Assessing sociodemographic differences in human papillomavirus vaccine impact studies in the United States: a systematic review using narrative synthesis.

OBJECTIVES: Sociodemographic disparities in the incidence and mortality of human papillomavirus (HPV)-associated conditions have been well documented in the pre-HPV vaccine era. It is still unknown if the introduction of routine vaccination has been effective in reducing these prevaccine era inequalities. The purpose of this review was to determine the utilization of sociodemographic variables to assess for disparities in population-level HPV vaccine impact research and to evaluate the current evidence for disparities in the reduction of HPV-associated conditions after vaccine introduction in the United States (US). STUDY DESIGN: A systematic review of the literature from January 2007 through March 2018 was carried out to identify studies evaluating the impact HPV vaccines have had on the rates of HPV infection, genital warts, and cervical dysplasia (cervical intraepithelial neoplasia grades 1+) in the US. An in-depth review was then performed to synthesize these data and to assess the way prior studies have reported and evaluated for potential disparities in the vaccine's impact within various racial, ethnic, and/or socio-economic subgroups of the population. METHODS: Vaccine impact studies measure the change in the population-level burden of disease prelicensure versus postlicensure of the vaccine. We systematically searched PubMed/Medline and Embase, combining search terms related to the HPV vaccine, sentinel surveillance, and HPV-associated conditions. Eligible studies were those with population-level, postvaccine introduction data that were conducted in the US. Finally, a cited reference search was conducted for all included articles using the Web of Science platform that accesses three major citation indexes: Science Citation Index, Social Sciences Citation Index, and Arts and Humanities Citation Index. This allowed us to screen not only the articles that were cited by our final collection of studies but also the articles that used our selected studies as one of their references. The study protocol is registered in PROSPERO (#CRD42018107579). RESULTS: Overall, 23 of the 4139 references retrieved assessed the population-level impact of HPV vaccines between January 1, 2007, and March 29, 2018. Among these, 13 (57%) reported sociodemographic data. Only two articles reported stratified results by sociodemographic factors, thereby allowing assessment for potential disparate impact. One of these studies described differences in the impact of the vaccine by race, ethnicity, and income. CONCLUSION: Although approximately half of the studies that assessed the impact of the HPV vaccine measured sociodemographic characteristics, few presented results in a way that allowed for the identification of potential differences in impact between the relevant subgroups of the population. Determining to what extent, if any, vaccines are reducing known sociodemographic disparities is an important public health priority and an essential step in developing immunization strategies that are beneficial for all.

Lyme disease in children.

Lyme disease is the most common vector-borne disease among children in the United States; the incidence of Lyme disease is higher among children than among adults. Extensive publicity in the lay press about the effects of Lyme disease has led to widespread anxiety about this illness that is out of proportion to the actual frequency of severe consequences, especially among children. The problem is exacerbated by the difficulty of documenting the diagnosis (or more often of ruling out the diagnosis in children with vague symptoms), especially when the diagnosis depends on serologic tests that are often inaccurate. This caveat applies particularly to commercial laboratories using prepackaged kits, which often give inaccurate results that should not be relied on by themselves to make a diagnosis. Careful prospective studies have found that nearly 90% of children with Lyme disease have erythema migrans. Although there has been great concern about congenital Lyme disease, no data suggest that it is a significant problem, nor has transmission of Lyme disease through breast milk been documented. Virtually all children will respond well to treatment for any stage of Lyme disease. Misdiagnosis is the most common reason for treatment failure. Long-term follow-up studies indicate that the prognosis for children with Lyme disease is excellent.

Pneumococcal vaccines: history, current status, and future directions.

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and bacterial meningitis. Although effective antimicrobial drugs have reduced case fatality, the pneumococcus remains a leading global cause of morbidity and mortality. Therefore, prevention of infection by vaccination with the pneumococcal polysaccharide vaccine is recommended for persons at high risk for serious pneumococcal disease, such as the elderly and individuals with certain underlying medical conditions. Pneumococcal polysaccharide vaccines are safe and effective for the prevention of invasive infection among immunocompetent children and adults but are not immunogenic in infants. Conjugation of pneumococcal polysaccharides to a carrier protein improves immune responses among infants, and conjugate vaccines are currently being evaluated in large efficacy trials. The role of pneumococcal conjugate vaccines in adults has not been determined. Pneumococcal vaccines directed against pneumococcal proteins and DNA vaccines that induce anti-pneumococcal antibodies have been evaluated in animal models and may someday provide complementary or alternative methods for preventing pneumococcal infection. Improved utilization of the pneumococcal polysaccharide vaccine and continued development of improved vaccines are essential, and the emergence of drug-resistant strains of S. pneumoniae highlights the importance of preventing pneumococcal infections by vaccination.

Efficacy of rifampin in eliminating pharyngeal carriage of Haemophilus influenzae type b.

Household contacts less than 6 years of age of children with Haemophilus influenzae type b meningitis are at increased risk of developing systemic H influenzae type b disease. Positive oropharyngeal cultures for H influenzae type b were found in 17/97 patients (18%) and 7/62 staff members (11%) at a chronic area facility at which two patients had developed ampicillin-resistant H influenzae type b meningitis. H influenzae type b colonization was eliminated in 8/9 carriers treated with a single daily oral dose of rifampin, 20 mg/kg/day (maximum 600 mg) for four days; colonization persisted in 9/10 control subjects (Fisher's exact test P < .001; corrected chi 2 P < .005). After treatment of additional H influenzae type b-positive individuals and the remaining control subjects, rifampin was found to have eradicated H influenzae type b in a total of 24/25 carriers (96%). All isolates of H influenzae type b were sensitive to rifampin at either 0.5 or 1.0 microgram/ml. Rifampin is effective in eliminating the H influenzae type b carrier state and may be useful in preventing associated H influenzae type b disease in close contacts of children with H influenzae type be meningitis.

Protective efficacy of Haemophilus influenzae type b polysaccharide vaccine.

There has been uncertainty and controversy about the protective efficacy of Haemophilus influenzae type b polysaccharide vaccine almost since it first was licensed in the United States. This article will briefly review the available epidemiologic data about the protective efficacy of this vaccine in children with no recognized underlying illnesses. H influenzae type b polysaccharide vaccine was licensed in the United States in April 1985, based on the results of a randomized clinical trial that was conducted in Finland. That study indicated that the vaccine's protective efficacy was 90% against invasive disease caused by H influenzae type b in children 18 to 71 months of age. Authorities recommended that all children receive the vaccine at 2 years of age and that it be administered to children up to the age of 60 months. The Immunization Practices Advisory Committee also recommended that children at increased risk (such as those who attend group day care) receive the vaccine at 18 months and again at 24 months of age because of its inconsistent immunogenicity when administered to 18-month-old children. Soon after its licensure, however, reports of vaccine failures began to appear. In some instances the vaccine failure could be attributed to an identifiable immune deficiency. However, Granoff et al reported 54 apparently normal children who had received the H influenzae type b polysaccharide vaccine but subsequently developed invasive disease caused by H influenzae type b. The majority of these children had normal serum concentrations of total immunoglobulins, IgG2, hemolytic complement, and antibody to tetanus toxoid (a T-cell-dependent antigen).(ABSTRACT TRUNCATED AT 250 WORDS)

Lyme arthritis in children: clinical epidemiology and long-term outcomes.

OBJECTIVE: Although Lyme disease has become a relatively common cause of arthritis among children in areas of the country in which the disease is endemic, little information is available about the clinical epidemiology and long-term outcomes of children with Lyme arthritis. We conducted a long-term follow-up study to determine the clinical epidemiology of Lyme arthritis in children as well as their long-term outcomes. PATIENTS AND METHODS: All children seen between 1982 and 1991 at the Pediatric Rheumatology Clinic at Newington Children's Hospital (Newington, CT) with an initial diagnosis of Lyme disease were identified. Medical records were reviewed and structured telephone interviews were conducted to obtain demographic, clinical, and follow-up data. RESULTS: A total of 90 children (63% boys) with a mean age of 8.3 years (range, 1.8-16 years) at the time of diagnosis of Lyme arthritis were evaluated. Lyme arthritis was preceded by early Lyme disease in 23 (26%) of the children; however, only 8 (35%) of these children had been treated with appropriate antimicrobial therapy at that early stage. Ninety percent of the children had arthritis of at least one knee, while small joints were rarely involved. For the 31 children who underwent arthrocentesis, the mean white blood cell count in the synovial fluid was 38 000 cells/mm3 (range, 7000-99 000 cells/mm3) with predominantly neutrophils. For the 79 children for whom an erythrocyte sedimentation rate was determined, the highest level for 61 (77%) was >20 mm/h and for 36 (46%) was >50 mm/h. Antimicrobial therapy was initiated 2 days to 5.5 years (median, 2 months) after the onset of symptoms. However, 5 of the children were never treated with antimicrobials. Fifty-one percent of the patients had a single episode of arthritis, while 49% reported recurrent episodes of arthritis over a period of 1 week to 8 years (median, 6 months). Two children (2%) developed chronic arthritis and underwent arthroscopic synovectomy. At the time of the telephone follow-up evaluation, performed 2 to 12 years (median, 7 years) after the onset of the Lyme arthritis, 4 children had ongoing musculoskeletal complaints that resulted in mild to moderate impairment of school or sports activities, but none of the children had evidence of active arthritis. CONCLUSION: The results of this investigation suggest that the prognosis for children with Lyme arthritis who are treated with appropriate antimicrobial therapy is excellent.

Does breast-feeding protect against infections in infants less than 3 months of age?

To determine whether breast-feeding protects infants from infections, a case-control study was conducted. The cases were previously healthy children who were admitted to Yale-New Haven Hospital for an infectious illness at or before 90 days of age. The controls were chosen from the log of births and matched to the cases for five important demographic variables. In addition, logistic regression models were used to adjust the results for other potential confounders. To minimize the potential surveillance bias that might occur if formula-fed and breast-fed infants with the same degree of illness have a different probability of being hospitalized, the case-control pairs were stratified by the severity of the medical condition of the case at the time of hospitalization. For the 281 case-control pairs, the matched odds ratio was .50 (95% confidence interval .32, .77; P less than .005), which indicates that breast-feeding is protective against infections. However, this apparent protective effect was diminished substantially when the data were stratified according to the severity of illness: the matched odds ratio for the 164 infants with serious illnesses was .79 (.47, 1.32; P less than .50), and for the 117 infants with mild illnesses it was .17 (.03, .44; P less than .001). These stratified results suggest that breast-feeding protects infants from hospitalization rather than from infections. Failure to consider the problem of surveillance bias may lead to erroneous conclusions about the protective effect of breast-feeding.

Early Lyme disease: a flu-like illness without erythema migrans.

The existence of a form of early Lyme disease characterized by a flu-like illness without erythema migrans is controversial. To confirm the existence and define the clinical characteristics of the flu-like illness without erythema migrans of localized Lyme disease, the authors studied patients from a Lyme disease endemic area of Connecticut who visited their primary care physicians with an undefined flu-like illness. Patients kept a diary of their symptoms. Acute and convalescent sera were obtained. The diagnosis of Lyme disease was based on the appearance of IgM or IgG antibodies to Borrelia burgdorferi as demonstrated by both enzyme-linked immunosorbent assay and immunoblot assay. Twenty-four untreated patients were studied. In five patients acute serologic evidence of Lyme disease developed. The flu-like illness in these five patients was characterized by fever and fatigue and resolved spontaneously in 5 to 21 days. Symptoms recurred in three of these five patients. The existence of a flu-like illness without erythema migrans of early Lyme disease has been clearly established. Prospective, controlled studies are needed to better define its incidence, characteristics, and prognosis so that appropriate diagnostic and therapeutic strategies can be developed.

Oral trimethoprim/sulfamethoxazole for prevention of bacterial infection during the induction phase of cancer chemotherapy in children.

We conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral trimethoprim/sulfamethoxazole (TMP/SMX) in the prevention of bacterial infections in children with cancer. Sixty-three patients with acute leukemia were studied during the induction phase of chemotherapy; 28 patients with solid tumors who were starting intensive chemotherapy were also enrolled and treated for 2 months. There was no significant difference in the frequency of febrile episodes between the 43 children receiving trimethoprim/sulfamethoxazole and the 48 receiving placebo. However, when the group of 74 children who experienced granulocytopenia (absolute granulocyte count less than 500/microL) was analyzed separately, significant reductions in the frequencies of confirmed bacteremia (2.6% v 20.0%, P = .02) and febrile episodes (35.9% v 65.7%, P = .01) were observed in the trimethoprim/sulfamethoxazole group. Furthermore, life table analysis showed that children with leukemia receiving trimethoprim/sulfamethoxazole had significantly more days without fever and without bacteremia. No benefits from prophylaxis were recognized in the subgroup with solid tumors. Although the frequency of oral thrush was greater (P = .02) in the trimethoprim/sulfamethoxazole group (25.6%) than in the placebo group (6.3%), invasive fungal infection did not occur. Although the mean duration of granulocytopenia was greater among those receiving trimethoprim/sulfamethoxazole (13.7 v 9.0 days, P = .05), this did not appear to increase the overall risk for bacterial infection. These data suggest that trimethoprim/sulfamethoxazole reduces the frequency of bacteremia and febrile episodes in granulocytopenic children undergoing induction chemotherapy for acute leukemia.

Infections of the urinary tract.

There are many options for the treatment of the child with pyelonephritis. Many children can be successfully treated without hospitalization. Appropriate use of studies to image the urinary tract to detect renal damage and treatable anatomical and functional abnormalities is a key aspect of the management of such patients. With appropriate interventions (such as antimicrobial prophylaxis for vesicoureteral reflux or surgery for obstructive lesions), subsequent renal damage can be averted and the morbidity of recurrent infections often can be eliminated.

Occult pneumococcal bacteremia: what happens to the child who appears well at reevaluation?

There is little information on the outcome of occult pneumococcal bacteremia in children who appear well at the time of first reevaluation. To determine the outcome of such children we reviewed the medical records of 364 children with blood cultures positive for Streptococcus pneumoniae managed at 2 hospitals in New Haven from 1973 to 1987. One hundred eighty of the 364 children were initially managed as outpatients; 111 of the 180 (62%) were afebrile and appeared well at the first reevaluation. Twenty-two of these 111 children (20%) were hospitalized and treated with intravenously administered antimicrobials at the first reevaluation visit; 2 of these 22 were still bacteremic, although no focal infection was found. Seventy-eight children (70%) were sent home after the first reevaluation visit with orally administered antimicrobials; 1 of these 78 children was still bacteremic and another subsequently was found to have meningitis that had been present at the first visit (culture of the cerebrospinal fluid obtained at the first visit subsequently grew S. pneumoniae). Eleven children (10%) were sent home from the reevaluation visit without antimicrobial treatment and none had persistent or recurrent pneumococcal infection. We conclude that the child who is afebrile and appears well at reevaluation for a blood culture positive for S. pneumoniae is unlikely to develop serious sequelae. Outpatient management with careful follow-up is essential for such children.

Prospective cohort study of children born to human immunodeficiency virus-infected mothers, 1985 through 1997: trends in the risk of vertical transmission, mortality and acquired immunodeficiency syndrome indicator diseases in the era before highly active antiretroviral therapy.

OBJECTIVES: To assess changes in the risk of vertical transmission of HIV and changes in both mortality and morbidity among children in southern Connecticut with HIV infection after the introduction of treatment of HIV-infected pregnant women with antiretroviral drugs and of regimens to prevent or to treat AIDS indicator diseases in infected children. METHODS: The risk of vertical transmission of HIV, the rates of death and of AIDS indicator diseases and temporal trends in each were determined for children born in the first 5 years of a prospective, longitudinal cohort study (Period 1: December 1, 1985, through November 30, 1990) compared with those for children born during the latter 7 years of the study (Period 2: December 1, 1990, through November 30, 1997). RESULTS: Of 347 infants enrolled, HIV infection status could be determined for 341; 44 (12.9%) were infected. The risk of vertical transmission declined from 20.7% among children born in Period 1 to 6.5% among children born in period 2 (rate ratio, 3.2; 95% confidence interval, 1.7 to 6.0; P = 0.0001). Of the 21 infected children who died, 11(52%) were < or =18 months of age and 18 (86%) were < or =36 months of age at the times of death. Approximately one-fourth of infected children born during each period died at < or =18 months of age. Among those < or =36 months of age, 15 deaths occurred during 878 person months of observation for those born in Period 1 compared with 3 deaths that occurred during 334 person months for those born in Period 2 (rate ratio, 1.9; 95% confidence interval, 0.5 to 10.3; P = 0.45). Of the 44 children infected with HIV, 32 had one or more AIDS indicator diseases (a total of 67 episodes), 73% of which occurred when the children were < or =36 months of age. Among children born in Period 2, none developed Pneumocystis carinii pneumonia and the rates of Mycobacterium avium complex disease and of wasting syndrome declined, but the differences in rates of disease were not statistically significant. CONCLUSION: A substantial and statistically significant decline in the risk of vertical transmission of HIV-1 occurred during the 12-year study period. In contrast although there was a trend toward a decrease in mortality among HIV-infected children < or =36 months of age and changes in the overall rates of AIDS indicator diseases among children born in Period 1 compared with Period 2, the differences were not statistically significant.

Willingness of directors of child care centers to care for children with chronic infections.

Directors of 150 child care centers were surveyed about their willingness to accept children with HIV or hepatitis B infection. Among 100 respondents 58% agreed to accept HIV-positive children and 23% would accept hepatitis B-positive children.

Outcome of children with occult bacteremia caused by Haemophilus influenzae type b.

For better definition of the clinical course and outcome of children with occult bacteremia caused by Haemophilus influenzae type b (Hib), we reviewed the medical records of children who were initially managed as outpatients and subsequently found to be bacteremic. At Yale-New Haven Hospital (1971 to 1987) and the Children's Hospital of Philadelphia (1982 to 1987), 69 previously healthy children were identified with occult Hib bacteremia. Their median age was 14 months (range, 4 to 89 months). Thirty-six (52%) of the 69 were either febrile and/or had a focus of serious infection at follow-up (meningitis (17), pneumonia (5), epiglottitis (3), cellulitis (5), and septic arthritis (3)). Although the remaining 33 children (48%) were afebrile and appeared well on reevaluation, 3 of these 33 were still bacteremic and another 5 subsequently developed focal Hib infections. These 8 children were significantly younger (median age, 8.5 months) than the 25 children who remained well (median age, 16 months; P = 0.03). Of the 28 children who had initially been treated with antimicrobials to which their organism was known to be susceptible, 12 (43%) were improved at reevaluation and remained well; 7 (23%) of the 31 patients who had not received such antimicrobials improved and remained well (P = 0.17). Children initially managed as outpatients and later found to have had Hib bacteremia are at risk of subsequently developing a serious focal infection.

Efficacy of Haemophilus influenzae type b vaccines in Massachusetts children 18 to 59 months of age.

Since 1987 Haemophilus influenzae b (Hib) conjugate vaccines have been licensed for use in children ages 18 months and older. Before licensure there were no clinical trials of a single dose of any conjugate vaccine in children ages 18 months or older. To fulfill this need we performed an age- and residence-matched case-control study of the efficacy of Hib vaccines. In our study population the protective efficacy (PE) of Hib-diphtheria toxoid conjugate vaccine was 88% (95% confidence interval, 45 to 98%). No vaccine failures were observed with Hib oligosaccharide CRM197 diphtheria protein conjugate vaccine, but usage was not sufficient to establish efficacy: PE = 100% (95% confidence interval, -37 to 100%). The protective efficacy of Hib capsular polysaccharide vaccine was 18% (95% confidence interval -487 to 89%). We conclude that for children ages 18 to 60 months a single dose of the Hib conjugate vaccine, PRP-D, is protective against invasive Hib infections. Consistent with most studies Hib polysaccharide vaccine provided suboptimal protection.

Predictive value of the human immunodeficiency virus 1 antigen test in children born to infected mothers.

Our objective was to examine the utility of the human immunodeficiency virus (HIV-1) antigen test as an early predictor of HIV-1 infection among children born to infected mothers and to collect information about its performance as a diagnostic test. The Abbott HIVAG-1 Enzyme Immunoassay was used to analyze serial serum samples from patients enrolled in a longitudinal cohort study of children born to mothers infected with HIV-1. There were 85 subjects who were followed from birth whose HIV-1 infection status could be definitely determined as of March, 1990. Of these 22 (26%) were infected with HIV-1 and 63 (74%) were uninfected. Overall the sensitivity of the test was 77% (95% confidence interval (CI), 55 to 92%) and the specificity was 97% (95% CI, 89 to 99%). The positive predictive value of a single positive test was 89% (95% CI, 67 to 99%) and of two or more positive tests was 100% (95% CI, 50 to 100%). The sensitivity of the test varied greatly with age. For 36 children from whom sera were collected during the first month of life the specificity of the antigen test was 100% but the sensitivity was only 20%. Overall in the first 6 months of life the sensitivity was less than 50%. The Abbott HIV-1 antigen test is useful as an early predictor of HIV-1 infection in children whose mothers are infected.

Predictors of recurrent febrile seizures. A prospective cohort study.

OBJECTIVES: To define the risk and identify predictors of single and multiple recurrent febrile seizures. METHODS: Children (n = 428) with first febrile seizures were prospectively identified and followed for 2 or more years. Parents were interviewed soon after their children's first febrile seizure and were called every 3 months to ascertain recurrent febrile seizures. Medical records of first and recurrent seizures were reviewed for additional information. RESULTS: A total of 136 children (31.8%) experienced recurrent seizures: 73 (17.1%) had only 1 recurrence, 38 (8.9%) had 2 recurrences, and 25 (5.8%) had 3 or more recurrences. Young age at onset, a history of febrile seizures in a first-degree relative, low degree of fever while in the emergency department, and a brief duration between the onset of fever and the initial seizure were strong independent predictors of recurrent febrile seizures. With these 4 factors combined, it is possible to define groups of children having very high and very low probabilities of having any recurrences (> 70% vs < 20%), having 2 or more recurrences (> 60% vs < 10%), and having 3 or more recurrence (12% vs about 0%). In children who had at least 1 recurrence, age at the time of the first recurrence and a family history of epilepsy were predictors of subsequent recurrences. CONCLUSIONS: In children who have had a first febrile seizure, recurrences are common. The risk for 1 or more recurrences can be meaningfully predicted at the time of the initial febrile seizure with a combination of the 4 factors identified in this study.

Prophylaxis for bacterial meningitis.

Close contact of patients with bacterial meningitis that is caused by either Haemophilus influenzae type b or Neisseria meningitidis are at an increased risk of developing invasive infections with these bacteria. Chemoprophylaxis with rifampin and immunoprophylaxis with vaccines may prevent some secondary infections.

The scholarship of application.

The scholarship of application encompasses a broad range of different types of scholarship in the sciences and humanities that involves translation of new knowledge to practical applications to solve problems of individuals and of society. The authors discuss this form of scholarship broadly, but focus on how it applies to patient-oriented research and to service performed by physicians. They distinguish between a clinician's use of his or her expertise (not scholarship) and a clinician's activities such as systematically assessing the effectiveness of different techniques and communicating the findings in a way that allows others to benefit (scholarship). They (1) review the importance of scholarship of application (i.e., society depends on the application of new knowledge), with special attention to the benefits to academic institutions; (2) discuss incentives for such scholarship (e.g., readiness of funding for directly applicable research) and disincentives (e.g., shortcomings in methods; lower prestige); (3) explain how it should be evaluated (create a more expansive peer-review process); (4) explain how it should be rewarded (rewards should be similar to those given for other forms of scholarship); and (5) describe how it should be nurtured (rigorous training in methodology, protected time for research, tangible support). They conclude that the interdependence of academic institutions and of society requires that the scholarship of application be conducted with rigor and relevance, and that institutions must develop strategies to promote applied scholarship.

New vaccines against Haemophilus influenzae type b.

Recently, great progress has been made in the development of vaccines against Hib. Four polysaccharide-protein conjugate vaccines are actively being tested. Three of these (PRP-D, HbOC, and PRP-OMP) are currently licensed for use in children at 15-18 months of age. Clinical trials of these vaccines in infants are currently being conducted in the United States. If these show the vaccines to be efficacious, licensure for infants will follow. Although much work remains to be done, it seems likely that the effective prevention of serious Hib infections in infants, as well as in older children, is a goal that may be within our reach in the next several years.