Reoviruslike agent in stools: association with infantile diarrhea and development of serologic tests.

Reoviruslike particles were visualized by electron microscopy in stool filtrates prepared from stools of infants and young children with severe acute gastroenteritis. Patients who had such particles in their stools and whose paired acute and convalescent serums were tested developed an antibody response to the reoviruslike agent, which was measured by immune electron microscopy and by complement fixation. The reoviruslike agent was antigenically related to the epizootic diarrhea of infant mice virus and the Nebraska calf diarrhea virus.

Limitations in the laboratory diagnosis of vertically acquired HIV infection.

At present, the only well-standardized and widely available diagnostic techniques for HIV infection are detection of IgG HIV antibodies and HIV antigen. The antibody detection is sensitive, but is useful only in infants and children older than 15 months because of the presence of maternal antibodies. The utility of HIV antigen testing in neonates and young infants has not been established. A number of sensitive techniques, such as PCR, ELISPOT, and detection of HIV-specific IgM and IgA antibodies, are under development and promise to be very useful in the early diagnosis of vertical HIV infection. However, we will be able to accurately establish the sensitivity or specificity of the individual tests only when we have results of large prospective studies. These studies should compare different diagnostic methods and correlate the results of tests performed sequentially in neonates and young infants with the natural history of their disease process and eventual clinical outcome.

Current approaches to the development of vaccines effective against parainfluenza and respiratory syncytial viruses.

Vaccines against parainfluenza (PIV) and respiratory syncytial viruses (RSV) that are currently being developed include both live and subunit vaccines. Candidate live PIV vaccines that have been found to be attenuated and efficacious in rodents or primate models are (1) cold-adapted, temperature-sensitive mutants of PIV-type 3 that have been serially passaged at low temperature (20 degrees C) in simian kidney tissue culture; (2) protease-activation mutants (PIV-1-Sendai), which have mutations that decrease the cleavability of their F glycoprotein by host cell protease; (3) an animal virus, bovine PIV-3 virus, which is antigenically related to the human PIV-3 virus, and (4) vaccinia recombinant viruses bearing RSV or PIV-3 glycoproteins. Subunit RSV and PIV-3 viruses are being produced and evaluated as immunogens. A major concern with these vaccines is the possibility of disease potentiation following virus infection as occurred previously with formalin-inactivated measles and RSV vaccines. Studies indicate that PIV-3 and RSV glycoprotein vaccines are immunogenic and efficacious in animals but insufficient data exist to estimate their capacity to potentiate disease. However, since a cotton rat model is available to detect potentiated disease resulting from infection of cotton rats previously immunized with formalin-inactivated RSV vaccine, it is now possible to systematically evaluate new vaccines in experimental animals for disease potentiation before studies are initiated in humans. It is likely within the next several years that one or more of these PIV or RSV vaccines will be tested in humans for safety and immunogenicity.

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.

Respiratory syncytial virus infections and intravenous gamma-globulins.

The respiratory syncytial virus (RSV) is a common cause of bronchiolitis and pneumonia in infants and young children. Throughout the world annual RSV epidemics result in numerous hospitalizations, substantial morbidity and some mortality. Until the recent introduction of ribavirin only supportive therapy has been available for treating these infections. The development of animal models of RSV infection and the observation that some lots of immunoglobulin prepared for intravenous administration contained substantial RSV-neutralization antibody titers, prompted a series of studies examining the safety and efficacy of immunoglobulin prepared for intravenous administration in the prophylaxis and treatment of RSV infections. This discussion will review our published, or soon to be published, studies on the use of Sandoglobulin for both immunoprophylaxis and immunotherapy of RSV infections in cotton rats. It will summarize studies utilizing both parenteral and topical (tracheal) Sandoglobulin therapy for RSV infections in owl monkeys. Finally the results of a small double blind trial of parenteral albumin or Sandoglobulin in the therapy of RSV bronchiolitis and/or pneumonia in hospitalized children will be reviewed. The data show that immunoprophylaxis and immunotherapy of RSV infections in laboratory animals was well-tolerated, was safe and induced highly significant reductions in RSV shedding from the lower respiratory tract. Further, immunotherapy of RSV infections in children was also well-tolerated, induced no short or long term evidence of toxicity or injury and caused significant improvements in oxygenation and reductions in RSV shed from the respiratory tract.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Ribavirin aerosol treatment of serious respiratory syncytial virus infection in infants.

Bronchiolitis is one of the most serious pulmonary infections commonly caused by respiratory syncytial virus (RSV). RSV disease occurs in yearly epidemics and is most severe in children 1 year of age or younger. Approximately 1 in 50 to 1 in 100 infants are hospitalized after their first infection, and mortality fluctuates between 0.5 and 5.0 per cent. Patients with underlying conditions such as congenital heart disease and bronchopulmonary dysplasia are at higher risk for morbidity and mortality. Methods for rapid diagnosis of RSV infection and the advent of specific therapy with aerosolized ribavirin have revolutionized the management of hospitalized patients with moderate to severe disease. A 3- to 5-day course of ribavirin plus supportive measures should be used in infants who prove to be infected by RSV and who are deteriorating on traditional supportive therapy, and/or who have underlying cardiac and/or pulmonary or immune defects.

Potential of attenuated respiratory syncytial virus vaccine for infants and children.

Respiratory syncytial virus (RSV) disease is a major cause of death and hospitalization in infancy and a frequent cause of morbidity throughout childhood. Serum antibody does not protect as is evident from the study of natural disease and use of killed vaccines. 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 vaccines: a 26 degrees 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 degrees 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.

Refining DRGs. The example of children's diagnosis-related groups.

Congress exempted certain types of specialty hospitals from the Medicare Prospective Payment System because it was recognized that Diagnosis-Related Groups (DRGs) may not properly define the case mixes in such institutions. This study is part of a larger investigation into case mix and payment in children's hospitals, one category of exempted institutions. A national sample of approximately 500,000 cases was developed with intentional oversampling of children's and university hospitals to allow detection of specialized types of cases. Five case-mix classification schemes--DRGs, Disease Staging, Patient Management Categories, Severity of Illness Score, and Pediatric Diagnosis System groups--were applied to the data set, and data items not included in the Uniform Hospital Discharge Data Set were collected. A set of Children's Diagnosis-Related Groups (CDRGs), based on modification of the current DRG system, resulted from the study. When CDRGs were applied to an independent sample of children's hospital data, length of stay variance was reduced by 47.6% compared with 32.3% for DRGs (length of stay outliers removed). These results suggest that incremental approaches to DRG refinement in other clinical areas where current definitions are inadequate may be better than rejecting the large amounts of statistical and clinical analyses existing in the DRG system. Similar methods can be used to correct problems brought on by changes in medical practice.

Simultaneous infections with different enteric and respiratory tract viruses.

Infants and young children with rotavirus (RV) or visualized adenovirus in their stools were tested for the simultaneous presence of a respiratory viral pathogen in their upper respiratory tract. Overall, at least 10.7% of 484 study subjects had such dual infections, including 8.3% of 385 RV-positive gastroenteritis patients and 24.3% of 37 RV-positive respiratory disease patients. Respiratory syncytial virus was present in 34.1% of 41 dual infections with RV and at least 40% of the 12 to 15 dual infections with visualized fecal adenovirus. Other pathogens found in the respiratory tract of patients with RV or visualized fecal adenovirus infections included influenza viruses, adenoviruses, parainfluenza viruses, rhinoviruses, and a cytomegalovirus.

Rapid presumptive recognition of diarrhea-associated adenoviruses.

The quantity of adenoviruses in a diarrhea stool provided a strong presumptive indication of the presence or absence of an adenovirus from subgenus F or G (proposed species 40 or 41). These adenoviruses were found in the stools of 91% of 56 acutely ill diarrhea patients with one or more than one adenovirus particle per min of direct electron microscopic viewing, as compared with 40% of 20 acutely ill diarrhea patients with less than one detected adenovirus particle per min of viewing.

Cell-mediated immunity to respiratory syncytial virus induced by inactivated vaccine or by infection.

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 hen's 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 had 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.