Biomedical subjects
R D Clover
Publications and source records attributed to R D Clover.
Age distribution of patients with medically-attended illnesses caused by sequential variants of influenza A/H1N1: comparison to age-specific infection rates, 1978-1989.
Since influenza A/H1N1 viruses reappeared during the 1977-1978 season, this subtype has contributed 27% of 6,609 documented influenza infections of persons with acute respiratory disease presenting to clinics serving as surveillance sites of the Influenza Research Center in Houston for the 12-year period ending June 1989. Wide differences in the distribution of H1N1 viruses occurred by age group: more than 50% of H1N1 infections were detected among persons aged 10-34 years, compared with 28% for influenza A/H3N2 and 35% for influenza B. Over age 35 years, the contribution of H1N1 viruses dropped to only 4%, compared with 20% and 16% for influenza A/H3N2 and influenza B, respectively. When birth dates of persons with positive cultures were examined, it was found that most of the H1N1-positive persons were born after 1950. Concurrently, longitudinal studies of families and other adults under intensive surveillance for infection, including cultures of all respiratory illnesses and tests for serum antibody rise over the respiratory disease season, revealed appreciable infection rates for adults born before 1950. Furthermore, the annual peak of hospitalization of older persons with pneumonia and other acute respiratory illnesses was significantly correlated with the peak of H1N1 virus activity in 1978-1979, a year when H1N1 viruses were the only influenza viruses prevalent. These observations indicate that many persons infected with influenza A/H1N1 viruses that circulated from 1946 through 1953 have immunity which has persisted for more than 25 years but this immunity is not complete. Reinfection that may result in serious illness in older vulnerable adults does occur but with lower frequency than with influenza A/H3N2 infection. Currently prevalent H1N1 variants are antigenically different from those that circulated in the 1950s; however, older adults readily acquire immunity to these new variants--perhaps as a result of immunologic priming that occurred in childhood.
Effect of rimantadine on the immune response to influenza A infections.
The effects of rimantadine on lymphocyte responses to mitogens CON-A and PHA, natural killer cell activity, and the development of serum and local antibodies were studied during an epidemic outbreak of influenza A (H3N2). Twenty-three families consisting of 38 adults and 46 children had a member who developed a flu-like illness and were randomly assigned to receive placebo or rimantadine either as treatment or post exposure prophylaxis. Nasal washings for virus isolation and IgG and IgA determination were collected on days 1, 5, and 10 of illness. Blood samples for immunologic studies were obtained on days 1 and 5 of clinical illness and on day 21. No differences in lymphocyte responses to CON-A and PHA or in natural-killer cell activity were noted between placebo and rimantadine groups. The development of neutralizing antibodies to influenza H3N2 was also not affected by rimantadine. However, the presence of IgA in nasal secretions was significantly diminished in the rimantadine group compared to the placebo group (0/9 vs. 6/9, P less than 0.005). The findings indicate that rimantadine had no adverse affect on the systemic immune system. However, local immune response was diminished in individuals taking rimantadine possibly due to the presence of less immunogen resulting from reduction of virus in secretions of individuals taking antivirals.
Comparison of heterotypic protection against influenza A/Taiwan/86 (H1N1) by attenuated and inactivated vaccines to A/Chile/83-like viruses.
Children (n = 192) aged 3-19 years from 98 families completed this double-blind, placebo-controlled study comparing the efficacy of a bivalent attenuated (CR) vaccine with trivalent inactivated (TI) vaccine. Both vaccines contained A/Chile/83 (H1N1)-like antigens. After vaccination the geometric mean titer to A/Taiwan/86 (H1N1) was 1:36 in the CR group, 1:92 in the TI group, and 1:5 in the placebo group. During the influenza A/Taiwan/86 (H1N1) epidemic, 21.4% of CR recipients, 16.7% of TI recipients, and 43.9% of placebo recipients were infected with influenza A/Taiwan. TI vaccine provided better heterotypic protection than did CR vaccine for children aged 10-18 years (infection rate, 0 vs. 24%, respectively; P less than .025); in contrast, in the younger children (3-9 years), CR vaccine tended to be more protective (19% vs. 26% for TI).
Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine.
The therapeutic activity of rimantadine and its relationship to the shedding of drug-resistant influenza A virus were assessed in two randomized, double-blind, placebo-controlled trials involving patients with laboratory-documented influenza A virus (H3N2 subtype) illness of 2 days' duration or less. In a family-based study, rimantadine treatment for 10 days (24 children and adults) was associated with significant decreases in the number of days to a 50% reduction in symptoms (mean difference, 2.5 days), days of fever (1.6 days), and days of restricted activity (1.5 days) compared with the results obtained with placebo-treated patients (32 children and adults). Drug-resistant virus was recovered from eight (33%) of the rimantadine recipients on day 5. No differences in patient demographics or illness severity at the time of enrollment in the study were apparent between those who shed resistant virus and those who did not. Illness resolution tended to be slower in those who shed resistant virus compared with that in those who did not. In a study of adults treated for 5 days (six treated with rimantadine, six treated with placebo), resistant virus was recovered in three rimantadine recipients by day 3 of treatment. The results indicate that drug-resistant influenza A virus (H3N2) can be recovered from rimantadine-treated children and adults as early as 2 days after starting treatment, but that rimantadine retains a net therapeutic benefit compared with that of placebo.
The effects of family functioning on infant birthweight.
A prospective cohort study was undertaken to evaluate the relationship of family functioning to infant birthweight adjusted for length of gestation. The mother's perception of family functioning was assessed at the initial prenatal visit using the Family Adaptability and Cohesion Evaluation Scales (FACES II). All obstetric patients at four family medicine clinics from April 1984 through April 1987 whose initial prenatal visits occurred by the 28th week of gestation were invited to participate; 95% chose to do so. Information was obtained on 833 mother-infant pairs. Listwise deletion on any one variable reduced the sample to 772 with no apparent bias in the dependent or predetermined variables. Twelve percent of the families were considered to be dysfunctional by scoring on the extremes of both the cohesion and adaptability continua of the self-report FACES II questionnaire. Infant birthweight was regressed on length of gestation and other known biomedical, anthropometric, risk-behavior, and sociodemographic determinants, as well as family functioning. Women who perceived their families as dysfunctional were delivered of infants who weighed on the average 126.4 g (95% CI 37.4, 215.4) less than infants born to women from functional families (P = .0055), after adjusting for other known determinants. Family functioning also was found to modify the effects of prepregnancy weight and infant sex on infant birthweight.
Live attenuated and inactivated influenza vaccine in school-age children.
In 1985, we enrolled 189 school-age children by family in a double-blind study to determine protection against influenza by a single dose of cold-recombinant bivalent A vaccine or commercial trivalent inactivated vaccine compared with placebo. All children in school or day care, 3 to 18 years of age, in an enrolled family received the same preparation. Following vaccination, 60% and 21% of cold-recombinant bivalent A vaccine recipients and 73% and 83% of trivalent inactivated vaccine recipients demonstrated fourfold or greater response in hemagglutination-inhibition antibody titer to A/H1N1 and A/H3N2, respectively. Sixty-seven percent of all trivalent inactivated vaccine recipients demonstrated a fourfold or greater serologic response to H1N1, H3N2, and influenza B following a single dose of vaccine. During the 1985-1986 influenza B/Ann Arbor epidemic, heterotypic protection afforded by the influenza B/USSR component of trivalent inactivated vaccine was 62% compared with placebo. A single dose of trivalent inactivated vaccine protected school-age children, 6 to 19 years of age, from influenza B infection; the rate of protection was 64% against infection and 73% against febrile illness.
Emergence and apparent transmission of rimantadine-resistant influenza A virus in families.
To determine whether rimantadine can protect family members from acquiring influenza A viral illness and to assess the possible selection of drug-resistant strains of virus, we conducted a randomized, double-blind, placebo-controlled study in three communities during two influenza seasons. When influenza A occurred in a family, the members (including the index patient) were given either rimantadine (adult oral dose, 200 mg per day) or placebo for 10 days. The presence of illness was monitored by daily recording of symptoms and temperature measurements; infection was determined by isolation of the virus and by serologic studies. Among households with documented influenza A infections, symptomatic illness occurred in one or more contacts in 10 of 28 families treated with rimantadine and in 10 of 209 families treated with placebo. Asymptomatic secondary influenza A infections were found in five families assigned to receive rimantadine and in four families assigned to receive placebo. Rimantadine-resistant strains of influenza A virus (H3N2 subtype) with mutations consisting of single amino acid changes in the M2 protein (residue 27, 30, or 31) were recovered from eight index patients and five contacts treated with rimantadine. There was apparent transmission of drug-resistant strains of virus in six contacts with secondary illnesses in five families. We conclude that when index patients are treated concurrently, rimantadine is ineffective in protecting household members from influenza A infection. If rimantadine is used for both treatment and postexposure prophylaxis in families, rapid selection and apparent transmission of drug-resistant influenza A viruses can occur.
Family functioning and stress as predictors of influenza B infection.
A prospective cohort study was designed to study the effects of family functioning and stress on the incidence of influenza infection. Families from the clinic roster, containing two adults and at least one child between the ages of 1 and 18 years, were asked to participate. Baseline (pre-influenza) data included a serum determination for influenza A and B antibodies, family functioning as measured by the Family Adaptability and Cohesion Evaluation Scales (FACES) II and the Family APGAR, and parental stress as measured by the social readjustment rating scale (SRRS). During the study all family members of patients with upper respiratory tract infection symptoms or fever were seen, and throat swabs were obtained for viral culture. Approximately 2 weeks after the influenza epidemic ended (March 1984), sera for antibodies were again collected on all family members. Chi-square analysis showed that infection (defined as a fourfold titer rise or a positive viral throat culture) was significantly associated with both cohesion and adaptability as measured by FACES II. Neither the Family APGAR nor the SRRS was associated with influenza B infection. It was concluded that family functioning affects the frequency of influenza B infection within families. This finding raises the possibility that family dysfunction may lead to altered immune responses, which increases susceptibility to infection.
Rimantadine prophylaxis in children: a follow-up study.
In a randomized, double-blind placebo-controlled clinical trial, we evaluated the prophylactic effectiveness of rimantadine in children (ages 1 to 18 years) against infection with influenza A (H3N2) and associated illness and the prevention of transmission of infection to adult members of the child's family. One hundred ten volunteers from 29 families completed this study during a naturally occurring outbreak of influenza A (H3N2). Influenza infections, defined as a positive viral throat culture or a 4-fold increase in antibody titer, occurred in 31.0% of children in the placebo group and 7.4% in the rimantadine group (P = 0.026). Clinical illness with laboratory evidence of influenza infection occurred in 24.1% of children in the placebo group and none in the rimantadine group (P = 0.007). Rimantadine was well-tolerated by the children, with no significant difference in reported adverse effects between the placebo and rimantadine groups. A combined analysis by families of these data and those of our similarly designed 1984 study, revealed that families in whom the children were given rimantadine had a significantly lower rate of influenza A infection and influenza-like illness compared with the families in whom the children were given placebo (68.8% vs. 18.8%, P less than 0.001) and (56.3% vs. 12.5%, P less than 0.001), respectively. We conclude that rimantadine prophylaxis of children appears to be an effective method to prevent influenza A (either H1N1 or H3N2) infection and illness in children.
Effectiveness of rimantadine prophylaxis of children within families.
With recent studies suggesting that children are the main introducers of influenza infections into families, we conducted a placebo-controlled, double-blind, randomized trial to study the prophylactic effectiveness of rimantadine hydrochloride in children on the transmission of influenza A infections within families. One hundred forty-five volunteers from 35 families completed this study during a naturally occurring outbreak of influenza A (H1N1) infection. Influenza infections, defined as a positive viral throat culture or a fourfold increase in antibody titer, occurred in 31.7% of children in the placebo group and 2.9% of children in the rimantadine group. Clinical illness with laboratory evidence of influenza infection occurred in 17.0% of children in the placebo group and 0% of children in the rimantadine group. Rimantadine was well tolerated by the children, with no significant difference in reported side effects between the placebo and rimantadine groups. Influenza A infection occurred in 19.0% of adults whose children were receiving a placebo and 8.8% of adults whose children were receiving rimantadine. On the basis of our study, rimantadine prophylaxis of children appears to be an effective method to prevent influenza A infection in children. Additional studies are needed to demonstrate the effects of rimantadine prophylaxis of children on the incidence of influenza A infection in their parents.