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.

Nutritional deficiencies such as iron, vitamin B12 and folate are recognized as etiologies for several cytopenias; although copper’s role in multiple metabolic enzymes is well-established, copper deficiency is often overlooked as a contributing entity. Frequently diagnosis is delayed, patients may undergo bone marrow investigations with findings overlapping a myelodysplastic process, which can lead to further testing and treatment considerations including hematopoietic stem cell transplant referral. We present a case of a young boy with cystic fibrosis with biliary dysplasia corrected with hepato-portoenterostomy and distal intestinal obstruction syndrome resulting in jejunal resection, with severe anemia and thrombocytopenia requiring transfusion support. Initial evaluation had been unremarkable, ongoing pancytopenia prompted bone marrow studies, which revealed vacuolated granulocytic and erythroid precursors and ring sideroblasts, suggestive of copper deficiency. Serum copper and ceruloplasmin were consistent with severe deficiency, attributed to insufficient absorption intestinal resection, chronic parenteral nutrition and prior zinc supplementation. Following enteral copper supplementation, anemia, leukopenia and thrombocytopenia significantly improved, however upon cessation, counts again worsened and has since been maintained on daily copper supplementation without further transfusion needs. Our experience exemplifies the importance of early consideration for copper deficiency in children with cytopenias, especially within context of intestinal malabsorption or inadequate nutritional intake which often occurs in children with cystic fibrosis.

BackgroundAspirations are frequent in children with neurological impairment. They significantly increase the risk for acute and chronic respiratory insufficiencies leading to high morbidity and mortality. Laryngeal sensation deficits have been linked to aspirations in adults and are a suspected cause for dysphagia in children. In a similar neurological circuit as swallowing, laryngeal receptors trigger coughing as a protective airway reflex. The aim of this study was to examine the association between impaired laryngeal sensation (ILS), aspiration and coughing in neurologically impaired children.Design and MethodsIn a retrospective study, 110 children with suspected dysphagia who underwent a clinical evaluation of swallowing and a flexible endoscopic evaluation of swallowing (FEES) between 2013 and 2019 in the children’s university clinic Düsseldorf were analyzed. Laryngeal sensation was tested by the endoscopic touch method. Associations were computed using χ2-test.ResultsFifty-four patients (49.1%) had neurological impairment, 56 patients (50.9%) had no or other comorbidities and served as a control cohort. Children with neurological impairment suffered from ILS significantly more often than children with no or other comorbidities (χ²(1) = 4.63, p = .031). ILS was associated with all other FEES variables but did not correlate with coughing. The symptom coughing correlated with aspiration in the group of neurologically impaired children and in children ILS.Conclusion ILS is a potential cause of aspirations in children with neurological impairment.  Physicians need to pay special attention to the occurrence of coughing in children with neurological impairment and/or ILS since it signals aspirations that took place.

Introduction Pseudomonas aeruginosa is the most commonly isolated organism in children with ventilator-associated tracheobronchitis (VAT). Enteral treatment with ciprofloxacin or levofloxacin is sometimes employed, but supportive data are limited. The purpose of this study was to evaluate the effectiveness and safety of enteral ciprofloxacin and levofloxacin administration for VAT in children. Methods This was a retrospective review of electronic medical records for children less than 18 years of age who received enteral ciprofloxacin or levofloxacin for the treatment of VAT from January 2013 through January 2020 at an academic children’s hospital. Results Seventy-six children (median age 9.5, IQR 3.6-13.1 years), received ciprofloxacin or levofloxacin for VAT treatment during the study period. Median treatment duration was 8 (range 7-10) days. Most tracheostomy cultures (n=70/82, 85%) were polymicrobial, with P. aeruginosa most commonly isolated (n=67/224 organisms, 30%). Sixty-five children (86%) were successfully treated with an enteral fluoroquinolone. Antibiotics were changed or extended for two (3%) children. Ten (13%) children were prescribed antibiotics and eight (11%) required hospitalization for a lower respiratory tract infection within 30 days of completion of their fluoroquinolone course. Six (8%) patients received a seizure rescue medication, seven (9%) experienced emesis, and one (1%) had elevated transaminases. Tendonitis, tendon rupture and QTc prolongation were not observed. Conclusions The results of this study suggest enteral fluoroquinolones may be effective for the treatment of VAT in children. Further study is warranted to clarify the role of these agents in pediatric VAT.

Background: Individuals with cystic fibrosis (CF) and fungal airway infection may present with fungal bronchitis, allergic bronchopulmonary aspergillosis (ABPA) or may appear unaffected despite fungal detection. We sought to characterize people with CF with frequent detection of fungi from airway samples and determine clinical outcomes. Methods: This retrospective study included individuals with CF with ≥ 4 lower airway cultures over a 2-year baseline period and ≥ 2 years of follow-up. We defined two groups: ≤ 1 positive fungus culture (rare) or ≥ 2 positive cultures during baseline (frequent). Clinical characteristics and outcomes were determined. Results: Between 2004-2016, 294 individuals met inclusion with 62% classified as rare and 38% as frequent fungi during baseline. Median follow-up was 6 years (range 2-9 years). Aspergillus fumigatus was the most common fungal species detected. Individuals with frequent fungi were older (13.7 vs. 11.7 yrs, p = 0.02) and more likely to have Stenotrophomonas maltophilia (35% vs 17%, p < 0.001) at baseline, but did not differ in lung function or ABPA diagnosis. During follow-up, those with frequent fungi were more likely to have chronic P. aeruginosa and S. maltophilia. Individuals with ABPA and frequent fungi had the highest rates of co-infection and co-morbidities, and a trend towards more rapid lung function decline. Discussion: Fungal infection in CF was associated with frequent P. aeruginosa and S. maltophilia co-infection even in those without ABPA. Individuals with frequent fungi and ABPA had worse outcomes, highlighting the potential contribution of fungi to CF pulmonary disease.

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.

Objectives The aim of our study was to identify, in mechanically ventilated neonates <30 weeks GA with clinical evidence of bronchopulmonary dysplasia (BPD), factors likely to be predictive of a first course of systemic dexamethasone leading to extubation within 14 days and remaining extubated for at least 7 days. Methods We studied a retrospective cohort of neonates (23+0-29+6 weeks GA), with evidence of BPD, prescribed their first course of systemic dexamethasone to aid in extubation from mechanical ventilation. The data collected only pertained to the first course of dexamethasone for any given neonate, with the primary outcome of interest of successful extubation within 14 days (i.e., extubated within 14 days of starting dexamethasone and remaining extubated for at least seven days). Binary logistic regression was employed. Results A total of 287 neonates were included. Each additional week of GA at birth led to a 1.53 increase in the odds of successful extubation (95% CI 1.122-2.096, p<0.01). Higher average fraction of inspired oxygen (FiO2) requirements in the preceding 24 hours resulted in a 0.94 decrease in the odds of successful extubation (p<0.05) and higher mean airway pressure (MAP) resulted in 0.76 decrease in odds of successful extubation (p<0.01). Conclusions Mechanically ventilated neonates born at <30 week GA, with evidence of BPD requiring dexamethasone to facilitate extubation, had a lower likelihood of successful extubation by day 14 if at the time of commencing steroids they were less mature at birth, had higher MAPs and higher oxygen requirements.

Noninvasive ventilation (NIV) use was initially reported in cystic fibrosis (CF) in 1991 as a bridge to lung transplantation, and over the decades the use of NIV has increased in the CF population. Individuals with CF are prone to various physiologic changes as lung function worsens, and they may benefit from NIV for advanced lung disease. As life expectancy in CF has been increasing due to advances such as highly effective modulator therapy, people with CF are now subject to the same co-morbidities that may benefit from NIV as their age matched cohorts. NIV can improve gas exchange, quality of sleep, exercise tolerance and augment airway clearance in CF, and it is important that CF providers are comfortable with this therapeutic modality. In this review, we will summarize the physiologic basis for NIV use in CF, describe indications for initiation of NIV, and postulate a practical approach for CF clinicians to take fin monitoring patients on NIV. We will discuss aspects unique to people with CF and the use of NIV. We hope that this serves as a resource for CF providers, especially those of us who do not have dedicated training in sleep medicine, as we continue to care for our patient population.

Background: There is a lack of studies on outcomes in cystic fibrosis (CF) in children from developing countries like India. Identifying risk factors for mortality may help identify the high-risk group and plan policy management of such patients. Objective: To determine the factors associated with outcomes among Indian children with CF. Design: Retrospective analysis of data collected from January 2010 to Dec 2020. Setting: Tertiary care hospital in Northern India. Participants: Children diagnosed with CF during the study period. Methods: We extracted data related to demography, clinical features, laboratory data and outcome from children’s medical records with CF. Bivariate and multivariate analysis was performed to identify variables associated with mortality. Results: We enrolled 178 children, and there were 32 (18.0%) deaths. Significant factors associated with mortality included history of neonatal complications; hazard ratio (HR): 8.5 (95% CI, 3.0 - 23.9, p < 0.001), low Z-scores for body mass index (BMI) at the time of diagnosis; HR: 7.1 (95% CI 2.3 - 22.0, p < 0.001), FEV1/FVC at the time of diagnosis; HR: 5.1 (95% CI, 1.65 - 15.4, p-value < 0.004), and FEV1 25-75; HR: 3.6 (95% CI, 1.1- 11.8, p-value = 0.03). Conclusions: Factors associated with increased risk of mortality included presence of neonatal complications, low BMI and lower pulmonary function test results. Low BMI and low PFT indices are modifiable and possibly can be improved by early diagnosis. A new-born screening test may help in early diagnosis and identification of the neonatal problem of CF.

Seasonal epidemics of influenza and the respiratory syncytial virus are the cause of substantial morbidity and mortality among children. During the global COVID-19 pandemic, the epidemiology of these viruses seems to have changed dramatically. In Australia and New Zealand, a significant decrease in both influenza and bronchiolities have been noticed during usual peak seasons. Data from early months of winter seasons in Europe are showing similar trends. This current scenario imposes a reconsideration of the paradigm that toddlers and young schoolchildren are the main drivers of seasonal RSV outbreaks and respiratory epidemics in general. In this paper, we summarize current literature, address current knowledge or role of adults in the respiratory syncitial virus epidemiology, describe the lessons learned from pertussis epidemics and call the international community to better understand the community transmission dynamics of respiratory infections in all age-groups. This can allow the establishment of better and more affordable preventive measures in the whole population level, which can ultimately save millions of child lives.

Clinical care in cystic fibrosis (CF) has continued to advance over the last several years, particularly with the widespread eligibility and use of highly effective modulator therapy. Awareness of the multisystem concerns that face persons with CF (PwCF) has also continued to be recognized as an important aspect of the burden of the disease. This review will cover a broad array of topics, from diagnosis to multisystem effects related to mental health, endocrine, palliative care, reproductive health, otolaryngology, and cardiac issues. Additionally, an understanding of worldwide care delivery will be reviewed, demonstrating variation in outcomes based on resources and populations served, ranging from the advances in care in the United States (US) to the challenges of disease recognition and diagnosis in low-and-middle-income countries (LMIC). This review is the third in a three-part CF Year in Review 2020 series, focusing on the multi-system effects of CF. Part one focused on the literature related to CFTR (cystic fibrosis transmembrane conductance regulator protein) modulators, while part two focused on pulmonary outcomes, radiographic and physiologic assessments, as well as infection and inflammation. Part three has been split into two individual parts, Part 3A presented here, and Part 3B related to CF specific nutrition and gastrointestinal publications will also be published this year. This review focuses on articles from Pediatric Pulmonology but also includes articles published in 2020 from other journals that are of particular interest to clinicians.

The multisystemic manifestations of cystic fibrosis (CF) involve all parts of the gastrointestinal (GI) system, including the pancreas, intestine and liver. As providers who care for people with CF (PwCF), knowledge of the manifestations, treatment and research related to nutrition and GI disease is important. This review is last installment of the CF Year in Review 2020 series, focusing on the multisystem effects of CF. Part one focused on the literature related to CFTR (cystic fibrosis transmembrane conductance regulator protein) modulators, while part two focused on pulmonary outcomes, radiographic and physiologic assessments, as well as infection and inflammation. Part three was split into Part 3A, focusing on the multisystem impact of CF, and this review, Part 3B, focusing on nutritional, gastrointestinal and hepatobiliary articles. Articles were chosen from Pediatric Pulmonology but also include articles published in 2020 from other journals that are of particular interest to clinicians.

Background: The marked heterogeneity in CF disease complicates selection of those most likely to benefit from existing or emergent treatments. Objective: We aimed to predict progression of bronchiectasis in preschool children with CF. Methods: Using data collected up to three years of age, in the Australian Respiratory Early Surveillance Team for CF (AREST CF) cohort study, clinical information, chest computed tomography (CT) scores and biomarkers from bronchoalveolar lavage were assessed in a multivariable linear regression model as predictors for CT bronchiectasis at age 5-6. Results: Follow-up at 5-6 years was available in 171 children. Bronchiectasis prevalence at 5-6 was 134/171 (78%) and median bronchiectasis score 3 (range 0-12). The internally validated multivariate model retained eight independent predictors accounting for 37% (Adjusted R2) of the variance in bronchiectasis score. The strongest predictors of future bronchiectasis were: pancreatic insufficiency, repeated intravenous treatment courses, recurrent lower respiratory infections in the first 3 years of life and lower airway inflammation. Dichotomizing the resulting prediction score at a bronchiectasis score of above the median resulted in a diagnostic odds ratio of 13 (95% CI 6.3-27) with a positive and negative predictive values of 80% (95%CI 72%-86%) and 77% (95% CI 69%-83%) respectively. Conclusion: Early assessment of bronchiectasis risk in children with CF is feasible with reasonable precision at a group level, which can assist in high-risk patient selection for interventional trials. The unexplained variability in disease progression at individual patient level remains high, limiting the use of this model as a clinical prediction tool.

Introduction: In the era of data-driven decision-making, an unacceptable haziness and inconsistency surrounds the yearlong scientific and public debate on the school closure policy in the COVID-19 pandemic mitigation efforts. Aim: The present literature review stems out of the need for a clear scaffold collecting in one place all current evidence, as well as helping organizing incoming future evidence, concerning both the role of schools in driving the Sars-CoV-2 community spread and the cost-effectiveness of school closure in containing such spread. Methods: References for this review were initially identified through searches of PubMed, Scopus and Cochrane Library for articles published from March, 2020, to March, 2021 by use of the terms “Schools” “COVID-19” “pandemic” “clusters” “outbreak” “seroprevalence”. Further search was undertaken through Google Scholar and ResearchGate, and finally through Google. Results: School closure at times of high background prevalence of COVID-19 should not be considered a measure implemented to protect the health of children. Children had lower secondary attack rates than adults and that they infrequently represented the index case. One year of pandemic has been sufficient for the emergence of one indication of concern: a potentially increased burden of paediatric mental health disorders. Conclusions: A fact-based understanding of what is currently known on such a consequential policy is required to provide a basis of evidence for an advocacy of either school closure or school opening at times of high intensity community transmission of Sars-CoV-2.

Objective: Asthma is a recognized comorbidity in children with sickle cell disease (SCD). It increases risk of acute chest syndrome (ACS), vaso-occlusive episodes, and early mortality. We aim to determine whether evaluation and management of children with sickle cell disease (SCD) and asthma by a pulmonologist reduces rate of asthma exacerbation and ACS. Methods: The study included 192 patients with SCD (0-21 years) followed at Children’s Hospital of Philadelphia Hematology between 01/01/2015 and 12/31/2018 with a diagnosis of asthma, wheeze, or cough. Patients were placed in two groups: those evaluated by a pulmonologist (SCD-A-P) and those not (SCD-A). Rates of emergency department (ED) visits and hospitalizations for asthma exacerbation and ACS were compared between groups and before/after initial pulmonology visit. Results: SCD-A-P (n=70) had lower baseline pulmonary function, hemoglobin, and hematocrit compared to SCD-A (n=122). SCD-A-P had a higher average rate of hospital visits for asthma exacerbation and ACS per year compared to SCD-A: 0.84 [0.56-1.12] versus 0.31 [0.18-0.43], (p<0.001). For SCD-A-P patients with at least one hospital visit (n=48), the average rate decreased from 3.93 [1.57-6.29] before initial pulmonary visit to 0.85 [0.48-1.23] after the visit (p=0.014). Conclusion: SCD-A-P had more severe baseline disease and higher rates of ED visits and hospitalizations for asthma exacerbation and ACS compared to SCD-A, but the rates significantly decreased following pulmonology consultation. These findings support the pulmonologist’s role in the multidisciplinary care of SCD patients. Further studies are needed to help establish evidence-based asthma guidelines for children with SCD.

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.

Objective: To analyze the proportion of backup ventilation during neurally adjusted ventilatory assist (NAVA) in preterm infants at different gestational ages and to analyze the trends in backup ventilation in relation to clinical deteriorations. Methods: A prospective observational study was conducted in 18 preterm infants born at a median (range) 27+4 (23+4–34+4) weeks of gestation with a median (range) birth weight of 1,100 (460–2,820) g, who received respiratory support with either invasive or noninvasive NAVA. Data on ventilator settings and respiratory variables were collected daily; the mean values of each 24-hour recording were computed for each respiratory variable. For clinical deterioration, ventilator data were reviewed at 6-hour intervals for 30 hours prior to the event. Results: A total of 354 ventilator days were included: 269 and 85 days during invasive and noninvasive NAVA, respectively. The time on backup ventilation (%/min) significantly decreased, and the neural respiratory rate increased with increasing postmenstrual age during both invasive and noninvasive NAVA. The median time on backup ventilation was less than 15%/min, and the median neural respiratory rate was more than 45 breaths/min for infants above 26+0 weeks of gestation during invasive NAVA. The relative backup ventilation significantly increased prior to the episode of clinical deterioration. Conclusion: The proportion of backup ventilation during NAVA showed how the control of breathing matured with increasing gestational age. Even the most immature infants triggered most of their breaths by their own respiratory effort. An acute increase in the proportion of backup ventilation anticipated clinical deterioration.

Background: Titration of inspired oxygen is a challenge in preterm infants with hypoxemic respiratory failure (HRF). Monitoring of brain oxygen by near infrared spectroscopy (NIRS) has been proven to minimize the burden of hyperoxia and hypoxemia, with better understanding of cerebral autoregulation (CAR). integrating NIRS and pulse oximetry (SpO2) for titrating inspired oxygen is a novel approach. Methods: We aimed to study the impact of integrated monitoring of oxygen saturation by SpO2 and cerebral regional tissue oxygen (crRTO) by NIRS during oxygen reduction test (ORT) on reducing oxygen requirement in preterm infants with HRF. The correlation between SpO2 with crRTO, and fractional oxygen extraction (FOE) was assessed, concordance levels (r>0.5) were determined during the assessment period, and was considered as a sign of impaired autoregulation. The primary outcome was the achievement of significantly lower FiO2 at 72 hours after start of the integrated monitoring. Results: Total of 38 preterm infants were included, 27 had normal cerebral autoregulation (CAR), (group 1) in whom SpO2 was poorly correlating with cerebral regional tissue oxygen (crRTO) with (r<0.5) and had significantly greater percentage of reduction below baseline in FiO2 (Mean:34%). Eleven infants had impaired CAR (group 2) with SpO2 significantly correlating with crRTO (r>0.5) and had a linear trend of FOE inverse to SpO2 and crRTO; this was considered as an arterial saturation dependent oxygen delivery (SadDO2). Conclusion: Integrated monitoring of preterm infants by SpO2 and crRTO was associated with easier weaning of oxygen with less burden of both hyperoxia and hypoxemia.