absence

of

fever differentiate this disease from the post-pericardiotomy syndrome. Atrial septal defects have been associated with pencardial disease.’7”8 There was no gross evidence of pericardial disease in our patient at the time of initial surgery.

It would appear that the pericardial changes and the hepatitis B infection were etiologically related in our patient. Although this relationship has not been definitely elucidated, it is possible that the pericarditis was mediated by metastatic complexes associated with the hepatitis B infec-lion. This mechanism of inflammatory disease could be

similar

to the serum sickness in animals described by Dixon et al.13 Surgical trauma to the pericardium may have been the triggering factor that

led

to the intense immune reaction to the hepatitis virus.

This case report further expands the clinical

spectrum of disease associated with hepatitis, and

reemphasizes the importance of effective and

sen-sitive screening for the presence of hepatitis B virus in donor blood.

REFERENCES

1. Onion DK, Crumpacker CS, Gilliland BC: Arthritis of hepatitis associated with Australia antigen. Ann

Intern Med 75:29, 1971.

2. Conrad ME, Schwartz FD, Young AA: Infectious

hepa-titis: A generalized disease. Am I Med 37:789, 1964.

3. Gocke DJ, Morgan C, Lockshin M, et al: Association between polyarteritis and Australia antigen. Lancet

2:1149, 1970.

4. Owen RL, Shapiro H: Pleural effusion, rash, and anergy in icteric hepatitis. N Engi I Med 291:963, 1974. 5. Alpert E, Isselbacher KJ, Sehur PH: The pathogenesis of

arthritis associated with viral hepatitis,

comple-ment component studies. N Engi I Med 285:185,

1971.

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ARTICLES 719

a case with massive hemorrhage in pericardial and

pleural cavities. JAMA 146:1414, 1951.

7. Miller AB, Waggoner DM: Cardiac disease, hepatic disease, and hepatitis B antigen. Ann Intern Med

79:276, 1973.

8. Nagaratnam N, De Silva DPKN, Gunawardene KRW: Myocardial involvement in infectious hepatitis.

Postgrad Med I 47:785, 1971.

9. Dehn H, Feil H, Rinderknecht RE:

Electrocardio-graphic changes in cases of infectious hepatitis. Am

HeartJ3l:183, 1946.

10. Bell H: Cardiac manifestations of viral hepatitis. JAMA

218:387, 1971.

11. Luck#{233}B: The pathology of fatal epidemic hepatitis. Am I Pathol 20:471, 1944.

12. Saphir 0, Amromin GD, Yokoo H: Myocarditis in viral (epidemic) hepatitis. Am I Med Sci 231:168, 1956.

13. Dixon FJ, Vasquez JJ, Weigle WO, Chochrane

CC-Pathogenesis of serum sickness. Arch Pathol 65:18, 1958.

14. Duffy J, LidSky MD, Sharp JT, et al: Polyarthritis,

polyarteritis and hepatitis B. Medicine 55:19,

1976.

15. Combes B, Shorey J, Barrera A, et al: Glomerulone-phritis with disposition of Australia

antigen-anti-body complexes in glomerular basement mem-brane. Lancet 2:234, 1971.

16. Ogra PL: Immunologic aspects of hepatitis-associated

antigen and antibody in human body fluids. I

Immunol 110:1197, 1973.

17. Semler HJ, Brandenburg RO, Kirklin JW: Pericardial

disease complicating congential heart lesions. Ann

Intern Med 53:494, 1960.

18. Just H, Mattingly TW: Interatrial septal defect and pericardial disease: Coincidence or causal relation-ship? Am Heart I 76:157, 1968.

THE SIZE OF CITIES

. . . records of urban populations suggest that for most of human history

cities did not generally grow beyond the 50,000 to 100,000 range. For most of its celebrated life the city of Athens hovered around 50,000 people, though at

periods of particular power the surrounding state may have grown to 150,000

or 200,000. The Italian cities that nurtured the Renaissance were no larger than 80,000, and most of them held closer to 50,000-the Rome of Michelang-elo had perhaps 55,000 people, the Florence of Leonardo 50,000, and Venice,

Padua, and Bologna at their height probably 50,000 to 80,000. Boston and Philadelphia at the time of the Revolution did not have more than 30,000 people, New York had even fewer. In fact, it seems that only rarely did historical cities go much beyond 100,000, and then only temporarily when serving as the capitals of empires. . . . The very existence of giant cities is so

recent as to be a mere eye-blink in recorded history. It was not until 1800 that

any city grew to more than one million people-that was industrialized

London-and by 1900 there were only ten others of that size.

The conclusion of the great Greek city planner Constantine Doxiades, who spent his life categorizing such things, seems on the mark: “If we look back into history . . . we find that, throughout the long evolution of human settlements,

people in all parts of the world have tended to create urban settlements which reached an optimum size of 50,000 people.” Indeed, he argues, the fact that the few larger cities did not survive for long suggests that humanity has solved the problems of living in cities of up to 50,000 or so, but not the problems of living in units much above that size.

, KIiuAmIcx SAi

Submitted by Student

From Sale K: The Polis perplexity: An inquiry into the size of cities. Working Papers for a New

Society, Januaiy-February 1978, p 64.

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1978;61;716

Pediatrics

Robert Adler, Masato Takahashi and Harry T. Wright, Jr.