Cardiac autonomic modulation assessed by heart rate variability in children with asthma.

OBJECTIVE: To assess cardiac autonomic modulation, measured by short-term frequency domain analysis of heart rate variability (HRV), in children with asthma. METHODS: We conducted an observational study at a tertiary care teaching hospital. The sample consisted of 119 children aged 7 to 15 years with asthma and 56 age-matched healthy controls. Frequency domain HRV measures included low-frequency (LF; 0.04-0.15 Hz), high-frequency (HF; 0.15-0.4 Hz), and LF/HF ratio. The LF and HF components were expressed in both absolute values of power (ms2 ) and in normalized units (nu). RESULTS: Compared with healthy controls, asthmatic children had significantly higher value of HF (nu) (mean ± standard deviation: 45.9 ± 14.6 vs 40.7 ± 13.6; P = .02), and lower values of LF (nu) (54.1 ± 14.6 vs 59.3 ± 13.6; P = .02) and LF/HF ratio (median, interquartile range: 1.12, 0.82-1.88 vs 1.59, 1.02-2.08; P = .03). We did not find significant differences between children with persistent and intermittent asthma, and between children with well-controlled and partially-controlled or uncontrolled asthma, in terms of HRV measures. CONCLUSIONS: Children with stable chronic asthma may have a cardiac autonomic imbalance with a possible enhanced parasympathetic modulation, as assessed by short-term frequency domain analysis of HRV. Neither asthma severity nor asthma control was significantly associated with HRV measures, but the study did not have enough power to draw a firm conclusion on this point.

Toxocariasis and childhood asthma: A case-control study.

OBJECTIVE: The objective of this study is to investigate the association between anti-Toxocara IgG seropositivity and asthma in children. METHODS: This was a case-control study conducted in a university hospital in south Brazil between May 2012 and June 2013. Were recruited 208 children up to 12 years old of whom 156 had asthma (cases) and 52 did not have asthma (controls), with a case-control ratio of 3:1 matched by age. Children's parents or guardians were interviewed using a structured questionnaire with closed questions. Serology was performed using enzyme-linked immunosorbent assay (ELISA) with excretory-secretory antigen of Toxocara canis (TES). RESULTS: The seroprevalence of IgG anti-T. canis antibodies was 12.8% in the cases and 7.7% in the controls. There was no significant association between seropositivity to T. canis and risk of asthma (adjusted odds ratio [OR]: 1.89, 95% CI: 0.52 to 6.89, p = 0.33). Household income < 2 minimum salaries, paternal school years < 9, allergic rhinitis in children, a positive family history of asthma and rhinitis and contact with cats were significantly associated with asthma, with adjusted ORs (95% CIs) of 3.05 (1.21 to 7.73), 2.83 (1.11 to 7.18), 10.5 (4.32 to 25.6), 2.65 (1.14 to 6.17), 2.49 (1.07 to 5.78) and 2.73 (1.03 to 7.27), respectively. CONCLUSIONS: This study did not find a statistically significant association between seropositivity to Toxocara sp. and risk of asthma in children. Low family income, low paternal education level, concomitant allergic rhinitis, family history of asthma and allergic rhinitis and contact with cats were independent factors associated with childhood asthma.

Nutritional status, adiposity and asthma severity and control in children.

AIM: To investigate association between nutritional status, adiposity and asthma severity and control in children. METHODS: We conducted a case control study at two teaching hospitals in Brazil. Cases were children (3-12 years) with persistent asthma and age-matched controls were those with intermittent asthma. Nutritional status was assessed by body mass index (BMI). Adiposity was assessed by sum of skinfolds and waist circumference (WC). Crude and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using conditional logistic regression or multinomial logistic regression as appropriate. RESULTS: Two hundred sixty-eight cases and 126 controls were included. Obesity (>2 BMI z-score for age) was significantly associated with persistent asthma (adjusted OR 2.62; 95% CI 1.39-4.95). There was a significant linear relationship between BMI z-scores (≤1, >1 to ≤2, >2) and risk of having persistent asthma (P = 0.003 for linear trend). Children with WC >90th percentile had a higher risk of persistent asthma when compared with those with WC ≤90th percentile (adjusted OR 3.38; 95% CI 1.26-9.06). No significant difference was found in terms of nutritional status and adiposity between children whose asthma was controlled by inhaled corticosteroids and those requiring inhaled corticosteroids plus other medications for asthma control. CONCLUSIONS: Obesity measured by BMI and increased abdominal adiposity are significantly associated with risk of persistent asthma but not type of controller medications.

Association between dietary habits and asthma severity in children.

OBJECTIVE: To investigate association between dietary habits and asthma severity in children. DESIGN: Cross-sectional study. SETTING: Two teaching hospitals in Brazil. PARTICIPANTS: Cases (n=268) were children (3-12yr) with persistent asthma and age-matched controls (n=126) were those with intermittent asthma. MAIN OUTCOME MEASURES: Dietary habits were determined based on food consumption in the past 12 months classified as frequent (≥3 times per week) or infrequent (never or <3 times per week).Nutritional status was classified into two categories according to WHO Child Growth Standards: obese: >2Z-score of BMI-for-age; non-obese: ≤2Z-score of BMI-for-age. RESULTS: After adjusting for confounding factors, maternal smoking during pregnancy, preterm birth and obesity were significantly associated with persistent asthma, with adjusted ORs (95% CI) of 2.11 (1.08- 4.13), 2.61(1.07-6.35) and 2.89 (1.49-5.61), respectively. No significant association was observed between frequency of consumption of specific foods, food groups, or dietary pattern (pro- or contra-Mediterranean diet) and the severity of asthma. CONCLUSIONS: This study did not find a significant association between dietary habits and asthma severity in children. Maternal smoking during pregnancy, preterm birth and obesity were independent factors associated with persistent asthma.

Inhaled corticosteroids in children with persistent asthma: effects on growth.

BACKGROUND: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. OBJECTIVES: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), 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 to look for potential relevant unpublished studies. The literature search was conducted in January 2014. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. MAIN RESULTS: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%. Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period. Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi(2) = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 µg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial. One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 µg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. AUTHORS' CONCLUSIONS: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma. PLAIN LANGUAGE SUMMARY: Do inhaled corticosteroids reduce growth in children with persistent asthma? Review question: We reviewed the evidence on whether inhaled corticosteroids (ICS) could affect growth in children with persistent asthma, that is, a more severe asthma that requires regular use of medications for control of symptoms. BACKGROUND: Treatment guidelines for asthma recommend ICS as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, parents and physicians always remain concerned about the potential negative effect of ICS on growth. Search date: We searched trials published until January 2014. Study characteristics: We included in this review trials comparing daily use of corticosteroids, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. KEY RESULTS: Twenty-five trials involving 8471 children with mild to moderate persistent asthma (5128 treated with ICS and 3343 treated with placebo or non-steroidal drugs) were included in this review. Eighty percent of these trials were conducted in more than two different centres and were called multi-centre studies; five were international multi-centre studies conducted in high-income and low-income countries across Africa, Asia-Pacifica, Europe and the Americas. Sixty-eight percent were financially supported by pharmaceutical companies. Meta-analysis (a statistical technique that combines the results of several studies and provides a high level of evidence) suggests that children treated daily with ICS may grow approximately half a centimeter per year less than those not treated with these medications during the first year of treatment. The magnitude of ICS-related growth reduction may depend on the type of drug. Growth reduction seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. Evidence provided by this review allows us to conclude that daily use of ICS can cause a small reduction in height in children up to 18 years of age with persistent asthma; this effect seems minor compared with the known benefit of these medications for asthma control. QUALITY OF EVIDENCE: Eleven of 25 trials did not report how they guaranteed that participants had an equal chance of receiving ICS or placebo or non-steroidal drugs. All but six trials did not report how researchers were kept unaware of the treatment assignment list. However, this methodological limitation may not significantly affect the quality of evidence because the results remained almost unchanged when we excluded these trials from the analysis.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2 -agonist and generally compared low (50 to 100 µg) versus low to medium (200 µg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma. PLAIN LANGUAGE SUMMARY: Does altering the dose of inhaled corticosteroids make a difference in growth among children with asthma? BACKGROUND: Asthma guidelines recommend inhaled corticosteroids (ICS) as the first choice of treatment for children with persistent asthma that is not well controlled when only a reliever inhaler is used to treat symptoms. Steroids work by reducing inflammation in the lungs and are known to control underlying symptoms of asthma. However, parents and physicians remain concerned about the potential negative effect of ICS on growth. REVIEW QUESTION: Does altering the dose of inhaled corticosteroids make a difference in the growth of children with asthma? WHAT EVIDENCE DID WE FIND?: We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device. We found 22 eligible trials, but only 10 of them measured growth or other measures of interest. Overall, 3394 children included in the review combined 17 group comparisons (i.e. 17 groups of children with mild to moderate asthma using a particular dose and type of steroid in 10 trials). Trials used different ICS molecules (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) either on their own or in combination with a long-acting beta2 -agonist (a drug used to open up the airways) and generally compared low doses of corticosteroids (50 to 100 µg) with low to medium (200 µg) doses of corticosteroids (converted in µg HFA-beclomethasone equivalent) over 12 to 52 weeks. RESULTS: We found a small but statistically significant group difference in growth over 12 months between these different doses clearly favouring the lower dose of ICS. The type of corticosteroid among newer molecules (ciclesonide, fluticasone, mometasone) did not seem to influence the impact on growth over one year. Differences in corticosteroid doses did not seem to affect the change in height, the gain in weight, the gain in bone mass index and the maturation of bones. QUALITY OF THE EVIDENCE: This review is based on a small number of trials that reported data and were conducted on children with mild to moderate asthma. Only 10 of 22 studies measured the few outcomes of interest for this review, and only four comparisons reported growth over 12 months. Our confidence in the quality of evidence is high for this outcome, however it is low to moderate for several other outcomes, depending on the number of trials reporting these outcomes. Moreover, a few outcomes were reported only by a single trial; as these findings have not been confirmed by other trials, we downgraded the evidence for these outcomes to low quality. An insufficient number of trials have compared the effect of a larger difference in dose, for example, between a high dose and a low dose of ICS and of other popular molecules such as budesonide and beclomethasone over a year or longer of treatment. CONCLUSIONS: We report an evidence-based ICS dose-dependent reduction in growth velocity in prepubescent school-aged children with mild to moderate persistent asthma. The choice of ICS molecule (mometasone, ciclesonide or fluticasone) was not found to affect the level of growth velocity response over a year. The effect of corticosteroids on growth was not consistently reported: among 22 eligible trials, only four comparisons reported the effects of corticosteroids on growth over one year. In view of parents' and clinicians' concerns, lack of or incomplete reporting of growth is a matter of concern given the importance of the topic. We recommend that growth be systematically reported in all trials involving children taking ICS for three months or longer. Until further data comparing low versus high ICS dose and trials of longer duration are available, we recommend that the minimal effective ICS dose be used in all children with asthma.

Acellular vaccines for preventing whooping cough in children.

BACKGROUND: Routine use of whole-cell pertussis (wP) vaccines was suspended in some countries in the 1970s and 1980s because of concerns about adverse effects. Following this action, there was a resurgence of whooping cough. Acellular pertussis (aP) vaccines, containing purified or recombinant Bordetella pertussis (B. pertussis) antigens, were developed in the hope that they would be as effective, but less reactogenic than the whole-cell vaccines. This is an update of a Cochrane review first published in 1999, and previously updated in 2012. In this update, we included no new studies. OBJECTIVES: To assess the efficacy and safety of acellular pertussis vaccines in children and to compare them with the whole-cell vaccines. SEARCH METHODS: We searched CENTRAL (2013, Issue 12), MEDLINE (1950 to January week 2, 2014), EMBASE (1974 to January 2014), Biosis Previews (2009 to January 2014) and CINAHL (2009 to January 2014). SELECTION CRITERIA: We selected double-blind randomised efficacy and safety trials of aP vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias in the studies. Differences in trial design precluded a meta-analysis of the efficacy data. We pooled the safety data from individual trials using a random-effects meta-analysis model. MAIN RESULTS: We included six efficacy trials with a total of 46,283 participants and 52 safety trials with a total of 136,541 participants. Most of the safety trials did not report the methods for random sequence generation, allocation concealment and blinding, which made it difficult to assess the risk of bias in the studies. The efficacy of multi-component (≥ three) vaccines varied from 84% to 85% in preventing typical whooping cough (characterised by 21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis), and from 71% to 78% in preventing mild pertussis disease (characterised by seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology). In contrast, the efficacy of one- and two-component vaccines varied from 59% to 78% against typical whooping cough and from 41% to 58% against mild pertussis disease. Multi-component acellular vaccines are more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with aP vaccines than with wP vaccines for the primary series as well as for the booster dose. AUTHORS' CONCLUSIONS: Multi-component (≥ three) aP vaccines are effective in preventing whooping cough in children. Multi-component aP vaccines have higher efficacy than low-efficacy wP vaccines, but they may be less efficacious than the highest-efficacy wP vaccines. Acellular vaccines have fewer adverse effects than whole-cell vaccines for the primary series as well as for booster doses.

Inhaled corticosteroids in children with persistent asthma: effects on growth.

BACKGROUND: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. OBJECTIVES: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), 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 to look for potential relevant unpublished studies. The literature search was conducted in January 2014. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. MAIN RESULTS: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 µg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 µg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. AUTHORS' CONCLUSIONS: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 µg) versus low to medium (200 µg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

Mortalidade por asma em crianças brasileiras de até 19 anos de idade no período entre 1980 a 2007 / Asthma mortality among Brazilian children up to 19 years old between 1980 and 2007

Objetivo: Avaliar a tendência de mortalidade por asma em crianças brasileiras de até 19 anos de idade no período de 1980 a 2007. Métodos: Foi realizado um estudo ecológico, de séries temporais, baseado em banco de dados do Departamento de Informática do Sistema Único de Saúde, do qual foi extraído o número de óbitos por asma e a popuação residente de até 19 anos de idade no país como um todo. O coeficiente de mortalidade foi calculado pelo número de óbitos por asma dividido pela população, multiplicando por 100.000. Utilizou-se o teste de regressão linear para avaliar a tendência temporal de mortalidade. Para a análise, estudaram-se separadamente três grupos etários: 1 a 4 anos, 5 a 9 anos e 10 a 19 anos. Resultados: No período estudado, ocorreram 9.051 óbitos por asma no Brasil em menores de 19 anos. Destes, 69% (6.270 registros) foram de menores de 5 anos. Observou-se um decréscimo significativo de mortalidade por asma no período em todos os grupos etários. A redução média anual do coeficiente de mortalidade por asma em crianças foi de 0,022 (p < 0,0001). De 1 a 4 anos foi de 0,076, de 5 a 9 anos foi de 0,005, e de 10 a 19 anos foi de 0,004 (p< 0,0001). Conclusão: A mortalidade por asma em crianças é baixa e mantém a tendência de queda no período estudado em todas as faixas etárias pediátricas.

Objective: To evaluate asthma mortality among Brazilian children up to 19 years old in 1980 to 2007 . Methods: This ecological time-series study used the database of the Brazilian Unified Health System, from which data were collected about the number of asthma deaths and the population under 19 years of age in Brazil. Mortality rates were calculated as the number of asthma deaths divided by population and multiplied by 100,000. Linear regression was used to assess the trend of mortality. For the analysis, participants were assigned to three separate age groups: 1-4 years, 5-9 years and 10-19 years. Results: During the study period, there were 9,051 deaths due to asthma in children under 19 years of age. Of these, 69% (6,270 records) of the children were younger than 5 years. There was a significant decrease in asthma mortality during the study in all age groups. The mean annual reduction of asthma mortality rates among children was 0.022 (p < 0.0001). The reduction was 0.076, 0.005 and 0.004 for the 1 to 4, 5 to 9 and 10 to 19 year-old age groups (p < 0.0001). Conclusion: Asthma mortality among Brazilian children is low and has kept a downward trend during the study in all pediatric age groups.

Inhaled corticosteroids increase the risk of oropharyngeal colonization by Streptococcus pneumoniae in children with asthma.

BACKGROUND AND OBJECTIVE: Recent studies have raised concerns about the link between use of inhaled corticosteroids (ICS) and risk of pneumonia in patients with chronic obstructive pulmonary disease. This cross-sectional study aimed to investigate the association between ICS and oropharyngeal colonization by Streptococcus pneumoniae (S. pneumoniae) among children (up to 18 years old) with asthma. METHODS: Two age-matched groups of patients were consecutively recruited: (i) exposed group: children who had persistent asthma and were being treated with daily ICS for at least 30 days and (ii) non-exposed group: children who had asthma and were not being treated with ICS at study entry. Oropharyngeal specimens from the tonsillar area and posterior pharyngeal wall were collected. S. pneumoniae was identified according to National Committee for Clinical Laboratory Standards recommendations. RESULTS: A total of 200 consecutive patients were recruited and 192 (96 in each group) were included in the analysis. In the exposed group, the mean daily dose of ICS was 400 µg of beclomethasone or equivalent and the mean duration of treatment was 8.6 months. The prevalence of oropharyngeal colonization by S. pneumoniae was higher in the exposed group compared with the non-exposed group (27.1% vs 8.3%, P = 0.001). After adjusting for potential confounders, use of ICS was an independent risk factor for oropharyngeal carriage of S. pneumoniae, with an adjusted prevalence ratio of 3.75 (95% confidence interval: 1.72-8.18, P = 0.001). CONCLUSIONS: Regular use of ICS is associated with an increased risk of having oropharyngeal colonization by S. pneumoniae in children with asthma.

Mortalidade por asma em crianças brasileiras de até 19 anos de idade no período entre 1980 a 2007 / Asthma mortality among Brazilian children up to 19 years old between 1980 and 2007

OBJETIVO: Avaliar a tendência de mortalidade por asma em crianças brasileiras de até 19 anos de idade no período de 1980 a 2007. MÉTODOS: Foi realizado um estudo ecológico, de séries temporais, baseado em banco de dados do Departamento de Informática do Sistema Único de Saúde, do qual foi extraído o número de óbitos por asma e a população residente de até 19 anos de idade no país como um todo. O coeficiente de mortalidade foi calculado pelo número de óbitos por asma dividido pela população, multiplicando por 100.000. Utilizou-se o teste de regressão linear para avaliar a tendência temporal de mortalidade. Para a análise, estudaram-se separadamente três grupos etários: 1 a 4 anos, 5 a 9 anos e 10 a 19 anos. RESULTADOS: No período estudado, ocorreram 9.051 óbitos por asma no Brasil em menores de 19 anos. Destes, 69% (6.270 registros) foram de menores de 5 anos. Observou-se um decréscimo significativo de mortalidade por asma no período em todos os grupos etários. A redução média anual do coeficiente de mortalidade por asma em crianças foi de 0,022 (p < 0,0001). De 1 a 4 anos foi de 0,076, de 5 a 9 anos foi de 0,005, e de 10 a 19 anos foi de 0,004 (p < 0,0001). CONCLUSÃO: A mortalidade por asma em crianças é baixa e mantém a tendência de queda no período estudado em todas as faixas etárias pediátricas.

OBJECTIVE: To evaluate asthma mortality among Brazilian children up to 19 years old in 1980 to 2007. METHODS: This ecological time-series study used the database of the Brazilian Unified Health System, from which data were collected about the number of asthma deaths and the population under 19 years of age in Brazil. Mortality rates were calculated as the number of asthma deaths divided by population and multiplied by 100,000. Linear regression was used to assess the trend of mortality. For the analysis, participants were assigned to three separate age groups: 1-4 years, 5-9 years and 10-19 years. RESULTS: During the study period, there were 9,051 deaths due to asthma in children under 19 years of age. Of these, 69% (6,270 records) of the children were younger than 5 years. There was a significant decrease in asthma mortality during the study in all age groups. The mean annual reduction of asthma mortality rates among children was 0.022 (p < 0.0001). The reduction was 0.076, 0.005 and 0.004 for the 1- to 4-, 5- to 9- and 10- to 19-year-old age groups (p < 0.0001). CONCLUSION: Asthma mortality among Brazilian children is low and has kept a downward trend during the study in all pediatric age groups.

Asthma mortality among Brazilian children up to 19 years old between 1980 and 2007.

OBJECTIVE: To evaluate asthma mortality among Brazilian children up to 19 years old in 1980 to 2007. METHODS: This ecological time-series study used the database of the Brazilian Unified Health System, from which data were collected about the number of asthma deaths and the population under 19 years of age in Brazil. Mortality rates were calculated as the number of asthma deaths divided by population and multiplied by 100,000. Linear regression was used to assess the trend of mortality. For the analysis, participants were assigned to three separate age groups: 1-4 years, 5-9 years and 10-19 years. RESULTS: During the study period, there were 9,051 deaths due to asthma in children under 19 years of age. Of these, 69% (6,270 records) of the children were younger than 5 years. There was a significant decrease in asthma mortality during the study in all age groups. The mean annual reduction of asthma mortality rates among children was 0.022 (p < 0.0001). The reduction was 0.076, 0.005 and 0.004 for the 1- to 4-, 5- to 9- and 10- to 19-year-old age groups (p < 0.0001). CONCLUSION: Asthma mortality among Brazilian children is low and has kept a downward trend during the study in all pediatric age groups.

Acellular vaccines for preventing whooping cough in children.

BACKGROUND: Routine use of whole-cell pertussis (wP) vaccines was suspended in some countries in the 1970s and 1980s because of concerns about adverse effects. Following such action, there was a resurgence of whooping cough. Acellular pertussis (aP) vaccines, containing purified or recombinant Bordetella pertussis (B. pertussis) antigens, were developed in the hope that they would be as effective, but less reactogenic than the whole-cell vaccines. OBJECTIVES: To assess the efficacy and safety of acellular pertussis vaccines in children. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to December week 4, 2011), EMBASE (1974 to January 2012), Biosis Previews (2009 to January 2012), and CINAHL (2009 to January 2012). SELECTION CRITERIA: We selected double-blind randomised efficacy and safety trials of aP vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias in the studies. Differences in trial design precluded a meta-analysis of the efficacy data. We pooled the safety data from individual trials using a random-effects meta-analysis model. MAIN RESULTS: We included six efficacy trials with a total of 46,283 participants and 52 safety trials with a total of 136,541 participants. Most of the safety trials did not report the methods for random sequence generation, allocation concealment and blinding, which made it difficult to assess the risk of bias in the studies. The efficacy of multi-component (≥ three) vaccines varied from 84% to 85% in preventing typical whooping cough (characterised by 21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis), and from 71% to 78% in preventing mild pertussis disease (characterised by seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology). In contrast, the efficacy of one- and two-component vaccines varied from 59% to 75% against typical whooping cough and from 13% to 54% against mild pertussis disease. Multi-component acellular vaccines are more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with aP vaccines than with wP vaccines for the primary series as well as for the booster dose. AUTHORS' CONCLUSIONS: Multi-component (≥ three) aP vaccines are effective and show less adverse effects than wP vaccines for the primary series as well as for booster doses.

Factors associated with asthma severity in children: a case-control study.

OBJECTIVE: To investigate factors associated with the severity of childhood asthma. METHODS: We conducted a case-control study in a group of Brazilian children (2-12 years old) with diagnosis of asthma attending the pediatric pulmonology clinic of a teaching hospital. The study sample consisted of cases (children with persistent asthma) and controls (children with intermittent asthma). Data were collected through an interview with the child's parent or caretaker using a standard questionnaire. Association between asthma severity and studied variables was assessed by calculating odds ratios (OR) and 95% confidence interval (95% CI) through logistic regression test. RESULTS: 171 children were included in this study, of which 104 (61%) had persistent asthma and 67 (39%) had intermittent asthma. Onset of the disease before 2 years of age, paternal educational level lower than 9 years, and low household income (≤1 minimum wage per month) were independent risk factors for persistent asthma, with adjusted OR (95% CI) of 2.56 (1.01-6.48), 2.49 (1.04-5.99), and 4.36 (1.06-17.87), respectively. Regular consumption of fruits during the last 30 days was inversely associated with the risk of having persistent asthma, with an adjusted OR (95% CI) of 0.19 (0.04-0.97). CONCLUSIONS: Early onset of the disease, low paternal education, and low household income are independent risk factors for persistent childhood asthma. Regular consumption of fruits appears to be a protective factor against more severe asthma in children.

Acute lower respiratory illness in under-five children in Rio Grande, Rio Grande do Sul State, Brazil: prevalence and risk factors.

This study aimed to determine the prevalence of acute lower respiratory illness and to identify associated factors among children less than five years of age in the city of Rio Grande, southern Brazil. Using a cross-sectional survey, a standardized household questionnaire was applied to mothers or guardians. Information was collected on household conditions, socioeconomic status, and parental smoking. Prenatal care attendance, nutritional status, breastfeeding pattern, and use of health services for the children were also investigated. Data analysis was based on prevalence ratios and logistic regression, using a conceptual framework. Among 771 children studied, 23.9% presented acute lower respiratory illness. The main risk factors were previous episodes of acute lower respiratory infection or wheezing, crowding, maternal schooling less than five years, monthly family income less than US$ 200, four or more people per room, asthma in family members, and maternal smoking. Mothers 30 years or older were identified as a protective factor. These results can help define specific measures to reduce morbidity and mortality due to acute lower respiratory illness in this setting.