The role of HLA-DR-DQ haplotypes in variable antibody responses to anthrax vaccine adsorbed.

Host genetic variation, particularly within the human leukocyte antigen (HLA) loci, reportedly mediates heterogeneity in immune response to certain vaccines; however, no large study of genetic determinants of anthrax vaccine response has been described. We searched for associations between the immunoglobulin G antibody to protective antigen (AbPA) response to Anthrax Vaccine Adsorbed (AVA) in humans, and polymorphisms at HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQA1, -DQB1, -DPB1) loci. The study included 794 European-Americans and 200 African-Americans participating in a 43-month, double-blind and placebo-controlled clinical trial of AVA (clinicaltrials.gov identifier NCT00119067). Among European-Americans, genes from tightly linked HLA-DRB1, -DQA1, -DQB1 haplotypes displayed significant overall associations with longitudinal variation in AbPA levels at 4, 8, 26 and 30 weeks from baseline in response to vaccination with three or four doses of AVA (global P=6.53 × 10(-4)). In particular, carriage of the DRB1-DQA1-DQB1 haplotypes (*)1501-(*)0102-(*)0602 (P=1.17 × 10(-5)), (*)0101-(*)0101-(*)0501 (P=0.009) and (*)0102-(*)0101-(*)0501 (P=0.006) was associated with significantly lower AbPA levels. In carriers of two copies of these haplotypes, lower AbPA levels persisted following subsequent vaccinations. No significant associations were observed amongst African-Americans or for any HLA class I allele/haplotype. Further studies will be required to replicate these findings and to explore the role of host genetic variation outside of the HLA region.

An assessment of the association between childhood asthma and HLA DRB1*03 using extended haplotype analysis.

Ancestral haplotypes between human leukocyte antigen (HLA) class I and class II alleles are well-recognized in the literature. We previously published a positive association between the class II HLA allele DRB1*03 and the subsequent development of asthma in a retrospective cohort of 383 children. To refine this association, we investigated whether DRB1*03-specific haplotypes extending across the HLA are associated with asthma incidence. We found evidence of strong HLA DRB1*03-dependent linkage disequilibrium across the region, but no association between DRB1*03 ancestral haplotypes and childhood asthma. We did, however, observe a trend toward a positive association between HLA DRB1*03 and asthma by adding non-ancestral DRB1*03 positive haplotypes. Our results suggest that the role of the HLA DRB1*03 in asthma susceptibility is independent of ancestral-haplotype-mediated linkage disequilibrium.

Associations between cytokine/cytokine receptor single nucleotide polymorphisms and humoral immunity to measles, mumps and rubella in a Somali population.

We genotyped a Somali population (n = 85; age < or =30 years) for 617 cytokine and cytokine receptor single nucleotide polymorphisms (SNPs) using Illumina GoldenGate genotyping to determine associations with measles, mumps and rubella immunity. Overall, 61 significant associations (P < or = 0.01) were found between SNPs belonging to cytokine receptor genes regulating T helper (Th)1 (IL12RB2, IL2RA and B) and Th2 (IL4R and IL10RB) immunity, and cytokine (IL1B, TNFA, IL6 and IFNB1) and cytokine receptor (IL1RA, IFNAR2, IL18R1, TNFRSF1A and B) genes regulating innate immunity and variations in antibody levels to measles, mumps and/or rubella. SNPs within two major inflammatory cytokine genes, TNFA and interleukin (IL) 6, showed associations with measles-specific antibodies. Specifically, the minor allele variant of rs1799964 (TNFA -1211 C>T) was associated with primarily seronegative values (median enzyme immunoassay index values < or =0.87; P = 0.002; q = 0.23) in response to measles disease and/or vaccination. A heterozygous variant CT for rs2069849 (IL6 +4272C>T; Phe201Phe) was also associated with seronegative values and a lower median level of antibody response to measles disease and/or vaccination (P = 0.004; q = 0.36) or measles vaccination alone (P = 0.008). Several SNPs within the coding and regulatory regions of cytokine and cytokine receptor genes showed associations with mumps and rubella antibody levels but were less informative as strong linkage disequilibrium patterns and lower frequencies for minor alleles were observed among these SNPs. Our study identifies specific SNPs in innate immune response genes that may play a role in modulating antibody responses to measles vaccination and/or infection in Somali subjects.

Timeliness of diagnosis of asthma in children and its predictors.

BACKGROUND: There is a paucity of literature using medical records to evaluate the timeliness of asthma diagnosis in children and the predictors associated with timeliness of asthma diagnosis. METHODS: Subjects were obtained from a convenience sample of 839 children, aged 5-13 years. We conducted comprehensive medical record reviews for these children to determine their asthma status by applying predetermined criteria for asthma. Predictors were evaluated for an association with timeliness of asthma diagnosis. RESULTS: Of 839 children, 276 children met the criteria for asthma before 18 years of age. Of these subjects, 97 had timely diagnosis of asthma while 179 did not have timely diagnosis of asthma with the median delay of 3.3 years. Children with definite asthma at the time of index date was three times more timely to be diagnosed with asthma [hazard ratios (HR) 3.3, 95% CI: 2.43-4.47, P < 0.001], compared to those with probable asthma. Children with a family history of asthma were more timely to be diagnosed with asthma (HR 1.36, 95% CI: 1.03-1.8, P = 0.031). Children with exercise-induced wheezing or bronchospasm were more timely to be diagnosed with asthma (HR 1.79, 95% CI: 0.95-3.36, P = 0.07), compared to those with spasmodic (or bronchospastic) cough. CONCLUSIONS: Many asthmatic children are not diagnosed with asthma in a timely manner, especially in those without the commonly recognized factors associated with asthma. Health care providers need to be reminded that asthma can still occur in those without commonly recognized risk factors. Asthma guidelines need to emphasize this aspect.

Failure to reach the goal of measles elimination. Apparent paradox of measles infections in immunized persons.

BACKGROUND: Measles is the most transmissible disease known to man. During the 1980s, the number of measles cases in the United States rose dramatically. Surprisingly, 20% to 40% of these cases occurred in persons who had been appropriately immunized against measles. In response, the United States adopted a two-dose universal measles immunization program. We critically examine the effect of vaccine failure in measles occurring in immunized persons. METHODS: We performed a computerized bibliographic literature search (National Library of Medicine) for all English-language articles dealing with measles outbreaks. We limited our search to reports of US and Canadian school-based outbreaks of measles, and we spoke with experts to get estimates of vaccine failure rates. In addition, we devised a hypothetical model of a school where measles immunization rates could be varied, vaccine failure rates could be calculated, and the percentage of measles cases occurring in immunized students could be determined. RESULTS: We found 18 reports of measles outbreaks in very highly immunized school populations where 71% to 99.8% of students were immunized against measles. Despite these high rates of immunization, 30% to 100% (mean, 77%) of all measles cases in these outbreaks occurred in previously immunized students. In our hypothetical school model, after more than 95% of schoolchildren are immunized against measles, the majority of measles cases occur in appropriately immunized children. CONCLUSIONS: The apparent paradox is that as measles immunization rates rise to high levels in a population, measles becomes a disease of immunized persons. Because of the failure rate of the vaccine and the unique transmissibility of the measles virus, the currently available measles vaccine, used in a single-dose strategy, is unlikely to completely eliminate measles. The long-term success of a two-dose strategy to eliminate measles remains to be determined.

The surprisingly high acceptability of low-efficacy vaccines for otitis media: a survey of parents using hypothetical scenarios.

OBJECTIVE: To determine parental thresholds for accepting vaccines for otitis media prevention given tradeoffs of efficacy, adverse effects, and administration mode. METHOD: We interviewed 601 randomly selected parents with children 0 through 6 years of age presenting to our community pediatric clinic. For each of five hypothetical vaccines, which varied administration mode from nasal spray to two injections and adverse effects from mild to severe, parents indicated the lowest number of otitis media episodes that the vaccine had to prevent in the next 6 months for them to accept the vaccine. RESULTS: About half the parents would accept any one of the vaccines if it would prevent three or more infections in the next 6 months. When the vaccine would prevent one episode of otitis media over the next 6 months, 33% of parents would accept the medial vaccine (one injection in the thigh, with some children getting a red, sore injection site and a few having a fever of < or = 102 degrees F for one day). Seventeen percent accepted a vaccine requiring two injections (influenza vaccine-like) or having increased adverse effects (pneumococcal vaccine-like) despite the vaccine only preventing one episode of otitis media over the next 6 months. No substantial differences in these proportions were found when compared among groups by reason-for-visit, recent occurrence of otitis media, or a history of recurrent otitis media in a sibling. CONCLUSION: Many parents will accept low efficacy vaccines for otitis media prevention. Parental acceptance does not vary with the child's otitis media experience but does vary with severity of adverse effects and administration mode of the vaccine.

High frequency of HLA-A*0103 allele in a Somali population.

We report the existence of class I HLA allele A*0103 in an ethnic group (Somali) where this allele has not been reported. This allele was discovered in a study to examine the relationship between HLA alleles and humoral antibody response to measles vaccine among recent immigrants from Somalia to Olmsted County, Minnesota. We initially used polymerase chain reaction-sequence-specific primers (PCR-SSP) to carry out HLA class I typing. Based on PCR-SSP, 55 subjects were assigned the allele HLA-A*0101. Following direct DNA sequencing of the PCR products, 37 of the 55 subjects (67.3%) that were initially assigned the A*0101 allele were found to actually be A*0103. Our data are significant because it demonstrates that many of the previously typed A*0101 individuals are actually A*0103 as the SSP or sequence-specific oligonucleotide probes method cannot distinguish between the two alleles. Lastly, this is the first identification of this allele in the homozygous state.

Epiglottitis in adults and children in Olmsted County, Minnesota, 1976 through 1990.

OBJECTIVE: To compare the initial clinical manifestations and sequelae of epiglottitis among children and adult residents of Olmsted County, Minnesota. MATERIAL AND METHODS: We conducted a population-based retrospective cohort study of all Olmsted County residents with the diagnosis of epiglottitis during the 15-year period from Jan. 1, 1976, through Dec. 31, 1990. RESULTS: From 1976 through 1990, 41 residents (20 children and 21 adults) of Olmsted County were diagnosed with epiglottitis. (One case in an adult was first diagnosed at autopsy and was included only in the incidence rates and analysis of seasonal and secular trends.) Children had a mean annual incidence rate of 4.25 per 100,000, whereas the rate in adults was 2.18 per 100,000. The age- and sex-adjusted incidence of epiglottitis decreased during the study period from 4.94 per 100,000 during 1976 through 1980 to 2.08 per 100,000 during 1986 through 1990. No seasonal effect was detected in adults or children. At initial assessment, adults tended to have pharyngeal symptoms (sore throat and odynophagia), cervical adenopathy, and ear pain, whereas children most often had respiratory (stridor, dyspnea, and retractions) and laryngeal symptoms. Proportionately, more children than adults received artificial airway support and had associated pneumonia. One death occurred in an adult, in whom the diagnosis was made at autopsy. CONCLUSION: The incidence of epiglottitis has decreased significantly in recent years. Children and adults have considerably different initial manifestations of epiglottitis.

Incidence of sudden infant death syndrome in Olmsted County, Minnesota: 1945 through 1992.

OBJECTIVE: To apply uniform diagnostic criteria for sudden infant death syndrome (SIDS) for an extended period for comparison of incidence rates from 1945 to 1992 in Olmsted County, Minnesota, to investigate the influence of a person-time or live birth denominator on the estimate of incidence, to calculate the proportionate mortality rate for SIDS over time, and to evaluate the accuracy of death certificates for case ascertainment and the role of interobserver variation in case classification. DESIGN: We retrospectively reviewed the autopsy results and complete medical records for all infant death from 1945 through 1992 for residents of Olmsted County, Minnesota. MATERIAL AND METHODS: Cases were identified from a computerized list of all Olmsted County deaths of infants occurring at ages 48 hours to 365 days. All resident cases were categorized as non-SIDS, possible SIDS, SIDS, or incomplete, on the basis of findings from autopsy and clinical history. Incidence rates were calculated for two different SIDS groups and with use of denominators of person-time and live births. RESULTS: For the study period, 82 cases of SIDS were identified (97% white and 3% Asian). The mean age at death was 12.5 weeks; male infants constituted 59% of cases. No significant trend in seasonal distribution was noted; 73% of deaths occurred between midnight and noon. The incidence rate, defined as SIDS definite and possible deaths per 1,000 resident live births, increased from 0.55 in 1950 through 1953 to 1.28 in 1990 through 1992. The secular trend was best described by a linear model with constant positive slope. Similar trends were observed with other definitions of incidence. During the study period, SIDS as a percentage of total infant deaths dramatically increased, ranging from 2.5 in 1950 through 1953 to 17.9 in 1990 through 1992. The death certificate diagnosis correctly predicted 72% of SIDS cases before 1970 and 100% of cases after 1970. CONCLUSION: Since 1945, the incidence of SIDS apparently has increased, although diagnostic transfer from other causes of death probably contributes to the observed trend. The comparison of live births versus person-time as denominators showed no significant difference in incidence rates. Interobserver reliability is modest for SIDS cases diagnosed before 1970 and may contribute to the variability in reported SIDS incidence rates.

Oxygen as a cause of blindness in premature infants: "autopsy" of a decade of errors in clinical epidemiologic research.

Several intellectual "autopsies" have recently reviewed errors in clinical epidemiologic studies of causation, such as the original claim that amyl nitrite "poppers" caused AIDS. The current autopsy was done to determine why it took more than a decade--1942 to 1954--to end an iatrogenic epidemic in which high-dose oxygen therapy led to retrolental fibroplasia (RLF) in premature infants, blinding about 10,000 of them. The autopsy revealed a museum of diverse intellectual pathology. When first noted, RLF was regarded as neither a new disease nor a postnatal effect. In early investigations, the ophthalmologists did not establish explicit criteria for diagnosis and confused RLF with malformations previously seen in full-term infants. Because the patients were not referred until months after birth, the ophthalmologists assumed that the lesion, which resembled an embryologic structure, must have occurred prenatally. Other events suggesting a prenatal cause for RLF were its strong statistical associations with fetal anomalies, multiple gestations, and maternal infections. Although these events were also associated with prematurity, it was ignored when the RLF cases were compared with controls who were mainly full-term infants. The postnatal timing of RLF was eventually recognized when investigators did cohort studies in premature infants and found that RLF could develop in eyes that were normal at birth. As the search for a cause turned to events occurring after birth, statistical associations were produced for agents such as light, vitamins, iron, vitamin E deficiency, and hypoadrenalism. Each study had its own methodologic flaws: controls were missing for light; co-maneuvers were ignored for vitamins and iron; objective diagnosis was not used for vitamin E deficiency; and the research on hypoadrenalism contained biases in susceptibility and detection as well as problems of a competing outcome event. When the role of oxygen administration was first considered, the statistical association with RLF was stronger for vitamin- and iron-therapy than for oxygen. In addition, many investigators were dissuaded by contradictory evidence from institutions in which RLF was either absent despite high-dose oxygen or persistent despite reduced dosage. The contradictory evidence was later regarded as erroneous because of unsatisfactory delivery systems for the oxygen or failure to check the actual oxygen concentrations. An alternative explanatory hypothesis, rejecting the role of high-dose and long-duration oxygen, was the idea that RLF was due to "relative hypoxia", produced by overly rapid weaning from oxygen therapy rather than the duration of oxygen treatment itself.(ABSTRACT TRUNCATED AT 400 WORDS)

Secondary failure rates of measles vaccines: a metaanalysis of published studies.

BACKGROUND: Recent measles outbreaks in highly vaccinated populations have highlighted the role of vaccine failure as a barrier to the elimination of measles. We sought to estimate the rate of secondary failure (clinical measles after vaccine-induced seroconversion) of measles vaccines using metaanalysis. METHODS: We identified 1411 studies of which 125 were relevant. From these we found 10 original studies of healthy subjects with sufficient details to calculate a pooled secondary failure rate. We performed a test for homogeneity before any pooling. RESULTS: Although significant heterogeneity prevented their pooling as a single group, the studies fell into three homogeneous groups suitable for pooling. Group A studies used killed vaccine whereas the other two groups (Groups B and C) of studies used live vaccine. These latter groups differ in that the studies in Group B share higher failure rates and are difficult to interpret with respect to the lack of verification of vaccination, immunization before 12 months of age and a non-North American study site and vaccine manufacturer. Those studies in Group C, in which US subjects were older than 12 months at vaccination and received a live US-manufactured vaccine that was documented in a medical record, had a failure rate of 0 of 2031 with a 95% confidence interval of 0.0 to 0.147%. CONCLUSIONS: Although reports of measles related to secondary failure exist, studies that permit the calculation of the rate of secondary failure demonstrate that the rate appears to be < 0.2%.

Relationship of HLA-DQA1 alleles and humoral antibody following measles vaccination.

BACKGROUND: The human leukocyte antigen (HLA)-DQA1 locus is only moderately polymorphic compared to other HLA class II loci; however, we hypothesized that these polymorphisms could be important in determining the humoral antibody response to measles vaccine virus. METHODS: The seroprevalence of measles antibody was determined in 881 school children who had been immunized with MMR-II at age approximately 15 months. All subjects resided in a geographic area with no circulating measles virus. The IgG antibody levels were determined by a measles-specific whole virus enzyme immunoassay (EIA) (BioWhittaker, Walkersville, MD). Subjects who were nonresponders (IgG seronegative or equivocal) (n = 46) and hyperresponders (upper 10th percentile of IgG levels of all subjects) (n = 64) were HLA-DQA1 typed using polymerase chain reaction with sequence-specific primers (PCR-SSP). The HLA-DQA1 allele frequencies, as well as homozygosity rates, were compared between the nonresponders and hyperresponders. RESULTS: The overall allele frequency distribution of alleles between the nonresponders and hyperresponders was significantly different (P = 0.05), with nonresponders having an excess of HLA-DQA1*05 alleles (P = 0.017) and hyperresponders having an excess of HLA-DQA1*01 alleles (P = 0. 016). The homozygosity rate among nonresponders was significantly higher than among hyperresponders (23.9% vs. 9.4%, P = 0.037). CONCLUSION: HLA-DQA1 alleles have important associations with the antibody response to measles vaccine. Specifically, the carriage of the HLA-DQA1*05 alleles is associated with nonresponse and that of HLA-DQA1*01 alleles with hyperresponse. In addition, HLA-DQA1 homozygosity is significantly associated with poor antibody response to measles vaccine.

The influence of the HLA-DRB1*13 allele on measles vaccine response.

BACKGROUND: Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. METHODS: We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. RESULTS: The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different (p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%;p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). CONCLUSIONS: The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.

The impact of a simulated immunization registry on perceived childhood immunization status.

We developed a simulated immunization registry to assess the impact on the perceived immunization status in a population-based sample of 2-year-olds living in Olmsted County, MN, in 1995. We compiled records of all immunizations by abstracting immunization data from all medical care facilities in the county. The data collected from each facility were analyzed separately to provide the immunization rate as perceived by each facility. This perceived rate was compared to the rate obtained by combining all recorded immunizations from all facilities (simulated registry). Information on children not receiving any carefrom facilities in Olmsted County was compiled from birth certificate data and community school lists. Data from the simulated registry indicated that 69.1% of all children in Olmsted County with medical records were up-to-date on their immunizations by 20 months of age. By 24 months, this increased to 74.2%. The immunization rate of 24-month-old children recorded at individual healthcare facilities in Olmsted County ranged from 24.3% to 79.5%. The addition of data from the simulated registry increased the immunization rate at each site: a 27.7% relative increase in the site with the lowest recorded immunization rate, a 14.0% increase in the site with the intermediate immunization rate, and a 6.9% increase in the site with the highest internally perceived immunization rate. The registry also identified excess immunizations in 5% of the county's 2-year-olds. Each healthcare facility in this community gained an immediate benefit from the development of a simulated immunization registry. This immediate improvement in one quality-of-care measure (up-to-date immunization rate) should be factored into the cost/benefit assessment of immunization registries.

Negative cross-resistance between dihydropyrazole insecticides and pyrethroids in houseflies, Musca domestica.

A series of insecticidal dihydropyrazoles and related compounds have been shown to exhibit negative cross-resistance to a resistant (super-kdr) strain of houseflies with site-insensitivity to pyrethroids. The level of cross-resistance is similar to that observed previously for a range of N-alkylamides against the same strain.

Estimating the predictive value of a diagnostic test. How to prevent misleading or confusing results.

The diagnostic process consists of a series of steps in which the estimated probability of particular disease is increased or decreased until either treatment can be instituted or the diagnosis excluded. The history and physical exam play an important role. If a therapeutic decision cannot confidently be made on clinical grounds alone, a diagnostic test may confirm or exclude a diagnosis or clearly indicate the need for further testing. An inappropriately chosen test or misinterpreted test result, however, may mislead the clinician and possibly harm the patient or simply be wasteful. Estimating the predictive values of a diagnostic test will help to avoid these pitfalls. This article shows the clinician a simplified way to do this.

The genetic basis for measles vaccine failure.

The US measles epidemics of 1989-1991 included a series of outbreaks resulting from vaccine failure. A series of studies was launched aimed at elucidating the mechanisms of this vaccine failure. A meta-analysis of the literature examining epidemics in vaccinated populations was conducted, which showed that the secondary vaccine failure rate (development of the disease despite an initial or primary vaccine success) is no more than 0.2%. The overwhelming proportion of measles vaccine failure was due to primary vaccine failure (failure to ever generate antibody from antigenic stimulation). This comparison of two geographically distinct communities revealed that 10% of children previously vaccinated against measles lacked antibody on follow-up and that these vaccine failures clustered in families. A study of monozygotic and dizygotic twins revealed a high degree of heritability of measles vaccine antibody level. Subsequent studies found associations with both class I and class II alleles in these population-based studies. In the future, detection of the specific peptides that interact with human leukocyte antigen (HLA) molecules may serve as the basis for improved vaccines and address vaccine failure that results from cold-chain problems, immaturity of the immune system, malnutrition and maternal immunity.