Metabolomic Profiling of Infants With Recurrent Wheezing After Bronchiolitis.

BACKGROUND: Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolomic analysis can be used to identify children with bronchiolitis who are at risk of developing recurrent wheezing. METHODS: Fifty-two infants <1 year old treated in the emergency department at University Hospital of Padova for acute bronchiolitis were enrolled (77% tested positive for respiratory syncytial virus [RSV]). Follow-up visits were conducted for 2 years after the episode of bronchiolitis. Untargeted metabolomic analyses based on mass spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses. RESULTS: We distinguished children with and those without postbronchiolitis recurrent wheeze, defined as ≥3 episodes of physician-diagnosed wheezing. Pathway overrepresentation analysis pointed to a major involvement of the citric acid cycle (P < .001) and some amino acids (lysine, cysteine, and methionine; P ≤ .015) in differentiating between these 2 groups of children. CONCLUSION: This is the first study showing that metabolomic profiling of urine specimens from infants with bronchiolitis can be used to identify children at increased risk of developing recurrent wheezing.

Assessing the Utility of Urine Testing in Febrile Infants Aged 2 to 12 Months With Bronchiolitis.

OBJECTIVES: The aims of the study were to investigate whether the prevalence of urinary tract infections (UTIs) in febrile infants aged 2 to 12 months with bronchiolitis is higher than the presumed prevalence of asymptomatic bacteriuria (1%) in similarly aged patients and thus to determine whether UTI testing is necessary for these patients. METHODS: This was a prospective cohort study in which we enrolled a convenience sample of febrile infants aged 2 to 12 months with a clinical diagnosis of bronchiolitis. All patients were seen in the emergency department at a large children's hospital between November 1, 2011 and April 15, 2012, had reported or documented fever higher than 38°C, and had urine collected for determination of the presence of UTI. After the conclusion of enrollment, a chart review was conducted to assess missed cases. RESULTS: Positive urine cultures were found in 6/90 (6.7%) patients (confidence interval, 2.5%-13.9%). The positive urine cultures and urinalysis results were found in 4/90 (4.5%) patients (confidence interval, 1.2%-11%). CONCLUSIONS: In our patient population, a significant proportion of infants aged 2 to 12 months who present with bronchiolitis and fever have a concurrent UTI. Obtaining a urine specimen for UTI testing should be considered in infants aged 2 to 12 months with bronchiolitis and fever. A larger multicenter study is needed to further assess the risk factors for UTIs in this patient population.

Blood eosinophil counts during bronchiolitis are related to bronchial hyper-responsiveness and lung function in early adolescence.

AIM: To assess whether inflammatory markers measured in urine and blood during acute bronchiolitis in infancy were associated with asthma, lung function, bronchial hyper-responsiveness (BHR) and atopy at 11 years of age. METHODS: We included 105 children hospitalised for bronchiolitis during their first year of life. At hospitalisation, urinary (U-) eosinophil protein X, U-leukotriene E4 , U-prostaglandin 9α, 11ß-PGF2 and blood eosinophil counts were measured. Ninety-five children (90%) were available for follow-up at 11 years of age. RESULTS: At follow-up, higher blood eosinophil counts obtained during bronchiolitis were observed in the group with asthma than in the group without asthma (median 0.27 versus 0.09 × 10(9) /L, respectively, p = 0.048). By regression analyses, blood eosinophil counts during the acute bronchiolitis were positively associated with BHR (p = 0.006) and negatively associated with forced expiratory volume in first second (p = 0.025) at 11 years of age. None of the other inflammatory markers were associated with asthma, lung function, BHR or atopy at 11 years of age. CONCLUSION: Eosinophil inflammation during bronchiolitis may have a long-term impact on lung function and airway responsiveness. The associations could be related to virus-host interactions during bronchiolitis or to predisposed children.

Hypotonic solution decreases serum sodium in infants with moderate bronchiolitis.

AIM: To investigate the influence of hypotonic parenteral hydration on serum and urinary sodium and osmolality in infants with moderate bronchiolitis. METHODS: We studied 36 infants (mean age 3.7 ± 2.3 months), with a diagnosis of moderate bronchiolitis admitted to a paediatric emergency unit in São Paulo, Brazil. Patients received a standard parenteral hypotonic solution, according to Holliday and Segar, during the first 24 h, due to respiratory distress. The disease was monitored by a respiratory severity score (RDAI-Respiratory Distress Assessment Instrument), respiratory rate and oxygen saturation. Serum and urinary sodium and osmolality were monitored at admission, 24 and 48 h after admission. RESULTS: All respiratory parameters improved during hospitalisation. Serum sodium and osmolality dropped after 24 h (136.8 ± 2.8 and 135.8 ± 2.6 mEq/L, p = 0.031; 283.4 ± 4.1 and 281.6 ± 3.9 mOsm/kg, p = 0.004 respectively) as well as urinary osmolality (486.8 ± 243.4 mOsm/kg and 355.7 ± 205.0 mOsm/kg, p < 0.001) when compared to admission. CONCLUSION: This study reinforces the occurrence of hyponatraemia in bronchiolitis even in patients with moderate disease and highlights the risk of serum sodium drop caused by hypotonic parenteral hydration.

Urinary club cell protein 16 (CC16): Utility of its assay during acute bronchiolitis.

Acute bronchiolitis is responsible for high morbidity in infants. Club cell protein 16 kDa (CC16) is a major pneumoprotein secreted by club cells of the bronchial epithelium and eliminated by the renal pathway. CC16 seems to be a biomarker of epithelial damage in asthma. However, its value as a marker of acute bronchiolitis severity and later recurrent wheezing are uncertain, especially the value of its urinary assay for this purpose. A prospective, observational, analytical study was conducted at Clermont-Ferrand University Hospital to correlate serum CC16 level with clinical severity of bronchiolitis in hospitalized infants aged less than 1 year. We analyzed correlations between serum and urinary CC16, CC16 levels and Wainwright score, immediate morbidity due to bronchiolitis, causal viruses, and recurrent wheezing 1 year after inclusion. In 166 infants, serum CC16 did not correlate with acute bronchiolitis severity (P = .49), but urinary CC16 did (P < .001). In multivariate analysis, urinary CC16 correlated mainly with urinary retinol binding protein (RBP; r = 0.70; P < .001). The logCC16u/logRBPu ratio correlated significantly with severity (P = .02). CC16 levels were not correlated with recurrent wheezing at 1 year. Urinary CC16 could be a useful biomarker in acute bronchiolitis for specific indications. This noninvasive assay would be particularly useful in the young infant population. Several factors must be taken into account in its interpretation, mainly tubular function. Further studies are needed to assess these factors.

Leukotriene synthesis during respiratory syncytial virus bronchiolitis: influence of age and atopy.

Respiratory syncytial virus (RSV) infection is the most common cause of bronchiolitis in infants and an important risk factor for the development of recurrent wheezing and asthma. Cysteinyl leukotrienes were implicated in the pathophysiology of these diseases, and are being targeted for their diagnosis and therapy. We measured urinary leukotriene E4 (LTE4) in infants with RSV bronchiolitis in comparison with controls without respiratory infection, and investigated whether medical and family history, age, and passive exposure to tobacco smoke are related to urinary leukotriene excretion. We studied 33 infants with bronchiolitis and 25 controls, 1-12 months of age. Demographic and historical data were obtained from informed-consent forms and questionnaires completed by the parents. RSV was detected in nasal secretions by enzyme-linked immunoassay. Urine samples were collected on day of admission and were analyzed for LTE4 with an enzyme-linked immunoassay. Urinary LTE4 was 8-fold higher in infants with bronchiolitis than in controls. Leukotriene excretion was significantly higher in infected infants <6 months of age with a medical history of eczema or dry cough and/or family history of asthma. Multivariate analysis revealed that eczema and dry cough are independently associated with high LTE4 excretion during bronchiolitis. Exposure to tobacco smoke did not affect urinary LTE4. Our study shows that leukotriene synthesis during bronchiolitis is particularly elevated in younger infants with an atopic/asthmatic background. Urinary LTE4 may become a valuable, noninvasive marker for the identification of patients who will benefit most from therapy with leukotriene modifiers for management of bronchiolitis.

Risks for bacteremia and urinary tract infections in young febrile children with bronchiolitis.

OBJECTIVE: To compare the risks for bacteremia and urinary tract injections (UTI) in young febrile children with and without bronchiolitis. DESIGN: A prospective cohort study. SETTING: The emergency departments of 3 pediatric referral hospitals. PATIENTS: A convenience sample of 432 previously healthy febrile patients aged 24 months or younger. Patients were divided into groups, based on the presence (n = 163, bronchiolitis group) or absence (n = 269, control group) of wheezing and/or retractions on examination. Blood cultures were obtained from all patients, and urine cultures were obtained from female patients, and male patients aged 6 months or younger. Chest radiographs were obtained on patients with lower respiratory tract signs, and those with lobar pneumonias were excluded (7 wheezing and 8 nonwheezing patients), leaving 156 patients with bronchiolitis and 261 control patients. OUTCOME MEASURES: Growth of any bacterial pathogens from the blood or 10(4) colony-forming units per milliliter or more from the urine. RESULTS: None of the 156 patients with bronchiolitis had bacteremia (95% confidence interval, 0%-1.9%) vs 2.7% of the 261 controls (95% confidence interval, 1.1%-5.4%; P = .049); 1.9% of the patients with bronchiolitis had UTI vs 13.6% of the controls (odds ratio, 0.12; 95% confidence interval, 0.02-0.55; P = .001). None of the subset of patients with bronchiolitis aged 2 months or younger (n = 36) had bacteremia or UTI; however, there were not enough of these younger patients to make statistically conclusive comparisons. CONCLUSIONS: Previously healthy febrile children aged 24 months or younger with bronchiolitis are unlikely to have bacteremia or UTI. Therefore, routine cultures of the blood and urine in these patients are unnecessary. More data are needed regarding the subset of febrile infants aged 2 months or younger with bronchiolitis.

[Clinical evaluation of urinary leukotriene e4 levels in children with respiratory syncytial virus infection].

The levels of leukotriene E4 (LTE4) of the urine were determined in 24 pediatric patients with infectious diseases due to respiratory syncytial virus (RSV), i.e., bronchitis, pneumonia, and bronchiolitis, and compared with those in controls without allergic disease. The level for LTE4 of the acute-phase urine was 620+/-562 pg/mg. cr in the pediatric patients infected with RSV, being significantly higher than 190+/-67 pg/mg. cr in controls (P<0.005). The levels for LTE4 of the urine in the recovery phase showed a tendency toward decrease, as compared to those in the acute phase. However, there was no significant difference in the level for LTE4 of the acute-phase urine between the presence and the absence of each of the following conditions: expiratory wheezing; the association of pneumonia; family history of allergic diseases; the association of atopic dermatitis; and a past history of expiratory wheezing. An allergological study also revealed that there was no significant difference in LTE4 level between the presence and the absence of peripheral eosinophilia or between the presence and the absence of the high total level for IgE of the serum or positivity for the specific IgE level in the serum. These results suggest that LT is involved with the pathological conditions of RSV infection, but there are no direct relation between atopic diathesis or expiratory wheezing and the amounts of LT production.

Neutrophil-mediated inflammation in respiratory syncytial viral bronchiolitis.

BACKGROUND: The involvement of neutrophil-mediated inflammation may play an important role in the pathogenesis of acute respiratory syncytial virus bronchiolitis. However, no measurable marker is sensitive enough to assess neutrophil-mediated inflammation in the airways. Released neutrophil elastase (NE) in intraluminal airways has been reported to induce pulmonary inflammation. The aim of this study was to determine whether the amount of urinary trypsin inhibitor (UTI) in serum, a degenerate induced by NE, reflects the degree of airway inflammation in children with respiratory syncytial viral (RSV) bronchiolitis and whether the severity of inflammation is evaluated. The pre-alpha-/inter-alpha-trypsin inhibitor is assumed to be precursors of the UTI. When NE degrades these inhibitors, UTI is liberated. METHODS: Serum UTI concentrations in infants admitted with RSV bronchiolitis, other viral infections, bacterial pneumonia and control subjects were measured by means of one-step sandwich-type enzyme immunoassay. RESULTS: Serum UTI concentrations in 25 patients on admission were significantly higher than the 15 infantile control values (mean +/- SEM, 22.126 +/- 2.317 and 6.701 +/- 0.719 U/mL, respectively; P < 0.0001). The elevated levels returned to baseline values with improvement in the respiratory symptoms. Higher levels of serum UTI with RSV infection were consistently associated with clinical symptoms and artificial ventilation. Serum NE concentrations of patients were elevated in some patients but not significantly different from controls in the patients who showed only upper respiratory symptoms with RSV infections. CONCLUSION: The findings strongly suggested that neutrophil-mediated events are involved in the pathogenesis of RSV bronchiolitis, and the monitoring of UTI concentrations might be useful for evaluating the neutrophil-mediated airway inflammation.

Estimation of the dose of fluticasone propionate inhaled by infants after bronchiolitis: Effect on urinary cortisol excretion.

BACKGROUND: Information on the dose of steroid infants inhale from spacer devices and its potential effect on adrenal suppression is limited. OBJECTIVE: We sought to determine the total dose of fluticasone propionate (FP) inhaled from a spacer device (Babyhaler) with face mask attachment by infants recovering from acute bronchiolitis and the effect of inhaled FP on the infants' overnight urinary cortisol/creatinine ratios (UCCRs). METHODS: Infants studied were recovering from acute bronchiolitis. In study 1, 22 infants inhaled 150 microg of FP through the Babyhaler. The likely inhaled dose was estimated by trapping it on a filter held within the face mask. In study 2, 40 infants had UCCRs measured before and during 3 months of treatment with either FP (150 microg twice daily, n = 20) or placebo (n = 20). RESULTS: In study 1 the mean +/- SD dose of captured FP was 12.8 +/- 6.9 microg (ie, 2.1 +/- 1.2 microg/kg). In study 2 the pretreatment UCCR medians (interquartile ranges) were as follows: FP, 22.8 (23.0) nmol/mmol; placebo, 24.0 (28.3) nmol/mmol. Within-group UCCR changes (median and interquartile range DeltaUCCR) were significantly different in the FP group (-8.9 and -20.6 nmol/mmol at 6 weeks and -12.6 and -25.9 nmol/mmol at 12 weeks, respectively; P =.0008) but not in the placebo group ( -5.8 and -10.7 nmol/mmol at 6 weeks and +0.3 and -17.9 nmol/mmol at 12 weeks, respectively; P =.45). Intergroup changes were insignificant in the follow-up period (6 weeks, P =.52; 12 weeks, P =.19). CONCLUSION: After bronchiolitis, infants are likely to inhale approximately 8 % of the nominal steroid dose from the Babyhaler. UCCRs can be used to monitor the bioavailability of inhaled steroids in young infants.

Relationship between urinary cotinine level and diagnosis in children admitted to hospital.

The reported association between passive smoking and respiratory illness in children has been based on the parents' assessment of their own level of smoking. To more critically evaluate a causal relationship between passive smoking and childhood ill health, we used urinary cotinine, which is the major metabolite of nicotine and has a long half-life, to objectively quantitate the level of passive smoking in children. Urine was collected from 609 children (median age 3.8 yr, range 1 month to 17 yr) on admission to hospital; cotinine levels were obtained in 491 of these samples, and a comprehensive respiratory questionnaire was completed for 468 children. Statistical analysis was carried out on transformed data using both parametric and nonparametric statistics. Cotinine levels in the children correlated with the parents' current smoking (p less than 0.001). Elevated levels were found in the 41 children admitted with bronchiolitis compared with a group of a similarly aged children with nonrespiratory illnesses (p less than 0.02). Elevated levels were not found for any other diagnosis. We conclude that the urinary cotinine approach has provided objective evidence linking passive smoking to hospital admission for bronchiolitis in infants.