Fetal lung fluid: Not the same as amniotic fluidAuthor: Hemananda Muniraman MBBS, FAAP, FRCPCHAffiliations:Creighton University School of Medicine, Phoenix Campus, Arizona, USCorresponding Author: Hemananda Muniraman, MBBS, FAAP, FRCPCHAssistant Professor of Pediatrics Affiliate, Creighton University School of MedicinePhoenix Campus, 350 W Thomas Rd, Phoenix, AZ, US 85013Email; [email protected], Phone: +16022564628 Fax: +16026276325Conflict of Interest Disclosure: I have no conflicts of interest relevant to this article to disclose. Funding/Support.No funding to be reportedKey words: Extreme preterm, neonates, pneumatocele, fetal lung fluidDear Dr MurphyEditor in chief, Pediatric PulmonologyI read with interest the recently published article “Pulmonary pneumatoceles in neonates” by Dr Rocha. [1] It is a well written comprehensive review of pulmonary pneumatoceles in neonates and an important resource for the clinicians in decision making, that I found to be very insightful whilst recently managing an extreme preterm with a large pneumatocele.However, I wanted to bring attention to a statement in the introduction where the author states that the “preterm infants’ lungs are filled with amniotic fluid”. This is not accurate and appears to be a common misconception, particularly among medical students and junior residents despite recognition of fetal lung fluid as being a separate entity from the amniotic fluid as originally described in 1948 by Jost and Policard. [2] I believe this is an important knowledge gap that needs to be addressed. Understanding of metabolism and role of fetal lung fluid in lung development and postnatal transition is essential to clinicians involved in the care of newborns and infants.Though a comprehensive review of fetal lung fluid is beyond the scope of this letter, I provide a brief basic overview of fetal lung fluid with references for more comprehensive reading.Fetal lung fluid is a chloride rich acidic fluid produced with in the fetal lungs by secretion of chloride across the distal lung epithelial cells and is a major determinant for fetal lung growth and development. The fluid lung volume is maintained by transglottic pressure gradient with periodic egress of excess fluid during fetal breathing. Decreased lung fluid volume is associated with pulmonary hypoplasia and conversely, upper airway lesions obstructing the egress of lung fluid leads to increase in fetal lung fluid and volume, a principle used in fetal interventions such as endoluminal tracheal occlusion to enhance pulmonary growth in conditions namely congenital diaphragmatic hernia. [2,3,4]As important the fetal lung fluid is for lung development, clearance of lung fluid is crucial for normal postnatal transition and establishment of air filled lungs for effective gas exchange. Clearance of lung fluid is a complex and coordinated process that starts before the process of birth itself. The rate of lung fluid secretion diminishes before labor at term gestation. Catecholamines namely epinephrine released during labor upregulates the epithelial sodium channels (ENaC) promoting influx of sodium and fluid from lumen into pulmonary interstitial space thereby reversing the direction of fluid movement in the perinatal period. Lung fluid is decreased to about 35% following active labor and birth which are further cleared with neonatal cry and breathing and inflow of air after birth. The fluid from the interstitial space is cleared over the next few hours via pulmonary circulation and lymphatic drainage. However this process is impaired in infants delivered by elective cesarean sections leading to increased retained lung fluid after birth and resulting in transient respiratory distress and tachypnea of newborn (TTN). In preterm infants, catecholamine induced fluid reabsorption via ENaC is limited and may contribute to respiratory distress after birth. Prenatal maternal steroids and triiodothyronine administration is known to induce expression of messenger RNA for ENaC subunits in the fetal lungs and may facilitate lung fluid clearance. [2,4]Lastly, amniotic fluid aspiration into fetal lungs, with and without meconium contamination, has been reported to be the cause of respiratory distress with case reports of massive amniotic fluid aspiration noted on postmortem histological examination of newborn lungs. [5]References:Rocha G. Pulmonary pneumatoceles in neonates. Pediatr Pulmonol. 2020 Jul 21. doi: 10.1002/ppul.24969. Epub ahead of print. PMID: 32691976.Katz C, Bentur L, Elias N. Clinical implication of lung fluid balance in the perinatal period. J Perinatol. 2011 Apr;31(4):230-5. doi: 10.1038/jp.2010.134. PMID: 21448181.Hooper SB, Harding R. Fetal lung liquid: a major determinant of the growth and functional development of the fetal lung. Clin Exp Pharmacol Physiol. 1995 Apr;22(4):235-47. doi: 10.1111/j.1440-1681.1995.tb01988.x. PMID: 7671435Kallapur S, Jobe A; Fetal Lung fluid. Richard J. Martin, Avroy A. Fanaroff, Michele C. Walsh. Fanaroff And Martin’s Neonatal-Perinatal Medicine : Diseases of the Fetus and Infant, 10th edition. Philadelphia, PA :Elsevier/Saunders, 2015Lavezzi AM, Poloniato A, Rovelli R, Lorioli L, Iasi GA, Pusiol T et al. Massive Amniotic Fluid Aspiration in a Case of Sudden Neonatal Death With Severe Hypoplasia of the Retrotrapezoid/Parafacial Respiratory Group. Front Pediatr. 2019 Apr 4;7:116. doi: 10.3389/fped.2019.00116. PMID: 31019904

Identification of Pediatric Bronchiolitis Obliterans Syndrome Post Hematopoietic Stem Cell Transplantation; Surveillance Is the KeyShivanthan Shanthikumar1,2,3, Liam Welsh1, 2, Nicole Westrupp1,2, Theresa Cole3,4, Katherine B Frayman1,2,3, Colin F Robertson1,2,3, Sarath C Ranganathan1,2,3Respiratory and Sleep Medicine, Royal Children’s Hospital, Melbourne, AustraliaRespiratory Diseases, Murdoch Children’s Research Institute, Melbourne, AustraliaDepartment of Paediatrics, University of Melbourne, Melbourne, AustraliaAllergy and Immunology, Royal Children’s Hospital, Melbourne, AustraliaCorresponding Author; Dr Shivanthan Shanthikumar; Respiratory Medicine, Royal Children’s Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia; [email protected]; The authors have no conflicts of interest to declareDear Editor,We read with great interest the article by Walther et al1 regarding long term outcomes of bronchiolitis obliterans syndrome (BOS) in children following haematopoietic stem cell transplantation (HSCT). The authors are to be commended on their study as it is an important contribution to a field where there is a relative paucity of evidence. Given the increasing numbers of HSCT being performed and improved outcomes, timely identification and management of pulmonary complications such as BOS is vital.In particular, the study used multibreath washout to calculate lung clearance index, a more sensitive test for BOS than traditional spirometry.2 In addition, the identification of three trajectories for children diagnosed with BOS; rapid persistent decline, persistent obstructive disease with secondary restriction, and resolution, is an important and novel description. This more nuanced understanding of the natural history of BOS in this setting will be an important consideration when designing therapeutic intervention trials. Given there are now ample data showing that around 4.8-6.5% children post HSCT will develop BOS, with significant associated morbidity and mortality, well designed intervention trials should be strongly considered.There are however limitations of Walther et al’s study that warrant more detailed discussion, as they limit the applicability of this single centre retrospective chart review to wider clinical practice. The manuscript does not adequately describe the institution’s clinical practice regarding evaluation for BOS post-HSCT, although the authors acknowledge a “lack of a standardised follow up protocol for lung function. ” This is not in keeping with current international practice. International guidelines3-5 consistently recommend scheduled lung function surveillance. In addition, in a recent survey of HSCT physicians and pediatric pulmonologists from North America and Australasia, 71.4% reported that a protocol for monitoring lung function post HSCT existed at their hospital and 53.6% reported adhering “well” or “very well” to surveillance protocols.6 A retrospective review of a centre with a screening program in place showed 75.2% of patients had a lung function test 12 months post HSCT.7 These data indicate that the majority of HSCT centres have a screening protocol in place, and within the limitations of self-reported and single centre data, protocols are adhered too. A potential explanation for the lack of a protocol in the study is that the review period started in 2000, which predates the guidelines. However, if the results are to influence contemporary practice, clinicians must be able to relate the reported findings to current standards of care. In the absence of a standardised follow up protocol, it would be useful if the authors reported the proportion of the 526 eligible patients who underwent lung function assessment, and what triggered a referral for testing (i.e. clinical symptoms, graft vs. host disease (GVHD) in another organ). If a high proportion of patients underwent testing then their findings will be more comparable to current international practice, however if only a small proportion underwent testing this is a significant limitation.The prevalence of BOS in the current study is lower than that reported in the wider literature. We suspect their prevalence is underestimated. The overall GVHD rate (45%) is higher than might be expected for a cohort that includes nearly 50% matched sibling donors.8, although GVHD grading is not reported. Given the high GVHD rate in this cohort it would be expected that the prevalence of BOS should also be higher or at least in keeping with the literature. The lack of a standardised protocol for screening lung function would likely lead to an underestimation of the prevalence of BOS. It is well established that the early phases of BOS are often asymptomatic and diagnosed based on lung function abnormality.9 All 14 BOS cases in this study were symptomatic, suggesting that asymptomatic early cases of BOS cases may have been missed due to lung function not being performed. In particular, this would underestimate BOS cases which follow the resolution trajectory as well as potentially the persistent obstruction trajectory. It also would affect two of the key conclusions of the paper; that BOS incidence is low and that BOS is associated with high mortality.In summary, the article by Walther et al is a useful contribution to what is an area of growing clinical importance. Strengths of the study include the use of the most sensitive test of small airway function (multibreath washout with calculation of the lung clearance index) and description of three trajectories post BOS diagnosis. However, the lack of a formal surveillance program and likely resultant underestimation of BOS cases is a significant limitation that should be acknowledged before efforts are made to prevent or attenuate lung function decline in BOS

Background: Multiple breath washout (MBW) is increasingly used in the clinical assessment of patients with cystic fibrosis (CF). Guidelines for MBW quality control (QC) were developed primarily for retrospective assessment and central overreading. We assessed whether real-time QC of MBW data during the measurement improves test acceptability in the clinical setting. Methods: We implemented standardized real-time QC and reporting of MBW data at the time of the measurement in the clinical pediatric lung function laboratory in Bern, Switzerland in children with CF aged 4-18 years. We assessed MBW test acceptability before (31 tests; 89 trials) and after (32 tests; 97 trials) implementation of real-time QC and compared agreement between reviewers. Further, we assessed the implementation of real-time QC at a secondary center in Zurich, Switzerland. Results: Before implementation of real-time QC in Bern, only 68% of clinical MBW tests were deemed acceptable following retrospective QC by an experienced reviewer. After implementation of real-time QC, MBW test acceptability improved to 84% in Bern. In Zurich, after implementation of real-time QC, test acceptability improved from 50% to 90%. Further, the agreement between MBW operators and an experienced reviewer for test acceptability was 97% in Bern and 100% in Zurich. Conclusion: Real-time QC of MBW data at the time of measurement is feasible in the clinical setting and results in improved test acceptability.

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.

Introduction Childhood cancer survivors (CSs) might face an increased lifelong risk of lung function impairment. The Lung Clearance Index (LCI) has been described as being more sensitive than spirometry in the early stages of some lung diseases. The aim of this study was to evaluate this index in a cohort of patients with a history of childhood cancer for the first time. Materials and Methods We evaluated 57 off-treatment CSs aged 0–18 years old and 50 healthy controls (HCs). We used the multiple breath washout (MBW) method to study LCI and spirometry. Results CSs did not show any differences from the controls in ventilation homogeneity (LCI 6.78 ± 1.35 vs. 6.32 ± 0.44, P: ns) or lung function (FEV1 99.9 ± 11.3% vs. 103.0 ± 5.9% of predicted, P: ns; FVC 98.2 ± 10.3% vs. 101.1 ± 3.3% of predicted). LCI significantly correlated with the number of years since the last chemotherapy (r = 0.35, P < 0.05). Conclusions Our study describes the trend of LCI in a cohort of CSs and compares it with the results obtained from healthy controls. The results show that patients maintain both good values of respiratory function and good homogeneity of ventilation during childhood. Moreover, the LCI identifies the tendency toward pulmonary fibrosis, which is typical of adult CSs, at an earlier time than spirometry.

Introduction: During the COVID-19 pandemic, pediatric visits due to acute lower respiratory infections (ALRIs) decreased, but most reports are from hospitalized patients. There is little information on this phenomenon in outpatients, who are the majority in IRABs. We evaluated the impact of the COVID-19 pandemic on ALRIs related outpatient visits in the City of Buenos Aires. Methods: Observational study including all outpatient visits of children under 2 years of age to the public health system of the City of Buenos Aires, between Jan 01, 2018 and Dec 31, 2022. We estimated the total number visits and the ALRIs-related visits, and their distribution throughout the study period. Results: A total of 704,426 visits were registered, 7.38% of them due to ALRIs. ALRIs-related visits decreased from the implementation of a national lockdown (2020) and increased again as the restriction measures decreased, particularly the return to full school attendance (2021). In general, the proportion of ALRIs-related vists was significantly higher in the cold months than in the warm ones (9.8% vs. 5.5%; OR: 1.76, 95%CI: 1.73-1.79; p<0.001). This difference was observed before (2018, 2019) and after the pandemic (2022), but not in 2020-2021. The peak of ALRIs-related visits occurred in the cold months in pre-pandemic years (2018-2019), did not appear in 2020, reappeared delayed in 2021 and recovered seasonality in 2022. Conclusion: Outpatient ALRIs-related visits decreased significantly in the city of Buenos Aires during the COVID-19 pandemic and currently seem to have recovered their magnitude and seasonality.

Bronchoalveolar Lavage in Children: Still the Gold StandardShivanthan Shanthikumar1,2,3 and Sarath C Ranganathan1,2,3Respiratory and Sleep Medicine, Royal Children’s Hospital, Melbourne, AustraliaRespiratory Diseases, Murdoch Children’s Research Institute, Melbourne, AustraliaDepartment of Paediatrics, University of Melbourne, Melbourne, AustraliaCorresponding Author; Dr Shivanthan Shanthikumar; Respiratory Medicine, Royal Children’s Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia; [email protected]; The authors have no conflicts of interest to declareDear Editor,We read with great interest the recent article by Craven et al , entitled “High levels of inherent variability in microbiological assessment of bronchoalveolar lavage samples from children with persistent bacterial bronchitis and healthy controls .”1 In a small study of 18 children, funded by GlaxoSmithKline, the authors demonstrate variability in the results of bronchoalveolar lavage (BAL) collected from controls and children with protracted bacterial bronchitis (PBB). Specifically, they show that when the BAL was divided and sent to two laboratories the results were discordant in terms of both the organisms isolated and their relative abundance. From these data the authors draw conclusions which include questioning “assumptions about this procedure being the gold standard .” Whilst these data are of interest, there are significant limitations to their value especially when considering existing literature.One of the key findings of the study is the discordant results between laboratories. A lack of detail regarding the methods used at each site is a major limitation. It is recognised that laboratory processes can affect the yield of samples collected from patients with chronic airway infection, and the need for a consistent approach has led to disease specific consensus guidelines on this topic.2 The discordant results seen in the study could result from different laboratory handling of specimens, and hence the findings of this study could purely be explained by a difference in practice between two centres, not least of which was the transport of samples to the second laboratory in STGG. Molecular studies have identified that even media considered sterile can contain numerous organisms albeit in low densities.3 We note that it was laboratory 2 where additional bacteria were cultured from the BAL.Hare et al analysed BAL samples from 655 children collected and analysed at two different sites compared with 18 samples in the study of Craven et al .4 They compared bacterial pathogen load (control, negative, 102 colony forming units per ml (CFU/ml), 103 CFU/ml, 104 CFU/ml, 105 CFU/ml) and inflammatory markers to determine an appropriate definition for infection. They found that a bacterial pathogen load of ≥104 CFU/ml was associated with increased markers of inflammation and hence an appropriate threshold for defining infection. This was in keeping with previous studies.4 Whilst the authors contend the current paper does not support the use of ≥104 CFU/ml, given it only includes 13 children with PBB an explanation of the findings of Hareet al in their considerably larger study and other studies needs explanation.Another key finding of the study was the limited correlation between semiquantitative and quantitative methods of measuring bacterial pathogen load. Whilst there has not been direct comparison of different methods of determining bacterial pathogen load in PBB and other paediatric suppurative disorders, a large amount of data speaks to the validity of using a semiquantitative or qualitative approach. For instance, the previously discussed Hare et al study utilised a semiquantitative approach, and was able to clearly identify a threshold for lower airway infection that was associated with inflammation. In addition, the qualitative approach used by AREST CF (the long running study of CF patients cited in the article) to define infection is supported by the fact that this definition is associated with important clinical outcomes. For example, in a recent AREST-CF study analysing 1161 BAL from 265 children with CF, the presence of early life infection using the AREST-CF definition, was associated with future risk of structural lung disease severity.5Further, we have used molecular studies to assess the microbiome in CF and shown considerable agreement between pathogen-dominated microbiota and routine laboratory bacterial culture even though these samples were assessed by two different techniques, in two laboratories in different continents and analysed two decades apart in time.6Despite the data that contradicts the findings of their study, and while not discussed by the authors themselves, we do contend that use of both quantitative and semi-quantitative microbiologic cultures are likely problematic given that bacterial density is influenced by the dilution from the 0.9% saline used to lavage the target lobe. Dilution further depends on the volume of return retrieved on suctioning. The consensus has been that standardising for this dilution is not required but data supporting this are few.In summary, there are significant issues that limit the value of the key findings of the study by Craven et al . A large amount of published data in PBB and cystic fibrosis support the use of BAL as a biological specimen associated with important clinical outcomes. These studies have been conducted in multiple centres, over many years, and included many children. While the findings of Craven et alhighlight there can be inconsistencies in results, this potentially speaks to the methods used by the laboratories involved in handing the small number of samples. When these findings are compared to the large amount of evidence already generated, they should prompt evaluation of local practices and not just a reconsideration of whether BAL is the gold standard method of sampling the lower airway of children with suppurative lung disease. While we believe that BAL remains the gold standard for the detection of lower respiratory infection we do not believe it is a perfect test and its use and many limitations need to be considered and minimised.Therefore, we agree with the authors that interpretation of microbial culture results utilizing BAL samples can be challenging. However, we disagree that assumptions about this procedure being the “gold standard” fail to take into account its many limitations as despite these BAL remains the best test to detect endobronchial infection that is associated with lower respiratory inflammation especially in CF.

Introduction: The COVID-19 pandemic has accelerated the move towards home spirometry monitoring, including in children. Our aim was to determine whether the remote supervision of spirometry by a physiologist improves the technical quality and failure rate of the manoeuvres. Method: Children with cystic fibrosis who had been provided with NuvoAir home spirometers were randomly allocated to either supervised or unsupervised home spirometry following a detailed training session. Home spirometry was performed every 2 weeks for 12 weeks. Tests were assigned a quality factor (QF) using our laboratory grading system as per ATS/ERS standards, with tests marked from A to D, or Fail. In our laboratory we aim for QF A in all spirometry tests, but report results of QF B or C with a cautionary note. QF A was therefore the primary outcome, and QF A-C the secondary outcome. Results: 61 patients were enrolled; 166 measurements were obtained in the supervised group, and 153 in the unsupervised group. Significantly more measurements achieved QF A in the supervised compared to unsupervised group (89% vs 74%; p= <0.001) whilst proportions reaching grade A-C were similar (99% vs 95%; p=0.1). All significant declines in spirometry results had a clinical rather than technical reason. Family/patient feedback for both arms was very positive. Conclusion: These results suggest that home spirometry in children should ideally be remotely supervised by a physiologist, but acceptable results can be obtained if resources do not allow this, provided that training is delivered and results monitored according to our protocol.

Abstract Objective: To analyze baseline clinical and laboratory characteristics and explore the possible predictors of lung necrosis severity in children with community-acquired necrotizing pneumonia (NP). Methodology: This retrospective observational study was performed in a tertiary referral center. A total of 104 patients aged <15 years with community-acquired pneumonia and radiologically confirmed NP were included. Patients were classified into the mild, moderate, or massive necrosis groups. Results: Among them, 29, 41, and 34 patients had mild, moderate, and massive necrosis, respectively. Moreover, 34.6% of the patients were admitted to the pediatric intensive care unit. Massive necrosis was more likely to occur during winter (p<0.05) and was associated with more severe clinical outcomes, such as longer duration of fever, longer hospitalization, increased mortality, and a higher risk of subsequent surgical intervention (p<0.05). Multivariate analysis demonstrated that the following were independent risk factors for massive necrosis: C-reactive protein (CRP) ≥ 122 mg/L (adjusted odds ratio [aOR], 8.780; 95% confidence interval [CI], 3.320–21.089; p=0.003), serum albumin ≤ 30.8 g/L (aOR, 11.608; 95% CI, 5.147–27.058; p=0.001), and immunoglobulin M (IgM) ≤ 95.7 mg/dL (aOR, 7.152; 95% CI, 2.240–17.692; p=0.021). Receiver operating characteristic analysis demonstrated that these variables showed good diagnostic performance for differentiating patients with massive necrosis from all patients with NP. Conclusion: NP is a potentially severe complication of pediatric community-acquired pneumonia. Different severities of lung necrosis can lead to different clinical outcomes. CRP, serum albumin, and IgM levels are independent predictors of the degree of lung necrosis.

Background: Bronchopulmonary dysplasia (BPD) is the most common cause of chronic lung disease in children born prematurely. There is little information about the epidemiology and severity of BPD places with high altitude. This study aimed to evaluate the frequency of BPD severity levels and the associated risk factors with severity in a cohort of preterm newborns ≤34 weeks of gestational age born in Rionegro, Colombia Materials and methods: We carried out a retrospective analytical cohort of preterm newborns without major malformations from Rionegro, Colombia between 2011-2018 admitted to neonatal intensive unit at high altitude (2200m above sea level). The main outcomes were the incidence and severity of bronchopulmonary dysplasia. Results: The bronchopulmonary dysplasia incidence was 25.7% (95% CI, 21.6-29.9). Bronchopulmonary dysplasia was moderate in 62.1% of patients and severe in 26.7%. After modeling regression analysis, the final variables associated with BPD severity levels were: sepsis (OR 2.37 CI 95% 1.04-5.40) and pulmonary hypertension (OR 3.79 CI95% 1.19-12). Conclusion: The incidence of BPD was higher and similar to cities with higher altitudes. In our population, the variables associated with BPD severity levels were: duration of oxygen therapy and pulmonary hypertension. It is necessary to increase the awareness of risk factors, the effect of clinical practices, and early recognition of bronchopulmonary dysplasia to reduce morbidity in patients with this pathology.

Background & local problem: Acute wheezing attacks are a leading cause of Pediatric Emergency Department (PED) attendances and inpatient admissions and are a considerable burden on the healthcare providers. Almost one-third of children vomit prednisolone in the PED, requiring anti-emetics and repeat dosing. Aim: This quality improvement (QI) intervention aimed to improve oral corticosteroid (OCS) tolerability, reduce emergency department length of stay (LOS), and reduce OCS drug costs for acute wheeze attendances in a PED, while not adversely affecting admissions, re-attendance, or mortality rates. QI Interventions: Included (1) a departmental protocol and (2) modification of the OCS type and dosage from prednisolone (3-day course of 1 mg/kg) to dexamethasone (600 mcg/kg, then single dose 300 mcg/kg). Methods: The study team reviewed the evidence and implemented the interventions. To assess the scale of improvement, we retrospectively collected data on attendance records for patients aged 2-14 years with acute wheeze requiring OCS. We collected data on 100 children who attended the PED between October and December for each year (2016, 2017, and 2018). We then assessed OCS tolerability, LOS, OCS drug costs, and, admission, re-attendance, and mortality rates. Results: Over a 48-month period, we increased OCS tolerability by 67.2% and achieved an 85.8% reduction in OCS drug costs (saving £41,553.14). There was no change in the LOS, admission, re-attendance, and mortality rates. Conclusions: Improved tolerability and substantial cost savings can be achieved by implementing a structured acute pediatric wheeze protocol and modifying the OCS to single-dose dexamethasone (300 mcg/kg).

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.

Abstract. Pseudomonas aeruginosa and Staphylococcus aureus are bacterial pathogens frequently associated with pulmonary complications and disease progression in cystic fibrosis (CF) patients. However, these bacteria increasingly show multiple resistance to antibiotics, necessitating novel management strategies. One possibility is phage therapy, where lytic bacteriophages (phages; bacteria-specific viruses) are administered to kill target bacterial pathogens. Recent publication of case reports of phage-therapy treatment of antibiotic-resistant lung infections in CF has garnered significant attention. These cases exemplify the renewed interest in phage therapy, as an older concept that is newly updated to include rigorous collection and analysis of patient data to assess clinical benefit, while informing the development of clinical trials. As outcomes of these trials become public, the results will valuably gauge the potential usefulness of phage therapy to address the rise in antibiotic-resistant bacterial infections. In addition, we highlight the further need for basic research on accurately predicting the different responses of target bacterial pathogens when phages are administered alone, sequentially or as mixtures (cocktails), and whether within-cocktail interactions among phages hold consequences for the efficacy of phage therapy in patient treatment.

Objective: Investigate the cardiorespiratory effects of non-invasive neurally adjusted ventilatory assist (NIV-NAVA), non-synchronized nasal intermittent positive pressure ventilation (NIPPV), and nasal continuous positive airway pressure (NCPAP) during the critical period shortly after extubation. Hypothesis: Levels of non-invasive pressure support provided and/or presence of synchronization can affect cardiorespiratory parameters. Study design: Randomized crossover trial. Patient-subject selection: Infants with birth weight (BW) ≤ 1250g undergoing their first planned extubation were randomly assigned to all 3 modes following extubation. Methodology: Electrocardiogram and electrical activity of the diaphragm (Edi) were recorded during 30min on each mode. Analysis of heart rate variability (HRV), diaphragmatic activity (Edi area, breath area, amplitude, inspiratory and expiratory times) and respiratory variability (RV) were compared between modes. Results: 23 enrolled infants had full data recordings and analysis: median [IQR] gestational age = 25.9 weeks [25.2-26.4], BW = 760g [595-900], and post-natal age 7 [4-19] days. There were no differences in HRV parameters between modes. During NIV-NAVA and NIPPV, diaphragmatic activity was significantly lower and RV higher than NCPAP. Delivered peak inflation pressures (PIPs) were lower during NIV-NAVA than NIPPV (14 cmH2O [13-16] vs cmH2O 16 [16-17]; p<0.001). However, due to a significantly higher proportion of assisted breaths (99% [92-103] vs. 51% [38-82]; p<0.001) NIV-NAVA provided a higher mean airway pressure (MAP)(9.4 cmH2O [8.2-10.0] vs. 8.2 cmH2O [7.6-9.3]; p=0.002). Conclusions: NIV-NAVA and NIPPV applied shortly after extubation were associated with positive cardiorespiratory effects. This effect was more evident during NIV-NAVA where patient-ventilator synchronization provided a higher MAP with lower PIPs.

Objective: To evaluate the relationship between lower respiratory tract infections (LRTI), in the first 2 years of life and lung function at school age in the Piccolipiù birth cohort (Italy). Methods: Data on LRTI (doctor diagnosis of bronchitis, bronchiolitis, pneumonia) and wheezing (≥3 episodes or a diagnosis of asthmatic bronchitis) in the first 2 years of life were obtained from parental questionnaires. Lung function was assessed at 7 years by spirometry and forced volume vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, forced expiratory flow between 25 and 75%, and at 75% of FVC (FEF25-75 and FEF75) were reported as z-scores. The associations between LRTI and spirometric variables were estimated with linear regression models. Results: Among 877 children studied, 22.1% had LRTI only, 5.4% wheezing only, 13.2% had both, and 59.3% had neither LRTI nor wheezing. Children with LRTI had lower FVC and FEV1 than children without (z-score differences: -0.18 (95% Confidence Intervals, -0.31; -0.06) and -0.15 ( 0.27; -0.03)). When children were stratified by history of both LRTI and wheezing, there was no association between LRTI only and spirometric values. Conversely, having had both LRTI and wheezing was inversely associated with all lung function measures: z-score differences of -0.24 ( 0.42; -0.07); -0.42 (-0.59; -0.24); -0.25 (-0.41; -0.08); -0.37 (-0.54; -0.21); -0.30 (-0.46; -0.14) for FVC, FEV1, FEV1/FVC, FEF25-75 and FEF75, respectively. Conclusion: Infants with wheezing and LRTI, but not those with LRTI only, had reduced lung function at school-age.

We read the letter to the editor “B-lines score: artifacts as a sign of neonatal specific disease?” by Quarato et al. and we are pleased by the interest aroused by our article “Neonatal lung ultrasonography score after surfactant in preterm infants: A prospective observational study” published on your journal. This study included preterm neonates with respiratory distress syndrome (RDS), requiring non-invasive ventilation and surfactant. The aim of our citated study was to asses changes of a validated neonatal lung ultrasonography score (nLUS) after surfactant treatment. Our data demonstrate a lowering of the nLUS 2h and 12h after surfactant treatment. In their letter to the editor Quarato et al. expressed criticism about the nLUS score validation and about the utility of the Lung Ultrasound (LUS) as a diagnostic tool. They conclude that “LUS can be used only for diagnosing minimal pleural effusion and, at least, as complementary imaging, in addiction to chest radiographs (CR), for monitoring the reduction of subpleural pneumonitic consolidations under therapy”. Our citated study hasn’t focused on validation of the nLUS score or on LUS as a diagnostic tool for neonatal RDS, so we don’t get how Quarato’s concerns can be addressed to our paper. Nevertheless, finding the debate about nLUS or LUS in the neonatal field an occasion to promote an improving in the care of the preterm babies, we will discuss objections raised in Quadrato’s work, point by point.

Pulmonary hypertension represents an increasingly important group of pediatric patients which commonly come to the attention, if not the primary care of pediatric pulmonologists around the world. There have been major advances in diagnosis and therapy over the past 25 years. To address potential gaps in knowledge, the authors were invited by the Editor of Pediatric Pulmonology to organize a series of manuscripts in a special supplement of the journal. Our authors include pulmonologists, pharmacists, intensivists, mid-level practitioners, neonatologists and cardiologists. We believe that this issue will be of great interest to most of the readership community that the Journal addresses.

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.