François D. Boucher

Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection

OBJECTIVE To describe differences in patients hospitalized with respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) at nine Canadian tertiary care hospitals. In addition, this study describes the variation in use of drug and other interventions. METHODS Data on patients hospitalized with RSV LRI and their outcomes were prospectively collected. Demographic data were obtained on enrollment by center study nurses. Data recorded daily included clinical assessment, oxygen saturation determination, and interventions (bronchodilators, steroids, ribavirin, antibiotics, intensive care, and mechanical ventilation) received during the day. Patients were divided into those with underlying diseases including congenital heart disease, chronic lung disease, immunodeficiency, or multiple congenital anomalies and those who were previously healthy. Mean RSV-associated length of stay and the proportion of patients receiving each intervention in each group were determined by hospital. RESULTS A total of 1516 patients were enrolled at nine hospitals during January 1 to June 30, 1993, and January 1 to April 30, 1994. Significant differences were observed among hospitals in the proportion of patients with underlying disease, postnatal age less than 6 weeks, hypoxia, and pulmonary infiltrate on chest radiograph. The mean length of stay varied among hospitals from 8.6 to 11.8 days and 4.6 to 6.7 days in compromised and previously healthy patients, respectively. Except for receipt of bronchodilators, compromised patients were significantly more likely to receive interventions than previously healthy patients. There was variation among hospitals in receipt of most interventions in compromised and previously healthy patients. This variation was statistically significant for previously healthy patients but not statistically significant in those with underlying disease, because the numbers of patients in the latter group were much smaller. The magnitude of the variation for each intervention, however, was not different between those with underlying disease compared with previously healthy patients. CONCLUSION Differences exist among tertiary pediatric hospitals in the nature of the patients admitted with RSV LRI. Variation occurred in the use of five interventions among the hospitals, regardless of whether the patient had underlying illness or was previously healthy. Given their current widespread use, high cost, and potential side effects, randomized clinical trials are needed to determine the efficacy of different drug treatments used to treat infants hospitalized with RSV.

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.

Variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease : a review of the PICNIC RSV database

OBJECTIVE We wished to compare outcomes of respiratory syncytial virus (RSV) infection in children with bronchopulmonary dysplasia (BPD) with those with other pulmonary disorders: cystic fibrosis, recurrent aspiration pneumonitis, pulmonary malformation, neurogenic disorders interfering with pulmonary toilet, and tracheoesophageal fistula. METHODS Children with RSV infection hospitalized at seven Canadian pediatric tertiary care hospitals in 1993 through 1994 and 9 hospitals in 1994 through 1995 were enrolled and prospectively followed. This study is a secondary analysis of data from this prospective cohort. RESULTS Of the 1516 patients enrolled the outcomes of 159 with preexisting lung disorders before RSV lower respiratory tract infection constitute this report. There were no significant differences among the 7 groups (BPD, cystic fibrosis, recurrent aspiration pneumonitis, pulmonary malformation, neurogenic disorders interfering with pulmonary toilet, tracheoesophageal fistula, other) for the morbidity measures: duration of hospitalization, intensive care unit (ICU) admission, duration of ICU stay, mechanical ventilation and duration of mechanical ventilation. Patients using home oxygen were more likely to be admitted to the ICU than those who had never or previously used home oxygen (current 57.1%, past 23.8%, never 33.3%, P = 0.03). CONCLUSIONS Children with other underlying diseases have morbidity similar to those with BPD. Prophylactic interventions against RSV should also be studied in these groups.

A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy

In order to study the epidemiology of herpes simplex type 2 (HSV-2) infections during pregnancy, we used an enzyme immunoassay to detect type-specific antibodies to HSV-2 glycoprotein G in serial blood samples obtained from a cohort of 1891 pregnant women. Blood samples obtained at about 17 and 32 weeks of gestation and at the time of delivery were assessed for antibody to HSV-2 glycoprotein G in order to evaluate the prevalence of past infections with HSV-2 and the rate of acquisition of HSV-2 infection during pregnancy. Three hundred eleven pregnant women (16.5%) were found to have had past infections with HSV-2. Four of the 1580 women who were initially seronegative developed antibodies to HSV-2 during pregnancy. The annualized rate of acquisition of HSV-2 infection in pregnant women was 0.58%. Three of four women had asymptomatic primary infections; all of the women had preexisting HSV-1 immunity. None of the women or their infants experienced any adverse consequences of gestational herpes. Based upon our very limited number of observations to date, asymptomatic primary episodes occurring in women with previous HSV-1 immunity may be of less consequence to the fetus and neonate than symptomatic true primary HSV-2 infections.

Study of interobserver reliability in clinical assessment of RSV lower respiratory illness: A pediatric investigators collaborative network for infections in Canada (PICNIC) study

Randomized trials of ribavirin therapy have used clinical scores to assess illness severity. Little information on agreement for these findings between observers has been published. We decided to determine interobserver agreement for (1) a history for apnea or respiratory failure; (2) assessment of cyanosis, respiratory rate, retractions, and oximetry; and (3) determination of reason for hospitalization (requirement for medications, supportive care, underlying illness, poor home environment). At eight centers 137 RSV‐infected patients were assessed by two observers blinded to the assessments by others with no interventions made between assessments. Observations were categorized, and agreement was summarized as percentage of observed agreement, Pearson correlation, or as a κ statistic. Observed agreement for a history of either apnea or a respiratory arrest was at least 90% at all centers, with seven of the eight centers in total agreement. At all centers except one, the agreement on the reason why the patient remained in hospital was at least 80%. The observed agreement for assessing cyanosis was at least 94% at all eight centers. The correlation coefficient for respiratory rate varied from 0.42 to 0.97 across centers. The κ values for agreement beyond chance for retractions varied from 0.05 to 1.00. The κ values for oxygen saturation measures varied from 0.31 to 0.70. Although not statistically significant, there appeared to be more variation as the time between assessments increased. In conclusion, agreement for historical findings and assessment of cyanosis was high. However, there was wide variation in agreement in the other assessments. Training to ensure consistent and reproducible assessment by different examiners will be necessary if these findings are to be used as outcome variables in clinical trials. Pediatr Pulmonol. 1996;22;23–27.

Effectiveness of Pandemic H1N1 Vaccine Against Influenza-Related Hospitalization in Children

OBJECTIVE: Young children are generally considered immunologically naive with respect to influenza exposure opportunities; thus, a 2-dose schedule is recommended when a child is first immunized with conventional influenza vaccine lacking adjuvant. We estimated the effectiveness of a single pediatric dose of AS03-adjuvanted vaccine against hospitalization for confirmed pandemic influenza A/H1N1 (pH1N1) infection in children aged 6 months to 9 years during the fall 2009 vaccination campaign. METHODS: In a matched case-control design, case subjects were children hospitalized for pH1N1 infection in the Fall of 2009, in Quebec, Canada. Controls were nonhospitalized children, matched by age and region of residence. Vaccination status in case subjects and controls was ascertained in relation to the case subjects date of illness onset. Vaccine effectiveness was estimated through conditional logistic regression. RESULTS: The overall effectiveness of a single pediatric dose of vaccine administered ≥14 days before illness onset was 85% (95% confidence interval [CI]: 61% to 94%), varying according to age category but with wide and overlapping CIs: 92% (95% CI: 51% to 99%) in 6–23 month-old children, 89% (95% CI: 34% to 98%) in 2–4 year-olds, and 79% (95% CI: −31% to 96%) in 5–9 year-olds. Overall vaccine effectiveness for immunization ≥10 days before illness onset was slightly lower at 80% (95% CI: 60% to 90%), with similar variation according to age. CONCLUSION: In children aged 6 months to 9 years, a single pediatric dose of the AS03-adjuvanted pH1N1 vaccine was highly protective against hospitalization beginning at 10 and 14 days after vaccination.

Is pertussis immune globulin efficacious for the treatment of hospitalized infants with pertussis? No answer yet.

In a multicenter, randomized, placebo-controlled clinical trial of pertussis immune globulin, intravenous (P-IGIV), 25 infants hospitalized with pertussis were enrolled in 24 months (15% of the target sample size) before the study was prematurely terminated because of expiration of the P-IGIV lots and unavailability of additional study product. Although well tolerated, there was no difference in the number or rate of improvement of symptoms (paroxysmal cough, whoop, apnea, bradycardia, oxygen desaturations) in P-IGIV recipients compared with placebo.

Safety of live-attenuated influenza vaccination in cystic fibrosis.

OBJECTIVES: Given the improved efficacy of the nasal live-attenuated influenza virus vaccine (LAIV) compared with the injectable vaccine in children, we aimed to determine its safety in individuals with cystic fibrosis (CF). METHODS: A cohort of 168 study participants, aged 2 to 18 years with CF, vaccinated with LAIV between October 1, 2012, and January 30, 2013, was followed prospectively for 56 days after initial vaccination in 3 pediatric CF clinics across the province of Quebec. Days 0 to 28 post-LAIV were considered the at-risk period for all outcomes of interest, and days 29 to 56 post-LAIV were considered the non–at-risk period. Incident respiratory deteriorations were defined as an unscheduled medical visit, hospitalization, or a new course of oral antibiotics for respiratory complaints. Using a self-controlled design, incidence rate ratios (IRR) were used to compare at-risk and non–at-risk periods. RESULTS: Comparing at-risk to non–at-risk periods, there was no significant increase in the rate of incident respiratory deteriorations (IRR, 0.72; 95% confidence interval, 0.11–4.27) or all-cause hospitalizations (IRR, 1.16; 95% confidence interval, 0.30–4.81). A greater proportion of participants reported experiencing at least 1 minor respiratory and/or systemic adverse event after immunization during the at-risk period compared with the non–at-risk period (77% vs 54%, respectively). During the first week after LAIV, 13 of 168 (8%) children reported some wheezing, with the vast majority, 9 of 13 (69%), on the day of vaccination. CONCLUSIONS: There was no increased risk of respiratory deterioration or all-cause hospitalization associated with LAIV in our study population. LAIV seems well tolerated in children and adolescents with CF.

Community-acquired pneumonia in children: A multidisciplinary consensus review

Community-acquired pneumonia (CAP) is common among children and may have viral, bacterial or, occasionally, other causes. The etiology is complex, with age-related trends, and differs from that in adult CAP, necessitating different management guidelines. There is an absence of current guidelines for the management of pediatric CAP (PCAP) that take into account changing etiologies, antimicrobial-resistance issues and the use of newly licensed antimicrobials. The present review does not provide specific guidelines, but it reviews the literature and presents currrent approaches to the treatment of PCAP. To compile the review, an expert panel was convened to provide a consensus. The review discusses the etiology, diagnosis and antimicrobial treatment of PCAP as well as indications for referral to a hospital emergency department. The goal of the review is to provide those involved with treatment of PCAP in the community setting with information that can be used to make effective treatment choices.

Predictors of hospitalization for lower respiratory tract infection in children aged <2 years in the province of Quebec, Canada

Young age, adverse environmental conditions and infectious agents are established risk factors of lower respiratory tract infection (LRTI), whereas pneumococcal conjugate vaccines may be protective. To explore their relative role as predictors of hospitalizations under the continental climate prevailing in the province of Quebec, Canada, an ecological study was performed. Records with a main diagnosis of LRTI in children born during 2007-2010 and observed up to their second-year anniversary were extracted from the provincial hospital administrative database. Respiratory virus surveillance data and statistics on ambient air temperature were obtained. Vaccine use in different birth cohorts was derived from the Quebec City Immunization Registry. Additive and multiplicative Poisson regression models were applied to estimate attributable fractions. Age, month of birth, ambient temperature, and respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza-positive test proportions were significant predictors of LRTI hospitalizations. No substantial differences were observed in cohorts exposed to the 7-valent or 10-valent pneumococcal conjugate vaccines. In the additive model, the fraction of hospitalizations explained by temperature variation was 37%, whereas RSV circulation explained 28%, hMPV 4% and influenza 1%. Complex interplay between biological, environmental and social mechanisms may explain the important role of ambient air temperature in predicting LRTI hospitalization risk in young children.