Vaccine safety--vaccine benefits: science and the public's perception.

The development of cowpox vaccination by Jenner led to the development of immunology as a scientific discipline. The subsequent eradication of smallpox and the remarkable effects of other vaccines are among the most important contributions of biomedical science to human health. Today, the need for new vaccines has never been greater. However, in developed countries, the public's fear of vaccine-preventable diseases has waned, and awareness of potential adverse effects has increased, which is threatening vaccine acceptance. To further the control of disease by vaccination, we must develop safe and effective new vaccines to combat infectious diseases, and address the public's concerns.

Haemophilus influenzae and Streptococcus pneumoniae infections in children with cerebrospinal fluid shunts.

OBJECTIVE: This paper reviews the frequency of central nervous system infections due to Haemophilus influenzae and Streptococcus pneumoniae associated with cerebrospinal fluid (CSF) shunts in pediatric patients. The need for immunizations in this patient population is also evaluated. PATIENTS: All patients with cerebrospinal fluid shunts except those with brain tumors seen in our clinics. METHODS: We reviewed data in three computer databases, kept prospectively recording details of CSF shunt procedures and CSF shunt-related infections. RESULTS: 1,226 patients underwent 3,889 shunt placements between 1957 and 2007. Twelve patients had 14 episodes of Haemophilus or pneumococcal infections. CONCLUSIONS: Children with CSF shunts are at high risk for infection with H. influenzae and S. pneumoniae. Routine immunizations during infancy in addition to the 23-valent polysaccharide pneumococcal vaccine should be highly and actively encouraged by health care providers caring for children with CSF shunts. Additional expanded-coverage vaccines should be utilized if and when they become available.

Diphtheria-tetanus-pertussis vaccine and serious neurologic illness: an updated review of the epidemiologic evidence.

A widespread impression that DTP vaccine does cause brain damage has been based first on historical precedent--smallpox and rabies vaccines were recognized as sometimes causing devastating neurologic illness; analogy to pertussis--the disease can cause encephalopathy; and more recently on anecdotal evidence, particularly case series. A noncausal relationship--coincidence--could explain the temporal relation between DTP vaccine and neurologic illness, inasmuch as DTP vaccine is given at the age of emergence of idiopathic neurologic disease. The relationship between DTP vaccine and neurologic illness lacks specificity. Case series have had an impact on both physicians' and the lay public's impression of the safety of pertussis vaccine greatly out of proportion to their scientific importance. Case series can be useful for generating hypotheses but cannot provide evidence that pertussis vaccine is causally related to acute neurologic illness or brain damage. Observational studies using cohort and ecologic designs did not find an association between DTP vaccine and serious neurologic illness, but they were not powerful enough to detect an association as rare as that observed by the NCES investigators. The case-control design offers the best chance of providing causal evidence regarding DTP vaccine and serious neurologic illness. The NCES is the only published case-control study of this issue. This study found a rare association between DTP vaccine and some types of acute neurologic illness. Bias and chance are unlikely to account entirely for the association demonstrated by the NCES. However, the association has not yet been replicated by other case-control studies. The NCES does not demonstrate that DTP vaccine causes permanent brain damage.

Childhood appendicitis: factors associated with perforation.

A retrospective study was performed to identify factors associated with perforation in 150 children with acute appendicitis. The children's parents were interviewed about the nature and timing of care, family history of appendicitis, and history of abdominal pain episodes, and the children's medical records were reviewed. Delay in treatment--the interval between first recognized symptoms of abdominal pain and surgery--was most predictive of perforation. A treatment delay of more than 36 hours was associated with a 65% or greater incidence of perforation. Mean delay for the group with perforation of the appendix was 66.7 hours compared with 35.8 hours for the group having appendicitis without perforation (P less than .01). Mean professional delay was significantly longer in the group with perforated appendicitis than in the group having appendicitis without perforation (P less than .01), but mean parental delay was not. Children aged 1 to 4 years and those aged 5 to 8 years had a 74% and 66% incidence of perforation, respectively, compared with a 30% to 42% incidence in older children (P less than .01). Age had a significant effect upon perforation even when adjusted for delay in treatment. Other factors associated with perforation were family history of appendicitis, social class, advice given by the first health professional contacted, and the presence of fecaliths. When all factors were considered simultaneously by using logistic regression techniques, delay in treatment, age, and absence of a family history of appendicitis were all significant predictors of perforation.

Advocacy training during pediatric residency.

Despite broad concerns about the welfare of children, most pediatric residents are not able to engage in child advocacy during their busy training years. Yet residency can provide an opportunity for young pediatricians to learn valuable advocacy skills by undertaking an independent project with an experienced mentor. We describe the University of Washington Pediatrics Residency Program's experience in training interested residents in child advocacy. Basic requirements are that advocacy projects must not interfere with clinical training, resident participation must be voluntary, and faculty with advocacy skills must be available to help guide the residents. Four resident projects are outlined and guidelines for instituting such programs are presented.

Use of bacterial antigen detection in the diagnosis of pediatric lower respiratory tract infections.

Two immunochemical methods were used to identify Haemophilus influenzae and Streptococcus pneumoniae capsular antigens in the urine and serum of 162 children with acute lower respiratory tract infection. These methods were compared with standard bacterial blood culture. Viral and mycoplasma cultures of respiratory secretions were obtained simultaneously to determine the frequency of antigenuria at the time of nonbacterial acute lower respiratory tract infection. Urine from groups of well children and children with acute otitis media was tested for capsular antigens to determine the incidence of antigenuria. Antigenuria was found in 24% of children 2 months to 18 years of age with acute lower respiratory tract infection compared with a 2% incidence of bacteremia. Antigenuria was found in 4% of asymptomatic children and 16% of children with acute otitis media. One third of children with symptoms of acute lower respiratory tract infection and viral isolates from the oropharynx had bacterial antigenuria. The sixfold increase in frequency of bacterial antigenuria in children at the time of lower respiratory symptoms suggests that bacterial acute lower respiratory tract infection may be more common than identified by traditional culture techniques. Because bacterial antigen may come from other sites such as the middle ear, further studies are needed to determine the role of antigen detection in the diagnosis of pediatric acute lower respiratory tract infection.

Lessons learned from a review of the development of selected vaccines. National Vaccine Advisory Committee.

BACKGROUND: Although the vaccine research and development network in the United States remains vibrant, its continued success requires maintaining harmonious interaction among its many components. Changing one component is likely to affect the system overall. An examination of case studies of the development of selected vaccines would allow an examination of the network as a whole. This article presents conclusions drawn from the case study review undertaken. OBJECTIVE: Successful development of vaccines is a time-intensive process requiring years of commitment from a network of scientists and a continuum of regulatory and manufacturing entities. We undertook this work to shed light on how well the vaccine development system in the United States performs. METHOD: The National Vaccine Advisory Committee examined the research and development pathways of several vaccines that reached licensure expeditiously (hepatitis B vaccine, Haemophilus influenzae type b conjugate vaccines); some that became licensed only after considerable delay (oral typhoid Ty21a vaccine, varicella vaccine); some that are at the point of imminent or recent licensure (reassortant Rhesus rotavirus vaccine, which was licensed by the Food and Drug Administration on August 30, 1998) or near submission for licensure (intranasal cold adapted influenza vaccine); and one for which clinical development is slow because of hurdles that must be overcome (respiratory syncytial virus vaccines). RESULTS: Some common themes emerged from the reviews of these vaccine "case histories": the expediting influence of a strong scientific base and rationale; the need for firm quantitation of disease burden and clear identification of target populations; the critical role played by individuals or teams who act as "champions" to overcome the inevitable obstacles; availability of relevant animal models, high-quality reagents and standardized assays to measure immune response; the absolute requirement for well designed, meticulously executed clinical trials of vaccine safety, immunogenicity, and efficacy; postlicensure measurements of the public health impact of the vaccine and a track record of the vaccine's safety and acceptance with large-scale use; and the critical need for international collaborations to evaluate vaccines against diseases of global importance that are rare in the United States (eg, typhoid fever). It was clear that the critical step-up from bench scale to pilot lots and then to large-scale production, which depends on a small group of highly trained individuals, is often a particularly vulnerable point in the development process. CONCLUSIONS: One fundamental lesson learned is that within the varied and comprehensive US vaccine development infrastructure, multiple and rather distinct paths can be followed to reach vaccine licensure. The National Vaccine Advisory Committee review process should be conducted periodically in the future to ascertain that the US vaccine development network, which has been enormously productive heretofore and has played a leadership role globally, is adapting appropriately to ensure that new, safe, and efficacious vaccines become available in a timely manner.

Purified protein derivative anergy in Kawasaki disease.

It was previously reported from Italy that all patients with Kawasaki disease had a positive tuberculin intradermal test. In this study from Seattle, WA, nine patients with Kawasaki disease showed no reaction to intradermal tuberculin. The difference in results might be caused by the different tuberculin products.

One-year experience with an inpatient asthma clinical pathway.

OBJECTIVE: To study the effects of an inpatient asthma clinical pathway on the processes and outcomes for children who were admitted to a hospital for the treatment of asthma. DESIGN: Before-and-after study. SETTING: A private nonprofit academic children's hospital in Seattle, Wash. PATIENTS AND METHODS: Three hundred forty-two admissions of 297 patients in the first year of the asthma clinical pathway were compared with 353 admissions of 292 similar patients in the previous year. Patients who required intensive care, were younger than 2 years, or had a major chronic disease were excluded. INTERVENTION: Asthma was chosen for the development of a clinical pathway because of its large number of admissions, involvement of multiple health care providers (nurses, physicians, and respiratory therapists), predictable hospital course, and variable lengths of hospital stay. The pathway was a consensus-based guideline for patient management that was intended to be adapted to the care of an individual patient. Prior to the implementation of the clinical pathway, nurses, attending physicians, house staff, and respiratory therapists were trained in its use. The main hospital chart of each patient who was admitted to the pathway had a flowchart that outlined day-to-day guidelines for monitoring and care. Nursing staff were responsible for documenting when a patient's care varied from the pathway, and these variances were entered into a computer database. OUTCOME MEASURES: Use of peak flowmeters, steroids, laboratory studies, radiological studies, and respiratory therapy was assessed by analyzing the patients' electronic billing records. For patients enrolled in the pathway, additional data on process of care were obtained by analyzing the variance database. For both groups, the total charges, length of stay, and rate of readmission to the hospital were measured by use of the billing records. RESULTS: There were no significant differences in the use of steroids or peak flowmeters, average lengths of stay, or total charges between the 2 groups. However, patients in the "pathway group" had significantly lower average charges for laboratory ($26 vs $39; P < .05) and radiology ($32 vs $55; P < .001) services. Variances from the pathway guidelines were most often related to the patients' responses to therapy. CONCLUSIONS: The asthma clinical pathway had no effect on clinical outcomes and small effects on the use of resources. Further development, including physician and nurse training, computer and administrative support, and clinical severity scales, are needed to develop the potential utility of the clinical pathway as a research and quality assurance tool.

The rotavirus vaccine's withdrawal and physicians' trust in vaccine safety mechanisms.

OBJECTIVE: To determine how the withdrawal from the market of the rotavirus vaccine has affected physicians' trust in vaccine safety mechanisms, future adherence to vaccine recommendations, and willingness to use a new rotavirus vaccine. DESIGN: National survey mailed to 1228 randomly selected pediatricians and family physicians. MAIN OUTCOME MEASURES: Confidence in vaccine safety mechanisms was defined by agreement with the statements that the system for determining vaccine safety before a vaccine is licensed works well and that the system for monitoring vaccine safety after vaccine licensure works well. Physicians who indicated that they would use a new rotavirus vaccine within 1 year of licensure and recommendation by professional organizations were classified as "early adopters." Logistic regression was used to assess the relationship between trust in vaccine safety mechanisms and future early adoption of new rotavirus vaccines. RESULTS: Following the withdrawal of the rotavirus vaccine, 83% of respondents believed the postlicensure surveillance system works well to monitor vaccine safety, while 22% of respondents believed the prelicensure system works well to determine vaccine safety. After adjusting for physician specialty and years in practice, respondents who believed the prelicensure vaccine safety system works well were significantly more likely to be early adopters than those with less confidence in prelicensure studies (adjusted odds ratio, 2.2 [95% confidence interval, 1.3-3.6]). CONCLUSIONS: Physicians have different levels of trust in prelicensure studies that determine vaccine safety and postlicensure surveillance systems that monitor vaccine safety. Trust in prelicensure vaccine safety evaluations may be associated with early adherence to new vaccine recommendations.

The pediatric intern retreat: 20-year evolution of a continuing investment.

For the past 22 years the interns in pediatrics at the University of Washington and Children's Hospital and Regional Medical Center have been relieved of all clinical duties in order to participate in a five-day retreat. The retreat provides an opportunity for the interns to learn more about their classmates, build stronger bonds, and provide mutual support. This retreat has been supported by the hospital, the department of pediatrics, faculty, fellows, and community physicians. The authors describe the history of the Intern Retreat, present its goals, daily activities, and faculty, and discuss how the retreat is funded and supported by the hospital and the medical community.