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There is clear evidence that corticosteroids benefit children with symptoms of croup that range from mild to severe.32-34 In a meta-analysis of data from 10 clinical trials that included children with severe croup who required intensive care, corticosteroid treatment decreased endotracheal intubation by fivefold (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.05 to 0.84).33A randomized clinical trial found that, in children admitted to hospital, corticosteroid treatment reduced length of hospital stay by one-third compared with placebo (duration of hospital stay: 12 h for dexamethasone and 13 h for budesonide v. 20 h for placebo, p < 0.03).35 In children who presented to emergency departments with moderate to severe croup included in a randomized clinical trial, cortico - steroid treatment reduced admission rates by half compared with placebo (35% v. 67%, p < 0.001).36 A randomized placebo-controlled trial included 720 children with mild croup seen in an emer- gency department and showed that corticosteroid treatment reduced return medical visits by half (7% v. 15%, p < 0.001), resulted in less stress and loss of sleep by parents, and reduced overall health care costs.37Whereas cortico ster oids appear to start reducing respiratory distress within an hour of oral administration,38,39 the drug effect continues to increase for at least 10 hours after administration.36 The reduction in the rate of use of health services, such as hospital admissions, is not significant until 3-6 hours after administration of corti co ster oids, which supports an observation period of that length before the decision is made whether to admit a child to hospital.36 The route of administration of corticosteroid (oral, nebulized or intramuscular injection) has received extensive study. Three randomized clinical trials comparing nebulized budesonide with either oral or intramuscular dexamethasone did not find a difference in duration of hospital stay (13 h for budesonide v. 12 h for intramuscular dexamethasone, nonsignificant),35 rate of admission to hospital (35% for budesonide v. 17% for intramuscular dexamethasone, p = 0.18)36 or clinical croup score at 4 hours (p = 0.70).44 Three randomized clinical trials have shown that intramuscular dexamethasone does not provide benefit over oral corticosteroid in either change in clinical croup score at 4 hours (p = 0.18),45 resolution of croup symptoms at 24 hours (2% for intramuscular v. 8% for oral administration, nonsignificant)46 or rate of return to medical care (32% for intramuscular v. 25% for oral administration, p = 0.198).47 The kinetics of oral dosing also show a rapid peak in serum levels occurring within 1 hour.48 However, nebulized administration could be considered in the rare case of a patient with sustained vomiting. Although comparatively few randomized trials have examined the benefit of nebulized epinephrine in children with croup,29,34,49,50 their results are sufficiently consistent and compelling to support its routine use to provide rapid, short-term relief of severe respiratory distress.51 These trials have shown onset of effect within 10 minutes and waning of effect between 1 and 2 hours.29,49,50 Whereas the few published trials have not shown any consistent benefit beyond short-term improvement in clinical score,51 data from an early historical cohort study showed a decreased number of intubations and deaths in children with croup following introduction of treatment with epinephrine.52 Evidence for the safety of using epinephrine in outpatients comes from 5 prospective cohort studies that included a total of 253 children who received epinephrine and dexamethasone.36,53-56 The studies found that 12 (5%) children returned for care within 48-72 hours after discharge, 6 (2%) were subsequently admitted to hospital and none had any other adverse event.36,53-56 A Cochrane review that included data from 8 randomized clinical trials found that treatment with nebulized epinephrine was associated with important clinical improvement in croup score 30 minutes following administration (standardized mean difference -1.56, 95% CI -2.23 to -0.89).51 In children admitted to hospital with croup, length of stay was shorter in the group that received nebulized epinephrine as compared with placebo (mean difference -32 h, 95% CI -59.1 to -4.9).51

Most children who present with acute onset of barky cough, stridor, and chest-wall indrawing have croup. A careful history and physical examination is the best method to confirm the diagnosis and to rule out potentially serious alternative disorders such as bacterial tracheitis and other rare causes of upper-airway obstruction. Epinephrine delivered via a nebuliser is effective for temporary relief of symptoms of airway obstruction. Corticosteroids are the mainstay of treatment, and benefit is seen in children with all levels of severity of croup, including mild cases.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator ( CFTR ), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n  = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n  = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1 , which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

ObjectivesAlthough croup is a common respiratory illness, there is little published regarding symptom course. We aimed to assess symptom progression and caregiver burden, and whether age, sex or season and initial severity of disease are associated with symptom duration.Design, setting and participantsWe conducted a secondary analysis of two Canadian prospective cohorts of children 0–16 years old diagnosed with croup; one recruited from a paediatric emergency department (ED) (307 children) between November 1999 and March 2000, and the other from 26 general EDs (1214 children) between September 2002 and April 2006. Baseline data included age, sex, season, corticosteroid treatment and clinical severity score based on the presence or absence of a barky cough, stridor at rest or with agitation and chest wall indrawing (mild, moderate or severe). For both cohorts, the child’s primary caregiver was telephoned daily to collect symptom progression and psychosocial data (caregiver stress, lost sleep and work) until the child was symptom-free for over 24 hours.ResultsThe paediatric and general ED cohorts are reported separately; croup symptoms peaked at initial ED presentation for 96% and 77%, respectively. The longest-lived symptom was a barky cough, resolving by 34 and 47 hours for 50%, and 78 and 119 hours for 90% of children, respectively. Neither sex nor severity at presentation were significantly associated with symptom duration in either cohort. Season of illness was associated in both; age was associated in the general but not the paediatric ED cohort. The primary caregiver lost a mean (SD) of 4.1 (4.9) and 2.8 (4.7) hours of sleep during the illness.ConclusionsMost children with croup presented for care at the peak of symptom severity. Symptoms resolved for half of the children in 1.5–2 days and for 90% in 3–5 days after presentation. Caregivers experienced a significant loss of sleep.

Background Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that immunoreactive trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF. Methods In this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016. Results Ninety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8–206.2) vs. 75.0 (61.0–105.9); P  < 0.0001). Infants with CRMS/CFSPID→CF ( n  = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID ( n  = 83) (median (interquartile range): 108.9 (72.3–126.8) vs. 73.7(60.0–96.0); P  = 0.02). Conclusions Amongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.

This placebo-controlled trial assessed the effectiveness of a single dose of dexamethasone in 720 children with mild croup who presented to the emergency department. Dexamethasone treatment was associated with more rapid resolution of symptoms, less loss of sleep, and a lower rate of return for medical care. Corticosteroid treatment can be of modest benefit for virtually all children with croup. Croup (acute laryngotracheobronchitis) is common, occurring yearly in 3 percent of children under six years of age. 1 Less than 5 percent of such children are hospitalized, and of these, 1 to 2 percent receive endotracheal intubation. 2 Corticosteroids are effective in moderate-to-severe croup, resulting in reductions in the frequency and duration of intubation 3 , 4 and hospitalization 5 – 7 and the frequency of administration of nebulized epinephrine, 5 , 7 a treatment reserved primarily for severe respiratory distress. At least 60 percent of children who present for emergency care have mild symptoms (defined as the presence of a barking cough, no audible stridor at rest, . . .

Background. Community-acquired pneumonia (CAP) is common within pediatrics and contributes disproportionately to morbidity and mortality. Necrotizing pneumonia is a well-documented complication of CAP. It is thought to be caused by necrosis and liquefaction of consolidated lung and can result in damage to lung parenchyma, including pneumatocele development. Management of necrotizing pneumonia with pneumatocele may include hospitalization, intensive care unit admission, and lengthy antibiotic courses. Severe cases may need invasive procedures. Case Presentation. We present a case of severe necrotizing pneumonia requiring prolonged venovenous extracorporeal membrane oxygenation (V-V ECMO) with development of persistent pneumatoceles, requiring pneumonectomy while on ECMO support to allow for decannulation and extubation. Conclusions. In critically ill patients with extensive unilateral necrotizing pneumonia with pneumatocele development, surgical intervention can be considered when attempts to wean ventilation have been unsuccessful. This case provides evidence that V-V ECMO and pneumonectomy is a viable salvage therapy in the most critically unwell children.

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Respiratory syncytial virus (RSV) infection in cystic fibrosis (CF) infants is associated with significant morbidities. This study’s objective is to evaluate the effectiveness and adverse events related to palivizumab (PVZ) in CF infants. Data on respiratory-related illness (RIH) and RSV hospitalizations (RSVH) were collected retrospectively in CF infants aged < 2 years in Alberta, Canada, from 2000 to 2017. Logistic regression models were used to compare the odds of RSVH or RIH in PVZ infants from the Canadian registry of palivizumab (CARESS) versus untreated (UPVZ) infants from Alberta, after adjusting for potential confounders. Illness severity was compared between cohorts using χ2 and t tests. A total of 267 CF infants were included: 183 (PVZ) and 84 (UPVZ). A total of 53.3% were tested for RSV. Fifty-five infants experienced a RIH and 10 had a RSVH. The PVZ cohort experienced similar odds of RSVH but decreased odds of RIH versus UPVZ, adjusting for gestational age, birth weight, birth during RSV peak months, and presence of siblings (Exp(B) = 0.23 [0.11–0.49], p < 0.0005). In RSVH-related subjects, PVZ subjects experienced shorter length of overall stay (LOS; t = 2.39 [df = 7], p = 0.048). In those with a RIH, the PVZ group had shorter overall intensive care unit (t = 3.52 [df = 15], p = 0.003) and hospital LOS (t = 2.11 [df = 52], p = 0.04). No serious adverse events were related to PVZ. The odds of RSVH were similar between groups, but PVZ subjects had decreased odds of RIH. The low number of RSV tests performed may explain the similarity in RSVH rates. Significant differences in LOS may indicate decreased RSVH and RIH illness severity in the PVZ versus UPVZ groups.