December 1975 The Journal o f P E D I A T R I C S
1103
Immunologic and virologic studies in the postpericardiotomy syndrome A prospective, triple-blind study was undertaken to determine whether antiheart antibody or a rise in titer to a virus occurred in patients after intrapericardial surgery and, i f so, whether either was related to clinical evidence of the postpericardiotomy syndrome. In 257 patients, A HA in high titer appeared in 62 (24%), all of whom had the syndrome. None o f the 102 patients with no A H A had the syndrome. In 137 subjects, a rise in titer to one or more viral agents occurred in 21 o f 31 (68%) o f those with A H A and PPS. This study suggests that an immunologic response and viral illness are related to PPS.
Mary Allen Engle, M.D., John B. Zabriskie, M.D., Laurence B. Senterfit, Sc.D., Daniel J. Tay, M.D., and Paul A. Ebert, M.D., New York, N.Y.
THE POSTPERICARDIOTOMY SYNDROME is the most common postoperative complication of cardiac surgery, affecting about 20% to 30% of individuals all ages whose surgery involves opening of the pericardium? -:' Usually, operative procedure includes use of the heart-lung machine and the opening of a cardiac chamber or great artery to repair a valve or close a defect, but the syndrome also occurs without cardiac bypass or cardiotomy, as for example when an intrapericardial anastomosis is created between ascending aorta and right pulmonary artery, or a band is placed on the pulmonary artery, or simply when the intrapericardial structures are explored. The complication increases the morbidity after operation and prolongs hospitalization beyond the usual 7 to i0 days for the uncomplicated case to several weeks or more. When unrecognized, it even accounts for postoperative mortality. 6 It has been suggested that the syndrome is related to early ambulation after operationJ Although changes have occurred through the years in operative procedures and in operating teams, the syndrome continues to appear with From the Departments o f Pediatrics, Surgery, and Microbiology, The New York Hospital-Cornell University Medical Center and Rockefeller University. Supported in part by N H L I Grant No. 1 RO1 H L 16246-01 and N H L I Training Grant No. 1 TO1 H L 05989-01 Presented at the Plenary Session o f the American Pediatric Society and the Society for Pediatric Research, Denver, Colorado, April 17, 1975.
about the same frequency as in the early days of intrapericardial surgery for congenital heart disease. '-~ The syndrome has been reported after percutaneous measurement of cardiac pressures '~ and after penetrating stab wounds of the chest ~' and nonpenetrating chest trauma. 1~The clinical symptoms and findings are similar to those occasionally seen after myocardial infarction in the so-called "Dressier syndrome. ''11 Common features that may be significant in the etiology of the syndrome following cardiac Surgery, percutaneous measurement of pressure, myocardial infarction, and crushing or penetrating chest trauma are damage to heart muscle and opportunity for intrapericardial bleeding. Abbreviations used' AHA: antiheart antibody PPS: postpericardiotomy syndrome VSD: ventricular septal defect
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The condition is diagnosed after the first postoperative week by persistence, or appearance, of fever and by signs of pericardial and sometimes pleural involvement. Pericardial reaction is indicated by precordial chest pain, sometimes referred to the shoulder and made worse by lying down or by inspiring deeply; by pericardial friction rub or effusion; and by serial electrocardiographic changes of pericarditis, which usually last longer than the
Vol. 87, No. 6, part 2, pp. 1103-1108
1 10 4
Engle et al.
The Journal of Pediatrics December 1975
Normal heart tissue
Normal It-globulin
No reaction
Normal heart tissue
Heart-reactive 7-globulin
Bound y-globulin
Bound ~'-globulin
(~) anti~'-globulin
Fluorescence
Fig. 1. Schema of technique of determination of antiheart antibody. With normal gamma globulin, there is no reaction to normal heart tissue, but with heart-reactive gamma globulin there is binding, which can be demonstrated by fluoresceinlabeling and read as intensity of fluorescence. other signs of pericardial abnormality. Unilateral or bilateral pleural effusions occur. During the febrile period the white blood cell count and the polymorphonuclear ceils are elevated. The condition is self-limited; it may recur months or years later. Hepatospienomegaly, arthritis, and skin rash are not part of the syndrome. These are distinguishing features from other postoperative febrile states, such as the postperfusion syndrome TM (with hepatosplenomegaly, atypical lymphocytosis, and cytomegolovirus infection) or serum sickness. It must be differentiated from other causes of postoperative fever, such as infective endocarditis, atelectasis, or pneumonia. Radiographically, the enlargement of the cardiac silhouette and the appearance of pleural effusions suggest cardiac failure, and that diagnosis may also erroneously be made at the bedside of the dyspneic patient with distended neck veins and hepatomegaly who has cardiac tamponade. ETIOLOGY The condition was first brought to medical attention when mitral commissurotomy was performed in adult patients with rheumatic mitral stenosis':'; thus it was logical to consider that it represented a reactivation of rheumatic fever. That explanation was disproved by observing the syndrome in children and adults undergoing surgery for congenital heart disease." ~ Alternative possibilities as to etiology were suggested: the syndrome might represent a hypersensitivity reaction to blood in the pericardial sac or it might be a viral infection." ~ Similarity of the syndrome to viral pericarditis, which also has
a tendency to recur, was noted. Some support for the autoimmune theory was forthcoming when Robinson and Brigden ~4 in 1963 and Van der Geld 1~ in 1964 demonstrated antiheart antibodies in some patients with the syndrome. In 1970 Burch and Colcolough '~ proposed that this syndrome might be caused by reactivation of a latent virus infection when there is trauma to the myocardial tissue. PROSPECTIVE
STUDY
In October, 1971, we undertook a prospective study of consecutive, long-term survivors of intrapericardial surgery to determine whether an autoimmune response, or a viral infection, or both were involved in pathogenesis of the p0stpericardiotomy syndrome. In the first part of the study, concurrent analyses were made on a double-blind basis preoperatively and postoperatively, at prescribed intervals in the hospital and after discharge, of circulating antiheart antibody and of clinical signs of the syndrome. The samples of blood were obtained t h e day before surgery and postoperatively on the seventh and tenth days, in the third and fifth weeks, and additionally as indicated. The antibody was determined from serum by an immunofluorescent technique and was ranked 0 to 4 +, based on intensity of staining?~ The principle of the method is shown in Fig. 1. Clinical course of the patients was evaluated by at least two pediatric cardiologists and presence or absence of the syndrome was noted. When present, it was judged to be mild, moderate, or severe, depending on the duration and intensity of manifestations. Physical examination was performed daily in the hospital and at the time of visits for postoperative follow-up. Electrocardiogram and teleoroentgenogram of the chest were obtained according to the schedule for blood sampling. Echocardiogram was recorded when pericardial effusion was suspected. Postoperative care was maintained as standard as possible. Antibiotics were administered for the first five days and not thereafter, unless in a rare circumstance there was clear evidence of a bacterial infection. In the first 110 patients, ambulation was delayed until the patient was afebrile for 48 hours; earlier ambulation as tolerated was permitted in subsequent patients. Diuretic agents (furosemide) were used in most patients with effusions. Neither salicylates nor steroids were employed except in 12 subjects with severe syndrome, to be mentioned later. Patients were discharged when they were afebrile for two days on ambulation and effusions were subsiding. Duration of hospitalization was therefore one determinant of severity (Fig. 2). Results of the immunologic and clinical evaluations were compared at intervals 17 1~and then a third investiga-
Volume 87 Number 6, part 2
Immunologic and virologic studies in P P S
1 10 5
HEART REACTIVE ANTIBODY TITER- 257 PATIENTS
HOSPITAL STAY, AVERAGE AND RANGE None
3 ~ild
Iii i i;;;;;ii!;i;!i:i !;ii!;ii i ;i !:il;i ::ii i ;i ;ili;;ii;f;i;:i;;tI I~ t?S. syndrome
& Moderate
Iii ;i i ;i i i !i i i ;i ~::ii!i!::!!~::~!~i~i~i~i~i!;ii;i i ~::~::~J::~;~:::;~::~::~::::~
e~
Severe
~iiiiiii~i~iiiiii~;i~!~!!~;!~;~9~;i;~ii~;~;;;~:~i~;~;~:~ ', IIIIIllll~ltll~l~l,rl 0 10 Hospital days
20
30
0
Negative (102 cases) ~ "
.=,,-_
1
1
I 40
Fig. 2. The mean and the range of days of hospitalization for patients with no postpericardiotomy syndrome and with syndrome that was mild, moderate, or severe. tion was added to make this a triple-blind study. On the same sample of serum in which heart-reactive antibody was determined, complement-fixation studies were performed to a battery of eight viruses (adenovirus, Coxsackie B 1-6, cytomegalovirus) and to Mycoplasma pneumoniae. The results of all three analyses were then compared. RESULTS Clinical evaluation. Of 257 consecutive survivors of intrapericardial surgery, 66 patients had the postopericardiotomy syndrome. It was judged to be mild in 22, moderate in 25, and severe in 16 patients. The last abnormality to disappear was electrocardiographic evidence of pericarditis. Three patients were readmitted within a month of discharge because of exacerbation of the syndrome. Two of these presented as severely ill children with cardiac tamponade. Immunologic studies. Preoperative sera were negative for heart-reactive antibody. Howeyer, in 155 subjects an antibody appeared toward the end of the first week. In 62, the staining was greater than 2 + and the antibody could be detected into the second month or beyond. This response was called positive (Fig. 3). In 93 patients the antibody rise began at the same time but the staining was less intense, and the antibody disappeared after one month (intermediate group,. Fig. 3). The antiheart antibody was specific for cardiac and for skeletal muscle, but it was not species specific for h u m a n cardiac muscle. There was litttle binding to smooth muscle and none to other organs such as lung, liver, thymus, spleen, or kidney. 17' TM Unlike the heart-reactive antibody demonstrated in patients with rheumatic fever, which binds to group A streptococcal membrane, 1~ this antiheart antibody did not.
0
10
I
I
,
20 30 Postoperative days
I
t
40
Fig. 3. Idealized curve of antiheart antibody as judged by immunofluorescentstaining to be negative (102 cases) or intermediate (less than 2 + in 93 cases) or positive (greater than 2 + in 62 cases). Antibody rise began toward end of first week, but in the positive group, it rose higher and persisted longer than in the intermediate group.
Virologic studies. In 137 patients studied, an elevation of titer for one or more' viruses was measured in 56 subjects. Twenty-five had a high titer on admission that did not change during the course, whereas 31 had a fourfold or greater rise in titer and then a decline during the period of observation. Of the latter group of 31, 21 had no detectable antiviral antibody prior to surgery. In six subjects there was a demonstrable titer to Mycopla, s'ma pneumoniae. Among the 31 patients with a significant rise in viral titer, this elevation was to one agent only in 24, but to two agents in three children, to three viruses in another three patients, and to four agents (cytomegalovirus and Coxsackie B1, 2 and 3) in one subject. No patient had a rise in titer against Coxsackie B4. Correlation of triple-blind data. Results of clinical evaluation of PPS and determination of antiheart antibody were compared in each patient (Fig. 4). When the comparisons for all subjects were analyzed, it was found that none of the 102 patients with negative antiheart antibody had the syndrome whereas all of the 62 with positive antibody had PPS. It was severe in 16, moderate in 28, and mild in 18. Of the 93 in the intermediate group, four had mild syndrome. A striking difference was noticed in incidence of syndrome and in antiheart antibody between the infants one year of age or less and those two years of age and older (Table I). Only one infant of 63 had the syndrome and positive antibody, an incidence of 1.6%. Beyond two years, the incidence was comparable at all ages, ranging from 29% to 40%.
1 10 6
Engle et al.
The Journal of Pediatrics December 1975
MODERATEP.RS. 4
0
~
R.P.
TEMPERATURE 3938 (~
......
VSD-AI
37 L
++++++++
FRICTIONRUB PLEURALEFFUSION PERICARDIALEFFUSION
+ oo
ECGABNORMALITIES +
+
+
+-F
+
+ + + q-
+
o +
o
o
o
o
o
o
o
o
o
o
-F
o
o
++
4
ANTIHEART ANTIBODY
I~ll,lL~llllllllllllll~,l
O 5 i0 DAYSPOSTOPERATIVE
15 20 28 DISCHARGEAI~2.1"
1 7O
Fig. 4. Chart of boy operated on for ventricular septal defect and aortic insufficiency. Fever persisted for two weeks. Pericardial friction rub was heard from the third through eleventh days; pleural and pericardial effusions developed then and lasted into the second week. Electrocardiographic abnormalities were the last signs to disappear. Antiheart antibody, initially negative, was intermediate at seven days but positive through discharge at three weeks; it remained elevated for more than two months.
Among the 137 patients tested for titer to viruses were 31 in whom a significant rise and then a drop in titer occurred (Table II). This rise was observed in three of 60 patients with negative antiheart antibody and no syndrome, an incidence of 5%; in seven of 46 with intermediate antiheart antibody (15%) and no syndrome; but in 21 of 31 with positive A H A and with the syndrome (67.7%). Of the 25 patients who had detectable antibody to one or more viruses prior to surgery and no change throughout the period of study, 18% (11 of 60 patients) had negative antiheart antibody, 17% (eight of 46) had intermediate response, and 19% (six of 31) had positive AHA and postpericardiotomy syndrome. The presence of detectable titer tO Mycoplasma pneumoniae in six of the 137 patients is regarded as a nonspecific indicator of respiratory illness. One patient with rise in titer to cytomegalovirus had early evidence of mild postperfusion syndrome, with hepatosplenomegaly and atypical lymphocytosis. Analysis was made of the most frequent types of cardiac surgery performed to see if there were a relation to
the syndrome, antiheart antibody, or viral titer (Table III). The same types of operation were performed in all age groups. The most frequent anomaly was tetralogy of Fallot, in which a right ventriculotomy was performed for excision of infundibular pulmonic stenosis and for closure of the ventricular septal defect with a patch of Teflon felt. Next most common was atrial septal defect. There appeared to be no difference in the response of patients with a simple secundum-type defect and those with an ostium primum who had a cleft in the mitral valve sutured at the same time, so these two types of septal defect were combined for the analysis; surgical repair was through a right atriotomy. A Teflon felt patch was used to close all the primum defects and for the large secundum defects. Simple ventricular septal defect, closed with a Teflon felt patch and usually through a right ventriculotomy,was the next most common anomaly; repair of a VSD plus some other lesion such as transposition a n d / o r pulmonic stenosis was the fourth most common. In the patients with immunologic and virologic studies, those with repair of tetralogy of Fallot and of VSD plus another lesion had the highest incidence of the syndrome, whereas none of those
Volume 87 Number 6, part 2
Immunologic and virologic studies in PPS
Table III. Operation and antiheart antibody in 257 patients and operation and viral rise in 137 patients
Table I. Age distribution antiheart antibody
Age (yr) 0-1 2-5 6-10 11-15 16-> Totals
I I I No. of patients 63 86 57 27 2._.4_4 257
No. with PPS 1 27 20 11 2 66
No. with A HA
% 1.6 31.4 35.1 40.7 29.2 25.7
%
1 26 17 11 ..]__7 62
1.6 30.2 29.8 40.7 29.2 24.1
Table II. Rise in titer viral agents in 137 patients
[Total
[
1 10 7
PPS patients
Adenovirus Coxsackie B
7
5
1
5
3
2 3
4 5
4 4
4
0
0
5 6 Cytomegalovirus
4 8 9
2 5 6
of 31 patients who had a rise in titerl seven had a rise to more than one agent.
with only transposition of the great arteries repaired by use of an interatrial perica'rdial baffle had the PPS syndrome. Early ambulation as tolerated, in contrast to that which was delayed until the child was afebrile for 48 hours, did not increase the incidence of the syndrome in the last 147 patients as compared with the first 110 individuals in the study. However, when they were febrile or did not feel well with the syndrome, some of the group permitted early ambulation voluntarily limited their activity. We do not think it advisable for patients with moderate or large effusion to be active. Two patients discharged with decreasing pericardial effusion returned critically ill with pericardial tamponade. Effect of therapy. In a self-limited condition of uncertain etiology, it is difficult to judge the effect of treatment, such as rest, administration of diuretic agents, and the two modalities often recommended: salicylates or steroid therapy. Six patients received salicylates for several weeks and became afebrile and began to improve gradually. The heart-reactive antibody did not drop immediately b u t followed the usual curve of decline. Six other patients received prednisolone in a dose of 2 m g / k g / d a y the first week, half that for the second week, and a quarter of that for the third week before the medication was discontinued. The clinical manifestations subsided promptly, and
e, a,o
gy
alvar
ASD
Antiheart antibody PPS 26 8 Patients 59 48 % 44.1 16.7 Viral rise PPS 11 1 Patients 36 17 % 30.6 5.9
only
plus
only
PS
4 33 12.1
11 28 39.3
0 21 0
3 17 17.6
2 22 9.09
7 18 38.9
0 11 0
0 7 0
Key to abbreviations: ASD = atrial septal defect; PS = pulmonie stenosis;TGA = transpositionof great arteries; VSD = Ventricularseptal defect. the antiheart antibody dropped to intermediate levels and disappeared earlier than in other patients with PPS. DISCUSSION It has been demonstrated that a heart-reactive antibody appears in the serum of some patients undergoing intrapericardial surgery and that its presence in high titer correlates with clinical evidence of the postpericardiotomy syndrome. This correlation is sufficiently high that it constitutes a diagnostic test. Furthermore, a rise in viral titer to one or more of the eight viruses tested occurred in two-thirds of the patients with the syndrome but in only 5% and 15%, respectively, of those with no syndrome and negative or intermediate levels of heart-reactive antibody. The freedom from the syndrome in infants may be related to their short period of experience with exposure to viruses and to viral illness; they may not react i m m u nologically to this new stress by having the postpericardiotomy syndrome. The greater chance of having the syndrome, with elevation of antiheart antibody and rise in anti-viral titer, in patients with tetralogy of Fallot or with VSD plus some other anomaly may be due to a greater a m o u n t of myocardial injury than in other operations. Though it is possible that neither the appearance of antiheart antibody nor the rise in viral titer has any connection with the syndrome or with each other, it seems to us that a reasonable working hypothesis at this time is as follows: The postpericardiotomy syndrome is the result of an immunologically determined response of the epicardial layer of myocardium, with inflammation and effusion and with "neighborhood" involvement of pleura. Heartreactive antibody in high titer appears in the sera, of a certain n u m b e r of individuals (25-30%) who, because of their age and previous immunologic experience, react to
1108
EngIe et al.
epicardial and myocardial injury incurred at pericardiotomy. This reaction may be triggered by a latent or fresh viral illness. The studies herein reported have shown some associations of factors that may be involved in path~ogenesis of this syndrome, but much remains to be done in this ongoing, prospective study. Prevention may follow an understanding of the mechanisms involved. If viruses are important, then it is interesting to speculate, as did Lerner, Wilson and Reyes ~~in their recent review of enteroviruses and the heart (with special emphasis on the probable role of Coxsackie viruses, Group B, types 1-5), that prophylaxis by vaccination is feasible. Meanwhile, the current trend to earlier age of open repair for symptomatic congenital heart disease means that more operations are being done in young infants than was true only a few years ago, and in these babies the risk of the syndrome is minimal. REFERENCES
1. Ito T, Engle MA, and Goldberg HP: Postpericardiotomy syndrome following surgery for nonrheumatic heart disease, Circulation 17:549, 1958. 2. Engle MA, and Ito T: The postpericardiotomy syndrome, Am J Cardiol 7:73, 1961. 3. Engle MA, and Marx, NR: The postpericardiotomy and postperfusion syndromes, Heart Bull 14:33, 1965. 4. Drusin LM, Engle MA, Hagstrom JWC, and Schwartz, MS: The pericardiotomy syndrome. A six-year epidemiologic study, N Engl J Med 272:597, 1965. 5. Engle MA: Postoperative syndromes, in Moss A J, and Adams FH, editors: Heart disease in infants and children, Baltimore, 1968, The Williams.& Wilkins Company, pp 1087-1101. 6. Somerville J, Yacoub M, Ross DN, and Ross K: Aorta to right pulmonary artery anastomosis (Waterston's operation) for cyanotic heart disease, Circulation 39:593, 1969. 7. McGuinness JB, and Taussig HB: The postpericardiotomy syndrome-its relationship to ambulation in the presence of "benign" pericardial and pleural reaction, Circulation 26:500, 1962.
The Journal of Pediatrics December 1975
8. Peter RH, Whalen RE, Orgain ES, and McIntosh HD; Postpericardiotomy syndrome as a complication of percutaneous left ventricular puncture, Am J Cardiol 17:718, 1966. 9. Segal F, and Tabatznik B: Postpericardiotomy syndrome following penetrating stab wounds in the chest: comparison with the posteommissurotomy syndrome, Am Heart J 59:175, 1960. 10. Goodkind M J, Bloomer WE, and Goodyer VN: Recurrent pericardial effusion after nonpenetrating chest trauma. Report of two cases treated with adreno-cortical steroids, N Engl J Med 263:874, 1960. 11. Dress|erW: Post-myocardial-infarction syndrome: Preliminary report of complication resembling idiopathic, recur~ rent, benign pericarditis, JAMA 160:1379, 1956. 12. Poloheimo JA, von Essen R, Klemola E, Kaarainen L, and Siltanen P: Subclinical cytomegalo-virus infections and cytomegalovirus mononucleosis after open heart surgery, Am J Cardiol 22:624, 1968. 13. Janton OH, Glover RP, O'Neil TJE, Gregory JE, and Froio GF: Results of the surgical treatment of rnitral stenosis, Circulation 6:321, 1952. 14. Robinson JF, and Brigden W: Immunological studies in the post-cardiotomy syndrome, Br Med J 2:706, 1963. 15. Van der Geld H: Anti-heart antibodies in the postpericardiotomy and the postmyocardial-infarction syndromes, Lancet 2:617, 2974. 16. Burch GE, and Colcolough HL: Postcardiotomy and postinfarction syndromes-a theory, Am Heart J 80:290, 1970. 17. McCabe JC, Ebert PA, Engle MA, and Zabriskie JB: Circulating heart-reactive antibodies in the postpericardiotomy syndrome, J Surg Res 14:158, 1973. 18. Engle MA, McCabe JC, Ebert PA, and Zabriskie J: The postpericardiotomy syndrome and antiheart antibodies, Circulation 49:401, 1974. 19. Zabriskie JB, Hsu KC, and Seegal BC: Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance, Clin Exp Immunol 7:147, 1970. 20. Lerner AM, Wilson FM, and Reyes MF: Enteroviruses and the heart (with special emphasis on the probable role of Coxsackieviruses, group B, types 1-5). I. Epidemiological and experimental studies, Mod Concepts Cardiovasc Dis 44:7, 1975.
1103
Immunologic and virologic studies in the postpericardiotomy syndrome A prospective, triple-blind study was undertaken to determine whether antiheart antibody or a rise in titer to a virus occurred in patients after intrapericardial surgery and, i f so, whether either was related to clinical evidence of the postpericardiotomy syndrome. In 257 patients, A HA in high titer appeared in 62 (24%), all of whom had the syndrome. None o f the 102 patients with no A H A had the syndrome. In 137 subjects, a rise in titer to one or more viral agents occurred in 21 o f 31 (68%) o f those with A H A and PPS. This study suggests that an immunologic response and viral illness are related to PPS.
Mary Allen Engle, M.D., John B. Zabriskie, M.D., Laurence B. Senterfit, Sc.D., Daniel J. Tay, M.D., and Paul A. Ebert, M.D., New York, N.Y.
THE POSTPERICARDIOTOMY SYNDROME is the most common postoperative complication of cardiac surgery, affecting about 20% to 30% of individuals all ages whose surgery involves opening of the pericardium? -:' Usually, operative procedure includes use of the heart-lung machine and the opening of a cardiac chamber or great artery to repair a valve or close a defect, but the syndrome also occurs without cardiac bypass or cardiotomy, as for example when an intrapericardial anastomosis is created between ascending aorta and right pulmonary artery, or a band is placed on the pulmonary artery, or simply when the intrapericardial structures are explored. The complication increases the morbidity after operation and prolongs hospitalization beyond the usual 7 to i0 days for the uncomplicated case to several weeks or more. When unrecognized, it even accounts for postoperative mortality. 6 It has been suggested that the syndrome is related to early ambulation after operationJ Although changes have occurred through the years in operative procedures and in operating teams, the syndrome continues to appear with From the Departments o f Pediatrics, Surgery, and Microbiology, The New York Hospital-Cornell University Medical Center and Rockefeller University. Supported in part by N H L I Grant No. 1 RO1 H L 16246-01 and N H L I Training Grant No. 1 TO1 H L 05989-01 Presented at the Plenary Session o f the American Pediatric Society and the Society for Pediatric Research, Denver, Colorado, April 17, 1975.
about the same frequency as in the early days of intrapericardial surgery for congenital heart disease. '-~ The syndrome has been reported after percutaneous measurement of cardiac pressures '~ and after penetrating stab wounds of the chest ~' and nonpenetrating chest trauma. 1~The clinical symptoms and findings are similar to those occasionally seen after myocardial infarction in the so-called "Dressier syndrome. ''11 Common features that may be significant in the etiology of the syndrome following cardiac Surgery, percutaneous measurement of pressure, myocardial infarction, and crushing or penetrating chest trauma are damage to heart muscle and opportunity for intrapericardial bleeding. Abbreviations used' AHA: antiheart antibody PPS: postpericardiotomy syndrome VSD: ventricular septal defect
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The condition is diagnosed after the first postoperative week by persistence, or appearance, of fever and by signs of pericardial and sometimes pleural involvement. Pericardial reaction is indicated by precordial chest pain, sometimes referred to the shoulder and made worse by lying down or by inspiring deeply; by pericardial friction rub or effusion; and by serial electrocardiographic changes of pericarditis, which usually last longer than the
Vol. 87, No. 6, part 2, pp. 1103-1108
1 10 4
Engle et al.
The Journal of Pediatrics December 1975
Normal heart tissue
Normal It-globulin
No reaction
Normal heart tissue
Heart-reactive 7-globulin
Bound y-globulin
Bound ~'-globulin
(~) anti~'-globulin
Fluorescence
Fig. 1. Schema of technique of determination of antiheart antibody. With normal gamma globulin, there is no reaction to normal heart tissue, but with heart-reactive gamma globulin there is binding, which can be demonstrated by fluoresceinlabeling and read as intensity of fluorescence. other signs of pericardial abnormality. Unilateral or bilateral pleural effusions occur. During the febrile period the white blood cell count and the polymorphonuclear ceils are elevated. The condition is self-limited; it may recur months or years later. Hepatospienomegaly, arthritis, and skin rash are not part of the syndrome. These are distinguishing features from other postoperative febrile states, such as the postperfusion syndrome TM (with hepatosplenomegaly, atypical lymphocytosis, and cytomegolovirus infection) or serum sickness. It must be differentiated from other causes of postoperative fever, such as infective endocarditis, atelectasis, or pneumonia. Radiographically, the enlargement of the cardiac silhouette and the appearance of pleural effusions suggest cardiac failure, and that diagnosis may also erroneously be made at the bedside of the dyspneic patient with distended neck veins and hepatomegaly who has cardiac tamponade. ETIOLOGY The condition was first brought to medical attention when mitral commissurotomy was performed in adult patients with rheumatic mitral stenosis':'; thus it was logical to consider that it represented a reactivation of rheumatic fever. That explanation was disproved by observing the syndrome in children and adults undergoing surgery for congenital heart disease." ~ Alternative possibilities as to etiology were suggested: the syndrome might represent a hypersensitivity reaction to blood in the pericardial sac or it might be a viral infection." ~ Similarity of the syndrome to viral pericarditis, which also has
a tendency to recur, was noted. Some support for the autoimmune theory was forthcoming when Robinson and Brigden ~4 in 1963 and Van der Geld 1~ in 1964 demonstrated antiheart antibodies in some patients with the syndrome. In 1970 Burch and Colcolough '~ proposed that this syndrome might be caused by reactivation of a latent virus infection when there is trauma to the myocardial tissue. PROSPECTIVE
STUDY
In October, 1971, we undertook a prospective study of consecutive, long-term survivors of intrapericardial surgery to determine whether an autoimmune response, or a viral infection, or both were involved in pathogenesis of the p0stpericardiotomy syndrome. In the first part of the study, concurrent analyses were made on a double-blind basis preoperatively and postoperatively, at prescribed intervals in the hospital and after discharge, of circulating antiheart antibody and of clinical signs of the syndrome. The samples of blood were obtained t h e day before surgery and postoperatively on the seventh and tenth days, in the third and fifth weeks, and additionally as indicated. The antibody was determined from serum by an immunofluorescent technique and was ranked 0 to 4 +, based on intensity of staining?~ The principle of the method is shown in Fig. 1. Clinical course of the patients was evaluated by at least two pediatric cardiologists and presence or absence of the syndrome was noted. When present, it was judged to be mild, moderate, or severe, depending on the duration and intensity of manifestations. Physical examination was performed daily in the hospital and at the time of visits for postoperative follow-up. Electrocardiogram and teleoroentgenogram of the chest were obtained according to the schedule for blood sampling. Echocardiogram was recorded when pericardial effusion was suspected. Postoperative care was maintained as standard as possible. Antibiotics were administered for the first five days and not thereafter, unless in a rare circumstance there was clear evidence of a bacterial infection. In the first 110 patients, ambulation was delayed until the patient was afebrile for 48 hours; earlier ambulation as tolerated was permitted in subsequent patients. Diuretic agents (furosemide) were used in most patients with effusions. Neither salicylates nor steroids were employed except in 12 subjects with severe syndrome, to be mentioned later. Patients were discharged when they were afebrile for two days on ambulation and effusions were subsiding. Duration of hospitalization was therefore one determinant of severity (Fig. 2). Results of the immunologic and clinical evaluations were compared at intervals 17 1~and then a third investiga-
Volume 87 Number 6, part 2
Immunologic and virologic studies in P P S
1 10 5
HEART REACTIVE ANTIBODY TITER- 257 PATIENTS
HOSPITAL STAY, AVERAGE AND RANGE None
3 ~ild
Iii i i;;;;;ii!;i;!i:i !;ii!;ii i ;i !:il;i ::ii i ;i ;ili;;ii;f;i;:i;;tI I~ t?S. syndrome
& Moderate
Iii ;i i ;i i i !i i i ;i ~::ii!i!::!!~::~!~i~i~i~i~i!;ii;i i ~::~::~J::~;~:::;~::~::~::::~
e~
Severe
~iiiiiii~i~iiiiii~;i~!~!!~;!~;~9~;i;~ii~;~;;;~:~i~;~;~:~ ', IIIIIllll~ltll~l~l,rl 0 10 Hospital days
20
30
0
Negative (102 cases) ~ "
.=,,-_
1
1
I 40
Fig. 2. The mean and the range of days of hospitalization for patients with no postpericardiotomy syndrome and with syndrome that was mild, moderate, or severe. tion was added to make this a triple-blind study. On the same sample of serum in which heart-reactive antibody was determined, complement-fixation studies were performed to a battery of eight viruses (adenovirus, Coxsackie B 1-6, cytomegalovirus) and to Mycoplasma pneumoniae. The results of all three analyses were then compared. RESULTS Clinical evaluation. Of 257 consecutive survivors of intrapericardial surgery, 66 patients had the postopericardiotomy syndrome. It was judged to be mild in 22, moderate in 25, and severe in 16 patients. The last abnormality to disappear was electrocardiographic evidence of pericarditis. Three patients were readmitted within a month of discharge because of exacerbation of the syndrome. Two of these presented as severely ill children with cardiac tamponade. Immunologic studies. Preoperative sera were negative for heart-reactive antibody. Howeyer, in 155 subjects an antibody appeared toward the end of the first week. In 62, the staining was greater than 2 + and the antibody could be detected into the second month or beyond. This response was called positive (Fig. 3). In 93 patients the antibody rise began at the same time but the staining was less intense, and the antibody disappeared after one month (intermediate group,. Fig. 3). The antiheart antibody was specific for cardiac and for skeletal muscle, but it was not species specific for h u m a n cardiac muscle. There was litttle binding to smooth muscle and none to other organs such as lung, liver, thymus, spleen, or kidney. 17' TM Unlike the heart-reactive antibody demonstrated in patients with rheumatic fever, which binds to group A streptococcal membrane, 1~ this antiheart antibody did not.
0
10
I
I
,
20 30 Postoperative days
I
t
40
Fig. 3. Idealized curve of antiheart antibody as judged by immunofluorescentstaining to be negative (102 cases) or intermediate (less than 2 + in 93 cases) or positive (greater than 2 + in 62 cases). Antibody rise began toward end of first week, but in the positive group, it rose higher and persisted longer than in the intermediate group.
Virologic studies. In 137 patients studied, an elevation of titer for one or more' viruses was measured in 56 subjects. Twenty-five had a high titer on admission that did not change during the course, whereas 31 had a fourfold or greater rise in titer and then a decline during the period of observation. Of the latter group of 31, 21 had no detectable antiviral antibody prior to surgery. In six subjects there was a demonstrable titer to Mycopla, s'ma pneumoniae. Among the 31 patients with a significant rise in viral titer, this elevation was to one agent only in 24, but to two agents in three children, to three viruses in another three patients, and to four agents (cytomegalovirus and Coxsackie B1, 2 and 3) in one subject. No patient had a rise in titer against Coxsackie B4. Correlation of triple-blind data. Results of clinical evaluation of PPS and determination of antiheart antibody were compared in each patient (Fig. 4). When the comparisons for all subjects were analyzed, it was found that none of the 102 patients with negative antiheart antibody had the syndrome whereas all of the 62 with positive antibody had PPS. It was severe in 16, moderate in 28, and mild in 18. Of the 93 in the intermediate group, four had mild syndrome. A striking difference was noticed in incidence of syndrome and in antiheart antibody between the infants one year of age or less and those two years of age and older (Table I). Only one infant of 63 had the syndrome and positive antibody, an incidence of 1.6%. Beyond two years, the incidence was comparable at all ages, ranging from 29% to 40%.
1 10 6
Engle et al.
The Journal of Pediatrics December 1975
MODERATEP.RS. 4
0
~
R.P.
TEMPERATURE 3938 (~
......
VSD-AI
37 L
++++++++
FRICTIONRUB PLEURALEFFUSION PERICARDIALEFFUSION
+ oo
ECGABNORMALITIES +
+
+
+-F
+
+ + + q-
+
o +
o
o
o
o
o
o
o
o
o
o
-F
o
o
++
4
ANTIHEART ANTIBODY
I~ll,lL~llllllllllllll~,l
O 5 i0 DAYSPOSTOPERATIVE
15 20 28 DISCHARGEAI~2.1"
1 7O
Fig. 4. Chart of boy operated on for ventricular septal defect and aortic insufficiency. Fever persisted for two weeks. Pericardial friction rub was heard from the third through eleventh days; pleural and pericardial effusions developed then and lasted into the second week. Electrocardiographic abnormalities were the last signs to disappear. Antiheart antibody, initially negative, was intermediate at seven days but positive through discharge at three weeks; it remained elevated for more than two months.
Among the 137 patients tested for titer to viruses were 31 in whom a significant rise and then a drop in titer occurred (Table II). This rise was observed in three of 60 patients with negative antiheart antibody and no syndrome, an incidence of 5%; in seven of 46 with intermediate antiheart antibody (15%) and no syndrome; but in 21 of 31 with positive A H A and with the syndrome (67.7%). Of the 25 patients who had detectable antibody to one or more viruses prior to surgery and no change throughout the period of study, 18% (11 of 60 patients) had negative antiheart antibody, 17% (eight of 46) had intermediate response, and 19% (six of 31) had positive AHA and postpericardiotomy syndrome. The presence of detectable titer tO Mycoplasma pneumoniae in six of the 137 patients is regarded as a nonspecific indicator of respiratory illness. One patient with rise in titer to cytomegalovirus had early evidence of mild postperfusion syndrome, with hepatosplenomegaly and atypical lymphocytosis. Analysis was made of the most frequent types of cardiac surgery performed to see if there were a relation to
the syndrome, antiheart antibody, or viral titer (Table III). The same types of operation were performed in all age groups. The most frequent anomaly was tetralogy of Fallot, in which a right ventriculotomy was performed for excision of infundibular pulmonic stenosis and for closure of the ventricular septal defect with a patch of Teflon felt. Next most common was atrial septal defect. There appeared to be no difference in the response of patients with a simple secundum-type defect and those with an ostium primum who had a cleft in the mitral valve sutured at the same time, so these two types of septal defect were combined for the analysis; surgical repair was through a right atriotomy. A Teflon felt patch was used to close all the primum defects and for the large secundum defects. Simple ventricular septal defect, closed with a Teflon felt patch and usually through a right ventriculotomy,was the next most common anomaly; repair of a VSD plus some other lesion such as transposition a n d / o r pulmonic stenosis was the fourth most common. In the patients with immunologic and virologic studies, those with repair of tetralogy of Fallot and of VSD plus another lesion had the highest incidence of the syndrome, whereas none of those
Volume 87 Number 6, part 2
Immunologic and virologic studies in PPS
Table III. Operation and antiheart antibody in 257 patients and operation and viral rise in 137 patients
Table I. Age distribution antiheart antibody
Age (yr) 0-1 2-5 6-10 11-15 16-> Totals
I I I No. of patients 63 86 57 27 2._.4_4 257
No. with PPS 1 27 20 11 2 66
No. with A HA
% 1.6 31.4 35.1 40.7 29.2 25.7
%
1 26 17 11 ..]__7 62
1.6 30.2 29.8 40.7 29.2 24.1
Table II. Rise in titer viral agents in 137 patients
[Total
[
1 10 7
PPS patients
Adenovirus Coxsackie B
7
5
1
5
3
2 3
4 5
4 4
4
0
0
5 6 Cytomegalovirus
4 8 9
2 5 6
of 31 patients who had a rise in titerl seven had a rise to more than one agent.
with only transposition of the great arteries repaired by use of an interatrial perica'rdial baffle had the PPS syndrome. Early ambulation as tolerated, in contrast to that which was delayed until the child was afebrile for 48 hours, did not increase the incidence of the syndrome in the last 147 patients as compared with the first 110 individuals in the study. However, when they were febrile or did not feel well with the syndrome, some of the group permitted early ambulation voluntarily limited their activity. We do not think it advisable for patients with moderate or large effusion to be active. Two patients discharged with decreasing pericardial effusion returned critically ill with pericardial tamponade. Effect of therapy. In a self-limited condition of uncertain etiology, it is difficult to judge the effect of treatment, such as rest, administration of diuretic agents, and the two modalities often recommended: salicylates or steroid therapy. Six patients received salicylates for several weeks and became afebrile and began to improve gradually. The heart-reactive antibody did not drop immediately b u t followed the usual curve of decline. Six other patients received prednisolone in a dose of 2 m g / k g / d a y the first week, half that for the second week, and a quarter of that for the third week before the medication was discontinued. The clinical manifestations subsided promptly, and
e, a,o
gy
alvar
ASD
Antiheart antibody PPS 26 8 Patients 59 48 % 44.1 16.7 Viral rise PPS 11 1 Patients 36 17 % 30.6 5.9
only
plus
only
PS
4 33 12.1
11 28 39.3
0 21 0
3 17 17.6
2 22 9.09
7 18 38.9
0 11 0
0 7 0
Key to abbreviations: ASD = atrial septal defect; PS = pulmonie stenosis;TGA = transpositionof great arteries; VSD = Ventricularseptal defect. the antiheart antibody dropped to intermediate levels and disappeared earlier than in other patients with PPS. DISCUSSION It has been demonstrated that a heart-reactive antibody appears in the serum of some patients undergoing intrapericardial surgery and that its presence in high titer correlates with clinical evidence of the postpericardiotomy syndrome. This correlation is sufficiently high that it constitutes a diagnostic test. Furthermore, a rise in viral titer to one or more of the eight viruses tested occurred in two-thirds of the patients with the syndrome but in only 5% and 15%, respectively, of those with no syndrome and negative or intermediate levels of heart-reactive antibody. The freedom from the syndrome in infants may be related to their short period of experience with exposure to viruses and to viral illness; they may not react i m m u nologically to this new stress by having the postpericardiotomy syndrome. The greater chance of having the syndrome, with elevation of antiheart antibody and rise in anti-viral titer, in patients with tetralogy of Fallot or with VSD plus some other anomaly may be due to a greater a m o u n t of myocardial injury than in other operations. Though it is possible that neither the appearance of antiheart antibody nor the rise in viral titer has any connection with the syndrome or with each other, it seems to us that a reasonable working hypothesis at this time is as follows: The postpericardiotomy syndrome is the result of an immunologically determined response of the epicardial layer of myocardium, with inflammation and effusion and with "neighborhood" involvement of pleura. Heartreactive antibody in high titer appears in the sera, of a certain n u m b e r of individuals (25-30%) who, because of their age and previous immunologic experience, react to
1108
EngIe et al.
epicardial and myocardial injury incurred at pericardiotomy. This reaction may be triggered by a latent or fresh viral illness. The studies herein reported have shown some associations of factors that may be involved in path~ogenesis of this syndrome, but much remains to be done in this ongoing, prospective study. Prevention may follow an understanding of the mechanisms involved. If viruses are important, then it is interesting to speculate, as did Lerner, Wilson and Reyes ~~in their recent review of enteroviruses and the heart (with special emphasis on the probable role of Coxsackie viruses, Group B, types 1-5), that prophylaxis by vaccination is feasible. Meanwhile, the current trend to earlier age of open repair for symptomatic congenital heart disease means that more operations are being done in young infants than was true only a few years ago, and in these babies the risk of the syndrome is minimal. REFERENCES
1. Ito T, Engle MA, and Goldberg HP: Postpericardiotomy syndrome following surgery for nonrheumatic heart disease, Circulation 17:549, 1958. 2. Engle MA, and Ito T: The postpericardiotomy syndrome, Am J Cardiol 7:73, 1961. 3. Engle MA, and Marx, NR: The postpericardiotomy and postperfusion syndromes, Heart Bull 14:33, 1965. 4. Drusin LM, Engle MA, Hagstrom JWC, and Schwartz, MS: The pericardiotomy syndrome. A six-year epidemiologic study, N Engl J Med 272:597, 1965. 5. Engle MA: Postoperative syndromes, in Moss A J, and Adams FH, editors: Heart disease in infants and children, Baltimore, 1968, The Williams.& Wilkins Company, pp 1087-1101. 6. Somerville J, Yacoub M, Ross DN, and Ross K: Aorta to right pulmonary artery anastomosis (Waterston's operation) for cyanotic heart disease, Circulation 39:593, 1969. 7. McGuinness JB, and Taussig HB: The postpericardiotomy syndrome-its relationship to ambulation in the presence of "benign" pericardial and pleural reaction, Circulation 26:500, 1962.
The Journal of Pediatrics December 1975
8. Peter RH, Whalen RE, Orgain ES, and McIntosh HD; Postpericardiotomy syndrome as a complication of percutaneous left ventricular puncture, Am J Cardiol 17:718, 1966. 9. Segal F, and Tabatznik B: Postpericardiotomy syndrome following penetrating stab wounds in the chest: comparison with the posteommissurotomy syndrome, Am Heart J 59:175, 1960. 10. Goodkind M J, Bloomer WE, and Goodyer VN: Recurrent pericardial effusion after nonpenetrating chest trauma. Report of two cases treated with adreno-cortical steroids, N Engl J Med 263:874, 1960. 11. Dress|erW: Post-myocardial-infarction syndrome: Preliminary report of complication resembling idiopathic, recur~ rent, benign pericarditis, JAMA 160:1379, 1956. 12. Poloheimo JA, von Essen R, Klemola E, Kaarainen L, and Siltanen P: Subclinical cytomegalo-virus infections and cytomegalovirus mononucleosis after open heart surgery, Am J Cardiol 22:624, 1968. 13. Janton OH, Glover RP, O'Neil TJE, Gregory JE, and Froio GF: Results of the surgical treatment of rnitral stenosis, Circulation 6:321, 1952. 14. Robinson JF, and Brigden W: Immunological studies in the post-cardiotomy syndrome, Br Med J 2:706, 1963. 15. Van der Geld H: Anti-heart antibodies in the postpericardiotomy and the postmyocardial-infarction syndromes, Lancet 2:617, 2974. 16. Burch GE, and Colcolough HL: Postcardiotomy and postinfarction syndromes-a theory, Am Heart J 80:290, 1970. 17. McCabe JC, Ebert PA, Engle MA, and Zabriskie JB: Circulating heart-reactive antibodies in the postpericardiotomy syndrome, J Surg Res 14:158, 1973. 18. Engle MA, McCabe JC, Ebert PA, and Zabriskie J: The postpericardiotomy syndrome and antiheart antibodies, Circulation 49:401, 1974. 19. Zabriskie JB, Hsu KC, and Seegal BC: Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance, Clin Exp Immunol 7:147, 1970. 20. Lerner AM, Wilson FM, and Reyes MF: Enteroviruses and the heart (with special emphasis on the probable role of Coxsackieviruses, group B, types 1-5). I. Epidemiological and experimental studies, Mod Concepts Cardiovasc Dis 44:7, 1975.
