ß2-Adrenergic receptor promoter haplotype influences the severity of acute viral respiratory tract infection during infancy: a prospective cohort study.

BACKGROUND: Despite the significant interest in ß2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections. METHODS: To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans. RESULTS: There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95% confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians. CONCLUSIONS: ADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy.

Objectives, design and enrollment results from the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure Study (INSPIRE).

BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) during infancy has been consistently associated with an increased risk of childhood asthma. In addition, evidence supports that this relationship is causal. However, the mechanisms through which RSV contributes to asthma development are not understood. The INSPIRE (Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure) study objectives are to: 1) characterize the host phenotypic response to RSV infection in infancy and the risk of recurrent wheeze and asthma, 2) identify the immune response and lung injury patterns of RSV infection that are associated with the development of early childhood wheezing illness and asthma, and 3) determine the contribution of specific RSV strains to early childhood wheezing and asthma development. This article describes the INSPIRE study, including study aims, design, recruitment results, and enrolled population characteristics. METHODS/DESIGN: The cohort is a population based longitudinal birth cohort of term healthy infants enrolled during the first months of life over a two year period. Respiratory infection surveillance was conducted from November to March of the first year of life, through surveys administered every two weeks. In-person illness visits were conducted if infants met pre-specified criteria for a respiratory illness visit. Infants will be followed annually to ages 3-4 years for assessment of the primary endpoint: wheezing illness. Nasal, urine, stool and blood samples were collected at various time points throughout the study for measurements of host and viral factors that predict wheezing illness. Nested case-control studies will additionally be used to address other primary and secondary hypotheses. DISCUSSION: In the INSPIRE study, 1952 infants (48% female) were enrolled during the two enrollment years and follow-up will continue through 2016. The mean age of enrollment was 60 days. During winter viral season, more than 14,000 surveillance surveys were carried out resulting in 2,103 respiratory illness visits on 1189 infants. First year follow-up has been completed on over 95% percent of participants from the first year of enrollment. With ongoing follow-up for wheezing and childhood asthma outcomes, the INSPIRE study will advance our understanding of the complex causal relationship between RSV infection and early childhood wheezing and asthma.

Increased healthcare resource utilization for acute respiratory illness among Latino infants.

OBJECTIVE: To examine healthcare resource utilization for acute respiratory illness in Latino infants compared with other racial/ethnic groups. STUDY DESIGN: We studied 674 term-born, previously healthy infants brought in for an unscheduled healthcare visit for an acute respiratory illness. The predictor variable was infant race/ethnicity, and the primary outcome was healthcare resource utilization, adjusted for age and disease severity. RESULTS: The cohort was 14% Latino, 52% white, 22% African American, and 12% other race/ethnicity. More than one-third (37%) of the mothers of Latino infants were Spanish-speaking. The bronchiolitis severity score was higher (indicating more severe disease) in white infants (median, 6.0; IQR, 3.0-9.0 on a scale of 0-12) compared with Latino (median, 3.0; IQR, 1.0-6.0) and African American (median, 3.5; IQR, 1.0-6.0) infants (P < .001 for the comparison of all groups). Disease severity was similar in Latino and African American infants (P = .96). Latino infants were the most likely to receive antibiotics (58%, compared with 47% of whites and 34% of African Americans; P = .005) and to have body fluid cultures drawn. Latino infants also were more likely than African American infants to undergo chest radiography and respiratory virus rapid antigen testing (P ≤ .01). Latino infants from Spanish-speaking families had a higher rate of respiratory syncytial virus testing compared with those from English-speaking families (76% vs 51%; P = .016). CONCLUSION: Providers caring for Latino infants with acute respiratory illness ordered more antibiotics and diagnostic testing for this group, particularly compared with African Americans, even though the 2 groups had similar disease severity and socioeconomic disparities. Language barrier may be a possible explanation for these differences.

Host and viral factors associated with severity of human rhinovirus-associated infant respiratory tract illness.

BACKGROUND: Risk factors for severe human rhinovirus (HRV)-associated infant illness are unknown. OBJECTIVES: We sought to examine the role of HRV infection in infant respiratory tract illness and assess viral and host risk factors for HRV-associated disease severity. METHODS: We used a prospective cohort of term, previously healthy infants enrolled during an inpatient or outpatient visit for acute upper or lower respiratory tract illness during the fall-spring months of 2004-2008. Illness severity was determined by using an ordinal bronchiolitis severity score, with higher scores indicating more severe disease. HRV was identified by means of real-time RT-PCR. The VP4/VP2 region from HRV-positive specimens was sequenced to determine species. RESULTS: Of 630 infants with bronchiolitis or upper respiratory tract illnesses (URIs), 162 (26%) had HRV infection; HRV infection was associated with 18% of cases of bronchiolitis and 47% of cases of URI. Among infants with HRV infection, 104 (64%) had HRV infection alone. Host factors associated with more severe HRV-associated illness included a maternal and family history of atopy (median score of 3.5 [interquartile range [IQR], 1.0-7.8] vs 2.0 [IQR, 1.0-5.2] and 3.5 [IQR, 1.0-7.5] vs 2.0 [IQR, 0-4.0]). In adjusted analyses maternal history of atopy conferred an increase in the risk for more severe HRV-associated bronchiolitis (odds ratio, 2.39; 95% CI, 1.14-4.99; P = .02). In a similar model maternal asthma was also associated with greater HRV-associated bronchiolitis severity (odds ratio, 2.49, 95% CI, 1.10-5.67; P = .03). Among patients with HRV infection, 35% had HRVA, 6% had HRVB, and 30% had HRVC. CONCLUSION: HRV infection was a frequent cause of bronchiolitis and URIs among previously healthy term infants requiring hospitalization or unscheduled outpatient visits. Substantial viral genetic diversity was seen among the patients with HRV infection, and predominant groups varied by season and year. Host factors, including maternal atopy, were associated with more severe infant HRV-associated illness.

Assessment of severity measures for acute asthma outcomes: a first step in developing an asthma clinical prediction rule.

OBJECTIVE: As a first step in the development of an asthma prediction rule, our primary objective was to assess the association of 8 candidate predictor variables with 2 clinically relevant asthma outcomes. METHODS: Among a cohort of 125 adults hospitalized with an asthma exacerbation, we examined models to identify clinical variables associated with length of stay (LOS) and clinically significant asthma exacerbations within 3 months after hospitalization (3-month exacerbation). Eight candidate predictor variables were chosen, including age, sex, race, pulsus paradoxus, prior endotracheal intubation for asthma, hospitalization within 5 years for asthma, and 2 chronic asthma severity scores. RESULTS: We found independent associations between LOS and pulsus paradoxus (P = .005), prior intubation (P = .03), sex (P = .03), and prior hospitalization (P = .019). Among men, 52% had a 3-month exacerbation in comparison with 25% of women; and in multivariable analysis, male sex was independently associated with 3-month exacerbation (adjusted odds ratio = 5.1; 95% confidence interval = 1.37-18.9; P = .015). Participants with 3-month exacerbation had higher Johns Hopkins Allergy and Asthma Composite (JHAAC) chronic severity scores (median = 77; interquartile range = 57-91) than those who did not (median = 54; interquartile range = 35-69; P < .001) (for 40-unit increase, adjusted OR for 3-month exacerbation = 1.54; 95% confidence interval = 1.16-2.03; P = .003). In multivariable analysis, male sex and the JHAAC severity score were independently associated with 3-month exacerbation. CONCLUSIONS: Elevated pulsus paradoxus, prior intubation for asthma, and 5-year asthma hospitalization are independently associated with LOS. Race, 5-year asthma hospitalization, and JHAAC score predict 3-month asthma exacerbation. These variables warrant consideration for use in the development of an asthma prediction rule.

Changes in urinary dinor dihydro F(2)-isoprostane metabolite concentrations, a marker of oxidative stress, during and following asthma exacerbations.

To investigate changes in oxidant stress during and following acute asthma exacerbations, this study measured 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (F(2)-IsoP-M), the major urinary metabolite of 15-F(2t)-IsoP, in eight asthmatic adults, during and following an asthma hospitalization. F(2)-IsoP-M concentrations at admission and follow-up were significantly higher than discharge (admission median: 4.12 ng/Cr mg, range 1.89-7.8; follow-up: 2.47 ng/Cr mg (1.56-6.86); discharge: 1.42 ng/Cr mg (0.7-4.44); both p<0.01), but not significantly different between admission and follow-up. F(2)-IsoP-M concentrations at follow-up were higher than a control group with stable asthma (0.68 ng/Cr mg (0.31-1.5), p=0.0008). In conclusion, asthma exacerbations requiring hospitalization are associated with 6-fold higher urinary F(2)-IsoP-M concentrations compared to stable asthmatics. F(2)-IsoP-M concentrations decreased significantly during hospitalization, but significant elevations 3 months following hospitalization suggest ongoing oxidative stress despite clinical improvement. Urinary F(2)-IsoP-M may be a clinically useful, simple non-invasive systemic measure of oxidative stress in asthmatics, providing information not captured by spirometry or symptoms.

Prenatal nicotine exposure transiently alters the lung mechanical response to hypoxia in young lambs.

To test the hypothesis that fetal nicotine exposure alters the lung mechanical response to hypoxia (10% O(2)) 10 lambs were exposed during the last fetal trimester to a low dose nicotine (LN) and 10 to a moderate dose (MN) (maternal dose 0.5 and 1.5mg/(kgday) free base, respectively). There were 10 controls (C). At 12 days, minute ventilation increased significantly less in MN compared with LN but not with C. In contrast to C and LN, MN did not show anticipated increases in dynamic compliance, specific compliance and FRC or decrease in lung resistance but had signs of airway hyperreactivity during hypoxia. Nicotine exposure did not alter the cardiovascular response. These adverse effects decreased with advancing age. In summary, prenatal nicotine exposure alters the lung mechanical response to hypoxia. We speculate that prenatal nicotine-induced alterations of lung mechanics during hypoxia may contribute to an increased vulnerability to hypoxic stress during infancy.

Clinical measures associated with FEV1 in persons with asthma requiring hospital admission.

OBJECTIVE: We sought to determine the association of select clinical measures of asthma severity with percent predicted forced expiratory volume in one-second (%FEV1). METHODS: We studied a prospective cohort of adult subjects (N = 129) with asthma exacerbations requiring hospital admission. Clinical data was acquired, including medical and social history, symptoms, vital signs, physical assessment, and spirometry. Predictor variables for this study included manually determined pulsus paradoxus (PP), percent predicted peak expiratory flow rate (%PEFR) and accessory muscle use. The outcome measure was %FEV1. Multiple linear regression analyses were performed to determine the independent associations between predictor variables and %FEV1. RESULTS: In univariate analysis, %PEFR correlated with %FEV1 (rho = 0.77, P < .001) and PP correlated negatively with %FEV1 (rho = - 0.384, P < .001). %FEV1 was significantly lower in participants with accessory muscle use (Median %FEV1 = 37.5%, IQR: 27.0-49.0) than in those without accessory muscle use (Median %FEV1= 55.0%, IQR: 39.0-69.0), (P = .004). In multivariable analysis including the covariates %PEFR, accessory muscle use, PP, age, sex, heart rate and respiratory rate, %PEFR (P < .0001) and accessory muscle use (P = .003) remained significantly associated with %FEV1, whereas PP did not (P = .52).

Respiratory Severity Score Separates Upper Versus Lower Respiratory Tract Infections and Predicts Measures of Disease Severity.

Background: A respiratory severity score (RSS) describing acute respiratory illness (ARI) severity would be useful for research and clinical purposes. Methods: A total of 630 term infants presenting with ARI had their RSS measured. Results: RSS was higher in those with lower respiratory tract infection (LRTI) compared with those with upper respiratory infection (URI; LRTI 6.5 [4-8.5]; URI 1 [0-2], p<0.001) and in hospitalized infants compared with outpatients (hospitalized 6.5 [4-9]; outpatient 1 [0-3], p<0.001). Conclusions: RSS is higher in LRTI compared with URI and in hospitalized compared with nonhospitalized infants.

Gastroesophageal Reflux Disease Increases Infant Acute Respiratory Illness Severity, but not Childhood Asthma.

It is unknown whether gastroesophageal reflux disease (GERD) during infancy affects infant bronchiolitis severity or childhood asthma inception. Four hundred thirty-two infants presenting with acute respiratory illness due to bronchiolitis or upper respiratory infection were studied. The primary exposure was the parental report of a previous GERD diagnosis. Outcomes included bronchiolitis severity at initial presentation and childhood asthma diagnosis at age 4. Infants with parentally reported GERD had a higher bronchiolitis severity score (range=0-12, clinically significant difference=0.5), indicating more severe disease, than infants without reported GERD (median 5.5 [interquartile range 3.5-9.0] among those with reported GERD versus 4.0 [1.0-7.0] among those without, P=0.005). This association persisted after adjusting for infant age, race, gender, and secondhand smoke exposure by a propensity score (adjusted odds ratio [OR] 1.99, 95% confidence interval [CI] 1.14-3.46, P=0.02). The parental report of GERD during infancy was not associated with the parental report of asthma diagnosis at age 4. GERD during infancy may contribute to acute respiratory illness severity, but is not associated with asthma diagnosis at age 4. Future prospective studies are needed to confirm these findings.

Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during 4 consecutive years.

BACKGROUND: Prospective data on viral etiology and clinical characteristics of bronchiolitis and upper respiratory illness (URI) in infants are limited. METHODS: This prospective cohort enrolled previously healthy term infants during inpatient or outpatient visits for acute URI or bronchiolitis during September to May 2004 to 2008. Illness severity was determined using an ordinal bronchiolitis severity score. Common respiratory viruses were identified by real-time reverse-transcriptase polymerase chain reaction. RESULTS: Of 648 infants, 67% were enrolled during inpatient visits and 33% during outpatient visits. Seventy percent had bronchiolitis, 3% croup and 27% URI. Among infants with bronchiolitis, 76% had respiratory syncytial virus (RSV), 18% human rhinovirus (HRV), 10% influenza, 2% coronavirus, 3% human metapneumovirus and 1% parainfluenza virus. Among infants with croup, 39% had HRV, 28% parainfluenza virus, 28% RSV, 11% influenza, 6% coronavirus and none human metapneumovirus. Among infants with URI, 46% had HRV, 14% RSV, 12% influenza, 7% coronavirus, 6% parainfluenza virus and 4% human metapneumovirus. Individual viruses exhibited distinct seasonal, demographic and clinical expression. CONCLUSIONS: The most common infections among infants seeking care in unscheduled medical visits for URI or bronchiolitis were RSV and HRV. Demographic differences were observed between patients with different viruses, suggesting that host and viral factors play a role in phenotypic expression of viral illness.

Fetal nicotine exposure increases airway responsiveness and alters airway wall composition in young lambs.

To test the hypotheses that fetal nicotine exposure alters airway wall composition and enhances the airway response to inhaled methacholine (MCh), lambs were exposed during the last fetal trimester to (1) a low dose (LN) (n=13, 0.5mg/kg/d (maternal weight) of free base nicotine, (2) a moderate dose (MN) (n=10, 1.5mg/kg/d) or (3) saline (n=14). Studies were performed at postnatal days 12, 26 and 52. Prenatal nicotine exposure induced a dose- and age-related hyper-responsiveness to MCh in the proximal airways. Moment analysis of nitrogen decay curves showed no nicotine or MCh effects on ventilation homogeneity or gas-mixing efficiency in the distal airways during MCh inhalations suggesting a bimodal response. Fetal nicotine exposure increased epithelial mucosubstance volume in central (LN, MN) and distal bronchi (LN), increased smooth muscle volume in distal bronchi and bronchioles (LN) and decreased bronchiolar diameter (MN). In conclusion, third trimester nicotine exposure causes hyperreactive proximal airways and alters proximal airway wall composition associated with airflow limitation.

The relationship of rhinovirus-associated asthma hospitalizations with inhaled corticosteroids and smoking.

BACKGROUND: Although rhinovirus (RV) respiratory infections trigger asthma exacerbations, the etiologic association between this virus and severe exacerbations, as well as the clinical characteristics of adults at risk for RV-associated asthma that necessitates hospitalization, have not been established. METHODS: During 1999-2003, we conducted a cohort study of 101 adults prospectively enrolled at hospital admission for an asthma exacerbation. Patient characteristics and frequencies of RV in nasal specimens were analyzed, by reverse-transcription polymerase chain reaction (RT-PCR), at asthma-related hospital admission and at a 3-month convalescent follow-up visit. RESULTS: RV was detected by RT-PCR in 21% of hospitalized patients over a 4-year period and in 1.3% of patients who returned for a 3-month follow-up visit. RV detection was strongly associated with hospitalization for asthma (adjusted odds ratio [OR], 15.1 [95% confidence interval {CI}, 1.88-121.4]). After adjustment for baseline asthma severity, RV-positive patients were more likely than RV-negative patients to be current smokers and nonusers of inhaled corticosteroids (ICSs) (adjusted OR, 11.18 [95% CI, 2.37-52.81]; P=.002). CONCLUSIONS: RV respiratory infection is an etiologic agent in severe asthma exacerbations necessitating hospitalization in adults. Compared with hospitalized patients with asthma who were RV negative, RV-positive patients were significantly more likely to be smokers and nonusers of ICSs.