Background: Effective yet safe treatment of latent tuberculosis is important for preventing the spread of tuberculosis and the progression to active disease in pediatric patients. As of 2017, the short course combination regimen of weekly isoniazid and rifapentine (3HP) administered by directly observed therapy (DOT) has replaced 9 months of isoniazid as the standard of treatment for latent tuberculosis in pediatric patients. The literature, limited in size, has established the 3HP regimen’s superior safety and adherence. Methods: We completed a retrospective chart review (n = 22) of pediatric patients at our institution receiving this regimen between 2017 and 2019. Frequencies of selected outcomes were compared to data collected in a literature review. Results: In this retrospective chart review, pediatric patients ages 2 to 20 years receiving 3HP with DOT for latent tuberculosis experienced higher adverse event rates, more severe adverse events, and higher treatment discontinuation than that which has been previously reported in the literature. A possible explanation for this finding is that our cohort’s race/ethnicity differed from the cohorts used in the literature. Conclusions: Our data suggests that the short course combination regimen for pediatric latent tuberculosis patients may have a higher adverse event rate than previously established. Although this sample size is small, this study urges further investigation of more diverse cohorts to better establish the regimen’s safety and tolerability.

Objective: Obstructive sleep apnea (OSA) is highly prevalent in children and requires an expensive and relatively unavailable sleep study for diagnosis. This study was undertaken to translate the previously validated OSA screening tool (POSAST) to the Thai language and assess its accuracy and test-retest reliability in at-risk symptomatic children. Study design: Prospective cross-sectional cohort study Methods: Pediatric patients clinically referred for suspected OSA who underwent overnight polysomnography (PSG) were recruited, and caregivers completed the Thai version of the POSAST. The same questionnaire was completed again after 2-4 weeks. Results: One hundred and ten subjects completed the study. The mean age was 8.4±2.9 years. The mean apnea-hypopnea index (AHI) was 10.9±11.9 events/hour. Test-retest reliability (Pearson correlation coefficient = 0.96, P<0.001) and internal consistency (Cronbach’s alpha coefficient = 0.82, P<0.001) between each question were excellent. A cumulative equation-derived score cut-off of 1.9 yielded 78.4% sensitivity and 50.0% specificity, while a numerical additive score cut-off of 8 corresponded to 81.1% sensitivity and 52.8% specificity for diagnosing moderate and severe OSA (AHI ≥5 events per hour) Conclusion: The internal consistency and reproducibility of the Thai version of the POSAST are satisfactory, display acceptable validity, and the instrument can be used for screening symptomatic Thai children for OSA.

Introduction: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional research and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. Methods: We included participants in the CF Foundation Patient Registry born 2010-2018 with age at first CF event (first sweat test, clinic visit or hospitalization) by age 365 days. We assessed age of center-reported diagnosis, age at first CF event, demographics and outcomes for three consecutive 3-year cohorts born in 2010-2012, 2013-2015, and 2016-2018. Results: In 6354 infants, median age at diagnosis was earlier than median age at first CF event, which decreased from 1st cohort to 3rd cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection rates decreased over time. About 1/3 of infants were hospitalized in the first year of life across cohorts. Conclusion: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts but improving nutritional deficits and reducing infant hospitalizations remain targets for improvement.

Numerous studies in the past 10 years have reported on the neurocognitive sequalae of pediatric Sleep Disordered Breathing (SDB). Variations in criteria used to define SDB in conjunction with the wide variety of neuropsychological measures selected to evaluate cognitive consequences of SDB have resulted in discrepancies within the literature. This review summarizes the extant literature regarding cognitive effects of pediatric SDB across domains of global intelligence, attention, executive function, memory, language, and visuospatial ability. This review also addresses the proposed etiology underlying neurocognitive consequences of pediatric SDB. The differences in findings across the literature are highlighted and discussed throughout.

Background: Asthma is a leading cause of pediatric hospitalization in the United States. Children hospitalized with asthma are often cared for in different care settings during a single hospitalization. Our objective was to study the reliability and safety of a new pediatric hospital-wide asthma severity score (HASS) across different care units within a single tertiary-care pediatric center. Methods. 150 patients between the ages of 2 and 18 years hospitalized with a principal diagnosis of status asthmaticus were included. Study patients were followed from initial triage in the emergency department until the time of medical readiness for discharge. Rates of medical errors, early transfers to a higher level of care and medically indicated hospital length of stay (LOS) were compared between 75 patients prior to and 75 patients after implementation of the HASS using retrospective chart review. Inter-rater reliability was determined by collecting independent HASS scores from blinded staff members after tandem or simultaneous patient assessment. Results. Inter-rater reliability among untrained staff members using the HASS was high. Rates of preventable adverse events and medical errors were low and not significantly different before and after implementation of the HASS. LOS was shorter after implementation of the HASS but without statistical significance. Rates of early transfer to a higher level of care were unchanged between study years. Conclusion. The HASS is a reliable asthma severity tool that can be used throughout hospitalization and also among multiple clinical providers to trend clinical progress and optimize communication, particularly during times of care handoffs.

Abstract Background: The effects of minimally invasive surfactant administration (MISA) in preterm infants with neonatal respiratory distress syndrome (NRDS) are unclear. Methods: We searched randomized controlled trials (RCTs) and compared MISA techniques with intubation for surfactant delivery in preterm infants with NRDS in PubMed, Embase, Cochrane Library, and Web of Science. Results: Thirteen RCTs (1931 infants) were included in the meta-analysis. The use of MISA techniques decrease the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks, pneumothorax, and hemodynamically significant patent ductus arteriosus (hsPDA) (Risk Ratio(RR) : 0.59, 95% confidence interval (CI) : 0.46 to 0.75, p < .0001; RR : 0.60, 95% CI : 0.39 to 0.93, p= .02 and RR : 0.88, 95% CI : 0.78 to 1.00, p= .04, respectively). In addition, infants in the MISA group required less mechanical ventilation within 72 h of life or during hospitalization (RR : 0.60, 95% CI : 0.48 to 0.75, p< .00001 and RR : 0.64, 95% CI : 0.49 to 0.82, p = .0005, respectively) compared with infants in the control group. However, the rate of surfactant reflux was higher in the MISA group than that in the control group (RR : 2.12, 95% CI : 1.37 to 3.29, p = .0008). There were no significant differences in mortality and other outcomes beteween the MISA group and the control group. Conclusions: The administration of surfactant with MISA techniques could lower the requirement for mechanical ventilation, and decrease the incidence of BPD at 36 weeks, pneumothorax, and hsPDA.

Background: Acute asthma exacerbations are a common cause for emergency department (ED) visits and hospitalizations in children. Since the outbreak of COVID-19 and the education system closure/ total lockdown in Israel on March 2020, we have noticed a decrease in pediatric ED visits and an increase in hospitalizations of asthma exacerbations. Objective: to examine the patterns of ED visits for asthma exacerbations during COVID-19 outbreak, in comparison to the previous year. Methods: a retrospective study comparing asthma related ED visits and hospitalizations among children aged 2-18 years at a tertiary center in southern Israel. Three time periods were selected: 2020A (pre- lockdown, 1/2/20-14/3/20), 2020B (lockdown, 15/3/20-15/5/20) and 2020 C (post- lockdown, 16/5/20-30/6/20) and compared to the three parallel time periods in 2019. Data regarding demographics, number of ED visits and clinical severity parameters were collected and analyzed. Results: 512 children visited the ED for asthma exacerbation: 273 children during 2019 and 239 children during 2020, with significantly fewer ED visits per day during the lockdown period (1.8 vs 1.43, p<0.001), compared to the parallel period in 2019. Significantly higher hospitalization rate (47.1% vs 33.7%, p=0.05) and longer length of stay (LOS) (3.15 vs 1.9 days, p= 0.03) were observed during the lockdown. Conclusion: lockdown is associated with fewer ED visits for asthma exacerbation, probably due to; reduced exposure to viral infections and environmental allergens, decreased availability of primary physicians and families’ reluctance to arrive to the ED. ED visits during lockdown were characterized by higher hospitalization rate and longer LOS.

Rationale: Methicillin resistant Staphylococcus aureus (MRSA) is prevalent and consequential in cystic fibrosis (CF). Whole genome sequencing (WGS) could reveal genomic differences in MRSA associated with poorer outcomes or detect MRSA transmission. Objectives: To identify MRSA genes associated with low lung function and identify potential MRSA transmission in CF. Methods: We collected 97 MRSA isolates from 74 individuals with CF from 2017 and performed short-read WGS. We determined sequence type (ST) and the phylogenetic relationship between isolates. We aligned accessory genes from 25 reference genomes to genome assemblies. We classified the MRSA by accessory gene content and correlated the accessory genome to clinical outcomes. Results: The most prevalent ST were ST5 (N=55), ST105 (N=14), and ST8 (N=14). Closely related MRSA strains were shared by family members with CF, but rarely between unrelated individuals. Three distinct clusters of MRSA were identified by accessory genome content. The first included ST5 and ST105 strains and was common among older patients with lower FEV1. The second cluster included ST8, which was generally identified in younger patients. Sputum density of MRSA and Pseudomonas aeruginosa was higher in cultures from patients with ST5/ST105 compared to patients with ST8 at similar ages. Conclusions: In this CF cohort, we identified MRSA subtypes that predominate at different ages and differ by accessory gene content. ST5 and ST105 represented the most prevalent cluster of MRSA. ST8 MRSA was more common in younger patients and thus has the potential to rise in prevalence as these patients age.

Respiratory syncytial virus (RSV) infection is the leading cause of bronchiolitis among infants <12 months old. It is widely known that coinfections between RSV and other viruses can worsen the clinical picture of affected patients. To evaluate the severity of clinical pictures of bronchiolitis in the 2019-2020 winter season, we performed a retrospective study of our third-level Pediatric Emergency Department (ED) admission charts. From February 2 to March 9, 2020 (start date of the Italian lockdown), we observed a peak of patients with a clinical picture of bronchiolitis requiring oxygen therapy of 55.1%, compared with 18% and 14.5% during the same period in 2017-2018 and 2018-2019, respectively (p<0.0001), without other clinically significant differences between the groups. Several authors hypothesized that SARS-CoV2 was present in northern Italy some weeks be-fore the first confirmed case. We suggest that one of the causes of this unexpected severe bronchiolitis peak may be a SARS-CoV2 - RSV coinfection in a period when SARS-CoV2 was already circulating in north-ern Italy. Given the lack of real-time polymerase chain reaction (RT-PCR) tests for SARS-CoV2 at that time, our suggestion remains a hypothesis.

This editorial is an invited response to “Adherence to the 2014 American Academy of Pediatrics Palivizumab Prophylaxis Recommendations”

Pulmonary defects are reported in pectus excavatum but the physiological impact on exercise capacity is unclear. To test the hypothesis that pectus deformities are associated with a pulmonary impairment during exercise we performed a retrospective review on pectus patients in our center who completed a symptom questionnaire, cardiopulmonary exercise test, pulmonary function tests (PFT), and chest magnetic resonance imaging. Of 259 patients studied, dyspnea on exertion and chest pain was reported in 64% and 41% respectively. Peak oxygen uptake (VO2) was reduced in 30% and classified as mild in two-thirds. A pulmonary limitation during exercise was identified in less than 3%. Ventilatory limitations on PFT was found in 26% and classified as mild in 85%. Obstruction was the most common abnormal pattern (11%) followed by a nonspecific ventilatory limitation and restrictive pattern (7% each). There were no differences between patients with normal or abnormal PFT patterns for the anatomic degree of pectus malformation, VO2, or percentage reporting dyspnea or chest pain. Scatter plots demonstrated significant inverse relationships between severity of the pectus deformity with lung volumes on PFT and VO2 but no correlation between the severity of the pectus deformity and lung volumes during exercise. We conclude that resting lung volume measurements were associated with the anatomic degree of pectus severity but respiratory limitations during maximal exercise are uncommon and PFT patterns have poor correlation with symptomatology or VO2. These findings suggest non-respiratory causes are more likely for the high rates of dyspnea and reduced aerobic fitness reported in pectus.

Introduction: Pediatric pulmonary embolism (PE) is rare but associated with adverse outcomes. We aimed to characterize PE cases admitted in a tertiary hospital and to evaluate sensitivity of PE diagnostic prediction tools. Methods: Retrospective, descriptive study of PE cases admitted from 2008 to 2020. Data was collected from hospital records. Patients were grouped according to PE severity and setting (outpatients, inpatients). Associations with demographic characteristics, risk factors, clinical presentation, management and outcomes were analyzed. PE diagnostic prediction tools were applied. Results: 29 PE episodes occurred in 27 patients, 62.9% female, mean age 14.1 years. Most PE were central and massive or submassive. One was diagnosed in autopsy. Outpatients (n=20), admitted for classic PE symptoms, were adolescents; in half the diagnosis had been missed previously. Risk factors included contraceptives (65%), thrombophilia (35%), obesity (20%) and auto-immunity (20%). Inpatients´ PE (n=8), diagnosed during cardiorespiratory deterioration (n=5) or through incidental radiological findings (n=3), were younger and had immobilization (87.5%), complex chronic diseases (75%), infections (75%) and central venous catheter (62.5%) as risk factors. Retrospectively, D-dimer testing and adults’ scores performed better than pediatrics’ scores (sensitivity 92.9-96% vs 85.7- 92.9%). Both pediatrics’ scores missed a case with a positive family history. Discussion: Pediatric PE diagnosis is often delayed or missed. To improve it, the development of pediatric prediction tools as from validated adult scores merits to be explored. We propose that clinical presentation and risk factors may be different in inpatients and outpatients. Family history should be included.

Background and objective: The number of children with complex physical and developmental pathologies, including chronic respiratory insufficiency, surviving and growing beyond early childhood continues to rise. No study has examined the clinical pathway of children on invasive LTMV in an Irish setting. Our data over a 10-year period was reviewed to see if our demographics and outcomes are in line with global trends. Methods: Children’s Health Ireland (CHI) at Crumlin, Dublin is Ireland’s largest tertiary paediatric hospital. A retrospective review analysed data from children in our centre commenced on LTMV via a tracheostomy over 10 years (2009 – 2018). This data was subdivided into two epochs for statistical analysis of longitudinal trends. Results: Forty-six children were commenced on LTMV from 2009 to 2018. Many had complex medical diagnoses with associated co-morbidities. Far less children, 30.4% (n=14) commenced on LTMV in the latter half of the 10-year period, they also fared better in all aspects of their treatment course. Focusing solely on children who have needed LTMV over this timeframe has enabled us to isolate trends specific to this cohort. Less patients commenced LTMV on a year on year basis, and for those that require tracheostomy and LTMV, their journey to decannulation tends to be shorter. Conclusion: Over the period reviewed, less patients over time necessitated long-term invasive therapy and those patients are being weaned and decannulated with ever more success. This has implications in terms of predicting numbers transitioning to adult services and allocation of hospital and community care resources.

Objective: To determine whether viral coinfection is a risk for severe lower respiratory tract infection (LRTI). Working Hypothesis: Children with viral coinfection had a higher risk for admission to the intensive care unit (ICU) than those with a single virus infection. Study Design: Retrospective, observational study for ten years. Patient-Subject Selection: Children between 1-60 months of age hospitalized with LRTI. Methodology: We defined severe LRTI as admission to the ICU for high-flow nasal cannula oxygen/bilevel positive airway pressure/invasive ventilation and assessed demographic and laboratory data with potential risk factors from the patients’ medical records. Results: Of 2115 children hospitalized with LRTI, 562 had severe, and 1553 had mild disease. Viral coinfection was present in 28.3% of all patients, and those with viral coinfection were at a higher risk of severe LRTI than those with a single virus infection (43.8% vs. 22.7%; aOR, 3.44; 95% CI, 2.74-4.53). Respiratory syncytial virus (RSV) and rhinovirus (except for between 25-60 months) coinfections were associated with severe LRTI in all ages, whereas parainfluenza virus-3 (PIV3; 7-24 months) and bocavirus (7-12 months) coinfections led to severe LRTI in early childhood. Moreover, influenza-A coinfection caused severe LRTI in children between 7-12 and 25-60 months. Other risk factors included young age, prematurity, history of atopy, exposure to tobacco smoke, underlying condition, neutrophilia, lymphopenia, and high CRP value. Conclusion: Children with viral coinfection, particularly with rhinovirus, RSV, influenza-A, PIV3, and bocavirus, may be followed closely regarding the clinical changes.

Introduction: COVID-19 emerged in China leading to worldwide morbidity and mortality, including depression and anxiety. As the pandemic spread throughout Italy and Europe, mental health concerns emerged for people with cystic fibrosis (pwCF), who are at increased risk. This led to development of a Telehealth Psychological Support Intervention to help adolescents/young adults with CF and caregivers cope with the stress and emotional challenges of the lockdown which began in Italy in March 2020. Methods: This intervention utilized cognitive behavioral skills (e.g., relaxation training, cognitive reframing). Participants included 16 adolescents/adults and 14 parents, who completed 4 individual video sessions with a psychologist. Stress ratings, PHQ-8 and GAD-7 were completed electronically. Feasibility and Satisfaction were rated. Results: Ratings of stress significantly decreased from pre to post-testing for both pwCF (paired t=-4.06 (14), p<.01) and parents (paired t=-5.2, p< 001). Most participants reported clinically elevated depression and anxiety at the pre-test, with statistically significant reductions in depression for pwCF (pre: M=8.0 to post M=4.7; paired t (14)=2.8, p <.05) but not anxiety (pre: M=6.9 to post: M=5.6, t (14)=1.2, p=NS). Reductions in depression were found for parents (pre: M=6.4 to post: M 5.1, (14) t=-2.5, p<.05) but not anxiety (pre: M=8.1 to post: M=7.9, t (14)=-0.2, p=ns). Positive ratings of Feasibility and Satisfaction were documented. Conclusion: This brief telehealth intervention yielded significant reductions in stress and depression for participants. Anxiety was not reduced, possibly because COVID was ongoing. This intervention was effective for improving mental health and was highly feasible and satisfactory.

Abstract Continuous intravenous (IV) sildenafil may avoid the acute systemic vasodilatory effects of bolus dosing in infants with pulmonary hypertension (PH). We aimed to examine the tolerability of different methods of IV sildenafil administration. Methods: We retrospectively evaluated subjects less than 12 months old with PH, who had been started on IV sildenafil. Vital signs, oxygen requirement, and vasoactive-inotropic score (VIS) before and after sildenafil initiation were noted, as was the need for discontinuation due to side effects. Results: Forty-three subjects were identified (23 continuous, 20 intermittent dosing). There were no statistically significant differences between groups in gender or gestational age, but higher baseline inspired oxygen (FiO2) and VIS in the continuous group suggested a higher baseline severity of illness (p=0.012). After sildenafil initiation, there were no significant differences in the change in blood pressure, oxygen saturation, FiO2, or VIS between groups, and no difference in the number of subjects requiring discontinuation due to side effects (4 in the continuous group, 1 intermittent, p=0.35). Eight subjects (34.8%) in the continuous group and 3 (15%) in the intermittent group died (p=0.024). Conclusions: In this small cohort of infants with PH treated with continuous or intermittent IV sildenafil, there were no statistically significant differences between groups in the change in vital signs, VIS, and oxygen requirement, or the need for discontinuation of therapy due to side effects. A higher mortality rate in the continuous infusion group may be explained by higher baseline illness severity.

Background: Cystic fibrosis (CF) pulmonary exacerbations (PEx) are associated with significant drop in pulmonary function. The clinical value of measuring bronchodilator (BD) responsiveness during treatment for PEx to monitor or predict recovery of lung function is unclear. Methods: A retrospective analysis of spirometry with BD response testing obtained during hospital admissions for PEx in pediatric CF patients. Repeated events were included for patients with BD testing during multiple admissions. Results: 249 spirometries with BD testing in 102 patients were completed around day 7 (day 4-10) of hospital admission for treatment of CF PEx. Median (IQR) forced expiratory volume in one second (FEV1) was 70.6% predicted (58.1, 84.6) prior to the PEx event (best FEV1 in 6 months prior to admission), 54.4% (41.5, 66.9) at admission, 62.3% (48.4, 74.7) around day 7 of admission and 67.1% predicted (53.8, 78.2) at end of treatment. BD response around day 7 correlated poorly with FEV1 prior to PEx (r=-0.16, p=0.02), and did not correlate with recovery to baseline FEV1 at end of treatment (r=0.08, p=0.22). Only 23/249 (9%) patients had a BD response of ≥12 % and 200 ml. BD response was not related to age or severity of lung disease and led to an immediate change in clinical management in only 4 cases. CONCLUSIONS: BD response in CF patients treated for PEx is poorly correlated with baseline pulmonary function and does not correlate with recovery of FEV1 with treatment. These data suggest that routine testing for BD response is not indicated during PEx.

An Association of the Arginase 1 Gene with Preschool Wheezing PhenotypesHartmut Grasemann and Fernando HolguinArginases are enzymes that metabolize L-arginine to form urea and L-ornithine. The two arginase isoforms, arginase I and arginase II, which are encoded by two different genes (ARG1 and ARG 2), are expressed in various cell types throughout the human body, including the lungs and airways. Arginase competes with nitric oxide synthase (NOS) for L-arginine as substrate, and increased arginase expression and activity in asthma reduces nitric oxide (NO) bioavailability, causing airways obstruction and contributing to reactive oxygen species production (1). Arginase also plays a role in allergen-induced airway remodeling in chronic asthma, presumably due to increased formation of L-ornithine, the precursor of L-proline and the polyamines (2). Proline is further metabolized to collagen and the polyamines putrescine, spermidine and spermine, which among other functions, also inhibit NOS. Increased production of endogenous NOS inhibitors including the polyamines as well as asymmetric dimethylarginine (ADMA), further contribute to the imbalance of NOS and arginases in asthma (figure 1).Previous studies of genetic variations or single nucleotide polymorphisms (SNPs) in arginase genes had shown associations with atopy and asthma. For example, SNPs in both arginase genes were associated with atopy and asthma in children and with risk for asthma in adults (3,4,5). Interestingly, ARG1 and ARG2 were also found to be associated with bronchodilator response in children and adults with asthma, and ARG1 with long term outcome on inhaled corticosteroid (ICS) therapy in adult asthma (5,6,7,8,9).Preschool wheeze is a common phenomenon, usually benign and mostly self-limited (10,11). Different phenotypes of preschool wheeze have been described, including early transient wheeze, late onset wheeze and persistent wheeze (12). A more recent classifications distinguishes multiple trigger wheeze (MTW) from episodic wheeze (EW), which is mainly caused by viral respiratory tract infections. The clinical usefulness of phenotype driven classifications has been questioned for a number of reasons including the longitudinal instability of phenotypes. However, some evidence suggests that MTW may be linked to later onset allergic asthma and MTW may therefore be more likely to respond to asthma treatment as compared to EW (13,14,15,16,17,18). Interestingly, a more recent analysis of the natural history of MTW and EW in two large independent birth cohorts demonstrated that phenotypes may track over time (19), suggesting that the two indeed represent different disease entities and not just differences in severity of the same disease.In a study by Gokmirza Ozdemir et al., published in this issue of theJournal , the authors report an association between arginase 1 gene polymorphisms and preschool wheezing phenotypes (20). In a cohort of 83 well characterized preschool wheezers with either multi trigger wheeze (MTW) or episodic wheeze (EW) phenotype of Turkish origin and matched controls, there was a difference in homozygous frequency of the ARG1 rs2781667T>C SNP between wheezing phenotypes and between patients with vs without allergic rhinitis. The homozygous frequency of this SNP in ARG1 was significantly higher in MTW vs EW, and in allergic rhinitis vs no allergic rhinitis. There were no associations of other tested SNPs in either ARG1 or ARG2 with preschool wheezing, allergic rhinitis, presence of aeroallergen sensitivity or tobacco exposure. Further analyses also showed significant differences in a number of haplotype frequencies in ARG1 between all wheezers and controls, and also between wheezing phenotypes. No associations were found with ARG2 in this study (20). Thus, these results show that in the population studied, variants in ARG1 but not ARG2 were associated with wheezing phenotypes in pre-school age.This observation is exiting as the genotype-phenotype association implies that arginase I could be involved in the development of preschool wheeze and wheezing phenotypes, possibly through an effect on L-arginine availability for nitric oxide synthase (NOS) or by affecting airway remodelling. However, the population studied here was relatively small and the findings have not yet been confirmed by others. Therefore, the results need to be interpreted with caution and additional studies are needed for confirmation. Similarly, it is unclear at this point, whether the SNPs and haplotypes found to be different in frequency between groups, alter arginase expression or activity, and what the biological or molecular explanation could be for the observed associations. Nevertheless, these observations by Gokmirza Ozdemir et al. are promising, and once confirmed in larger and independent cohorts, also have the potential to help develop a genetic test for wheezing pre-schoolers that may predict future asthma risk and response to asthma therapies.References1) North ML, Grasemann H, Khanna N, Inman MD, Gauvreau GM, Scott JA. Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma. Am J Respir Cell Mol Biol. 2013 Jun;48(6):694-702.2) Maarsingh H, Dekkers BG, Zuidhof AB, Bos IS, Menzen MH, Klein T, Flik G, Zaagsma J, Meurs H. Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur Respir J. 2011 Aug;38(2):318-28.3) Donthi S, Neela VSK, Gaddam S, Mohammed HH, Ansari SS, Valluri VL, Sivasai KSR. Association of increased risk of asthma with elevated arginase & interleukin-13 levels in serum & rs2781666 G/T genotype of arginase I. Indian J Med Res. 2018 Aug;148(2):159-168.4) Li H, Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, Estela Del Rio-Navarro B, Kistner EO, Gjessing HK, Lara-Sanchez Idel C, Chiu GY, London SJ. Genetic polymorphisms in arginase I and II and childhood asthma and atopy. J Allergy Clin Immunol. 2006 Jan;117(1):119-26.5) Vonk JM, Postma DS, Maarsingh H, Bruinenberg M, Koppelman GH, Meurs H. Arginase 1 and arginase 2 variations associate with asthma, asthma severity and beta2 agonist and steroid response. Pharmacogenet Genomics. 2010 Mar;20(3):179-86.6) Duan QL, Gaume BR, Hawkins GA, Himes BE, Bleecker ER, Klanderman B, Irvin CG, Peters SP, Meyers DA, Hanrahan JP, Lima JJ, Litonjua AA, Tantisira KG, Liggett SB. Regulatory haplotypes in ARG1 are associated with altered bronchodilator response. Am J Respir Crit Care Med. 2011 Feb 15;183(4):449-54.7) Litonjua AA, Lasky-Su J, Schneiter K, Tantisira KG, Lazarus R, Klanderman B, Lima JJ, Irvin CG, Peters SP, Hanrahan JP, Liggett SB, Hawkins GA, Meyers DA, Bleecker ER, Lange C, Weiss ST. ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts. Am J Respir Crit Care Med. 2008 Oct 1;178(7):688-94.8) Sy HY, Ko FW, Chu HY, Chan IH, Wong GW, Hui DS, Leung TF. Asthma and bronchodilator responsiveness are associated with polymorphic markers of ARG1, CRHR2 and chromosome 17q21. Pharmacogenet Genomics. 2012 Jul;22(7):517-24.9) Scaparrotta A, Franzago M, Marcovecchio ML, Di Pillo S, Chiarelli F, Mohn A, Stuppia L. Role of THRB, ARG1, and ADRB2 genetic variants on bronchodilators response in asthmatic children. J Aerosol Med Pulm Drug Deliv. 2019 Jun;32(3):164-173.10) Kurukulaaratchy RJ, Matthews S, Holgate ST, Arshad SH. Predicting persistent disease among children who wheeze during early life. Eur Respir J. 2003 Nov;22(5):767-71.11) Caudri D, Wijga A, A Schipper CM, Hoekstra M, Postma DS, Koppelman GH, Brunekreef B, Smit HA, de Jongste JC. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol. 2009 Nov;124(5):903-10.e1-7.12) Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995 Jan 19;332(3):133-8.13) Schultz A, Devadason SG, Savenije OE, Sly PD, Le Souëf PN, Brand PL. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr. 2010 Jan;99(1):56-60.14) Sonnappa S, Bastardo CM, Wade A, Saglani S, McKenzie SA, Bush A, Aurora P. Symptom-pattern phenotype and pulmonary function in preschool wheezers. J Allergy Clin Immunol. 2010 Sep;126(3):519-26.e1-7.15) Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, Frey U, Gappa M, Garcia-Marcos L, Grigg J, Lenney W, Le Souëf P, McKenzie S, Merkus PJ, Midulla F, Paton JY, Piacentini G, Pohunek P, Rossi GA, Seddon P, Silverman M, Sly PD, Stick S, Valiulis A, van Aalderen WM, Wildhaber JH, Wennergren G, Wilson N, Zivkovic Z, Bush A. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008 Oct;32(4):1096-110.16) Brand PL, Caudri D, Eber E, Gaillard EA, Garcia-Marcos L, Hedlin G, Henderson J, Kuehni CE, Merkus PJ, Pedersen S, Valiulis A, Wennergren G, Bush A. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J. 2014 Apr;43(4):1172-7.17) Garcia-Marcos L, Martinez FD. Multitrigger versus episodic wheeze in toddlers: new phenotypes or severity markers? J Allergy Clin Immunol. 2010 Sep;126(3):489-90.18) van Wonderen KE, Geskus RB, van Aalderen WM, Mohrs J, Bindels PJ, van der Mark LB, Ter Riet G.Stability and predictiveness of multiple trigger and episodic viral wheeze in preschoolers. Clin Exp Allergy. 2016 Jun;46(6):837-47.19) Spycher BD, Cochrane C, Granell R, Sterne JAC, Silverman M, Pedersen E, Gaillard EA, Henderson J, Kuehni CE. Temporal stability of multitrigger and episodic viral wheeze in early childhood. Eur Respir J. 2017 Nov 2;50(5):1700014.20) Gokmirza Ozdemir, P, Eker D, Celik V, Beken B, Gurkan H, Yazicioglu M, Sut N. The relationship between arginase genes polymorphisms and preschool wheezing phenotypes. Pediatr Pulmonol. 2020 ….