Inhalations of hypertonic saline is a known therapy for infants diagnosed with acute bronchioliti... more Inhalations of hypertonic saline is a known therapy for infants diagnosed with acute bronchiolitis. Recent meta-analysis has shown that it can reduce the length of hospitalization and decrease the chances of admission. To assess the extent of use of hypertonic saline inhalations in the pediatric wards in Israel in 2018. During October 2018 a detailed questionnaire was emailed to all the managers of pediatric wards in Israel. The questions related to treatments given to infants with acute bronchiolitis in pediatric wards and emergency departments in 2018. All results underwent statistical analysis. A total of 22/28 (78%) of all pediatric wards managers completed the questionnaire; 17/22 (77%) routinely use hypertonic saline in their wards. In 15 out of the 17 wards the hypertonic saline is also provided at their emergency department. In 12 wards (70%) the saline is provided together with a bronchodilator, in 4 (24%) with inhaled steroids, and in 2 (12%) with adrenaline. In most pedia...
Transmission of Pseudomonas aeruginosa among cystic fibrosis patients attending health camps has ... more Transmission of Pseudomonas aeruginosa among cystic fibrosis patients attending health camps has been reported previously. To determine the transmission of P. aeruginosa among CF patients during three winter camps in the Dead Sea region in southern Israel. Three consecutive CF patient groups were studied, each of which spent 3 weeks at the camp. The patients were segragated prior to camp attendance: patients who were not colonized with P. aeruginosa constituted the first group, and colonized patients made up the two additional groups. Sputum cultures were obtained upon arrival, at mid-camp and on the last day. Environmental cultures were also obtained. Patients were separated during social activities and were requested to avoid social mingling. Isolates were analyzed by antibiotic susceptibility profile and by pulsed field gel electrophoresis. Ninety isolates from 19 patients produced 28 different fingerprint patterns by PFGE. Isolates from two siblings and two patients from the sam...
Background 25(OH) vitamin D levels are inversely associated with respiratory infections and child... more Background 25(OH) vitamin D levels are inversely associated with respiratory infections and childhood wheezing. Objective To evaluate serum 25(OH) vitamin D levels in infants and toddlers with acute bronchiolitis, compared to subjects with non-respiratory febrile illness . Methods A prospective cross-sectional case-control study which compared serum 25(OH) vitamin D levels between infants and toddlers diagnosed with acute bronchiolitis to subjects with non-respiratory febrile illness. Multivariate logistic regression, adjusted for age, sex, ethnicity and nutrition was performed. Correlation between serum vitamin D levels and bronchiolitis severity was assessed via Modified Tal Score and length of hospital stay (LOS). Results One hundred twenty-seven patients aged < 24 months were recruited; 80 diagnosed with acute bronchiolitis and 47 patients with non- respiratory febrile illnesses. Both groups had similar demographics aside from age (median [IQR] 5 [3–9] vs. 9 [5–16] months in ...
OBJECTIVES: Children with nonsevere obstructive sleep apnea (OSA) benefit from alternative therap... more OBJECTIVES: Children with nonsevere obstructive sleep apnea (OSA) benefit from alternative therapeutic interventions such as leukotriene modifiers. We hypothesized that montelukast might improve OSA in children. We tested this hypothesis in a double-blind, randomized, placebo-controlled fashion. METHODS: Of 50 possible candidates, we recruited 46 children with polysomnographically diagnosed OSA. In this prospective, doubleblind, randomized trial, children received daily oral montelukast at 4 or 5 mg (,6 or .6 years of age, respectively) or placebo for 12 weeks. Polysomnographic assessments, parent questionnaires, and radiographs to assess adenoid size were performed before and after therapy. RESULTS: Compared with the 23 children that received placebo, the 23 children that received montelukast showed significant improvements in polysomnographic measures of respiratory disturbance (obstructive apnea index), children’s symptoms, and adenoid size. The obstructive apnea index decreased ...
BACKGROUND Rehabilitation camps can improve exercise tolerance and nutrition in cystic fibrosis p... more BACKGROUND Rehabilitation camps can improve exercise tolerance and nutrition in cystic fibrosis patients. OBJECTIVES To assess weight gain, pulmonary function tests and daily symptoms in European CF patients attending a rehabilitation camp at the Dead Sea, Israel. METHODS We conducted a retrospective study assessing 94 CF patients who participated in winter camps held at the Dead Sea, Israel from 1997 to 2000. The camp program included daily physiotherapy, physical activities, and a high caloric diet. We assessed weight gain, pulmonary function tests, oxyhemoglobin saturation and daily symptoms before (pre), on departure (dep), and up to 3 months after the 3 week rehabilitation camp (post). All data were analyzed by ANOVA for repetitive measurements. P < 0.05 was considered significant. RESULTS Lung function tests and oxyhemoglobin saturation taken before, on departure and 3 months after camp were available for 35 patients. Forced expiratory volume in the first second (% predicte...
Obstructive sleep apnea syndrome (OSA) is associated with cardiovascular morbidity in adults and ... more Obstructive sleep apnea syndrome (OSA) is associated with cardiovascular morbidity in adults and children. NFκB activity is enhanced in circulating monocytes of adults with OSA, that decreases following positive pressure therapy. OSA children’s serum activates NFκB in a cell line. We hypothesized that OSA children’s serum can activate NFκB in cardiomyocytes (CM) and effect their viability. In order to explore the role played by NFκB in OSA cardiovascular pathophysiology, rat, mouse and human immortalized CM were exposed to human serum drawn from OSA children and matched controls. Increased expression of NFκB classical subunits p65/p50 as well as major morphological changes occurred in cardiomyocytes following OSA’s serum exposure. OSA children’s serum induced NFκB activity as measured by p65 nuclear translocation in immortalized human CM and rat cardiomyocytes as well as dense immunostaining of the nucleus. Trypan blue and XTT assays showed that OSA sera induced CM apoptosis. We con...
Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is t... more Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is the leading cause of death in this disease. Based on our previous work with transformed cell lines and primary rat cardiomyocytes, we determined that upon incubation with sera from pediatric OSAS patients, the cell’s morphology changes, NF-κB pathway is activated, and their beating rate and viability decreases. These results suggest an important link between OSAS, systemic inflammatory signals and end-organ cardiovascular diseases. In this work, we confirmed and expanded these observations on a new in vitro system of beating human cardiomyocytes (CM) differentiated from human embryonic stem cells (hES). Our results show that incubation with pediatric OSAS sera, in contrast to sera from healthy children, induces over-expression of NF-κB p50 and p65 subunits, marked reduction in CMs beating rate, contraction amplitude and a strong reduction in intracellular calcium signal. The use of human ...
Interpregnancy interval (IPI) is defined as the period between a live birth and the conception of... more Interpregnancy interval (IPI) is defined as the period between a live birth and the conception of a subsequent fetus. Both short (IPI < 6 months) and long IPI (IPI > 60 months) have been shown to increase the risk for adverse perinatal outcomes, some of which, are known risk factors for obstructive sleep apnea syndrome (OSAS) in the offspring.
Background: Acute asthma exacerbations are a common cause for emergency department (ED) visits an... more 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.
BACKGROUND Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory... more BACKGROUND Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection. METHODS This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49. FINDINGS Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug. INTERPRETATION Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation. FUNDING Ablynx, a Sanofi Company.
OBJECTIVE To assess whether increment of vitamin D daily intake results in improved serum 25 (OH)... more OBJECTIVE To assess whether increment of vitamin D daily intake results in improved serum 25 (OH) vitamin D levels and reduced respiratory morbidity in premature infants. METHODS A randomized double-blind clinical pilot trial, including preterm infants born at 32+6 to 36+6 weeks of gestation. The control group received 400 IU of cholecalciferol daily compared to 800 IU daily in the intervention group. Levels of 25 (OH) vitamin D were measured at birth, 6 and 12 months of age. Respiratory morbidity was followed until 1 year of age. RESULTS Fifty subjects were recruited during the study period; the median measured 25 (OH) vitamin D levels in the control vs. intervention groups were: 26.5 vs. 34 nmol/L (p-value 0.271) at birth, 99 vs. 75.5 nmol/L (p-value 0.008) at 6 months and 72.5 vs. 75 nmol/L (p-value 0.95) at 12 months of age. Infants with insufficient vitamin D (< 75 nmol/L) levels had higher respiratory morbidity. Serum vitamin 25 (OH) D is a fair predictor for respiratory symptoms (AUC 0.697, 95%CI 0.509-0.885, p-value 0.047) and for recorded acute respiratory illnesses (AUC 0.745, 95%CI 0.569-0.922, p-value 0.012). CONCLUSION Doubling the daily intake of vitamin D in premature infants did not increase serum 25 (OH) vitamin D level, due to poor compliance in the intervention group. We found an inverse association between serum 25 (OH) vitamin D and respiratory symptoms, indicating vitamin D deficiency is a fair predictor for respiratory morbidity. This article is protected by copyright. All rights reserved.
Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cau... more Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin >7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO2 ≥92%, and time to m...
ABSRACT Objective: Poor adherence to asthma therapy is a major problem in the management of asthm... more ABSRACT Objective: Poor adherence to asthma therapy is a major problem in the management of asthma. We aimed to assess if a designed coaching program in children with asthma, coming from low socioeconomic background, will reduce respiratory morbidity and health care utilization. Methods: A prospective interventional pilot study enrolling children aged 3–18 years, admitted to Soroka University Medical Center (SUMC) between October 2015 and May 2016 due to asthma exacerbation. The intervention group was part of a coaching program, which was conducted by medical and paramedical personnel and included a diagnostic and personal educational office visit and a house visit by a nurse educator for asthma. The control group comprised of demographically matched children with asthma, who were admitted to the SUMC, but did not go through any intervention. Medications purchase and health care utilization were extracted from the participants' HMO databases, during 1-year of follow-up. Results: 41 children were enrolled to the intervention group, with 63 children as a control group. No differences were found in asthma-related drugs purchase, number of clinic visits, ER admissions and hospitalizations during the follow-up year, although the intervention group showed a trend towards having a shorter length of stay (2.3 vs. 4.5 days, Cohen's D = 0.44, p = 0.06). The intervention group demonstrated subjective improvement in asthma control, as reflected in Asthma Control Test questionnaires. Conclusions: In this pilot study of coaching program for children with asthma coming from low income families, no decrease in health care utilization was shown. Larger and longer intervention programs are needed.
Acute viral bronchiolitis is the most common lower respiratory infection in early infancy and a l... more Acute viral bronchiolitis is the most common lower respiratory infection in early infancy and a leading cause of infant hospitalization. The treatment of bronchiolitis is largely supportive. Inhaled nitric oxide (NO) has pulmonary vasodilatory properties and has been approved for the treatment of persistent pulmonary hypertension of the newborn. Furthermore, preclinical studies show that high-dose NO possesses anti-bacterial and anti-viral properties. In a recent pilot study, we have shown safety and tolerability of high-dose NO (160 ppm) in infants with moderately severe bronchiolitis. In this study, we are conducting a randomized, multicenter, double-blind, controlled pivotal trial comparing the efficacy of intermittent 160 ppm NO (30min, 5 times/day, up to 5 days) with standard supportive care (O2/air) in 94 infants (0-12 months old, clinical score 7-10, requiring >24hr hospitalization) admitted to 10 hospitals across Israel. All subjects receive standard of care treatment. The primary outcome measure is the length of hospital stay (LOS). The secondary outcome measures are time to reach clinical score of 5 and below (Modified Tal score) and time to reach O2 saturation of 92% and above in room air. Adverse events (AE’s) and NO-related AE’s including methemoglobin and nitrogen dioxide levels are closely monitored. At the time of submission, the trial is ongoing with 46 out of 94 subjects enrolled at 5 sites. We anticipate demonstrating efficacy by reducing LOS and improving clinical symptoms in infants treated with NO. We predict completing the trial by April 30, 2018 and present final results at the next 2018 ERS International meeting, Paris.
To further validate the use of the Modified Tal Score (MTS), a clinical tool for assessing bronch... more To further validate the use of the Modified Tal Score (MTS), a clinical tool for assessing bronchiolitis severity, by physicians with varying experience and training levels, and to determine the ability of the MTS to predict bronchiolitis severity. This prospective cohort study included infants of <12 months of age who were diagnosed with bronchiolitis and assessed via MTS. We calculated the intra-class correlation coefficient (ICC) among four groups of raters: group 1, board-certified pediatric pulmonologists; group 2, board-certified pediatricians; group 3, senior pediatric residents; and group 4, junior pediatric residents. Clinical outcomes were determined as length of oxygen support and length of stay (LOS). We assessed MTS's prediction of these outcomes. Relative risk (RR) for clinical severity was calculated via a Generalized Linear Model. Twenty-four physicians recorded a total of 600 scores for 50 infants (average age 5 ± 3 months; 56% male). The ICC values with grou...
The aims of this pilot study were to determine safety, tolerability (primary outcome) and efficac... more The aims of this pilot study were to determine safety, tolerability (primary outcome) and efficacy (secondary outcome) of high-dose inhaled nitric oxide for the treatment of infants with moderately severe bronchiolitis. This was a pilot, double-blinded, randomized controlled study (phase IIa). Intermittent inhalations of nitric oxide 160 ppm for 30 min or oxygen/air (control) were given 5 times/day to hospitalized infants (2-11 months) with acute bronchiolitis. Oxygen saturation, methemoglobin, and nitric dioxide (NO2 ) levels and vital signs were monitored. Forty-three infants were enrolled. Baseline characteristics were comparable in both study groups. Mean clinical score, comprised of four components: respiratory rate, use of accessory muscles, wheezes and crackles, and % room-air oxygen saturation, was 7.86 (±1.1) and 8.09 (±1.2) in the NO and control groups, respectively, consistent with moderate severity. The overall frequency of adverse events was similar between the groups. ...
Inhalations of hypertonic saline is a known therapy for infants diagnosed with acute bronchioliti... more Inhalations of hypertonic saline is a known therapy for infants diagnosed with acute bronchiolitis. Recent meta-analysis has shown that it can reduce the length of hospitalization and decrease the chances of admission. To assess the extent of use of hypertonic saline inhalations in the pediatric wards in Israel in 2018. During October 2018 a detailed questionnaire was emailed to all the managers of pediatric wards in Israel. The questions related to treatments given to infants with acute bronchiolitis in pediatric wards and emergency departments in 2018. All results underwent statistical analysis. A total of 22/28 (78%) of all pediatric wards managers completed the questionnaire; 17/22 (77%) routinely use hypertonic saline in their wards. In 15 out of the 17 wards the hypertonic saline is also provided at their emergency department. In 12 wards (70%) the saline is provided together with a bronchodilator, in 4 (24%) with inhaled steroids, and in 2 (12%) with adrenaline. In most pedia...
Transmission of Pseudomonas aeruginosa among cystic fibrosis patients attending health camps has ... more Transmission of Pseudomonas aeruginosa among cystic fibrosis patients attending health camps has been reported previously. To determine the transmission of P. aeruginosa among CF patients during three winter camps in the Dead Sea region in southern Israel. Three consecutive CF patient groups were studied, each of which spent 3 weeks at the camp. The patients were segragated prior to camp attendance: patients who were not colonized with P. aeruginosa constituted the first group, and colonized patients made up the two additional groups. Sputum cultures were obtained upon arrival, at mid-camp and on the last day. Environmental cultures were also obtained. Patients were separated during social activities and were requested to avoid social mingling. Isolates were analyzed by antibiotic susceptibility profile and by pulsed field gel electrophoresis. Ninety isolates from 19 patients produced 28 different fingerprint patterns by PFGE. Isolates from two siblings and two patients from the sam...
Background 25(OH) vitamin D levels are inversely associated with respiratory infections and child... more Background 25(OH) vitamin D levels are inversely associated with respiratory infections and childhood wheezing. Objective To evaluate serum 25(OH) vitamin D levels in infants and toddlers with acute bronchiolitis, compared to subjects with non-respiratory febrile illness . Methods A prospective cross-sectional case-control study which compared serum 25(OH) vitamin D levels between infants and toddlers diagnosed with acute bronchiolitis to subjects with non-respiratory febrile illness. Multivariate logistic regression, adjusted for age, sex, ethnicity and nutrition was performed. Correlation between serum vitamin D levels and bronchiolitis severity was assessed via Modified Tal Score and length of hospital stay (LOS). Results One hundred twenty-seven patients aged < 24 months were recruited; 80 diagnosed with acute bronchiolitis and 47 patients with non- respiratory febrile illnesses. Both groups had similar demographics aside from age (median [IQR] 5 [3–9] vs. 9 [5–16] months in ...
OBJECTIVES: Children with nonsevere obstructive sleep apnea (OSA) benefit from alternative therap... more OBJECTIVES: Children with nonsevere obstructive sleep apnea (OSA) benefit from alternative therapeutic interventions such as leukotriene modifiers. We hypothesized that montelukast might improve OSA in children. We tested this hypothesis in a double-blind, randomized, placebo-controlled fashion. METHODS: Of 50 possible candidates, we recruited 46 children with polysomnographically diagnosed OSA. In this prospective, doubleblind, randomized trial, children received daily oral montelukast at 4 or 5 mg (,6 or .6 years of age, respectively) or placebo for 12 weeks. Polysomnographic assessments, parent questionnaires, and radiographs to assess adenoid size were performed before and after therapy. RESULTS: Compared with the 23 children that received placebo, the 23 children that received montelukast showed significant improvements in polysomnographic measures of respiratory disturbance (obstructive apnea index), children’s symptoms, and adenoid size. The obstructive apnea index decreased ...
BACKGROUND Rehabilitation camps can improve exercise tolerance and nutrition in cystic fibrosis p... more BACKGROUND Rehabilitation camps can improve exercise tolerance and nutrition in cystic fibrosis patients. OBJECTIVES To assess weight gain, pulmonary function tests and daily symptoms in European CF patients attending a rehabilitation camp at the Dead Sea, Israel. METHODS We conducted a retrospective study assessing 94 CF patients who participated in winter camps held at the Dead Sea, Israel from 1997 to 2000. The camp program included daily physiotherapy, physical activities, and a high caloric diet. We assessed weight gain, pulmonary function tests, oxyhemoglobin saturation and daily symptoms before (pre), on departure (dep), and up to 3 months after the 3 week rehabilitation camp (post). All data were analyzed by ANOVA for repetitive measurements. P < 0.05 was considered significant. RESULTS Lung function tests and oxyhemoglobin saturation taken before, on departure and 3 months after camp were available for 35 patients. Forced expiratory volume in the first second (% predicte...
Obstructive sleep apnea syndrome (OSA) is associated with cardiovascular morbidity in adults and ... more Obstructive sleep apnea syndrome (OSA) is associated with cardiovascular morbidity in adults and children. NFκB activity is enhanced in circulating monocytes of adults with OSA, that decreases following positive pressure therapy. OSA children’s serum activates NFκB in a cell line. We hypothesized that OSA children’s serum can activate NFκB in cardiomyocytes (CM) and effect their viability. In order to explore the role played by NFκB in OSA cardiovascular pathophysiology, rat, mouse and human immortalized CM were exposed to human serum drawn from OSA children and matched controls. Increased expression of NFκB classical subunits p65/p50 as well as major morphological changes occurred in cardiomyocytes following OSA’s serum exposure. OSA children’s serum induced NFκB activity as measured by p65 nuclear translocation in immortalized human CM and rat cardiomyocytes as well as dense immunostaining of the nucleus. Trypan blue and XTT assays showed that OSA sera induced CM apoptosis. We con...
Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is t... more Obstructive sleep apnea syndrome (OSAS) patients suffer from cardiovascular morbidity, which is the leading cause of death in this disease. Based on our previous work with transformed cell lines and primary rat cardiomyocytes, we determined that upon incubation with sera from pediatric OSAS patients, the cell’s morphology changes, NF-κB pathway is activated, and their beating rate and viability decreases. These results suggest an important link between OSAS, systemic inflammatory signals and end-organ cardiovascular diseases. In this work, we confirmed and expanded these observations on a new in vitro system of beating human cardiomyocytes (CM) differentiated from human embryonic stem cells (hES). Our results show that incubation with pediatric OSAS sera, in contrast to sera from healthy children, induces over-expression of NF-κB p50 and p65 subunits, marked reduction in CMs beating rate, contraction amplitude and a strong reduction in intracellular calcium signal. The use of human ...
Interpregnancy interval (IPI) is defined as the period between a live birth and the conception of... more Interpregnancy interval (IPI) is defined as the period between a live birth and the conception of a subsequent fetus. Both short (IPI < 6 months) and long IPI (IPI > 60 months) have been shown to increase the risk for adverse perinatal outcomes, some of which, are known risk factors for obstructive sleep apnea syndrome (OSAS) in the offspring.
Background: Acute asthma exacerbations are a common cause for emergency department (ED) visits an... more 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.
BACKGROUND Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory... more BACKGROUND Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection. METHODS This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49. FINDINGS Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug. INTERPRETATION Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation. FUNDING Ablynx, a Sanofi Company.
OBJECTIVE To assess whether increment of vitamin D daily intake results in improved serum 25 (OH)... more OBJECTIVE To assess whether increment of vitamin D daily intake results in improved serum 25 (OH) vitamin D levels and reduced respiratory morbidity in premature infants. METHODS A randomized double-blind clinical pilot trial, including preterm infants born at 32+6 to 36+6 weeks of gestation. The control group received 400 IU of cholecalciferol daily compared to 800 IU daily in the intervention group. Levels of 25 (OH) vitamin D were measured at birth, 6 and 12 months of age. Respiratory morbidity was followed until 1 year of age. RESULTS Fifty subjects were recruited during the study period; the median measured 25 (OH) vitamin D levels in the control vs. intervention groups were: 26.5 vs. 34 nmol/L (p-value 0.271) at birth, 99 vs. 75.5 nmol/L (p-value 0.008) at 6 months and 72.5 vs. 75 nmol/L (p-value 0.95) at 12 months of age. Infants with insufficient vitamin D (< 75 nmol/L) levels had higher respiratory morbidity. Serum vitamin 25 (OH) D is a fair predictor for respiratory symptoms (AUC 0.697, 95%CI 0.509-0.885, p-value 0.047) and for recorded acute respiratory illnesses (AUC 0.745, 95%CI 0.569-0.922, p-value 0.012). CONCLUSION Doubling the daily intake of vitamin D in premature infants did not increase serum 25 (OH) vitamin D level, due to poor compliance in the intervention group. We found an inverse association between serum 25 (OH) vitamin D and respiratory symptoms, indicating vitamin D deficiency is a fair predictor for respiratory morbidity. This article is protected by copyright. All rights reserved.
Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cau... more Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin >7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO2 ≥92%, and time to m...
ABSRACT Objective: Poor adherence to asthma therapy is a major problem in the management of asthm... more ABSRACT Objective: Poor adherence to asthma therapy is a major problem in the management of asthma. We aimed to assess if a designed coaching program in children with asthma, coming from low socioeconomic background, will reduce respiratory morbidity and health care utilization. Methods: A prospective interventional pilot study enrolling children aged 3–18 years, admitted to Soroka University Medical Center (SUMC) between October 2015 and May 2016 due to asthma exacerbation. The intervention group was part of a coaching program, which was conducted by medical and paramedical personnel and included a diagnostic and personal educational office visit and a house visit by a nurse educator for asthma. The control group comprised of demographically matched children with asthma, who were admitted to the SUMC, but did not go through any intervention. Medications purchase and health care utilization were extracted from the participants' HMO databases, during 1-year of follow-up. Results: 41 children were enrolled to the intervention group, with 63 children as a control group. No differences were found in asthma-related drugs purchase, number of clinic visits, ER admissions and hospitalizations during the follow-up year, although the intervention group showed a trend towards having a shorter length of stay (2.3 vs. 4.5 days, Cohen's D = 0.44, p = 0.06). The intervention group demonstrated subjective improvement in asthma control, as reflected in Asthma Control Test questionnaires. Conclusions: In this pilot study of coaching program for children with asthma coming from low income families, no decrease in health care utilization was shown. Larger and longer intervention programs are needed.
Acute viral bronchiolitis is the most common lower respiratory infection in early infancy and a l... more Acute viral bronchiolitis is the most common lower respiratory infection in early infancy and a leading cause of infant hospitalization. The treatment of bronchiolitis is largely supportive. Inhaled nitric oxide (NO) has pulmonary vasodilatory properties and has been approved for the treatment of persistent pulmonary hypertension of the newborn. Furthermore, preclinical studies show that high-dose NO possesses anti-bacterial and anti-viral properties. In a recent pilot study, we have shown safety and tolerability of high-dose NO (160 ppm) in infants with moderately severe bronchiolitis. In this study, we are conducting a randomized, multicenter, double-blind, controlled pivotal trial comparing the efficacy of intermittent 160 ppm NO (30min, 5 times/day, up to 5 days) with standard supportive care (O2/air) in 94 infants (0-12 months old, clinical score 7-10, requiring >24hr hospitalization) admitted to 10 hospitals across Israel. All subjects receive standard of care treatment. The primary outcome measure is the length of hospital stay (LOS). The secondary outcome measures are time to reach clinical score of 5 and below (Modified Tal score) and time to reach O2 saturation of 92% and above in room air. Adverse events (AE’s) and NO-related AE’s including methemoglobin and nitrogen dioxide levels are closely monitored. At the time of submission, the trial is ongoing with 46 out of 94 subjects enrolled at 5 sites. We anticipate demonstrating efficacy by reducing LOS and improving clinical symptoms in infants treated with NO. We predict completing the trial by April 30, 2018 and present final results at the next 2018 ERS International meeting, Paris.
To further validate the use of the Modified Tal Score (MTS), a clinical tool for assessing bronch... more To further validate the use of the Modified Tal Score (MTS), a clinical tool for assessing bronchiolitis severity, by physicians with varying experience and training levels, and to determine the ability of the MTS to predict bronchiolitis severity. This prospective cohort study included infants of <12 months of age who were diagnosed with bronchiolitis and assessed via MTS. We calculated the intra-class correlation coefficient (ICC) among four groups of raters: group 1, board-certified pediatric pulmonologists; group 2, board-certified pediatricians; group 3, senior pediatric residents; and group 4, junior pediatric residents. Clinical outcomes were determined as length of oxygen support and length of stay (LOS). We assessed MTS's prediction of these outcomes. Relative risk (RR) for clinical severity was calculated via a Generalized Linear Model. Twenty-four physicians recorded a total of 600 scores for 50 infants (average age 5 ± 3 months; 56% male). The ICC values with grou...
The aims of this pilot study were to determine safety, tolerability (primary outcome) and efficac... more The aims of this pilot study were to determine safety, tolerability (primary outcome) and efficacy (secondary outcome) of high-dose inhaled nitric oxide for the treatment of infants with moderately severe bronchiolitis. This was a pilot, double-blinded, randomized controlled study (phase IIa). Intermittent inhalations of nitric oxide 160 ppm for 30 min or oxygen/air (control) were given 5 times/day to hospitalized infants (2-11 months) with acute bronchiolitis. Oxygen saturation, methemoglobin, and nitric dioxide (NO2 ) levels and vital signs were monitored. Forty-three infants were enrolled. Baseline characteristics were comparable in both study groups. Mean clinical score, comprised of four components: respiratory rate, use of accessory muscles, wheezes and crackles, and % room-air oxygen saturation, was 7.86 (±1.1) and 8.09 (±1.2) in the NO and control groups, respectively, consistent with moderate severity. The overall frequency of adverse events was similar between the groups. ...
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