Background: Reaching early and definitive diagnosis in infants with cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID) is a priority of all CF newborn screening programs. Currently, sweat testing is the gold standard for CF diagnosis or exclusion. We assessed outcomes in a cohort of Italian CRMS/CFSPID infants who underwent repeat sweat testing in the first year of life. Methods: This multicentre, prospective study analysed clinical data and outcomes in CRMS/CFSPID infants born between September 1, 2018 and December 31, 2019, and followed until June 30, 2020. All subjects underwent CF transmembrane conductance regulator (CFTR) gene sequencing and the search for CFTR macrodeletions/macroduplications, and repeat sweat testing in the first year of life. Results: Fifty subjects (median age at end of follow-up, 16 months [range, 7–21 months]) were enrolled. Forty-one (82%) had the first sweat chloride in the intermediate range. During follow up, 150 sweat tests were performed (range, 1–7/infant). After a median follow-up of 8.5 months (range 1–16.2 months), 11 (22%) subjects were definitively diagnosed as follows: CF (n=2 [4%]) at 2 and 5 months, respectively; healthy carrier (n=8 [16%]), at a median age of 4 months (range 2–8 months); and healthy (n=1 [2%]) at 2 months of age. Inconclusive diagnosis remained in 39 (78%) infants. Conclusions: Early repeat sweat testing in the first year of life can shorten the time to definitive diagnosis in screening positive subjects with initial sweat chloride levels in the intermediate range.

Children with sickle cell disease (SCD) have an increased risk of sleep disordered breathing (SDB) compared with the general pediatric population. There has been a growing research interest on this field in recent years, yet many questions regarding risk factors and clinical implications of SDB remain unclear. The aim of this review is to provide a concise narrative and systematic synthesis of the available evidence on the epidemiology, clinical presentation, complications and management, of SDB in children with SCD. An electronic search was conducted on studies published from the 1st of January 2000 to the 31st of December 2020 in PubMed/Medline, Scopus and Cochrane databases. All studies focusing on SDB in children with SCD aged from 0 to 20 years were included. Studies were eligible for inclusion if available in the English language. A quantitative synthesis of the included studies was performed. Only studies focusing on specific treatment outcomes were included in a meta-analytic process. A total of 190 papers were initially identified. After screening the title and abstract, 112 articles were evaluated for eligibility. At the end of the selection process, 62 studies were included in the analysis. Sleep-disordered breathing is associated with worse neurological, neurocognitive and cardiological outcomes, whereas the association with frequency or severity of vaso-occlusive pain events and acute chest syndrome was not clarified. Therapeutic interventions like adenotonsillectomy or oxygen supply may result in a significant increase in mean nocturnal oxygen saturation but effective clinical implications remain still unclear.

Lung transplantation is recognized as a treatment option for selected patients with end-stage lung disease and pulmonary vascular disorders. Overall, pulmonary hypertension (PH) is the second most frequent indication for children requiring lung transplantation. Pediatric lung transplantation can be complex; in PH patients timing for listing and the perioperative management can be particularly challenging making interdisciplinary collaboration with the referring PH team essential. Because pediatric patients typically have preserved cardiac index and exercise tolerance even with advanced disease, they should be referred early even if they do not meet the proposed criteria for listing by ISHLT published in 2015: NYHA functional class III or IV without improvement, cardiac index < 2 liters/min/m^2, mean right atrial pressure of > 15 mmHg. Bridging strategies with extracorporeal support should be determined at time of listing prior to transplantation anticipating the possibility of clinical deterioration. Bilateral lung transplantation using cardiopulmonary bypass to provide hemodynamics stability is the standard practice in pediatric centers. The immediate post-transplant period is characterized by dramatic normalization of PVR as well as changes in the RV and LV physiology and function which can be life-threatening. Induction, immunosuppression, prophylaxis and surveillance are not different from patients without PH. Overall, outcomes in pediatric lung and heart-lung transplant patients for PH are not different from those children undergoing lung or heart-lung transplant for other indications. In fact, long-term survival is superior in children with idiopathic PH compared to other diseases, there is also a dramatic improvement in quality of life in most recipients

Bronchiectasis (BE) is defined as a permanent, irreversible dilation of the bronchial tree. In the pediatric population, this disease process is most commonly associated with patients with Cystic Fibrosis (CF). However, bronchiectasis unrelated to cystic fibrosis is increasingly noted as a cause of chronic respiratory related morbidity worldwide. Chronic inflammation and recurrent infection result in cellular cascades that lead to irreversible structural changes of the airways. When these architectural changes occur, they confer extensive risks to morbidity usually due to continued infections. In the adult population, bronchiectasis has been associated with chronic obstructive pulmonary disease, which is mainly caused by cigarette smoking. In this report, the authors reviewed various cases of bronchiectasis in the pediatric population where the only inciting factor was electronic cigarette use.

ABSTRACT Background: Necrotizing pneumonia (NP) is a severe complication of community-acquired pneumonia. The impact of 13-valent pneumococcal conjugate vaccine (PCV13) on the epidemiology of NP in children has not been formally assessed. Patients and methods: Medical records of children <18 years admitted with NP to two pediatric hospitals in Italy between 2005 through 2019 were retrospectively reviewed. The following 4 periods were defined: 2005-2010 (pre-PCV13), 2011-2013 (early post-PCV13), 2014-2016 (intermediate post-PCV13), and 2017-2019 (late post-PCV13). Results: Forty-three children (median age, 44 months) were included. Most of them (93%) were previously healthy. No differences in age, sex, season of admission, comorbidity, clinical presentation, or hospital course were identified between pre-PCV13 and post-PCV13 periods. A significant decrease in the rate of NP-associated hospitalizations was found between the early (1.5/1000 admissions/year) and the intermediate (0.35/1000 admissions/year) post-PCV13 period (p=0.001). Streptococcus pneumoniae was the most common agent detected in both periods (pre-PCV13: 11/18, 61%; post-PCV13: 13/25, 52%). Serotype 3 was the most common strain in both periods (pre-PCV13: 3/11, 27%; post-PCV13; 4/13, 31%). There were no changes in the bacterial etiology over time, but most patients with Streptococcus pyogenes or Staphylococcus aureus infection were admitted during the post-PCV13 period. Conclusions: The hospitalization rate for NP in children decreased a few years after the implementation of PCV13 immunization in Italy. However, an increased trend in admissions was found thereafter. S. pneumoniae was the most frequent causal agent in both pre- and post-PCV13 periods. Pneumococcal serotypes were mainly represented by strain 3.

Spirometry, a gold standard technique for measuring lung functions, has been restricted to a select cohort of patients in current COVID-19 pandemic due to the enhanced risk of disease dissemination. To monitor pulmonary functions in various obstructive (e.g., asthma) and restrictive diseases (e.g., COVID-19 pneumonia) on in- and out-patients serially, there is an urgent requirement of an alternate reliable test. Impulse Oscillometry (IOS) measures lung functions by working at tidal volumes and thus reduces the risk of potential aerosol generation. Feasibility of IOS in smaller children and its ability to detect parenchymal and peripheral airway involvement are other advantages over conventional spirometry. IOS could be a potential solution to periodically monitor lung functions in current pandemic situation to keep a check on diseases affecting lung functionality.

Background: Early hypocapnia in preterm infants is associated with intraventricular haemorrhage (IVH) and bronchopulmonary dysplasia (BPD). Volume targeted ventilation (VTV) has been shown to reduce hypocapnia in moderately preterm infants. Less is known of VTV in infants born at <26 weeks gestational age (wGA). Objectives: Our aim was to investigate the short- and long-term benefits of early VTV as compared to assist-control ventilation (ACV) in extremely preterm infants on incidence of hypocapnia, days on ventilatory support, IVH and BPD. Study Design: A retrospective observational study of 104 infants born at 22-25 wGA (24+0±1+1wGA; birth weight 619±146g), ventilated with either VTV (n=44) or ACV (n=60) on their first day of life. Ventilatory data and blood gases were collected at admission and every fourth hour during the first day of life, together with perinatal characteristics and outcomes. Results: Positive inspiratory pressure (PIP) was lower in the VTV-group than in the ACV-group during the first 20 hours of life (p<0.05), without any difference in end-expiratory pressure, respiratory rate or FiO2. Incidence of hypocapnia (PaCO2<4.5kPa) was lower with VTV than ACV during the first day of life (32% vs 62%; p<0.01). Infants in the VTV-group were more frequently extubated at 24 hours (30% vs 13%; p<0.05). IVH grade ≥3, BPD and time on mechanical ventilation did not differ between the groups. Conclusions: VTV is safe to apply in infants born at <26 wGA and was observed to have lower incidence of hypocapnia compared to infants ventilated by ACV, without any differences in outcomes.

It was recently reported that due to the COVID-19 pandemic, in the European winter 2020-2021, bronchiolitis had practically disappeared. But early reports from the southern hemisphere (Australia) raised concerns about a late spring / summer peak. After a full winter season and now ending the summer, we report that there was no peak of common respiratory viruses in late spring / summer in South America.

OBJECTIVE: Sustained pharyngeal inflation (SPI) with pharyngeal oxygen and nose-close (PhO2-NC) can create positive peak inflation pressure (PIP) inside the pharyngolaryngeal space (PLS). This study measured and compared effects of four different SPI durations in the PLS. METHOD: In this prospective observational study, 20 consecutive infants aged less than 3 years, scheduled for elective flexible-bronchoscopy were enrolled. SPI was performed twice in four different durations (0, 1, 3 and 5 seconds) sequentially in each infant. PIP was measured for each SPI in the pharynx, and simultaneously took images at two locations of oropharynx and supra-larynx. Infants’ demographic details and PIP levels, lumen expansion scores and images of PLS were measured and analyzed. RESULTS: Twenty infants with 40 measurements were collected. The mean (SD) age and weight were 11.6 (9.1) months and 6.8 (2.4) kg, respectively. The measured mean (SD) pharyngeal PIPs were 4.1 (3.3), 21.9 (7.0), 42.2 (12.3) and 65.5 (18.5) cm H2O at SPI duration of 0, 1, 3 and 5 seconds, respectively; which showed significant positive association (p<0.001). At assigned locations, the corresponding PLS images also show significant increase in lumen expansion scores and number of detected lesions with increase in SPI duration (p<0.001). The mean (SD) study time was 5.7 (1.2) minutes. No study related complication was noted. CONCLUSIONS: SPI with PhO2-NC up to 5 seconds is a simple, safe and feasible clinical ventilation modality. It may provide enough PIP to expand the PLS and facilitate flexible-bronchoscopy performance in infants.

Background: Asthma exacerbations, a common reason for Pediatric Emergency Department (PED) referral, can be triggered by multiple factors, including infections, air pollution and allergens. Lockdown measures and other public health interventions during the SARS-CoV-2 pandemic determined radical changes to behavioral and social habits, that were reflected by a reduction in the transmission of all respiratory pathogens and in the emissions of relevant air pollution anthropogenic sources. Objective: This study aims to describe how restrictions during SARS-CoV-2 pandemic impacted the PED referral for asthma exacerbations and their potentially associated environmental triggers in densely populated urban areas. Methods: PED referrals for acute asthma from 2015 to 2020 were compared to air pollution and pollen data. To this purpose, historical daily concentration records of PM2.5, PM10 (including specific chemical tracers), as well as NO2, C6H6, tree, grass and weed pollen were analyzed. Results: In 2020, asthma-related PED referrals decreased up to 85%, compared to the average referral rate of the previous 5 years (P<0.01). The drastic drop in PED referrals was associated with a reduction of high-priority cases by 50-60%, unlike PED referrals for overall diagnoses, showing a larger contribution for severe outcomes. A concomitant diminished contribution of traffic-related air pollution was shown. Conclusions: The lower rate of asthma exacerbations in childhood can be related to synergic interactions of the multiple effects of lockdown measures which induced lower viral infection rates and decreased exposure to outdoor allergens. The reduction of traffic-related air pollution determined a weakening of inflammatory properties of urban PM.

Background: Chronic pulmonary infection is the leading cause of mortality and morbidity in patients with cystic fibrosis (CF). The most common pathogens isolated in CF are Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa). Chronic infection of P. aeruginosa and MRSA are associated with worse survival and antibiotic eradication treatment is recommended for both. This study evaluates the efficacy of intravenous (IV) vs. non-IV antibiotics in the eradication of P. aeruginosa and MRSA. Methods: This was a single-center retrospective study at a large CF center. All respiratory specimen cultures of 309 CF patients and eradication regimens between 2015-2019 were reviewed. The primary analysis was the comparison of the percentage of successful eradication after receiving IV and non-IV eradication regimens. Demographic and clinical risk factors for eradication failure were also analyzed. Results: 102 patients with P. aeruginosa isolations and 48 patients with MRSA were analyzed. At one year, 21.6% in P. aeruginosa group and 35.4% in MRSA group were successfully eradicated. There was not any statistically significant difference between IV vs. non-IV antibiotic regimens on eradication in either group. Additionally, none of the clinical risk factors was significantly associated with eradication failure in P. aeruginosa and MRSA groups. Conclusion: In the eradication of P. aeruginosa and MRSA, IV and non-IV treatment regimens did not show any superiority to one another. Non-parenteral eradication could be a better option in eradication considering the cost-effectiveness and the treatment burden of IV treatments due to hospitalization and the need for IV access.

Introduction Cystic fibrosis (CF) related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator which has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in LFTs and drug-drug interactions with several immunosuppressant medications. Objective The purpose of this case series was to explore if the use of elx/tez/iva is safe and tolerable in patients with CF post-liver transplantation. Methods A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed. Results Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and median time from transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in 7 patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body-mass-index, and maintained or improved lung function. Conclusion Initiation of elx/tez/iva in patients with CF who received a liver transplantation may be safe with clinical benefits.

Background: Premature infants who cannot achieve full oral feeds may need a gastrostomy tube (GT) to be discharged from the neonatal intensive care unit (NICU). We previously developed a model to predict which infants born <30 weeks (w) gestational age (GA) will require a GT before discharge. Here we report the detailed respiratory variable data to describe the general respiratory course for infants in the NICU <30w GA at birth and the association between different levels of respiratory support with postmenstrual age (PMA) at the time of first oral feeding attempt (PMAff), including later need for GT for discharge. Methods: Retrospective chart review of 391 NICU admissions comprising test (2015-2016) and validation (2017-2018) cohorts. Data, including respiratory support, were collected on 204 infants, 41 GT and 163 non-GT, in the test cohort, and 187 infants, 37 GT and 150 non-GT, in the validation cohort. Results: Respiratory data were significantly different between GT and non-GT infants. Infants who required GT for discharge were on significantly higher respiratory support at 30 days of age, 32w PMA, and 36w PMA. Respiratory parameters were highly correlated with PMAff. Conclusion: Respiratory status predicts PMAff, which was the variable in our previously described model that was most predictive of failure to achieve full oral feeing. These data provide a catalyst to develop strategies for improving oral feeding outcome for infants requiring prolonged respiratory support in the NICU.

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been described to partially overlap with Kawasaki disease (KD) with regard to clinical symptoms, but they are unlikely to share the same disease entity. We conducted a systematic review and meta-analysis to characterize the laboratory parameters of MIS-C compared with those of KD and Kawasaki disease shock syndrome (KDSS). Databases were searched for studies on laboratory parameters of MIS-C (hematology, inflammatory markers, cardiac markers and biochemistry) through May 31, 2021. Twelve studies with 3073 participants yielded 969 MIS-C patients. In terms of hematology, MIS-C patients had lower levels of leukocytes, absolute lymphocyte count and platelet count (PLT) than KD patients and had similar absolute neutrophil count (ANC) and hemoglobin (Hb) levels. In terms of inflammatory markers, MIS-C patients had higher levels of C-reactive protein, D-dimer and ferritin than KD patients and had similar levels of procalcitonin and ESR. In terms of cardiac markers, MIS-C patients had higher CPK levels than KD patients. The levels of NT-proBNP, troponin and AST were not significantly different between MIS-C and KD patients. In terms of biochemistry, MIS-C patients had lower levels of albumin, sodium and ALT and higher levels of creatinine than KD patients. In addition, MIS-C patients had lower levels of PLT, Hb and ESR and higher levels of ANC than KDSS patients. Measurement of laboratory parameters might assist clinicians with accurate evaluation of MIS-C and further mechanistic research.

Background: During the current ongoing COVID-19 pandemic, studies had reported that patients with asthma would experience increased asthma-associated morbidity because of the respiratory virus SARS-CoV-2 infection, based on experience with other respiratory viral infections. However, some studies suggested that there was no apparent increase in asthma related morbidity in children with asthma, it is even possible that due to reduced exposures due to confinement, such children may have improved outcomes. In order to understand the impact of Covid-19 on asthma control in children, we performed this systematic review and meta-analysis. Methods: We searched PubMed, Embase, and Cochrane Library to find literature from December 2019 to June 2021 related to Covid-19 and children’s asthma control, among which results such as abstracts, comments, letters, reviews and case reports were excluded. The level of asthma control during the COVID-19 pandemic was synthesized and discussed. Results: A total of 20456 subjects were included in 7 studies. Random effect model is used to account for the data. Compared to the same period before the COVID-19 pandemic, asthma exacerbation, asthma admission, emergency room visit reduced a lot. The outcome of use of inhaled corticosteroids and Beta-2 agonists shows no significant difference. Conclusion: Compared to the same period before the COVID-19 pandemic and the measures in response to it, the level of asthma control has been significantly improved. We need to understand the exact factors leading to these improvements and find methods to sustain it.

People with cystic fibrosis (CF) have an amazing outlook with the treatment availability of highly effective modulators. Unfortunately, not all PwCF are eligible for modulators leading to continued pulmonary exacerbations and advanced lung disease. Additionally, optimizing diagnosis and evaluation for CF in the newborn period continues to be an area of focus for research. This review article will work to cover articles published in 2021 with high clinical relevance related to the above topics, however due to the extensive body of research published, this review will not be comprehensive.

The current system for disclosing financial conflicts of interest (COIs) can be traced back to the “Uniform requirements for manuscripts submitted to medical journals,” published in 1997. Meanwhile, new molecular and genetic therapies are transforming clinical medicine and these therapies have radically altered the financial landscape of drug development. The average price of new drugs has risen sharply, and in niche areas like rare diseases, the cost of new therapies can be stratospheric. Now, even rare or “orphan” diseases are funded by private investment. With high profitability, there is a new pathway for drug development involving unprecedented ties between industry and academia. The potential for COIs has greatly expanded and decisions that were once science-driven have become profit-driven. As a result, the risk that marginally effective, ineffective and even hazardous treatments will make their way to patients has greatly increased. In this editorial, we propose a system built on process-based COIs. This new system would trace the developmental journey of a drug from the lab to patients. All financial ties that institutions and individuals have to the drug would be disclosed at each developmental step. The goal would be to create a healthy skepticism and debate over the studies behind new drugs, restoring a scientific focus to the assessment of drug efficacy. When society’s limited resources are used to pay for drugs whose excessive cost primarily benefits investors and corporations, it derails scientific objectivity, harms patients, and threatens the financial stability of our health care systems.

BACKGROUND: Mathematical models based on the physiology when programmed as a software can be used to teach cardiorespiratory physiology and to forecast the effect of various ventilatory support strategies. We developed a cardiorespiratory simulator for children called “SimulResp”. The purpose of this study was to evaluate the quality of SimulResp. METHODS: SimulResp quality was evaluated on accuracy, robustness, repeatability and reproducibility. Blood gas values (pH, PaCO 2, PaO 2 and SaO 2) were simulated for several subjects with different characteristics and in different situations and compared to expected values available as reference. The correlation between reference and simulated data was evaluated by the coefficient of determination and Intraclass correlation coefficient. The agreement was evaluated with the Bland & Altman analysis. RESULTS: SimulResp produced healthy child physiological values within normal range (pH 7.40 +/- 0.5; PaCO2 40 +/- 5 mmHg, PaO2 90 +/- 10 mmHg; SaO2 97% +/- 3%) starting from a weight of 25 to 35 kg, regardless of ventilator support. SimulResp failed to simulate accurate values for subjects under 25 kg and/or affected with pulmonary disease and mechanically ventilated. Based on the repeatability was considered as excellent and the reproducibility as mild to good. SimulResp’s prediction remains stable within time. CONCLUSIONS: The cardiorespiratory simulator SimulResp requires further development before future integration into a clinical decision support system.