Viral Infections of Toronto Children During 1965: I. Enteroviral Disease

Enteroviruses were isolated from feces and/or cerebrospinal fluid of 29 of 43 Toronto children who contracted aseptic meningitis, pleurodynia, abdominal pain or febrile upsets between June and October, 1965. Coxsackie A9 virus was the dominant agent in aseptic meningitis and Coxsackie B1 virus in pleurodynia and other syndromes. Sero-logical evidence of recent Coxsackie B1 and Echo 6 infection was obtained in two additional patients with aseptic meningitis who did not yield virus, and elevated Coxsackie B1 antibody titres were found in one patient with pericarditis. A newborn infant died with myocarditis due to Coxsackie B1 virus following infection of the mother during the immediate antenatal period. Paired sera collected only two to four days apart from patients with enteroviral syndromes or mumps meningoencephalitis frequently showed four-fold or greater increases of antibody levels.     

A mixed epidemic of poliomyelitis and Bornholm's disease (pleurodynia)

Summary During a mixed epidemic of poliomyelitis and Bornholm's disease in the summer of 1951, evidence was obtained of the involvement of at least 6 different immunological types of Coxsackie virus, among which the Albany A₂ type dominated. Poliomyelitis virus was isolated from the stools of 6 out of 20 patients suffering from paralytic poliomyelitis; Coxsackie virus from 1, and both poliomyelitis and Coxsackie virus from 2 out of these 20 patients. During the whole year, Coxsackie virus was recovered from the stools of patients suffering from paralytic poliomyelitis, aseptic meningitis, pleurodynia and summer grippe in approximately equal percentages (11 to 14%), but during the epidemic months from July to October, 25% of the patients with poliomyelitis, and 16% of the patients with pleurodynia gave positive results for Coxsackie virus. The sparing or the enhancing effect of Coxsackie virus infection on the development of paralysis in patients with dual infections is discussed. Aided by a grant from the National Health Research Council T.N.O.     

Rash Associated with Coxsackie A9 Infection

Coxsackie A9 virus was identified by the authors during the fall of 1965 in Montreal in six children with fever and exanthem. Three of the six children were siblings. The exanthem was centrally distributed as described by Lerner et al. and consisted of discrete maculopapules 3 to 4 mm. in diameter. The viral agent was recovered and identified in tissue culture in five cases, while in the sixth Coxsackie type-A lesions were produced in suckling mice. Serological confirmation was obtained in two patients from whom sera were available. In contrast, no exanthem was observed in three older patients with a diagnosis of aseptic meningitis associated with Coxsackie A9 virus. In only one of 16 patients with Coxsackie B virus infection was an exanthem observed during the same period.The true incidence of Coxsackie A9-associated exanthems is difficult to determine because of the benign nature of the disease.     

Enteroviral Syndromes in Toronto, 1964

Virological or serological investigations of 72 children in Toronto and environs, who were hospitalized between January and October 1964 with a variety of syndromes, revealed evidence of enteroviral infection in 29 subjects. Coxsackie B2 was the dominant enterovirus, being isolated from feces and/or cerebrospinal fluid (CSF) of three children with aseptic meningitis, three with pleurodynia, one with myalgia and one with pericarditis; four additional patients showed rising antibody titres to this virus. Coxsackie B1 virus, which has not been isolated in Toronto since 1950, was recovered from feces of three patients with pleurodynia, CSF of one patient with myalgia, and peritoneal fluid of a child with primary peritonitis; one patient with pericarditis showed a rising antibody titre to Coxsackie B1 virus. Coxsackie B3, B4 and Echo 23 viruses were associated with one case each of pleurodynia. Coxsackie B5 virus infected five patients with aseptic meningitis, and one each with pericarditis and myocarditis.     

The hemagglutinating properties and adsorption on erythrocytes of Coxsackie B-3 viruses and their selected bentonite variants

The paper is devoted to the study of the Coxsackie B-3 viruses and their bentonite variants passaged on the primary and transplanted cell cultures for their hemagglutinating (HA) properties and a degree of adsorption on erythrocytes. It is shown possible to detect the HA activity of the Coxsackie B-3 viruses which are passaged on the transplanted cell cultures: the variant Abent has the hemagglutinating activity relative to human and rabbit erythrocytes. The variant Abent+ of the Coxsackie B-3 virus passaged on the cell culture Vero is established not to be absorbed on erythrocytes. The variant Abent and the initial population of the Coxsackie B-3 virus are adsorbed on the human erythrocytes by 90-99%. Coxsackie B-3 virus and its bentonite variants reproduced on the primary cell culture of human embryonic fibroblasts and possessing the hemagglutinating activity are 100-1000 times better adsorbed on human erythrocytes than the viruses passaged in the transplanted culture.     

Coxsackie B virus infection

A case of a 27-year patient with a clinical syndrome of Coxsackie B viral infection is presented. The symptoms included pleurodynia, myocarditis and the acute gastritis. The diagnosis was confirmed with serological tests which showed high titre of antibodies neutralizing Coxsackie B3. The symptoms of myocardial infarction dominated in both clinical course and autopsy. The authors suggest that serological tests specific for Coxsackie B infection should be performed in the young patients with the symptoms of myocardial infarction.     

Experimental diabetes in mice infected with Coxsackie viruses

The influence of Coxsackie B4 and AI3 viruses on the pancreas of mice (resistant and susceptible to diabetes) was studied. Glucose intolerance and changes in the synthesis of immunoreactive insulin were detected in all the treated groups of animals. Biochemical changes were more prominent in male DBA/2 mice, infected with Coxsackie B4 virus, in FI (CBA X C57Bl/6) hybrids and in female DBA/2 mice infected with Coxsackie AI3 virus and alloxan.     

Enterovirus Infections: Etiologic,Epidemiologic and Clinical Aspects

The term enteroviruses was introduced in 1957 to bring together in one large family the polioviruses, Coxsackie A and B and echoviruses, all agents for which the human alimentary tract is the natural habitat. At present more than 60 distinct members are recognized: three polioviruses, 24 Coxsackie A, six Coxsackie B and 30 echoviruses. The list of new members, particularly in the echo-group, grows regularly. The viruses are frequently widely disseminated in the summer and fall of the year, circulating chiefly among young children, causing both apparent and inapparent infection. The enteroviruses are responsible for a wide spectrum of clinical manifestations, including non-specific febrile illness, sometimes with rash, aseptic meningitis, paralytic disease, respiratory infections, pericarditis and myocarditis. There is considerable overlap in biologic behavior, and the same syndrome can be induced by many different agents.In a few instances the clinical pattern is distinct enough to suggest the group of agents involved. Thus, herpangina is associated with the Coxsackie A viruses and epidemic myalgia (devil''s grip) with the Coxsackie B group. Paralytic disease is caused primarily by the polioviruses, but recently it has been found that other members, particularly the Coxsackie B viruses and Coxsackie A7 can also cause “paralytic poliomyelitis.”The ultimate potential of enteroviruses in terms of central nervous system disease and other manifestations is unpredictable. Great variety in terms of clinical and epidemiologic behavior of known and “new” viruses has been the pattern in the past, and is likely to continue.     

Coxsackie virus in Southern California; isolation of a strain from stools of a patient

Thirty-three stool specimens from 29 patients were examined for Coxsackie virus by the inoculation of suckling mice. Such a virus, designated "California I," was obtained from two stool specimens collected on successive days from a patient with so-called nonparalytic poliomyelitis. Neutralizing antibodies for the California I strain of Coxsackie virus could not be demonstrated in serum obtained from the patient early in the illness, but were present in convalescent serum.Serum from the patient's daughter, who previously had had a similar illness, neutralized the strain of virus isolated from the father. In pathologic examination of the skeletal muscles of mice infected with the California I virus, lesions typical of those produced by Coxsackie virus, group A, were noted. California I strain of the virus was not neutralized by immune serum prepared from several other strains of Coxsackie virus.     

Coxsackie viruses; a review of pathologic,epidemiologic, diagnostic and etiologic observations

Coxsackie disease comprises three clinical entities-herpangina, so-called non-paralytic poliomyelitis, and epidemic pleurodynia. Several strains of antigenically-related viruses, Groups A and B, designated as Coxsackie virus have been isolated from stool specimens and from material from the throat of many patients with the diseases mentioned. Inasmuch as the virus has also been recovered from normal persons, there is as yet uncertainty as to causal relationship between the presence of the virus and the disease. Reports of the isolation of Coxsackie virus and poliomyelitis virus from the same patient make difficult the interpretation of the findings. The diagnosis of Coxsackie disease entails animal inoculation and serologic procedures. Emphasis is placed on the necessity of obtaining stool specimens, throat washings, and "paired" blood specimens from patients suspected of the disease.     

COXSACKIE VIRUS IN SOUTHERN CALIFORNIA—Isolation of a Strain from Stools of a Patient

Thirty-three stool specimens from 29 patients were examined for Coxsackie virus by the inoculation of suckling mice. Such a virus, designated “California I,” was obtained from two stool specimens collected on successive days from a patient with so-called nonparalytic poliomyelitis.Neutralizing antibodies for the California I strain of Coxsackie virus could not be demonstrated in serum obtained from the patient early in the illness, but were present in convalescent serum.Serum from the patient''s daughter, who previously had had a similar illness, neutralized the strain of virus isolated from the father.In pathologic examination of the skeletal muscles of mice infected with the California I virus, lesions typical of those produced by Coxsackie virus, group A, were noted.California I strain of the virus was not neutralized by immune serum prepared from several other strains of Coxsackie virus.     

Cardiac Manifestations During a Coxsackie B5 Epidemic

During a widespread Coxsackie B5 epidemic which occurred in Finland in the autumn of 1965 18 patients with acute myopericarditis were admitted to Kuopio Central Hospital (530 beds, representing a hospital district with 270,000 inhabitants) within a period of three months.The mean age of these patients was 28 years. Twelve were males and six were females.In 12 cases Coxsackie B5 virus and in one case Coxsackie A9 virus were isolated from the faeces. A significant increase in neutralizing antibodies or high antibody titres (≥1:128) were noted in 16 cases against Coxsackie B5 and in one case against Coxsackie A9. In two cases the cause of the myopericarditis remained obscure.All the patients had fever. Six showed all classical criteria of pericarditis: chest pain, pericardial rub, E.C.G. changes, and radiologically observable enlargement of the heart. As regards the various criteria, E.C.G. changes were found in all cases. Signs of cardiac tamponade were observed in one patient. Five, in addition, showed aseptic meningitis.All the patients recovered. Twelve were re-examined at an average of seven months after discharge from hospital. All were symptom-free except one, who still showed E.C.G. changes.     

Participation of Coxsackie B viruses in the occurrence and recurrence of infectious-allergic myocarditis (a serological study)

The serological study of sera from patients with infectious allergic myocarditis and from healthy persons has revealed essential differences in the occurrence and titers of antibodies to Coxsackie virus B. In patients with infectious allergic myocarditis the infectious process has been found to be significantly more frequently linked with Coxsackie viruses B, serovars 2 and 4.     

COXSACKIE VIRUSES—A Review of Pathologic,Epidemiologic, Diagnostic and Etiologic Observations

Coxsackie disease comprises three clinical entities—herpangina, so-called non-paralytic poliomyelitis, and epidemic pleurodynia. Several strains of antigenically-related viruses, Groups A and B, designated as Coxsackie virus have been isolated from stool specimens and from material from the throat of many patients with the diseases mentioned. Inasmuch as the virus has also been recovered from normal persons, there is as yet uncertainty as to causal relationship between the presence of the virus and the disease. Reports of the isolation of Coxsackie virus and poliomyelitis virus from the same patient make difficult the interpretation of the findings.The diagnosis of Coxsackie disease entails animal inoculation and serologic procedures. Emphasis is placed on the necessity of obtaining stool specimens, throat washings, and “paired” blood specimens from patients suspected of the disease.     

Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease.

Keshan disease is a cardiomyopathy of unknown origin reported in some areas of China. Because of epidemiologic features, this disease was ascribed to an infectious agent, likely a Coxsackie virus, but it has also been thought to depend on selenium deficiency, mainly because selenite is effective in its prophylaxis. We examined the hypothesis that pharmacological activity of selenite on Coxsackie virus growth was associated with prevention of Keshan disease. We studied the antiviral effects of three selenium compounds on Coxsackie virus B5 replication: five microM selenite reduced viral replication, whilst 10 microM selenate and selenomethionine did not exhibit any antiviral activity. The inhibitory activity of selenite on viral replication was due to its toxicity following its interaction with thiols, as that activity could be blocked by dithiothreitol, a sulfhydryl-protecting agent known to reverse several toxic effect of selenite. Zinc, another inhibitor of selenite toxicity, also counteracted the antiviral effect of selenite. The selenium compounds showed only limited activity against herpes simplex 1 virus and IHD strain of vaccinia virus. A direct inhibitory effect of selenite on Coxsackie virus replication might explain the efficacy demonstrated by this compound in the prophylaxis of Keshan disease.     

Immunity status against coxsackie viruses B in 25 patients with acute myocarditis

Viruses are an important cause of myocarditis, particularly the enterovirus group B coxsackievirus. Viral infection may be suspected on the basis of history and presentation and can be proved by direct or serological identification of virus. Twenty-five patients were diagnosed with acute myocarditis and were investigated with a serologic test battery covering Coxsackie viruses group B types 1 to 5 at the National Reference Center for Enteroviruses in Cantacuzino Institute Bucharest, Romania. A possible Coxsakie B virus etiology could be documented in 11 from 25 cases with acute myocarditis and high titers against Coxsackie virus B type 2 (1 patient), type 3 (5 patients) and type 5 (in 4 patients) were detected. In one HIV positive patient (17 years old), a concomitant infection with Coxsackie virus B types 2 and 4 was detected. The earlier detection of enterovirus myocarditis could be followed by antiviral therapies with a potential therapeutic role.     

Coxsackie B4 virus crystal formation in mouse pancreas.

For the first time, Coxsackie B4 virus crystals are demonstrated in tissues of animals inoculated with the virus. Until this report, Coxsackie B4 virus had never been found to form crystalline aggregates in tissues of any kind. The viral crystals which were located in the pancreas of newborn mice were associated with ultrastructural damage to the pancreas not observed in control animals, thereby indicating that viruses directly invade and damage these tissues. Thus, this virus must be considered among etiologic factors in pancreatic disease.     

Tinnitus and Coxsackie B infections: a case series

Tinnitus is a frequent and often debilitating condition. There is consensus in the scientific community that there exist various forms of tinnitus, which differ in their pathogenesis. Here we report a series of five cases where the onset of tinnitus was associated with viral infections. In all five patients elevated antibodies against Coxsackie B have been detected. This observation suggests that Coxsackie B Virus infections might be involved in the development of some cases of tinnitus and indicate that further systematic investigations are warranted.     

Effect of poly(I).poly(C12U) (Ampligen) on enteric virus (rotavirus, poliovirus and Coxsackie B3 virus) infections

The effects of poly(I) poly(C₁₂U) (Ampligen) on infections with enteric viruses (rotavirus, poliovirus and Coxsackie B3 virus) were studied in vitro. Ampligen exhibited antiviral activity against rotavirus, especially when treatment was performed prior to inoculation of the virus. It was partially effective against Coxsackie B3 virus, but not against poliovirus. It is suggested that the observed effects may be due to the production of interferon induced by Ampligen.