Recurrent Lower Respiratory Tract Symptoms Research Articles

Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia.

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.

Lung Function, Airway Remodeling, and Inflammation in Infants: Outcome at 8 Years

K Malmstrom, LP Malmberg, R O’Reilly Ann Allergy Asthma Immunol 2015;114(2):90–96 To determine the predictive value of lung function and airway pathology in infancy for asthma, lung function, airway responsiveness, and purchase of asthma medications at 8 years of age. The study included 47 of 53 children who had undergone pulmonary function testing and bronchoscopy in infancy because of recurrent lower respiratory tract symptoms who were available for follow-up at 8 years of age, compared with 63 healthy, age-matched controls who were able to perform spirometry. Current or past symptoms, physician-diagnosed asthma, use of inhaled …

Factors Associated With Elevated Exhaled Nitric Oxide Fraction in Infants With Recurrent Respiratory Symptoms

A Kotaniemi-Syrjanen, LP Malmberg, K Malmstrom, AS Pelkonen, MJ Makela. Eur Respir J. 2013;41(1):189–194 To evaluate the relationship between exhaled nitric oxide fraction (FeNO) and increased airway responsiveness, and to clarify whether there are any associations between these measures and risk factors for respiratory morbidity in infants with recurrent lower respiratory tract symptoms. Studied subjects were 444 children aged <3years with recurrent lower respiratory tract symptoms including wheeze, dry or productive cough, and/or shortness of breath. Subjects were assessed for FeNO, lung function tests, and the …

Factors associated with elevated exhaled nitric oxide fraction in infants with recurrent respiratory symptoms

Exhaled nitric oxide fraction (F(eNO)) has been proposed as a noninvasive marker of eosinophilic bronchial inflammation in active asthma, and supposed to reflect responsiveness to corticosteroid therapy. There are several factors influencing F(eNO), and its role in early childhood respiratory disorders needs to be established. Between 2004 and 2008, 444 children aged <3 yrs with recurrent lower respiratory tract symptoms were referred to a tertiary centre for further investigation. 136 full-term, steroid-free, infection-free infants, median age of 16.4 months (range 4.0-26.7 months), successfully underwent measurement of F(eNO), lung function tests, and a dosimetric methacholine challenge test. The median level of F(eNO) was 19.3 ppb (interquartile range 12.3-26.9 ppb). Elevated F(eNO) (≥ 27 ppb, the highest quartile) was associated with maternal history of asthma (adjusted OR 3.2, 95% CI 1.3-8.1; p=0.012), and increased airway responsiveness (the provocative dose of methacholine causing a 40% fall in maximal expiratory flow at functional residual capacity ≤ 0.30 mg) (adjusted OR 4.1, 95% CI 1.4-12.7; p=0.012). Atopy, blood eosinophilia and lung function were not associated with elevated F(eNO). In conclusion, maternal history of asthma, and increased airway responsiveness are associated with elevated F(eNO) in infants with recurrent lower respiratory tract symptoms.

Clinical findings associated with abnormal lung function in children aged 3–26 months with recurrent respiratory symptoms

To evaluate whether there are any associations between parentally reported symptoms, clinical findings and lung function in young children with recurrent lower respiratory tract symptoms. In 2000-2003, 148 children, aged 3-26 months, with recurrent lower respiratory tract symptoms underwent physical examination, investigation of a chest radiograph, whole body plethysmography and skin prick testing to common food and inhalant allergens. Lung function was considered abnormal (i.e. functional residual capacity z-score of > or =1.65 and/or specific conductance z-score of < or =-1.65) in 83 (56%) children. Findings of increased work of breathing (p < 0.001) and nonspecific noisy breathing sounds (p < 0.001) in the physical examination, as well as an abnormal chest radiograph (p = 0.028) were independently associated with abnormal lung function, explaining up to 34% of the variation in lung function. In contrast, parentally reported respiratory symptoms, environmental exposures or atopic trait were not associated with lung function abnormalities. The results of this study emphasize the importance of the meticulous clinical examination in the evaluation of early childhood respiratory disorders. As physical examination alone cannot predict lung function abnormalities reliably in preschool children with troublesome respiratory symptoms, lung function testing may be considered in such patients to obtain additional objective information.

Infants with recurrent lower respiratory tract symptoms - who benefits of extensive investigations?

There is limited information on lung function and exhaled nitric oxide fraction (FeNO) in infants with recurrent lower respiratory tract symptoms. In 2000–2003, 201 recurrently symptomatic infants were referred to a tertiary center for further investigation. As part of the clinical investigation, whole-body plethysmography, tidal FeNO measurements, and skin prick tests were performed. In addition, 77 (38%) of the children underwent bronchoscopy. Increased work of breathing in clinical examination (in 22%), and abnormal chest radiograph (in 30%), were associated with decreased airway conductance (sGaw z-score ≤−1.65) (p

Airway responsiveness: associated features in infants with recurrent respiratory symptoms

Increased airway responsiveness (AR) is one of the main pathophysiological manifestations of asthma. The present study aimed to define the clinical features associated with increased AR in infants with recurrent lower respiratory tract symptoms. AR was evaluated by performing a novel dosimetric methacholine challenge test. Increased AR to methacholine, defined as a methacholine dose of < or =0.90 mg producing a 40% fall (PD(40)) in the maximal flow at functional residual capacity (V'(max,FRC)), was associated with atopy (odds ratio (OR) 4.1; 95% confidence interval (CI) 1.3-13.3), a history of physician-confirmed wheezing with respiratory syncytial virus (OR 32.9; 95% CI 2.5-428.8) or of a nonspecified aetiology (OR 4.9; 95% CI 1.1-22.5), functional residual capacity z-score > or =2 (OR 36.8; 95% CI 2.9-472.6), and V'(max,FRC) z-score (OR 0.5; 95% CI 0.2-0.9) at baseline, when compared with infants with only mild or no responsiveness to methacholine (PD(40) V'(max,FRC) >0.90 mg). In conclusion, in recurrently symptomatic infants, increased airway responsiveness is associated with reduced baseline lung function, an atopic trait of the child, a history of physician-confirmed wheeze and viral aetiology of wheeze. Future intervention studies are needed to confirm the role of airway responsiveness in respiratory morbidity during infancy.

Effect of Atopy on the Natural History of Symptoms, Peak Expiratory Flow, and Bronchial Responsiveness in 7- and 8-Year-Old Children with Cough and Wheeze: A 12-Month Longitudinal Study

Recurrent lower respiratory tract symptoms are common and disabling in childhood, but little is known of their natural history and relationship to asthma. We report a 12-month longitudinal study designed to determine the influence of atopy on respiratory symptoms and bronchial responsiveness in 7- and 8-yr-old children. A postal questionnaire inquiring into the presence of respiratory symptoms was sent to 3,698 children aged 7 and 8 yr. Those reporting either current wheeze (14.8%) or current cough in the absence of wheeze (12.8%) were randomized, and a sample was invited to attend for skin testing. The following groups of symptomatic children entered the longitudinal study: 48 atopic children with cough, 48 atopic children with wheeze, 48 nonatopic children with cough, and 48 nonatopic children with wheeze. All children recorded twice daily the best of three peak expiratory flow (PEF) measurements and completed a 10-point symptom score card, each day for 1 yr. They also recorded all treatment taken and made a note of relevant life events. Each child was seen monthly for general assessment and for measurement of methacholine bronchial responsiveness. Despite the arduous nature of the study 183 of the 192 children (95.3%) successfully completed the 12 months of observation. Symptom groups were compared with regard to FEV1, bronchial responsiveness, symptom chronicity and severity, and diurnal and day-to-day variation in PEF. Atopy was associated with a lower FEV1, increased prevalence of bronchial hyperresponsiveness, greater within-day and between-day variation in PEF, and greater severity of respiratory symptoms compared with the absence of atopy. Wheeze was associated with lower FEV1, increased prevalence of bronchial hyperresponsiveness, greater within-day and between-day variation in PEF1 and greater severity of respiratory symptoms compared with cough [corrected].

Acute and long-term effects of viral bronchiolitis in infancy

About 1% of infants are admitted to hospital with acute bronchiolitis; 85% of cases are caused by infection with Respiratory Syncytial Virus (RSV). The pathophysiological changes during the acute illness are inflammatory obstruction in the small airways with submucosal cellular infiltration, epithelial necrosis and mucous plugging; FRC increases and dynamic compliance falls. Failure to respond to bronchodilator drugs suggests that muscle spasm contributes relatively little to the airway narrowing. Affected infants become increasingly dyspnoeic and hypoxic for 3-4 days then spontaneously improve. After an attack of acute bronchiolitis up to 75% of children have recurrent lower respiratory tract symptoms, many continue to have hyperinflated lungs and bronchial hyperresponsiveness. In the majority, symptoms of cough and wheezing have subsided by the time they start school, but abnormalities of small airway function are detectable at least 13 years later. Children with a genetic predisposition to atopy do not appear to have an increased risk of developing bronchiolitis. Evidence of genetic predisposition to bronchial hyperresponsiveness in those with persistent wheezing is controversial. There is little to suggest that neonatal lung damage or an adverse home environment are important factors in determining susceptibility to post-bronchiolitis wheezing. IgE antibodies to RSV, and leukotriene C4, are found more frequently in the respiratory secretions of infants who wheeze during and after bronchiolitis than in those who do not. The possibility of viral-induced alteration of the immune response at the time of infection needs further investigation.

Esophagitis and Findings of Long‐Term Esophageal pH Recording in Children with Repeated Lower Respiratory Tract Symptoms

Summary:Esophagoscopy was performed on 116 children with recurrent lower respiratory tract symptoms; esophagitis of various degrees was detected in 45% of the cases. The presence of verified esophagitis correlated with endoscopic findings of bile‐stained gastric contents, suggesting a role of bile reflux in the pathogenesis. Esophageal pH recordings covering an 18‐24‐h period were performed on 22 patients with esophagitis and 19 patients without esophagitis. Gastroesophageal reflux (GER) during the sleeping period was detected in 95% of children with esophagitis, as compared to 42% in children with no esophagitis (p &lt; 0.001). The percentage of time with esophageal pH below 4 of the total registration time was significantly greater (p &lt; 0.05) in children with esophagitis (9.5%) than in those with no esophagitis (4.0%)—the difference being due to a greater share of nocturnal GER of the recording time. These criteria could be applied to a search for clinically significant GER in children with recurrent lower respiratory tract symptoms and to select patients for esophagoscopy.

Esophagitis and Findings of Long-Term Esophageal pH Recording in Children with Repeated Lower Respiratory Tract Symptoms

Esophagoscopy was performed on 116 children with recurrent lower respiratory tract symptoms; esophagitis of various degrees was detected in 45% of the cases. The presence of verified esophagitis correlated with endoscopic findings of bile-stained gastric contents, suggesting a role of bile reflux in the pathogenesis. Esophageal pH recordings covering an 18-24-h period were performed on 22 patients with esophagitis and 19 patients without esophagitis. Gastroesophageal reflux (GER) during the sleeping period was detected in 95% of children with esophagitis, as compared to 42% in children with no esophagitis (p less than 0.001). The percentage of time with esophageal pH below 4 of the total registration time was significantly greater (p less than 0.05) in children with esophagitis (9.5%) than in those with no esophagitis (4.0%)--the difference being due to a greater share of nocturnal GER of the recording time. These criteria could be applied to a search for clinically significant GER in children with recurrent lower respiratory tract symptoms and to select patients for esophagoscopy.