Ensuring quality in AFRINEST and SATT: clinical standardization and monitoring.

BACKGROUND: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. METHODS: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. CONCLUSIONS: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials' results.

Epidemiologic and clinical features of Bell's palsy among children in Northern California.

BACKGROUND: Bell's palsy (BP) is an acute, idiopathic, and usually unilateral paralysis of the facial nerve. Large population-based studies of BP among children are lacking. We determined epidemiologic and clinical features of BP among children enrolled in a large integrated health care delivery system. METHODS: From 2001 through 2006, all children ≤18 years of age diagnosed with BP within the population of Kaiser Permanente Northern California were identified using the International Classification of Diseases, 9th Revision, code 351.0. All cases were adjudicated by an otolaryngologist and categorized as definite, probable, or rejected. Using chart abstraction forms, epidemiologic and clinical features of BP were determined. RESULTS: Of a total of 977 cases initially identified, 822 (84.1%) were adjudicated as a definite or probable case. The overall incidence rate of BP during the study period was 18.8 (95% CI 17.6-20.2) per 100,000 person-years. The incidence rate increased by age and was higher in females than males across all age strata. There was no evidence for a seasonal pattern in the occurrence of BP (p for trend = 0.81). CONCLUSIONS: BP among children may be more common than previously recognized.

Immunization and Bell's palsy in children: a case-centered analysis.

Bell's palsy (BP) is an acute and idiopathic paralysis of the facial nerve, with an estimated incidence ranging from 11.5 per 100,000 person-years to 53.3 per 100,000 person-years in different populations. BP has been reported following immunization with inactivated trivalent influenza vaccine (TIV) and hepatitis B virus (HBV) vaccine. Epidemiologic studies examining this association among children are lacking. From 2001 through 2006, all children aged ≤18 years diagnosed with BP within the Kaiser Permanente Northern California population were identified using International Classification of Diseases, Ninth Revision, code 351.0. All electronically identified cases were reviewed and adjudicated by an otolaryngologist (n = 233). Using a case-centered approach, the authors examined the risk of BP during 3 risk intervals. Immunization with TIV (odds ratio (OR) = 0.7, 95% confidence interval (CI): 0.2, 2.8), HBV vaccine (OR = 0.8, 95% CI: 0.2, 2.4), or any vaccine (treating all vaccines combined; OR = 0.9, 95% CI: 0.6, 1.4) was not associated with increased risk of BP 1-28 days after immunization. Similarly, no association was found between vaccines and BP during the periods 1-14 and 29-56 days following immunization. Results of this study suggest that there is no association between immunization and BP in children.

Clinically based surveillance of invasive meningococcal disease in young children admitted to selected US hospitals between January 2000 and June 2009: a retrospective cohort study.

Invasive meningococcal disease (IMD) is under-reported in countries that do not employ polymerase-chain reaction for surveillance because culture-negative cases are omitted. To evaluate a clinically based, case-finding method, we developed case definitions for "probable," "compatible with," and "possible, but unlikely" IMD, respectively, based on supportive documentation (e.g., discharge diagnosis of meningococcal infection, culture-negative bacterial meningitis, petechiae/purpura, Gram-negative diplococci on Gram stain) and weight of clinical evidence, which we then applied to electronic health records for all children aged ≤5 y who were admitted to approximately 100 US hospitals between January 2000 and June 2009. Among 47,863 qualifying admissions, 16 children had culture-positive IMD, 5 had "probable" IMD, and 5 had illness "compatible with" IMD. Five additional children had disease considered "possible but unlikely" IMD. Our case-finding methods suggest that culture-based ascertainment may underestimate the number of IMD cases by 31-63%, supporting findings in other nations that culture-based reporting provides incomplete information on disease incidence and therefore underestimates the potential benefits of routine vaccination of young children against meningococcal disease.

Benefits and risks of live attenuated influenza vaccine in young children.

OBJECTIVE: To examine the benefit-risk profile of live attenuated influenza vaccine (LAIV) across a range of clinical scenarios in which we varied assumptions regarding both the percentage of children who would receive LAIV in lieu of trivalent inactivated influenza virus (TIV) and the extent of off-label use. STUDY DESIGN: Model of expected benefits and risks of immunization of young children against influenza. METHODS: We estimated expected numbers of cases of influenza illness (FLU), medically significant wheezing (MSW), and hospitalization in a single influenza season under alternative assumptions regarding use of LAIV in lieu of TIV, based on projections from a large phase III trial. RESULTS: Assuming no use of LAIV in nonindicated children (aged <24 months and those with history of recurrent wheezing or asthma), and 50% use in lieu of TIV among children in the indicated population, there would be 2099 fewer FLU cases per 100,000 children aged 12 to 59 months, and no change in MSW or hospitalization. If LAIV also were used in lieu of TIV among 20% of children aged 12 to 23 months and 20% of children aged 24 to 59 months with a history of recurrent wheezing or asthma, there would be a further reduction of 397 FLU cases and 12 hospitalizations per 100,000 children aged 12 to 59 months, but 51 additional MSW cases. CONCLUSIONS: Our study suggests that even if LAIV were sometimes used inadvertently in clinical practice in young children for whom it is not indicated, the overall balance of expected benefits and risks would remain favorable.

7-Valent pneumococcal conjugate vaccine and lower respiratory tract infections: effectiveness of a 2-dose versus 3-dose primary series.

BACKGROUND: Immunogenicity studies suggest antibody responses from a 7-valent pneumococcal conjugate vaccine (PCV7) regimen consisting of 2 doses in the primary series are less immunogenic, for at least several vaccine serotypes, compared with a regimen consisting of 3 doses; evidence of effectiveness for prevention of invasive pneumococcal disease for both regimens is available but comparative data are lacking for prevention of lower respiratory tract diseases (LRTD). METHODS: We compared rates of LRTD between children who were born in 2002 and received 2 versus 3 PCV7 doses in the primary series, both before and after receipt of the booster dose, using a retrospective matched-cohort design and health insurance claims data. Two-dose and 3-dose children were matched (1:1) using propensity scoring. Cumulative rates of hospital admissions and outpatient visits for LRTD were tallied during the post-primary/pre-booster period and the post-booster period (to age 3 years), respectively. RESULTS: During the post-primary/pre-booster period, 3-dose children (n=3293) had 7.8 (95% CI: 0.8 to 14.8) fewer LRTD-related hospital admissions (per 1000 children) and 57 (95% CI: -6 to 128) fewer LRTD-related outpatient visits (per 1000 children) than matched 2-dose subjects (n=3293). During the post-booster period, the numbers of LRTD-related hospital admissions and outpatient visits did not differ significantly between 3-dose and 2-dose children. CONCLUSIONS: Our findings suggest that a 2-dose PCV7 primary series, while conferring savings from reduced vaccine costs in comparison with a 3-dose primary series, also may confer less protection against LRTD in the first year of life, at least during the period soon after the vaccine is introduced.

Strengthening the supply of routinely administered vaccines in the United States: problems and proposed solutions.

At the request of the Assistant Secretary for Health of the United States Department of Health and Human Services, the National Vaccine Advisory Committee organized workshops in February 2002 and January 2005 to identify the reasons for vaccine shortages and to develop strategies to prevent shortages in the future. This supplement to Clinical Infectious Diseases includes presentations outlining the problems associated with and proposed solutions for strengthening the supply of routinely administered vaccines in the United States.

Strengthening the supply of routinely recommended vaccines in the United States: recommendations from the National Vaccine Advisory Committee.

Between late 2000 and the spring of 2003, the United States experienced shortages of vaccines against 8 of 11 preventable diseases in children. In response, the Department of Health and Human Services requested that the National Vaccine Advisory Committee (NVAC) make recommendations on strengthening the supply of routinely recommended vaccines. The NVAC appointed a Working Group to identify potential causes of vaccine supply shortages, develop strategies to alleviate or prevent shortages, and enlist stakeholders to consider the applicability and feasibility of these strategies. The NVAC concluded that supply disruptions are likely to continue to occur. Strategies to be implemented in the immediate future include expansion of vaccine stockpiles, increased support for regulatory agencies, maintenance and strengthening of liability protections, improved communication among stakeholders, increased availability of public information, and a campaign to emphasize the benefits of vaccination. Strategies requiring further study include evaluation of appropriate financial incentives to manufacturers and streamlining the regulatory process without compromising safety or efficacy.

Amoxicillin/clavulanate for infections in infants and children: past, present and future.

Chemical synthesis of the penicillin nucleus in the 1950s made introduction of a broad array of new and important antimicrobials, including ampicillin and amoxicillin, possible. Ampicillin was introduced in 1962 in oral and parenteral forms as the first of the semisynthetic penicillins to provide increased activity against Gram-negative bacteria. Amoxicillin replaced oral ampicillin beginning in 1974 because amoxicillin resulted in higher and more prolonged serum concentrations than did equivalent doses of ampicillin. Amoxicillin/clavulanate (Augmentin) was introduced in the United States in 1984 to enhance the activity of amoxicillin by addition of the beta-lactamase inhibitor, clavulanic acid. During the past 20 years, amoxicillin/clavulanate has proven effective for a variety of pediatric infectious diseases, particularly acute otitis media (AOM). In 2001, a new pediatric formulation, high dose amoxicillin/clavulanate (Augmentin ES-600) was approved for use in the United States. The high dose preparation addressed the needs of pediatricians by providing greater amounts of amoxicillin while maintaining the same daily dose of clavulanic acid as the regular strength formulation. Doubling the dose of amoxicillin for management of recurrent and persistent AOM was recommended in 1999 by the Centers for Disease Control and Prevention because of concern about the increased incidence of nonsusceptible strains of Streptococcus pneumoniae. The original formulation combined amoxicillin/clavulanate in a 4:1 ratio and was followed by a 7:1 ratio formulation. The high dose formulation (600 mg of amoxicillin per 5 ml) provides a 14:1 ratio of amoxicillin to clavulanate. Although management of AOM will likely undergo changes in the coming years, amoxicillin is expected to remain first line therapy for AOM. For children who fail initial therapy with amoxicillin, high dose amoxicillin/clavulanate, an oral cephalosporin or parenteral ceftriaxone is recommended.