Mid Sweden University

Background Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. Although treatment with ICS is generally considered to be safe in children, the potential adverse effects of these drugs on growth remains a matter of concern for parents and physicians. Objectives To assess the impact of different inhaled corticosteroid drugs and delivery devices on the linear growth of children with persistent asthma. Search methods We searched the Cochrane Airways Trials Register, which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, Embase, CINAHL, AMED and PsycINFO. We handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials. gov and manufacturers' clinical trial databases, or contacted the manufacturer, to search for potential relevant unpublished studies. The literature search was initially conducted in September 2014, and updated in November 2015, September 2018, and April 2019. Selection criteria We selected parallel-group randomized controlled trials of at least three months' duration. To be included, trials had to compare linear growth between different inhaled corticosteroid molecules at equivalent doses, delivered by the same type of device, or between different devices used to deliver the same inhaled corticosteroid molecule at the same dose, in children up to 18 years of age with persistent asthma. Data collection and analysis At least two review authors independently selected studies and assessed risk of bias in included studies. The data were extracted by one author and checked by another. The primary outcome was linear growth velocity. We conducted meta-analyses using Review Manager 5.3 software. We used mean differences (MDs) and 95% confidence intervals (CIs) as the metrics for treatment effects, and the random-effects model for meta-analyses. We did not perform planned subgroup analyses due to there being too few included trials. Main results We included six randomized trials involving 1199 children aged from 4 to 12 years (per-protocol population: 1008), with mild-to-moderate persistent asthma. Two trials were from single hospitals, and the remaining four trials were multicentre studies. The duration of trials varied from six to 20 months. One trial with 23 participants compared fluticasone with beclomethasone, and showed that fluticasone given at an equivalent dose was associated with a significant greater linear growth velocity (MD 0.81 cm/year, 95% CI 0.46 to 1.16, low certainty evidence). Three trials compared fluticasone with budesonide. Fluticasone given at an equivalent dose had a less suppressive effect than budesonide on growth, as measured by change in height over a period from 20 weeks to 12 months (MD 0.97 cm, 95% CI 0.62 to 1.32; 2 trials, 359 participants; moderate certainty evidence). However, we observed no significant difference in linear growth velocity between fluticasone and budesonide at equivalent doses (MD 0.39 cm/year, 95% CI -0.94 to 1.73; 2 trials, 236 participants; very low certainty evidence). Two trials compared inhalation devices. One trial with 212 participants revealed a comparable linear growth velocity between beclomethasone administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) and beclomethasone administered via chlorofluorocarbon- metered dose inhaler (CFC-MDI) at an equivalent dose (MD-0.44 cm/year, 95% CI -1.00 to 0.12; low certainty evidence). Another trial with 229 participants showed a small but statistically significant greater increase in height over a period of six months in favour of budesonide via Easyhaler, compared to budesonide given at the same dose via Turbuhaler (MD 0.37 cm, 95% CI 0.12 to 0.62; low certainty evidence). Authors' conclusions This review suggests that the drug molecule and delivery device may impact the effect size of ICS on growth in children with persistent asthma. Fluticasone at an equivalent dose seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is likely to have less adverse effect on growth than Turbuhaler when used for delivery of budesonide. However, the evidence from this systematic review of head-to-head trials is not certain enough to inform the selection of inhaled corticosteroid or inhalation device for the treatment of children with persistent asthma. Further studies are needed, and pragmatic trials and real-life observational studies seem more attractive and feasible.

The first studies of treatment of bronchiolitis in infants and toddlers with inhalation of hypertonic saline showed that the treatment was beneficial but later studies have challenged these results. Here, we review four systematic reviews from 2015-2017 and two more recent studies not included in the reviews. Our conclusions are that in moderately severe bronchiolitis, the benefits of treatment are small or absent and inhalations should not be routine. In severe cases, inhalation of hypertonic saline may be considered but benefits are not proven. Water is an irritant to the lower respiratory tract and saline is therefore doubtful as a placebo. We found only one study with conservative placebo (no inhalation). It showed no benefit of hypertonic NaCl and should be repeated.

Aim

Adverse neurological symptoms have been linked to vitamin B12 deficiency in infants. This explorative study described the clinical presentation associated with vitamin B12 deficiency in this age group.

Methods

The study comprised infants who were born between 2004 and 2012 and were tested for vitamin B12 levels after they were admitted to a hospital with neurological symptoms at less than one year of age. Vitamin B12 deficiency was defined as low cobalamin in serum and/or increased homocysteine and/or increased methylmalonate. It was diagnosed according to the applicable International Classification of Diseases, 10th revision, and recorded as vitamin B12 deficiency in the medical records. All information was retrieved from medical records and compared to symptomatic infants with normal levels.

Results

Of the 121 infants tested, 35 had vitamin B12 deficiency and 86 had normal levels. Vitamin B12 deficiency was diagnosed at an average age of 1.7 months and was more common among boys. Seizures and apparent life-threatening events were the most common symptoms among infants with B12 deficiency compared to infants with normal levels.

Conclusion

Vitamin B12 deficiency was more common in infants than we expected and presented with severe symptoms, such as seizures and apparent life-threatening events.