Gilbert Dalldorf

THE COXSACKIE VIRUS GROUP

It seems to me that, doubtless, we must have more facts before we can hope to devise an enduring taxonomy for the Coxsackie viruses but that, without a provisional classification, we are likely to waste a good deal of effort and be delayed in assaying their role in nature. We need a uniform nomenclature to understand one another. The name “Coxsackie~’ has served well. It is a distinctive word that Westerners, a t any rate, pronounce without trouble. There is nothing in the literature with which to confuse it. It is already well established. It does not pretend to describe the diseases that the Coxsackie viruses may induce or hypothetical lesions no one has yet seen. I suggest we keep the name for a genus of viruses. The definition we originally proposed so far has withstood the challenge of subsequent observations. The Coxsackie viruses are selectively pathogenic for immature mice and hamsters, inducing in them necrosis of the skeletal muscles, with or without lesions of the brain and fat tissues. Strains are being encountered that are less selective for suckling mice than were the original types but, as yet, there is no record of freshly isolated strains that are pathogenic for adult animals. The facts that certain strains may be adapted to older animals, that older animals are more susceptible following cortisone treatment, and that limited organic lesions may be induced in older mice by certain strains do not, it seems to me, seriously challenge the propriety of the definition. They only show how much of an alchemist the modern virologist has become. So far as the record goes, age susceptibility plus the morbid response in test animals still stand as a serviceable definition. It is well known, of course, that immature mice are much more susceptible than adult ones to many viruses, but I know of no virus, other than those producing Coxsackie lesions, that is pathogenic only for young animals and, so far, of none that has as striking an age selectivity. It may well be that there will be others, but they are still to be described. In this connection, it may be noted that the lesion of fat has never been observed in other circumstances. It may be quite specific. Subdivision of the Coxsackie group seems to me to be both desirable and sensible. We have long suspected that the distinction between those strains that produce generalized muscle necrosis, and those that produce scattered muscle necrosis plus encephalomalacia and lesions of the fat pads might prove to be of practical importance. Anyone who has worked with both varieties knows that the behavior of the sick mice is quite different. Visitors to our animal quarters who have known only one kind have no difficulty in deciding whether their strains are A’s or B’s once they see the two side by side. The two groups differ in other respects. The Group-A strains are easily isolated, while the Group-B strains are troublesome at times. Sometimes the latter are

Serologic differences among strains of the Coxsackie group of viruses.

Summary Among 13 virus strains which have been isolated from fecal specimens of patients with a tentative diagnosis of poliomyelitis, and which induce muscle injury in suckling mice, 3 serologic types have been encountered.

Creatinine, Potassium, and Virus Content of the Muscles following Infection with the "Coxsackie Virus".

Summary Infection of unweaned mice with certain strains of “Coxsackie virus” is followed by loss of muscle potassium and creatinine and by creatinuria. The muscles of paralyzed mice are highly infectious.

The Effect of Unrelated Vaccines on the Localization of Paralysis in Mouse Encephalomyelitis

Conclusions Mice injected in a foreleg with pertussis vaccine alone or combined with precipitated diphtheria-tetanus toxoids were frequently paralyzed in the injected foreleg following infection with mouse encephalomyelitis virus. The frequency of paralysis in the inoculated extremity was 7 or more times greater than among the untreated controls. Precipitated diphtheria-tetanus toxoid had less effect and typhoid-paratyphoid vaccine had none. The injection of vaccines did not increase the frequency of paralysis, irrespective of location, but pertussis vaccine consistently shortened the period between the introduction of virus and the onset of paralysis.

Accident prevention and the general practitioner

For general practitioners, in whose practice is included a major proportion of the medical management of infants and children, and for the specializing pediatrician as well, Postgraduate Medicine presents this special regular department devoted to brief discussions by recognized authorities on their preferred methods of the treatment and management of diseases and problems of infancy and childhood.

Simultaneous Distemper and Lymphocytic Choriomeningitis in Dog Spleen and the Sparing Effect on Poliomyelitis

While continuing the study of canine distemper in monkeys, evidence accumulated which indicated that our virus-source material was a mixture. This has been verified by the recovery of the virus of lymphocytic choriomeningitis from 4 different samples of dog spleen containing the virus of canine distemper and by its presumptive demonstration in 7 other instances. The present report submits evidence that the virus of lymphocytic choriomeningitis occurs in the dog and to correct our earlier description of canine distemper in the monkey and the sparing effect of distemper on experimental poliomyelitis. 1 2 Three bacteriologically sterile 20% suspensions of pooled dog spleens taken from separate harvests of canine-distemper virus of the same strain were inoculated intracerebrally in 0.03 cc amounts into groups of mice. A uniform clinical response resembling Traubs description of lymphocytic choriomeningitis followed. 3 Part of one suspension was inoculated subcutaneously into 2 puppies. Fifteen days later these were moribund with canine distemper and were sacrificed. Six mice inoculated with splenic emulsion of one of these puppies also sickened and died. Fourteen of 18 examined mice had lymphocytic chorioiditis. At the same time a considerable number of mice from the same colony were inoculated intracerebrally with dog-spleen suspensions secured from other sources and containing canine-distemper virus, with various other suspected materials and with sterile broth. All remained well. The data of representative groups have been incorporated in Table I as evidence both of the freedom of our stock animals from spontaneous lymphocytic choriomeningitis as well as the presence of a virus, capable of producing the clinical response of lymphocytic choriomeningitis, in the original materials. Three guinea pigs were inoculated subcutaneously (0.5 cc) with one of the pooled dog-spleen suspensions and developed the symptoms of lymphocytic choriomeningitis, emaciation, dyspnea, and conjunctivitis. All 3 died. Two of these were demonstrated to have the lesions of lymphocytic chorioiditis (heavy round-cell infiltrate of the chorioid plexus and liver).

Neue Virusarten und neue Krankheiten

E. J . , and L. C. CRAm: J. Amer. chem. See. 74, 3083 (1952): BORNSTE;N, J . A . : Aust. J . exp. Biol. Med. Sci. 28, 87 ( 1 9 5 0 ) . ~ LAZ~OW, A.: Diabetes 6, 222 ( 1 9 5 7 ) . ts LOWELl, F. C.: Prec. See. exp. Biol. (N. Y.) ~0, 167 (1942). ~ W A S S E ~ N , P., and I. A. M~RSKY: Endocrinology ~1, 115 (1942). tSINDERBrrZIN, R., and H. M]~YE~: Int. Arch. AUergy ~, 62 (1954). ~ STAWUTS:~¥, A . B . : Unpublished observations. ~ so M~m~ACK, J . R.: The chemistry of antigens and antibodies, 2. edit. London, His Majestys Statione~w Office 1939. s~ A~VILLA, E . R . , and A. B. STXV4TS~V: Unpublished observations. ~ BOYDEN, S. V. : J . exp. Med. 9~, 107 (1951). ~SHI~L, B.M., and A . G . O s ~ : J . Immunol. 7~, 146 (1955). ~ K v ~ s , W.: Personal communication. ~ EISEN, H .N . , H. S. PENEFSKr and M. T~BAC]~~ICK: Fed. Prec. 14, 461 (1955). ~ ss KABAT, E. A., and M. NI. NI~yEg: Experimental Immunochemistry. Springfield, Illinois: Ch. C. Thomas 1948. s~ LOWELL, F .C . : J . elin. Invest. 26, 57 (19~7). ~ ss DITU]~I, B. : New Engt. J. Med. 2~1, 13 (1954). ss LOVELESS, M. : Quart. Rev. Allergy 10, 374 (1956). so SANGER, F. : Nature (Lend.) 164, 529 (1949). 81 FIELD, J . B . , and D. STE~TEN: Amer. J . Med. 21, 339 (1956). s~ VALLA~C]~-OwEN, J. , and F. D. W. LUKENS: Endocrinology 60, 625 (1957). ~ ¥ o u ~ s , F. G. : Recent Progr. Hormone

Recognition of Mouse Ectromelia

Summary Two viruses believed to be neurotropic human infections have been identified as mouse ectromelia. The behavior of ectro-melia in young mice inoculated intracerebrally is described.

DISCUSSION: PART I

JOHN F. EKDERS (Research Division of Infectious Diseases, Children’s Medical Center, Boston, Mass.) : Through reviews of the literature and the presentation of new findings, other contributors to this monograph make it clear that there is now good reason for accepting certain of the Coxsackie viruses as etiologic factors in herpangina and in a significant proportion of cases of aseptic meningitis. To these diseases we must add epidemic pleurodynia on the basis of convincing evidence already accumulated, but that has not been recounted in detail in these pages. Suggestive evidence that still other diseases, as Parrott has indicated, may be caused by these agents has also been forthcoming. The most recent of such illnesses and, to my mind, perhaps the most important, is acute aseptic myocarditis of infants. In this paper I propose to summarize very briefly observations that strongly support the hypothesis that Coxsackie B viruses may give rise to this serious condition. In so doing, I shall give particular emphasis to the essential findings in a case of this disease that was studied by my associate, Sidney Kibrick and by Kurt Benirschke of the Pathology Department of the Children’s Hospital. These investigators have allowed me to present an abstract of their material in this publication. During the period from 1937 to 1944 in certain districts of Munich, Germany, so many cases of acute myocarditis occurred in young children that Stoeber,’ who reviewed the findings in 140 autopsies in 1952, was led to refer to the disease as “epidemic myocarditis of infancy.” Sudden loss of appetite, vomiting, cyanosis, and dyspnea, together with tachycardia, were characteristic features. Hepatomegaly and, occasionally, splenomegaly were noted. The highest incidence was in children about one year of age. In fatal cases, the heart was dilated and sometimes hypertrophic. Histological examination in 68 patients revealed myocarditis of varying extent, with little or no evidence of inflammatory changes in the pericardium or endocardium. Since no association with pathogenic bacteria could be demonstrated, Stoeber believed that a virus might be responsible and suggested the possibility that either agents of the encephalomyocarditis or Coxsackie groups might be involved. No definite evidence, however, was obtained to support the presence of members of either group. Not long ago, E. L. French of the Walter and Eliza Hall Institute, Royal nIelbourne Hospital, Melbourne, Victoria, Australia visited our laboratory and told Kibrick of an outbreak of myocarditis that occurred in 1953 among newborn children in a nursery in Victoria, Australia. French has kindly permitted citation of his remarks. The illness, which closely resembled that described by Stoeber, terminated fatally in 5 instances. Examination of the heart showed macroscopic and microscopic changes comparable to those seen by Stoeber. Attempts to demonstrate Coxsackie virus by inoculation of suckling mice with suspensions of brain, heart muscle, and feces were unsuccessful, however.

Immunologic Relationships pf MM, Lansing Poliomyelitis and Mouse Encephalomyelitis Viruses

Conclusion Neutralization and cross immunity tests indicate a relationship between MM and Lansing poliomyelitis but no relationship between MM and TO (Theiler original or low virulence strains) mouse encephalomyelitis. Complement-fixation tests relate MM virus and the GDVII strain of Theilers virus. The results support he view that a group of poliomyelitis viruses exists which may be related by serologic tests.