Certain strains of coxsackievirus A-9 induce minimal necrosis and interstitial inflammation of the murine heart (1, 2). Although affected mice appear well, cardiac size is increased. During the first 2 wk of infection, virus is present in the heart. When examined later, these myocardia are normal in size and are free of histologic change (3-5). Swimming increases myocardial replication of virus but does not alter the benignity of the process (6).On the other hand, when weanling mice are inoctflated with coxsackievirus B-3 (Nancy), a necrotic carditis involving 25-50% of the entire myocardiUm results. As with coxsackievirus A-9, coxsackievirus B-3 may be isolated only very early. Here, too, the infected baby mice continue to appear well. However, in the case of coxsackievirus B-3, healing is accompanied by myocardial fibrosis, deposition of calcium, and continuing inflammation. Since the continuing carditis is not associated with virus multiplication, we have called the entire process a myocardiopathy (7-9).Human cardiac disease occurs, similar to that caused by the benign coxsackievirus A-9 and having lesions similar to the murine lesions caused by the virulent coxsackievirus B-3. The present experiments bring striking data to bear upon the role of the exercise induced by swimming upon routine coxsackievirus B-3 myocardiopathy. Materials and MethodsMice.--Pregnant albino Swiss ICR mice were obtained at term. After delivery, each mother with its brood was housed in a separate cage. Nurslings were weaned at about 3 wk and, thereafter, were fed standard Rockland rat chow.

In April 1976 the attack rate of chills and fever with or without falls in blood pressure increased in association with cardiac catheterizations. Fevers were associated with coronary angiography and right and left heart catheterizations. Blood cultures were negative, and reactions did not correlate with amounts of contrast materials infused or with procedures done by a single operator. Significant numbers of Acinetobacter calcoaceticus (var. anitratus) and a Pseudomonas species were cultured from hospital-reservoir distilled water when it was flushed through a catheter before gas sterilization. This same water after ethylene oxide sterilization contained 2 x 10(5) ng/mL of endotoxin by limulus lysate test and was positive by rabbit pyrogen test. When washed reusable cardiac catheters were sterilized daily or when disposable catheters were substituted, febrile reactions ended. Pyrogenic reactions in patients undergoing cardiac catheterizations correlated with emptying retained endotoxin with injected contrast material from reused washed-sterilized catheters.

No abstract

The purposes of this study were to determine whether the febrile and hypotensive reactions to the administration of polyriboinosinic-polyribocytidylic acid [poly (I)-poly (C)] complexed with poly-L-lysine and carboxymethylcellulose (poly ICLC) (9S) encountered in humans could be duplicated in rabbits, and when such duplication was demonstrated, to ascertain whether these untoward reactions could be avoided by (i) administration of hydrocortisone (HC), (ii) alteration of the route of delivery, or (iii) administration of poly ICLC (4S) an interferon inducer of lower molecular weight. Responses to intravenous poly ICLC (9S) in rabbits reproduced adverse reactions in humans, namely fever and hypotension, and were accompanied by high titers of serum interferon. Continuing investigations showed that (i) intravenous pretreatment of rabbits with HC ameliorated hypotensive responses but markedly diminished interferon induction. When HC was given after poly ICLC (9S), both interferon and hypotension induction were likewise depressed. (ii) Intramuscular or subcutaneous poly ICLC (9S) produced neither high titers of serum interferon nor toxic effects. (iii) Poly ICLC (4S) induced high titers of serum interferon and fever, but no hypotension. Poly ICLC (4S) warrants further study.When megaunits of human leukocyte interferon are given to patients, interferon is potentially a potent therapeutic agent (5, 11). Unfortunately, to date, quantities of exogenous human interferon available for clinical trials are limited (7). Therefore, interferon inducers are being sought. One such promising agent is polyriboinosinic-polyribocytidylic acid [poly IC] complexed with poly-L-lysine (Miles Laboratories, Inc., Elkhart, Ind.) and carboxymethylcellulose (Hercules Powder Co., Wilmington, Del.) [poly ICLC (9S)]. This modified complex [poly ICLC (9S)], unlike the parent poly IC, is quite resistant to nucleases in primate serum and induces high titers of serum interferon in mice, monkeys, and chimpanzees. In these species, only mild deleterious effects have been noted due to the administration of poly ICLC (9S) (4,10,12,14).In a phase 1 clinical trial in humans with serious viral illnesses, poly ICLC (9S) injected intravenously (i.v.) induced high titers of serum interferon which were ordinarily somewhat higher than those produced by exogenous human leukocyte interferon. Unfortunately, fever and significant falls in blood pressure also occurred in some patients (3). To attempt to reproduce and, hopefully, ameliorate the hypotensive effects in an animal model, poly ICLC (9S) was given to rabbits, a species known to be very sensitive to poly IC. Here, we report results of initial studies with poly ICLC (9S) in rabbits, along with our initial attempts to alter favorably the toxicity which we fmd. MATERIALS AND METHODSGeneral plan of studies. Young male New Zealand white rabbits (2.5 to 3.5 kg) were obtained from Oakhill Co. (Otsego, Mich.). They were housed in individual cages (25°C) and fed standard rabbit chow (Novi Supply, Novi, Mich.) with wa...