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The effect of viral infection on nasopharyngeal carriage of Streptococcus pneumoniae during childhood is not well known. We studied dynamics of pneumococcal colonization by quantitative PCR during the natural course of viral bronchiolitis. At time of admission, 47 (47%) of 100 patients with bronchiolitis carried pneumococci. In patients with viral bronchiolitis who did not receive antibiotics, pneumococcal load decreased from time of admission to discharge (n = 35, cycle threshold 23 vs. 25, P = 0.0017) and from discharge to follow-up (n = 22, cycle threshold 25 vs. 40, P = 0.003). We conclude that viral respiratory infection is negatively associated with pneumococcal colonization of the upper airways. Pediatr Pulmonol. 2016;51:863-867. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Viral bronchiolitis is a major cause of hospitalization in infancy, with increased asthma risk in later childhood. However, the principal mechanisms behind post-bronchiolitic asthma have remained unclear. Previously, different cytokine polymorphisms have been associated with asthma occurrence, but no previous follow-up study has investigated cytokine polymorphisms in relation to post-bronchiolitic asthma. We hypothesized that former bronchiolitis patients with cytokine gene variants associating with Th2 cell up-regulation are at asthma risk at preschool age. Our emphasis was in IL10 rs1800896, since IL-10 has an important role in immune tolerance, and lower production of IL-10 has been associated with Th2-type immunology, and accordingly, with increased asthma risk. IL10 rs1800896, IFNG rs2430561, and IL18 rs1872387 polymorphims and their associations with asthma and allergy were studied in 135 preschool-aged children hospitalized for bronchiolitis at age 0-6 months. Parents were interviewed to record asthma and allergy from infancy to present. At age 6.4 years (mean), asthma was present in 17(12.6%), atopic eczema in 47(34.8%) and allergic rhinitis in 36(26.7%) children. IL10 rs1800896 SNP associated significantly with asthma; only 1/32 (3.1%) of those with G/G genotype had asthma (P = 0.04). In logistic regression adjusted for gender, age and atopy, the carriage of allele A (rs1800896) was a significant risk factor for preschool asthma. IFNG rs2430561 or IL18 rs1872387 SNP's had no associations with asthma or allergy. In conclusion, IL10 rs1800896 SNP was significantly associated with preschool asthma after severe lower respiratory tract infection in early infancy., (© 2013 Wiley Periodicals, Inc.)

Bronchiolitis in infancy is a risk factor for development of asthma in the first decades of life, although the majority may be asymptomatic at school age. Respiratory symptoms are common in early life, and prediction of later asthma may be challenging. We aimed to study if simple clinical variables assessed at 2 years of age could predict asthma at 11 years of age and thereby provide a basis for follow-up and treatment after bronchiolitis in infancy. The study included 105 children hospitalized for bronchiolitis during their first year of life. Of these, 101 (96.2%) participated in the first follow-up at 2 years of age and 93 (88.6%) in the second follow-up at age 11. The overall prevalence of asthma at 11 years of age was 22.6%. Among the risk factors assessed at 2 years of age, recurrent wheeze appeared most important (odds ratio for later asthma: 7.2; 95% confidence interval: 1.3, 41.6; P = 0.015). Tested separately, recurrent wheeze had high sensitivity (90.5%), but low specificity (58.3%), low negative likelihood ratio (LR) (0.2) and low negative post-test probability (4.5%); indicating that absence of recurrent wheeze was better suited to exclude than to predict asthma at 11 years of age. Combining recurrent wheeze with either parental atopy, parental asthma or atopic dermatitis improved the specificity (>80), positive LR (>3) and positive post-test probability (∼50%), rendering the combinations more appropriate for the prediction of later asthma. In conclusion, after bronchiolitis in infancy, simple clinical non-invasive variables assessed at 2 years of age could predict asthma at 11 years of age with reasonable accuracy. However, the data were better suited to exclude than to predict later asthma., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: (1) To examine whether infants with severe bronchiolitis, fulfilling criteria for further respiratory support, could be managed outside a Pediatric Intensive Care Unit (PICU) with non-invasive ventilation (NIV) alone. (2) To study the characteristics, clinical course and outcome of NIV responders and non responders to assess safety and efficacy and inform guideline construction., Hypothesis: Infants with severe bronchiolitis can be safely managed with NIV outside a PICU., Study Design: Retrospective case review., Patient Selection: Cohort of infants with objective evidence of severe bronchiolitis requiring respiratory support nursed in a Pediatric High Dependency Unit (PHDU) and/or Intensive Care Unit (ICU) between 2001 and 2007., Methodology: Analysis of patient characteristics and respiratory parameters at admission and initiation of ventilation, changes after 2 and 4 hr of NIV or invasive ventilation, complications, short and long-term outcomes were analyzed., Results: One thousand and thirty-five infants with bronchiolitis were admitted with 67 ventilation episodes identified from 65 patients. Fifty-five episodes, including 34 with apnea, were treated exclusively with NIV. Six infants failed to respond and were invasively ventilated. Six patients were invasively ventilated at presentation. Non-responders had a significantly higher rate of bacterial infection. Significant improvements in respiratory parameters in responders occurred by 2 hr and sustained at 4 hr. Duration of hospital stay, ventilation requirement and oxygen requirement were significantly shorter in responders. Short and longer-term follow up data did not identify any adverse effects related to NIV., Conclusions: NIV was effective in 80% of infants receiving respiratory support for severe bronchiolitis., (Copyright © 2012 Wiley Periodicals, Inc.)

Study Objectives: To examine the hypothesis that children who suffered from severe respiratory syncitial virus (RSV) bronchiolitis during infancy may be at higher risk for obstructive sleep apnea (OSA) later in childhood., Methods: Survey of Kosair Children's Hospital medical records allowed for identification of potential candidates for the study. Twenty-one randomly selected children (mean age +/- SD: 5.2 +/- 1.5 years) with a history of verified RSV-induced bronchiolitis during their first year of life underwent overnight sleep study (NPSG). Children recruited from the general population with no history of RSV bronchiolitis served as a control group. After matching for age, gender, ethnicity, gestational age at birth, body mass index (BMI) z scores, household cigarette smoking, history of asthma and allergies, 63 control subjects (mean age +/- SD: 5.1 +/- 0.7 years) were also studied., Results: Children who had RSV bronchiolitis as infants had significantly higher obstructive apnea/hypopnea index compared to controls (2.3 +/- 1.9 vs. 0.6 +/- 0.8 /hr total sleep time (TST); P < 0.05). In addition, significantly higher respiratory arousal indices were apparent among children with previous RSV bronchiolitis compared to controls (1.3 +/- 1.0 vs. 0.1 +/- 0.2 /hr TST; P < 0.05). There were no significant differences between the groups in the lowest SpO(2), ETCO(2), and sleep indices., Conclusions: RSV bronchiolitis may contribute to the pathophysiology of OSA in vulnerable children.

To evaluate whether KL-6 concentration is a useful biomarker of the severity of respiratory syncytial virus (RSV) bronchiolitis, we determined KL-6 concentrations in patients with RSV bronchiolitis with or without chronic heart disease (CHD). We enrolled 52 patients who had been diagnosed with RSV bronchiolitis and required admission to the hospital at the Department of Pediatrics of Fukushima Medical University School of Medicine from 2004 to 2005. These patients were divided into two groups: Group 1 consisted of patients without any underlying disease, and Group 2 consisted of patients with CHD. These patients were assigned to three categories. Stage A consisted of patients without oxygen dosage, stage B of patients who required oxygen dosage, and stage C of patients required artificial respiration. We evaluated baseline characteristics, clinical features, and serum KL-6 concentration in Group 1, Group 2, and a control group (healthy infants without infection). Mean serum KL-6 concentrations in patients with RSV bronchiolitis were higher than those in the control group (471.8 +/- 236.9 and 127.1 +/- 69.1 U/ml, respectively). Mean serum KL-6 concentration was higher in Group 2 than in Group 1 (692.8 +/- 313.1 and 390.4 +/- 132.7 U/ml, respectively). Mean serum KL-6 concentrations were higher in stage C than in stages A and B, and mean serum KL-6 concentrations were higher in stage B than in stage A. These findings suggest that serum KL-6 is associated with the severity of RSV bronchiolitis and that it may be a useful biomarker for the severity of RSV bronchiolitis., ((c) 2009 Wiley-Liss, Inc.)

Objectives: The purpose of this study was to report the clinical features and outcome of all children with a laboratory proven diagnosis of respiratory virus infection admitted to a university Pediatric Intensive Care Unit (PICU)., Methods: Retrospective study between January 2003 and April 2007 was carried out in the PICU. Every child with a laboratory-confirmed viral infection was included., Results: 54 viruses were identified in 49 children (27 M, 22 F) over a 52-month period. The three respiratory virus species, respiratory syncytial virus (RSV) (n = 17), influenza (n = 13) and parainfluenza (n = 12), accounted for 86% of these 49 cases. PICU admissions due to influenza A (n = 10) were more common than influenza B (n = 3), whereas parainfluenza type 3 (n = 7) was the commonest subtype of parainfluenza infection. Comparing these three common viruses, the mean age of children admitted with RSV was lower than with influenza or parainfluenza (1.2 years vs. 5.6 years vs. 2.4 years, P = 0.003). Pre-existing conditions such as prematurity and chronic lung disease were only present in children with RSV infection. These respiratory viruses caused both upper (croup) and lower respiratory tract diseases (bronchiolitis, pneumonia). Extrapulmonary presentations were less prevalent and included encephalitis, seizures, cardiac arrest, coexisting diabetes ketoacidosis and acute lymphoblastic leukemia. One patient with RSV and another with influenza A died during their PICU stay. Nearly half of these patients required ventilatory support or received systemic corticosteroids, and 88% received initial broad spectrum antibiotic coverage. Approximately one in five of them had nebulised adrenaline, airway endoscopies or bacterial co-infections. Adenovirus was isolated in four patients and two (both with adenovirus type 3) died during the PICU stay., Conclusions: In PICU, respiratory viral infections were associated with significant morbidity and life-threatening conditions., ((c) 2008 Wiley-Liss, Inc.)

Acute respiratory syncytial virus (RSV)-induced bronchiolitis is often associated with continuing respiratory symptoms following hospitalization. To date, there is no validated objective measure to evaluate symptoms of RSV-induced bronchiolitis. We report on the reliability, validity, and responsiveness of the bronchiolitis caregiver diary (BCD) of symptoms and healthcare utilization associated with postacute RSV. The BCD measures four symptoms (daytime cough, wheeze, trouble breathing, and nighttime cough), healthcare utilization, and rescue medication for worsening of lung symptoms. Data from the 4-week treatment period of the reported prospective, placebo-controlled trial of montelukast for treatment of postacute RSV were used to assess reliability (internal consistency and test-retest), construct validity (cross-sectional and longitudinal correlations), discriminant validity (known-groups analyses), and responsiveness. The primary outcome of this study was the percentage of symptom-free days (SFD). The secondary outcome was a composite symptom score (CSS; average of daytime cough, wheezing, and trouble breathing). Cronbach's alpha of 0.85 indicated that the four symptoms were internally consistent, supporting a unidimensional scale structure. Test-retest reliabilities for the percentage of SFD and CSS were above the recommended cut point of 0.70. Cross-sectional and longitudinal correlations were sizeable and statistically significant, demonstrating construct validity. Hypothesized known-group differences were statistically significant in the appropriate direction. Responsiveness analyses indicated moderate effect sizes for percentage of SFD. In conclusion, the BCD provides a valid, reliable, and responsive tool for the assessment of symptoms of postacute RSV-induced bronchiolitis, capable of measuring moderate effect sizes, and demonstrating responsiveness to therapy., (Copyright 2005 Wiley-Liss, Inc.)

The objective of this study was to evaluate the presence of indicators of aspiration in previously healthy infants with respiratory syncytial viral (RSV) bronchiolitis who experienced rapid deterioration in their respiratory status. Lipid-laden macrophage index (LLMI) was assessed in 6 previously healthy infants with RSV bronchiolitis and no prior history of aspiration, who had a rapid deterioration of their respiratory status requiring mechanical ventilation. Five of 6 infants had a LLMI of more than 100, a level that is very suggestive of aspiration. We conclude that aspiration is likely to play a role when rapid deterioration occurs in infants with RSV bronchiolitis., (Copyright 2002 Wiley-Liss, Inc.)

We performed a prospective observational study to define the clinical course and the prognostic factors of 31 patients with postinfectious bronchiolitis obliterans. All patients presented with an episode of acute bronchiolitis in the first 2 years of life, and respiratory symptoms and signs persisted since then. Other diseases which may cause chronic airflow obstruction were excluded. The patients were followed after their inclusion in the study and the clinical findings were recorded in a standardized questionnaire and form. Repeated chest radiographs and lung perfusion scans were obtained in all 31 patients and semiannual spirometry was performed in 8 older patients. Eight patients had lung biopsies. The clinical course varied in the 31 patients during a mean of 3.5 years of follow-up. The outcome of the patients included clinical remission (22.6%), persistence of respiratory symptoms and signs (67.7%), and death (9.7%). An older age at onset of illness and presence of atopy as suggested by an elevated serum IgE appeared to predispose to a poor prognosis., (Copyright 2000 Wiley-Liss, Inc.)

Airway responsiveness to inhaled methacholine was assessed in 18 infants, 4 and 10 months old, following bronchiolitis. Pulmonary function was measured from partial expiratory flow-volume curves generated by the rapid compression technique. Sleeping infants inhaled increasing concentrations of methacholine until maximal expiratory flows at functional residual capacity (VmaxFRC) decreased by 30% or 2.5 mg/mL was inhaled. Airway responsiveness was quantitated by: 1) the threshold concentration (log TC) required to decrease VmaxFRC by 2 standard deviations from baseline; 2) the concentration required to decrease VmaxFRC by 30% (log PC30); and 3) the slope of the dose-response curve between TC and PC30 (log SPC30). At both the first and second evaluation, the bronchiolitic infants had lower baseline VmaxFRC (% pred.) than 24 control infants. In addition, the bronchiolitic infants had heightened airway responsiveness compared to controls, demonstrating lower values for logTC and logPC30 and steeper slopes to their dose-response curves (logSPC30). After accounting for the relationship between airway responsiveness and age, the occurrence of bronchiolitis was found to be a significant independent factor 10 months but not 4 months following bronchiolitis. The bronchiolitic infants did not demonstrate the decline in airway responsiveness with increasing age that occurs in normal infants. We conclude that infants exhibit heightened airway responsiveness following bronchiolitis.

We determined the effects of an immediately antecedent viral lower respiratory tract infection (LRI) on the severity of clinical illness, changes in lung function and airway histamine responsiveness produced by a subsequent LRI in 9-12 week old beagle puppies inoculated with canine adenovirus 2, followed in 2 weeks by inoculation with canine parainfluenza 2 virus (CAV2-CP12, n = 7). We compared their acute responses to puppies infected with CP12 alone (n = 5), CAV2 alone (n = 7), and no infection (control, n = 6). Puppies inoculated with either virus alone developed a LRI 3 to 6 days after inoculation which resolved by 12-14 days after inoculation. However, the illness was more severe in the CAV2 group. In the CAV2-CP12 group, CP12 infection following CAV2 infection resulted in a clinical illness nearly comparable to that observed with CAV2 alone. Whereas in control and CP12 puppies, lung resistance (RL) decreased and dynamic lung compliance (Cdyn) increased during the study due to normal growth, RL increased and Cdyn remained unchanged in the CAV2 group. In contrast, RL did not change and Cdyn increased in the CAV2-CP12 group. Airway histamine responsiveness in the CAV2-CP12 group increased during infection with CP12 and was similar to that observed with CAV2 alone. In contrast, infection with CP12 alone produced a small, but non-significant increase in histamine responsiveness. The duration of the increase in histamine responsiveness was not prolonged in the CAV2-CP12 group in comparison to CP12 or CAV2 alone. However, the length of clinical illness was extended in the CAV2-CP12 group in comparison to the other infected groups. These data suggest that an immediately antecedent viral LRI can potentiate the clinical and physiologic effects of a subsequent viral LRI.

It has been suggested that thoracic gas volume (TGV) measured in infants in a plethysmograph most accurately represents true lung volume when calculated from end-inspiratory airway occlusions. The rationale proposed is that pressure measured at the mouth underestimates alveolar pressure more at end-expiration than at end-inspiration, presumably due to small airway closure, and this results in greater overestimation of TGV. To investigate this possibility we calculated TGV in 40 wheezy infants from occlusions at both end-inspiration (TGVei) and end-expiration (TGVee) using a 60 L whole body plethysmograph. TGV was corrected for equipment dead space and tidal volume. When a significant change in TGV was defined as lying outside the 95% confidence interval of the TGVee measurements, 8 of the 40 infants tested had significantly higher TGV values measured from occlusions made at end-expiration, while two infants had significantly lower TGV values measured from occlusions made at end-expiration. This trend was not more common in infants with "concave" flow-volume curves. Although it is technically easier to make occlusions at end-expiration, occluding at end-inspiration may minimize errors of TGV measures in a few individuals due to small airway closure at low lung volumes.

Partial expiratory flow-volume curves are commonly used in infant pulmonary function testing. The flow measurements are volume dependent and thoracic gas volume (TGV) is often measured in conjunction with forced expiratory maneuvers. Since it is not possible to make continuous, simultaneous measurements of TGV during forced expiration, it is assumed that lung volume returns to its original value after forced expiration. To test this assumption we measured TGV using a whole body plethysmograph in 14 wheezy infants before and after a series of forced expirations produced with an inflatable jacket. Forced expiration did not cause a significant change in group mean TGV measurements. Examination of individual data did not show any systematic difference between TGV measured before and after forced expiration. These results suggest that repeated forced expirations do not alter TGV within the time scale of usual pulmonary function testing protocols.

An unusually large number of infants (82) were admitted to Stanford University Hospital from November 1, 1983, through May 31, 1985, with a diagnosis of bronchiolitis requiring oxygen therapy. A larger percentage of these infants (17/82 = 21%) than generally expected required mechanical ventilation for respiratory failure. Fourteen infants had respiratory syncytial virus (RSV) infections, and three had parainfluenza virus infections. Ten patients had respiratory difficulties as neonates. The mechanical ventilation of the children requiring respiratory assistance was characterized by high minute ventilation with high tidal volumes (15 to 20 ml/kg) and slow respiratory rates (16 to 22 breaths/min). Peak inspiratory pressure averaged (mean +/- SD) 35 +/- 6 cm H2O in the RSV group and 34 +/- 6 cm H2O in the parainfluenza group. The mean number of days on the ventilator was 9.7 +/- 3.1 for the RSV group and 8.3 +/- 2.9 for the parainfluenza group. All were extubated within 17 days of presentation and discharged within 28 days. The complications encountered included pneumothorax and acute pulmonary hypertension.

A prospective follow-up of 48 infants hospitalized with respiratory syncytial virus bronchiolitis in the first year of life revealed that 44 of these infants had symptoms suggestive of asthma in the 5 years following their initial illness (cumulative prevalence 92%). Symptoms became less frequent and less troublesome during the follow-up period. Thirty-five of these children visited the laboratory for clinical examination, pulmonary function testing, and histamine challenge. Twenty-five children were believed to have clinical evidence of asthma at the time of the laboratory visit (point prevalence 71%). Five children were unable to perform pulmonary function tests; 25 of the remaining 30 (67%) had a positive histamine challenge test. No relationship could be demonstrated between a clinical diagnosis of asthma, a family history of atopy, and the results of histamine challenge testing. These results question the relationship between the results of bronchial provocation tests and clinical asthma in this age group.

Lung function was measured in nine infants, ages 15-36 weeks, who had persistent wheezing, apparently following acute bronchiolitis, before and after 2 weeks of treatment with either inhaled nebulized beclomethasone dipropionate (BDP) or placebo in a randomized, double blind, crossover trial. The effect of nebulized albuterol (Salbutamol) was measured before and after the steroid treatment. Thoracic gas volume (TGV) and specific airway conductance (SGaw) were determined using a whole body plethysmograph, and forced expiratory flow at resting lung volume (VmaxFRC) was determined with a thoracoabdominal compression jacket. All infants had marked airways obstruction before treatment with mean +/- SE VmaxFRC of 24 +/- 4% predicted and SGaw of 37 +/- 5% predicted. Two weeks of placebo treatment had no significant effect on lung function, but after 2 weeks of BDP inhalation there was a significant rise in SGaw to 61 +/- 7% (P less than 0.005). VmaxFRC increased to 42 +/- 13% but the difference did not reach significance. Respiratory rate and clinical score for retractions and wheezing also fell significantly with BDP therapy (P less than 0.01 and P less than 0.001 respectively). Albuterol had no effect on lung function either before or during steroid therapy. Steroids may have a role in the management of persistent wheezing following bronchiolitis.

Airway reactivity and the effects of bronchodilators in infants are controversial. We studied the response to bronchodilator treatment in 14 mechanically ventilated infants (mean age, 2.74 months; range, 0.6-5.9) in respiratory failure caused by respiratory syncytial virus (RSV)-associated bronchiolitis. Sixteen infants without lung disease, undergoing elective surgery, provided normal values. Maximum expiratory deflation flow-volume (DFV) curves were produced by manual inflation of the lungs with an anesthesia bag to a predetermined static airway pressure followed by rapid deflation with a negative airway pressure before and after administration of bronchodilator. At baseline, the bronchiolitis group had a forced vital capacity (FVC) of 34.5 +/- 3.6 ml/kg compared with 41.8 +/- 1.5 ml/kg in the normal group; maximum expiratory flow rate at 25% of FVC (MEF25) was 10.2 +/- 2.0 ml/kg/s compared with 27.3 +/- 2.0 ml/kg/s in the normal group. The clinical and radiologic impression was severe lower airway obstruction and air trapping. After administration of bronchodilator, FVC did not increase significantly, but MEF25isov increased by over 30% in 13 of 14 infants. Mean MEF25 increased by 148 +/- 43.2% to 21.7 +/- 3.9 ml/kg/s (P less than 0.02). These findings indicate that during the acute phase of severe RSV-positive bronchiolitis most infants have airway reactivity that responds positively to bronchodilator treatment.