Hyun Wha Kim

Human Reovirus-like Agent as the Major Pathogen Associated with Winter Gastroenteritis in Hospitalized Infants and Young Children

We found a human reovirus-like agent in the stools of 42 per cent of 143 infants and young children hospitalized with acute gastroenteritis between January, 1974, and June, 1975. Half the patients studied by electron microscopy and serologic technics had evidence of infection with the agent. The infection had a seasonal pattern: 59 per cent of those admitted during the cooler months (November to April) shed the agent, with a peak of 78 per cent in December, 1974, and January, 1975, combined. None of the patients admitted during the warmer months (May to October) shed the agent. None of 275 Escherichia coli isolates from 32 patients with diarrhea produced heat-labile enterotoxin, whereas 17 of the 32 had evidence of infection with the reovirus-like agent. In addition, 14 of 40 parents of 37 patients with diarrhea associated with the reovirus-like agent were also infected, but most infectious were inapparent. This agent appears to be the major cause of diarrheal illness in the young during the cooler months.

Epidemiology of human rotavirus Types 1 and 2 as studied by enzyme-linked immunosorbent assay.

To determine the relative importance of two known serotypes of human rotavirus, we developed an enzyme-linked immunosorbent assay to differentiate serotype-specific rotavirus antigen and antibody. Using this technic, we studied the epidemiology of the two serotypes in acute gastroenteritis. Seventy-seven per cent of 414 rotavirus isolates were Type 2, and the remainder were Type 1. The serotype distribution was similar in specimens from children in Washington, D.C., and other parts of the world. Sero-epidemiologic studies revealed that most children living in the Washington, D.C., area acquired antibody to both types by the age of two years. An analysis of children who were reinfected indicated that sequential infections usually involved different serotypes and that illness caused by one serotype did not provide resistance to illness caused by the other serotype. These results suggest that, to be completely effective, a vaccine must provide resistance to both serotypes.

Cell-mediated Immunity to Respiratory Syncytial Virus Induced by Inactivated Vaccine or by Infection

Extract: Transformation and increased mitotic activity in donor lymphocytes exposed to specific antigens is considered by many to be a manifestation of cell-mediated immunity. In attempts to understand the apparent “sensitization” of individuals to respiratory syncytial virus (RSV) as a result of receiving inactivated RSV vaccine, in vitro lymphocyte transformation studies were carried out on infants who had received inactivated RSV vaccine and on infants who had received a similarly prepared inactivated African green monkey kidney (AGMK) cell-grown parainfluenza type 1 virus vaccine or a trivalent parainfluenza vaccine prepared in hens eggs. Each group included some infants who had, and others who had not, undergone natural RSV infection under our observation before the lymphocyte studies.Lymphocytes were studied from 21 infants and young children who had received the inactivated RSV vaccine, 14 who received a similarly prepared inactivated parainfluenza 1 vaccine, and 5 who received a trivalent parainfluenza vaccine. Twelve of the RSV vaccinees and 14 of the parainfluenza vaccinees had been naturally infected with RSV as indicated by virus recovery and/or antibody rise between the time of vaccination and the lymphocyte studies. In comparing the arithmetic mean for RSV-specific transformation and mitotic activity there was a significant difference between RSV vaccinees and parainfluenza vaccinees whether one compared those who had undergone natural RSV infection or those who had not undergone natural infection. The difference between RSV vaccinees who had not undergone natural RSV infection and RSV-infected parainfluenza vaccinees also was significant. There was a greater level of transformation and mitotic activity in those who had experienced natural infection than those who had not among both RSV vaccinees and parainfluenza vaccinees, but these differences were not significant statistically.Speculation: We take these findings to mean that natural RSV infection probably stimulates a systemic cell-mediated immunity response and that such a response is definitely induced after administration of killed RSV antigen. These findings are consistent with the hypothesis that cell-mediated sensitization may in some way contribute to the altered response to natural infection which occurred after use of inactivated RSV vaccine. Our findings do not support the hypothesis that systemic cell-mediated immunity per se is important in protecting against RSV infection. The findings also suggest the possibility that transplacentally conferred RSV lymphocyte sensitization might play a part in the pathogenesis of nonvaccine related RSV bronchiolitis which characteristically occurs during early infancy, frequently in the presence of measurable serum antibody.

Longitudinal study of rotavirus infection and gastroenteritis in families served by a pediatric medical practice: clinical and epidemiologic observations.

During 29 months of prospective longitudinal study of diarrhea in the home, human rotaviruses (HRVs) infected one or more members in 51% of 65 families, 35 of 126 children (28%) and 16 of 124 adults (13%). Within the 33 affected families, 57% of 62 children and 25% of 65 adults were infected. HRV gastroenteritis peaked at 40/100 person years at ages 12 to 23 months and decreased to 5 episodes/100 person years in adults. Among 25 children 0 through 36 months of age who had HRV infection, 88% were symptomatic. Of the 22 children with symptomatic HRV infection, 1 required hospitalization and 8 were seen by their physician for supportive care. HRVs were found in 12% of 216 stools obtained during gastrointestinal illness, but in only 0.2% of 1238 non-illness stools tested. HRV infections were noted as early as October and as late as April. Of 33 families who were studied for 2 seasons, at least 1 individual in each of 3 families experienced HRV infections in both years, but only one, an adult, shed virus and had symptoms in both seasons.

Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease

Thirty children 1 to 33 months of age were enrolled in a study of aerosolized ribavirin therapy for respiratory syncytial virus lower respiratory tract illness. Twenty patients received ribavirin and 10 received placebo. There were no significant differences between the groups in chronologic or gestational age or in days of illness prior to admission. Among patients with pneumonia 17% of 6 placebo patients vs. 64% of 11 ribavirin patients had radiographic evidence that multiple lung lobes were affected (P = 0.06). Placebo patients received 42.5 to 94.7 hours (mean, 58.6) of aerosol therapy, whereas ribavirin patients received 36.3 to 95.6 hours (mean, 55.7). Seventy-seven percent of all study patients were discharged within 5 days of starting treatment. Severity of illness was evaluated daily using a scale of 0 (normal) to 4+ (most severe). Ribavirin patients initially had a mean severity score 0.5 higher than placebo patients. By Day 2, their rate of improvement was significantly greater than that of placebo patients (P = 0.001). By Day 5, 36% of ribavirin patients with rales showed improvement, whereas rales persisted in 100% of placebo patients. The rate of improvement of oxygen saturation from first to last day of treatment was statistically significant only for ribavirin patients (P = 0.02). On Day 3, 65% of ribavirin patients (13) vs. 50% (5) placebo patients shed 10-0.5 50% tissue culture infective dose virus per 0.2 ml of nasal wash. No side effects or toxicity were associated with aerosol therapy. A short course of ribavirin treatment (approximately 3 days) proved safe and beneficial.

Antigenic relationships among five reovirus-like (RVL) agents by complement fixation (CF) and development of new substitute CF antigens for the human RVL agent of infantile gastroenteritis.

Summary The human reovirus-like (HRVL) agent, Nebraska calf diarrhea virus (NCDV), epizootic diarrhea of infant mice (EDIM) virus, simian agent (SA)-11, and the “O” (offal) agent were found to be similar, if not identical, in reciprocal complement fixation (CF) tests employing hyperimmune animal sera. In addition, in CF tests with paired sera from 35 diarrhea patients who shed the HRVL agent, 74% developed serologic evidence of infection with the HRVL antigen, 43% with NCDV, 51% with EDIM virus, 57% with SA-11, and 71% with the “O” agent. Thus, in addition to the NCDV, which had previously been described as a suitable substitute CF antigen for the HRVL agent, the SA-11, “O,” and EDIM viruses may also be utilized as substitute antigens for the HRVL agent. However, the “O” agent appears to be the most efficient of the four substitute CF antigens and thus should be used preferentially when the HRVL agent is not available. The “O” agent was about as efficient as the HRVL agent and significantly more efficient than the NCDV for detecting seroresponses. The greatest efficiency for detecting infection with the HRVL agent resulted when sera were tested with both the HRVL and “O” agents as 31 (89%) of the patients developed serologic evidence of infection with one or both antigens. The finding of additional substitute CF antigens for the HRVL agent may have implications in the immuno-prophylaxis against human disease. We thank Dr. D. W. Alling for assistance in statistical analyses and Mr. C. E. Banks, Mr. E. Williams, Mr. B. Andrews, Mr. J. P. Jackson, Miss D. M. Bertran, Mrs. S. J. Kelly, Mr. Robert P. Chames, Mrs. L. P. Kendrick, Mr. C. S. Osborne, Mrs. B. V. Armiger, and Mrs. C. L. Armiger for assistance in these studies.

Respiratory syncytial virus in infants and children

Abstract Respiratory syncytial virus (RSV) disease is a major cause of death and hospitalization in infancy and a frequent cause of morbidity throughout childhood. An epidemic occurred in the Washington, D. C. area in each of 16 respiratory disease seasons between 1957 and 1970. During the peak month of a “composite epidemic” 70% of bronchiolitis patients and 56% of all respiratory disease inpatients exhibited evidence of RSV infection. Approximately one-half of infants followed longitudinally were infected during their first RSV epidemic and almost all children were infected after living through two RSV epidemics. RSV infection does not produce solid resistance. First infection may have a 40% incidence of febrile pneumonitis; illness with reinfection is usually much less severe. Serum antibody does not protect as evident from the study of natural disease and the use of killed vaccine. Local antibody responses occur in natural illness. Possibly serum antibody in the absence of local antibody plays a part in illness. We have studied local and serum antibody response to potential attenuated vaccine: a 26°C-adapted RSV and a ts mutant RSV. Both produced the desired infection as evidenced by virus recovery, serum, and local antibody response. However, both appear to have had residual pathogenicity for young infants. This included mild bronchitis after the 26°C RSV and mild rhinitis, which might be acceptable, but also fever and otitis in one infant after the ts RSV. Also, some of the virus recovered in the ts studies had wild-type characteristics. An acceptable RSV vaccine strain will (a) infect without undergoing reversion or other genetic changes, (b) induce resistance to wild-type virus, (c) cause no or very mild inflammatory changes such as the rhinitis associated with the vaccines thus far tried.

Isolation from Man of “Avian Infectious Bronchitis Virus-like” Viruses (Coronaviruses) similar to 229E Virus, with Some Epidemiological Observations

Albert Z. Kapikian, Harvey D. James, Jr. Sara J. Kelly, Jane H. Dees, Horace C. Turner, Kenneth Mcintosh, Hyun Wha Kini,t Robert H. Parrott4 Monroe M. Vincent,^ and Robert M. Chanock From the Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases, Bethesda, Maryland.

Respiratory syncytial virus neutralizing activity in nasal secretions following natural infection.

Summary The development of RS virus neutralizing activity in nasal secretions was documented in 7 of 17 infants and children who were hospitalized for RS virus lower respiratory tract disease. Most of the patients in whom a rise in secretory neutralizing activity did not occur possessed moderately high levels of such activity in secretions collected at the time of admission to the hospital. At present we favor the view that this acute phase neutralizing activity represents antibody which developed early in the course of infection (possibly earlier than serum antibody) rather than the alternate possibility of nonspecific inhibitors in secretions.

Genetic Alteration in a Temperature-Sensitive Mutant of Respiratory Syncytial Virus After Replication in Vivo

Summary In the course of a clinical trial of a temperature-sensitive mutant RSV vaccine, a proportion of the virus recovered exhibited genetic alteration. Some of the altered virus showed a temperature-sensitivity pattern intermediate between that of the temperature-sensitive vaccine virus and the temperature-insensitive wild type. Possible genetic mechanisms which might have produced these findings are discussed.