A breath of fresh air: Does spontaneous breathing and early repair in neonates with very mild congenital diaphragmatic hernia lead to earlier discharge? Dear Editor:We read with great interest the article by Kipfmueller et al. that investigated the feasibility and outcomes of a spontaneous breathing approach (SBA) versus immediate intubation in neonates with prenatally diagnosed very mild CDH and found that it appears to be feasible and beneficial1. The authors present an approach that is quite novel - spontaneous breathing and enteral feeding in the pre-surgical repair phase. We compliment the authors for their attempt to address an issue very relevant to the acute management of CDH. Nonetheless, we feel compelled to highlight some aspects that should be considered for adequate interpretation of their findings.The study’s sample size is quite small (n=24), but the fact that the investigators found statistical significance for numerous associations despite such a small sample size demonstrates the strength of the relationships.  It is a common misconception that statistical significance due to chance (i.e., Type I error) is more likely when the sample size is small, although low power due to the small sample size is actually difficult to overcome2. However, when evaluating Table 1, after matching on observed-to-expected lung-to-head-ratio (o/e LHR), liver position, gestational age at delivery, birth weight, and defect size, we note that prerepair characteristics such as early feeding, Oxygenation Index (OI) and FiO2, and Apgar at 10min are still significantly imbalanced between the SBA and standard treatment groups, which raises concerns about potential confounding. For this reason, we recommend the authors complement the unadjusted analyses they report with multivariable regression analyses that compare SBA versus standard treatment after controlling for Apgar 10, OI and FiO2, although the study sample size of n=24 would typically be considered too small for this kind of multivariable regression analysis. Per the authors, 39 patients met their prenatal eligibility criteria. A better and more meaningful comparison of outcomes would be to compare the 8 patients that underwent SBA versus the remaining 31 patient that met their predetermined ’eligibility criteria’ and did not undergo planed SBA. Using this approach would diminish the potential differences in cohort caused by severity of hernia defect, given the fact that some patients in the standard treatment group required patch repair. In the study, the authors incorporated the post natally determined CDH defect size into the matching process; we would advise against using defect size for matching as it cannot be replicated prospectively.The authors utilized the Mann-Whitney U test and Fisher’s exact test to compare the SBA versus standard treatment groups in terms of quantitative and categorical variables, respectively.  These methods ignore the dependence structure in the data resulting from matching. Although this type of oversight is common, we would recommend analyzing the data differently. Utilizing mixed-effects linear models and generalized estimating equations for quantitative and categorical outcomes, respectively, would appropriately accommodate the clustering of study patients due to matching.We were impressed by the decision to initiate enteral feeding prior to surgery and wonder if this approach could be a gut priming strategy favoring outcomes beyond the need for parenteral nutrition3. However, while novel and potentially beneficial, this strategy carries with it risks and will need to be investigated further before others will choose to adopt such a practice.Overall, the authors tackle an important subject and their findings raise questions on whether routine intubation is beneficial for infants with mild CDH. As SBA infants were compared to those with more severe hernias, the observed differences noted between groups are likely a reflection of the severity of lung hypoplasia and not a result of the intervention. We encourage the authors to further explore this strategy with a larger multicenter study to draw meaningful conclusions from the study results.Clinicians should be cautious of implementing guideline changes based on retrospective studies, as prospective studies do not always validate inferences derived from retrospectives studies, such as permissive hypercapnia to prevent bronchopulmonary dysplasia in extremely low birth weight infants (ELBW)4. Centers that perform early repair could consider an SBA approach for a well-defined cohort of infants with mild CDH, as it appears this can decrease the duration of ventilation and length of hospital stay. However, this precision-based medicine approach would be best evaluated by a prospective study to assess the benefits and risks of implementing this strategy.1. Kipfmueller F, Leyens J, Pugnaloni F, et al. Spontaneous breathing in selected neonates with very mild congenital diaphragmatic hernia.Pediatr Pulmonol. 2024;59(3):617-624.2. Jones SR, Carley S, Harrison M. An introduction to power and sample size estimation. Emerg Med J. 2003;20(5):453-458.3. Ratsika A, Codagnone MC, O’Mahony S, Stanton C, Cryan JF. Priming for Life: Early Life Nutrition and the Microbiota-Gut-Brain Axis.Nutrients. 2021;13(2):423.4. Thome UH, Genzel-Boroviczeny O, Bohnhorst B, et al. Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO(2) targets: the PHELBI follow-up study.Arch Dis Child Fetal Neonatal Ed. 2017;102(5):F376-F382.The authors have disclosed no conflicts of interest.

Misconceptions on Behavioral Cough Suppression Therapy for Pediatric Nonspecific Cough: A Response to Weinberger and Buettner’s Commentary on Fujiki et al.Laurie Slovarp, PhD, School of Speech, Language, Hearing, & Occupational Sciences, University of MontanaMarie Jette, PhD, Department of Otolaryngology – Head and Neck Surgery, University of Colorado Anschutz Medical CampusJane Reynolds, PhD, School of Speech, Language, Hearing, & Occupational Sciences, University of MontanaAmanda Gillespie, PhD, Department of Otolaryngology and Head and Neck Surgery, Emory UniversityJulie Barkmeier-Kraemer, PhD, Division of Otolaryngology – Head and Neck Surgery, University of UtahMary Sandage, PhD, Speech, Language, and Hearing Sciences, Auburn UniversityJaclyn Smith, PhD, Biology, Medical and Health Sciences, The University of ManchesterJemma Haines, BSc(Hons), Medical and Health Sciences, The University of Manchester, Manchester University NHS Foundation TrustAnne Vertigan, PhD, School of Medicine and Public Health, University of NewcastleStuart Mazzone, PhD, Department of Anatomy and Physiology, University of MelbourneCorresponding author: Laurie Slovarp, PhD,School of Speech, Language, Hearing, & Occupational Sciences, University of Montana, Missoula, MT, 59812. [email protected] (p) 406-243-2107 (f) 406-243-2362 Orcid ID: 0000-0002-3547-4092Key words : pediatric chronic cough, habit cough, suggestion therapy, speech-language pathologyFunding : noneConflicts of Interest: The authors declare no conflicts of interest.Author Contributions :Laurie Slovarp: conceptualization, writing original draft, review and editingMarie Jette: conceptualization, writing original draft, review and editingJane Reynolds: conceptualization, writing original draft, review and editingAmanda Gillespie: conceptualization, writing original draft, review and editingJulie Barkmeier-Kraemer: review and editingMary Sandage: review and editingJaclyn Smith: review and editingJemma Haines: review and editingAnne Vertigan: review and editingStuart Mazzone: writing, review, and editingAbstract/Summary : This commentary responds to Weinberger and Buettner’s critique of Fujiki et al.’s study on behavioral cough suppression therapy (BCST) for pediatric chronic cough. While acknowledging their contributions, it addresses inaccuracies and clarifies key aspects of BCST. The commentary highlights discrepancies in terminology, challenges assertions regarding diagnostic evaluations, and emphasizes the need for controlled trials to assess treatment efficacy.In their engagement with the study by Fujiki et al.1, Weinberger and Buettner2 bring attention to critical aspects of behavioral cough suppression therapy (BCST) and pediatric chronic cough treatment. While their contributions are valued, it is imperative to address certain inaccuracies and clarify key aspects of the study and BCST provided by specialized speech-language pathologists (SLPs).Firstly, Weinberger & Buettner inaccurately state that Fujiki et al. identified the children as having ”behavioral cough.” The term ”behavioral cough” in the paper was used only in the context of ”behavioral cough suppression therapy,” describing the treatment rather than the children’s cough diagnosis. The authors, in fact, used the term ”nonspecific cough/tic cough” in accordance with current CHEST and ERS guidelines3-5. Weinberger & Buettner’s assertion that ”historical evidence and current practice support “habit cough” as the appropriate diagnosis” lacks substantiation and contradicts contemporary CHEST guidelines5. We are particularly puzzled by Weinberger & Buettner’s advocacy for the term habit cough when Dr. Weinberger is listed as an author on a 2015 CHEST guidelines publication that explicitly advises against the use of these terms, deeming them ”out of date and inaccurate”5.Weinberger & Buettner also criticize the use of extensive evaluations for the children in the sample, arguing that “habit cough” can be diagnosed based on clinical presentation alone—specifically in the presence of a barking or honking cough and absence of the cough during sleep. Interestingly, the same CHEST guidelines, of which Weinberger is an author, specifically cautions against using the diagnostic terms of “psychogenic” or “habit cough” solely based on a barking or honking sound or the absence of cough during sleep, stating that these three clinical presentations lack specificity5. A barking or honking cough can occur with other diseases such as tracheomalacia or bronchiectasis6; and it is well documented that sleep inhibits the cough reflex in adults even when an organic disease process is identified7; 8. Without evidence to the contrary, it is should be assumed that sleep similarly suppresses cough in children. Further, the purpose of Fujiki et al.’s paper was to examine whether BCST improves cough in children and to describe cough characteristics and comorbidities, not to advocate for extensive assessments. Although, it is noteworthy that laryngoscopy revealed structural laryngeal pathology in several cases, challenging Weinberger & Buettner’s assertion that the described assessments were unjustified.Regarding the treatment described in Fujiki et al., Weinberger & Buettner characterize BCST as an “alternative to suggestion therapy.” This overlooks that BCST instructs in strategies to suppress cough, akin to his “suggestion therapy.” Therefore, it seems that BCST is not necessarily an alternative but rather a similar therapy with a different name. This overlap emphasizes the need for clarity in terminology. Importantly, in adults with chronic cough a loss of centrally (brain) mediated cough suppression has been demonstrated using functional brain imaging9.  Although empirical data in children is not available, it seems conceivable that similar mechanisms may be in operation, providing a neurobiological basis for why cough suppression training is often beneficial and supporting the use of terminology that emphasizes this aspect of the therapy.Additionally, Weinberger & Buettner’s argument that 45 pediatric pulmonologists ”already indicate they readily diagnose habit cough and successfully treat with suggestion therapy,” implies a stance against SLP treatment. However, considering there are thousands of pediatric pulmonologists in the U.S. alone, the sample size of 45 falls short of substantiating the claim that ”many” pulmonologists universally adopt this approach or that additional clinicians, such as SLPs, are unnecessary to assist these patients effectively. The argument lacks robust evidence and fails to account for the role of additional clinicians, such as SLPs, to address pediatric chronic cough effectively. Further, a substantial proportion of children in Fujiki et al.’s sample presented with phonotraumatic lesions (e.g., vocal nodules), which SLPs are specifically trained to address through behavioral treatment.Lastly, Weinberger & Buettner suggest that conducting a controlled trial for suggestion therapy is impractical due to the reported low frequency of referrals. We disagree that the size of the population is a valid argument for not conducting a randomized controlled trial. A control group is needed to robustly assess the efficacy of any treatment, particularly in the case of cough interventions which are particularly vulnerable to placebo effect10; 11. Weinberger & Buettner suggest that it would be unethical to withhold suggestion therapy for the sake of a randomized clinical trial; however, one could easily design a study that allowed for those randomized to a control treatment to be eligible for suggestion therapy upon completion of the control arm. Given Dr. Weinberger’s data suggests suggestion therapy eliminates nonspecific/tic cough in less than one week, such children would need to wait no more than one to two weeks before becoming eligible for suggestion therapy and it should be possible to demonstrate such a substantial effect in a relatively small number of subjects in a randomized controlled trial.We agree with Dr. Weinberger that SLP skills vary. As is the case with any clinical discipline, there are many subspecialties in the field of speech-language pathology and varying levels of skill and expertise within those subspecialties. BCST training is not standard in SLP training programs, and, therefore, requires special training.In conclusion, we think these clarifications underscore the importance of understanding Fujiki et al.’s paper in its correct context, and will advance a more nuanced and informed discussion on pediatric cough disorders and BCST’s role in treatment. We acknowledge Weinberger & Buettner’s contribution to pediatric cough management. The data reported in this letter and other publications12; 13, although anecdotal, suggests that behavioral treatment focused on cough suppression is effective. Given this, we encourage Weinberger and Buettner to complete a randomized controlled efficacy trial. If the data confirms efficacy, the study would significantly elevate the legitimacy of the treatment, increasing its use by other practitioners and benefitting pediatric patients with chronic cough.REFERENCES1. Fujiki RB, Wright ML, Fujiki AE, Thibeault SL. 2023. Factors influencing behavioral cough suppression therapy in children with nonspecific chronic cough. Pediatr Pulmonol. 58(12):3466-3477.2. Weinberger M, Buettner D. 2024. The habit cough syndrome. Pediatr Pulmonol. 59(2):260-262.3. Chang AB, Oppenheimer JJ, Irwin RS, Panel CEC. 2020. Managing chronic cough as a symptom in children and management algorithms: CHEST guideline and expert panel report. Chest. 158(1):303-329.4. Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Domingo Ribas C, Hilton Boon M, Kantar A, Lai K, McGarvey L et al. 2020. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 55(1).5. Vertigan AE, Murad MH, Pringsheim T, Feinstein A, Chang AB, Newcombe PA, Rubin BK, McGarvey LP, Weir K, Altman KW et al. 2015. Somatic cough syndrome (previously referred to as psychogenic cough) and tic cough (previously referred to as habit cough) in adults and children: CHEST guideline and expert panel report. Chest. 148(1):24-31.6. Spinou A, Lee KK, Sinha A, Elston C, Loebinger MR, Wilson R, Chung KF, Yousaf N, Pavord ID, Matos S et al. 2017. The objective assessment of cough frequency in bronchiectasis. Lung. 195(5):575-585.7. Lee KK, Birring SS. 2010. Cough and sleep. Lung. 188 Suppl 1:S91-94.8. Power JT, Stewart IC, Connaughton JJ, Brash HM, Shapiro CM, Flenley DC, Douglas NJ. 1984. Nocturnal cough in patients with chronic bronchitis and emphysema. Am Rev Respir Dis. 130(6):999-1001.9. Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. 2016. Neural correlates of cough hypersensitivity in humans: Evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 71(4):323-329.10. Eccles R. 2009. Central mechanisms iv: Conscious control of cough and the placebo effect. Handb Exp Pharmacol. (187):241-262.11. Eccles R. 2010. Importance of placebo effect in cough clinical trials. Lung. 188 Suppl 1:S53-61.12. Lokshin B, Lindgren S, Weinberger M, Koviach J. 1991. Outcome of habit cough in children treated with a brief session of suggestion therapy. Ann Allergy. 67(6):579-582.13. Weinberger M, Hoegger M. 2016. The cough without a cause: Habit cough syndrome. J Allergy Clin Immunol. 137(3):930-931.

Atypical presentation and management of a neonate with alveolar capillary dysplasia: A case reportTo the Editor,Alveolar capillary dysplasia with misalignment of capillary veins (ACD/MCV) is a rare interstitial lung disease caused by maldevelopment of alveoli and capillaries. Neonates typically present with intractable pulmonary hypertension within the first 48 hours of life and have a very short life expectancy 1. However, atypical cases have been described with a late, less fulminant clinical presentation and prolonged survival on pulmonary vasodilators, providing a window for bilateral lung transplantation 2.Case presentationOur patient is a female neonate born at 37 weeks of gestation, weighing 3080 gr after an uncomplicated pregnancy. She was admitted to the neonatal intensive care unit (NICU) at the age of two hours due to pneumothorax, which was managed conservatively and absorbed. On the second day of life, she was intubated due to worsening respiratory distress. Over the next several days, unsuccessful extubation trials were attempted. Eventually, she was weaned off oxygen on the 11th day. However, on postnatal day 16, significant respiratory deterioration was noted. Echocardiography revealed moderate pulmonary hypertension, and sildenafil and dopamine were initiated. The patient’s clinical condition and echocardiography findings gradually deteriorated. High-frequency oscillatory ventilation (HFOV) was commenced with a fraction of inspired oxygen (fiO2) up to 1.0. As our patient continued to deteriorate (maximum oxygenation index OI:32 on day 23), we used intravenous iloprost as a pulmonary vasodilator, titrated up to 20 ng/kg/min in combination with levosimendan up to 0.1 mcg/kg/min, to improve cardiac contractility and reduce afterload and pulmonary resistance. Of note, nitric oxide was unavailable in our center at this time. Although gradual improvement in pulmonary hypertension was noticed, our patient developed severe pulmonary edema, which was managed with a continuous intravenous infusion of furosemide titrated up to 0.4mg/kg/h. Intravenous medications were gradually withdrawn, and we could switch to conventional ventilation on the day of life 34. The infant was extubated ten days later.Computed tomography of the lungs showed bilateral symmetrical ground-glass opacification, and genetic testing with whole exome sequencing (WES) revealed a heterozygous missense variant of the FOXF1 gene (c.229T>C;p.Phe77Leu) in exon 1.Our patient remained stable on a high-flow nasal cannula (HFNC) until the 68th day when she was reintubated, and echocardiography revealed severe pulmonary hypertension. On the 72nd day of life, she was transferred to another NICU at the request of her parents. She remained intubated, treatment with pulmonary vasodilators was continued, and finally, a tracheostomy was performed. She eventually died at five months of age. The parents have consent to report the medical details of the neonate.

Clinical Correspondence

Objectives: To determine the time to ventilator liberation and decannulation after tracheostomy placement in children with bronchopulmonary dysplasia (BPD) and pulmonary hypertension. Methods: A prospective cohort study included all children (<18 years old) who underwent tracheostomy between 2015 and 2021 with or without a diagnosis of BPD. The primary outcome measures were times to mechanical ventilator liberation, tracheostomy decannulation, or death with tracheostomy in place. Patient demographics, associated comorbidities, and outcomes were compared between groups. Results: A total of 318 children met inclusion with a median (interquartile, IQR) age at tracheostomy of 6.9 (IQR: 4.1 – 49.2) months and 54% (N=170) were male. A diagnosis of BPD was made for 43% (N=136) and this group was younger at tracheostomy placement (5.2 vs. 24.5 months, P<.001) and more often had pulmonary hypertension (65% vs. 24%, P<.001) than children without BPD. Children with BPD spent a median of 2.92 years (IQR: 1.60 – 4.03) on mechanical ventilation compared to 1.84 years (IQR: 0.84 – 3.60) for children without BPD ( P=.003). Unadjusted estimation of time to decannulation was longer for children with BPD (HR=0.92, 95% CI: 0.62 – 1.38). The adjusted survival analysis for time to mortality included pulmonary hypertension as a variable of significance (aHR= 2.5, 95% CI: 1.43 – 4.40). Conclusion: The presence of BPD is associated with an increased duration of mechanical ventilation and time to tracheostomy decannulation. Pulmonary hypertension is associated with an increased mortality risk among this vulnerable population of children.

Opportunities for Trauma-Informed Medical Care in Cystic FibrosisTo the Editor:People living with Cystic Fibrosis (PwCF) face a lifetime of potentially traumatic medical experiences. These experiences can range from invasive medical treatments (e.g. venipuncture, nasogastric tube placement) to daily illness-related events (e.g. illness related bullying). These experiences place PwCF at high risk for a type of posttraumatic stress called Medical Traumatic Stress (MTS)[1]. With the growing recognition of the high prevalence and impact of MTS, we anticipate that cystic fibrosis care teams may soon be tasked with integrating trauma-informed medical care into their clinical practices. CF care teams are well poised to prevent and screen for MTS because they 1) create the environment for many illness-related experiences; 2) have established workflows for mental health screening; and, in many cases, 3) have trusting relationships with PwCF and their families. Here, we seek to highlight the opportunities for implementing trauma-informed medical care within the cystic fibrosis-specific context.MTS is defined as the psychological and physiological responses of children and their families to pain, injury, serious illness, medical procedures, and invasive or frightening treatment experiences[2]. MTS is common in PwCF – 55% of these youth report experiencing potentially traumatic medical experiences and 30% report MTS symptoms[1]. MTS symptoms have the potential to impact medical care, health outcomes and quality of life[3].While highly effective modulator therapies may decrease the frequency and severity of medical care, PwCF have identified these therapies as an additional source of potentially traumatic experiences[4]. New potentially traumatic medical experiences in modulator-eligible PwCF can include lost sense of purpose as their identity shifts from a “sick” person to a “well” person; survivor guilt from benefiting from therapies not available to others; and financial distress as they face planning for a longer than anticipated life expectancy [4]. The challenge of navigating the healthcare system, such as advocating with care teams and insurance companies, has been identified as potentially traumatic by PwCF, particularly those who are modulator-ineligible[4].A trauma-informed approach to medical care may be helpful for cystic fibrosis care teams to mitigate MTS. The Pediatric Psychosocial Preventive Health Model (PPPHM) provides a framework for tiered implementation of trauma-informed medical care[5]. It includes recommendations for universal practices gauged towards all children and families, targeted approaches for those at high risk of developing MTS, and treatment for those with severe, escalating, or persistent MTS symptoms (Figure 1).Universal MTS interventions for PwCF include prevention and screening. Preventive interventions can include MTS awareness education for all PwCF, family members of PwCF and cystic fibrosis care team members. This education can highlight approaches to modifying potentially traumatic medical experiences and identifying MTS symptoms that indicate the need for further support. Universal systems interventions may also include the implementation of workflows to minimize the traumatic potential of healthcare experiences (e.g. workflows to minimize needle distress with comfort positioning, numbing cream, and distraction as part of standard care. Care teams can also integrate shared decision-making processes to optimize patient perception of control and implement systems that facilitate communication between cystic fibrosis care team and PwCF.While annual mental health screening for depression and anxiety is the current recommendation for all PwCF, healthcare providers should consider integrating routine MTS screening into their practice. Screening workflows can include screening for patient risk factors and MTS symptoms, as well as family member symptoms of MTS. Currently, there are no screening tools designed to specifically capture the cystic fibrosis experience of MTS; however, acute stress screeners such as the Acute Stress Checklist for Children can aid in the identification of MTS, thereby guiding providers on who to refer for further mental health assessments or support. One common concern regarding screening for MTS is managing the burden of time as well as supporting those PwCF who screen at-risk. Thus, in planning for MTS screening, teams ought to consider the time required for screening, appropriate training for those performing the screening, and the development of a clear workflow for management and referrals. While these barriers require a thoughtful approach to processes and care, the benefits outweigh the consequences of not screening. MTS is present for many regardless of if screening occurs and screening allows the medical team to optimize overall healthcare.The second tier of the PPPHM recommends targeted approaches to MTS for those with risk factors or early symptoms. Possible MTS risk factors in PwCF include parent posttraumatic stress disorder, high daily medication burden, and emergency room and intensive care [1]. Interventions for PwCF who have MTS risk factors or early symptoms may include increasing support during potentially traumatic medical experiences (e.g. having a child life expert prepare a patient before a procedure); altering the medical care plan when possible (e.g. minimizing daily medication burden); educating family members on what to say to PwCF before, during, and after potentially traumatic medical experiences; and integrating patient-specific resilience factors into individualized coping and support plans. In some cases, brief therapeutic psychological interventions may help address specific symptoms (e.g., targeted CBT needle phobia interventions, behavioral sleep interventions, brief psychoeducation interventions).The third tier of the PPPHM recommends treatment for MTS symptoms that impact medical care or impair daily functions. PwCF with significant MTS symptoms should be referred to a mental health provider with expertise in the treatment of trauma symptoms. Ideally, the provider should have familiarity with chronic medical conditions, and, ideally, cystic fibrosis specifically. While we do not yet have evidence-based MTS-specific interventions for PwCF, approaches may include cognitive behavioral techniques such as restructuring of hospital-related thoughts, behavioral activation, or trauma-focused cognitive behavioral therapy. Mental health providers could also collaborate with families and cystic fibrosis care teams to develop an individualized plan for minimizing re-traumatization and reducing the impact of MTS on medical care and quality of life.In summary, given the substantial impact that MTS can have on PwCF, cystic fibrosis care teams should consider integrating trauma-informed approaches into the medical care of PwCF to optimize overall health (including mental health). Comprehensive approaches to MTS mitigation in PwCF include 1) universal awareness, prevention, and screening, 2) targeted interventions for those at high risk, and 3) individualized MTS treatment administered by mental health professionals. To optimize cystic fibrosis care with attention to MTS, future research should prioritize more definitive identification of MTS risk factors, the development of validated cystic fibrosis-specific MTS screening tools, the creation and dissemination of evidence-based MTS prevention programs, and the development of evidence-based MTS mental health interventions tailored to PwCF.Figure 1: Application of the Pediatric Psychosocial Preventative Health Model to Cystic Fibrosis. Adapted with permission from the Center for Healthcare Delivery Science at Nemours Children’s Health System 2018-2019. All rights reserved[5].

Rationale: In the outpatient setting, inhaled corticosteroids (ICS) are frequently given to children with bronchopulmonary dysplasia (BPD) for treatment of respiratory and asthma associated symptoms. In this study we sought to determine if correlations existed between ICS use and ICS initiation and patient characteristics and outpatient respiratory outcomes. Methods: This study included children with the diagnosis of BPD (n=661) who were seen in outpatient pulmonary clinics at the Children’s Hospital of Philadelphia between 2016-2021. Chart review was used to determine patient demographics, use and timing of ICS initiation, asthma diagnosis and acute care usage following initial hospital discharge. Results: At the first pulmonary visit, 9.2% of children had been prescribed an ICS at NICU discharge, 13.9% had been prescribed an ICS after NICU discharge but before their first pulmonary appointment, and 6.9% were prescribed an ICS at completion of initial pulmonary visit. Children started on an ICS as outpatients, had a higher likelihood of ER visits (adjusted OR: 2.68 ±0.7), hospitalizations (4.81 ± 1.16) and a diagnosis of asthma (3.58 ± 0.84), compared to children never on an ICS. Of those diagnosed with asthma, children prescribed an ICS in the outpatient setting received the diagnosis at an earlier age. No associations between NICU BPD severity scores and ICS use were found. Conclusions: This study identifies an outpatient BPD phenotype associated with ICS use and ICS initiation independent of NICU severity score. Additionally, outpatient ICS initiation correlates with a subsequent diagnosis of asthma and acute care usage in children with BPD.

Medication Utilization and Lung Function Changes

Introduction This study aimed to describe the epidemiology and etiologies of critical respiratory diseases of ex-premature infants (EPIs) admitted to pediatric intensive care unit (PICU). In addition, we described the outcomes and resources used of EPIs and identified associated factors for mortality of these infants. Materials and Methods Infants ≤2 years old with acute respiratory illnesses admitted to PICU of Vietnam National Children’s Hospital from November 2019 to April 2021 were enrolled. We compared respiratory pathogens, outcomes, and PICU resources utilized between term infants and EPIs. Univariate followed by multivariable regression analysis were used to evaluate the association between risk factors and mortality. Results Among 1,183 patients aged ≤2 years were admitted for critical respiratory illness, 202 (17.1%) were EPIs. Respiratory viruses were detected in 53.5% and 38.2% among EPIs and term infants, respectively. Compared to term infants, a higher proportion of EPIs required mechanical ventilation (MV) (66.5 vs. 85.6%, p<0.005) and vasopressor support (10.7 vs. 37.6%, p<0.005). EPIs had a longer median duration of PICU stay (11.0 [IQR: 7; 22] vs. 6.0 days [IQR: 3; 11], p=0.09), hospital stay (21.5 [IQR: 13; 40] vs. 10.0 days [IQR: 5; 18], p<0.005) and case fatality rate (31.3% vs. 22.6%) compared to term infants. In EPIs, PIM3 score [ (aOR): 1.51; 95% (CI): 1.30-1.75] and PELOD2 score at admission (aOR: 1.41; 95% CI: 1.08-1.85) were associated with mortality. Conclusion EPIs with critical respiratory illnesses constituted a significant population in the PICU and required more PICU support and had worse clinical outcomes compared to term infants.

FEV 1/FVC normally decreases through childhood, increases briefly during early adolescence, and then declines throughout life. The physiology behind this temporary increase during early adolescence is not well understood. The objective of this study was to determine if this pattern also occurs in children with asthma. Design: Single-center, cross-sectional, retrospective analysis of pulmonary function tests (PFTs) obtained over a 5-year period in children 5 to 18 years of age with persistent asthma. Results: 1,793 patients satisfied all inclusion and exclusion criteria. Mean age (± SD) was 10.4 ± 3.8 years. 48% were female. Mean FEV 1 /FVC was 0.83 ± .09. FEV 1 /FVC in children with persistent asthma declined from age 5 to age 11 by 5.7 % compared to 7.3% in healthy girls, and 5.8% compared to 9.4% in healthy boys. FEV 1/FVC increased by 1.2% until age 16 in children with asthma, compared to 2.2% in healthy girls, and 2.5% compared to 2.3% in healthy boys. The ratio was lower in obese children with asthma at all ages but demonstrated the same curvilinear shape as in healthy children. In absolute terms, FEV 1 grew proportionately more than FVC during early adolescence, so the ratio of FEV 1/FVC increased during that period. The curvilinear shape of the curve remained in postbronchodilator testing, though significantly blunted. Conclusions: The “Shepherd’s Hook” pattern in the FEV 1/FVC curve is preserved in children with persistent asthma. This was also true in obese patients with asthma, although their FEV 1/FVC ratios were lower throughout all stages of childhood and adolescence.

Real-time ultrasound guided segmental bronchoscopic insufflation in a Tay-Sachs patient with atelectasisMatej Šapina, MD, PhD1,2,3*, Bojana Olujić, MD1,2, Tihana Nađ, MD1,2, Hrvoje Vinković, MD1,2, Zdravka Krivdić Dupan, MD1,2, Nikolina Hamidović, MD1, Mia Damašek, MD1,2, Krešimir Milas, MD1, Željko Zubčić, MD, PhD1,2, and Ivan Erić, MD, PhD1,21University hospital center Osijek, 31000 Osijek, Croatia2Medical faculty Osijek, 31000 Osijek, Croatia3Faculty of dental medicine and health Osijek, 31000 Osijek, Croatia*Corresponding author: [email protected]: +385 31 512 279Keywords: bronchoscopy, atelectasis, Tay-Sachs diseaseIntroductionTo the Editor,Atelectasis is the collapse of lung tissue and is a common problem in patients suffering from severe neurological diseases. Treatment depends on the underlying cause, and ranges from respiratory physiotherapy, mucus clearance methods, and in some cases bronchoscopic interventions. If left untreated recurrent infections may occur, along with impaired gas exchange and in the long run fibrosis of the affected area1.A female patient at the age of 3 years with Tay-Sachs disease and consequent severe global psychomotor delay and epilepsy was initially admitted due to a respiratory infection to the neuropediatric department, where she developed an epileptic status and desaturation, prompting a transfer to the Intensive Care Unit. The refractory epileptic status resolved only with several antiepileptics, which lead to intubation requiring invasive mechanical ventilation, after which the patient stabilized.An attempt to reduce sedation the next day resulted in repeated seizures. On the third day, inflammatory parameters increased, with a radiological finding suggestive of pneumonia and a large left atelectasis confirmed by ultrasound. Antibiotics were empirically started, and Moraxella catarrhalis and Adenovirus in the respiratory tract were obtained in the cultures.Lung ultrasound showed a large consolidation in the dorsal upper two thirds of the left hemithorax. Due to the size of the atelectasis, we decided to perform bedside bronchoscopy.A single use paediatric flexible bronchoscope (Ambu® aScope™ 5 Broncho) was introduced through the ETT. The tracheobronchial morphology did not show any obstructions. We applied our recently published modified segmental insufflation technique, however without the use of surfactant2.First, a bronchoalveolar lavage was performed for microbiological and cytological analysis, followed by ultrasound guided bronchoscopic treatment of the affected area. The patient was positioned on the right lateral decubitus position. As described previously, a cuff pressure manometer (AG Cuffill Cuff) and a 50 ml syringe were attached to a three-way stopcock connected to the bronchoscope’s working channel. Pressure controlled segmental insufflation of the lingula and upper lobe was performed directly observing an aeration of the atelectatic areas on the ultrasound with no complications.Subsequent ultrasound monitoring resulted in total expansion of the affected lung and resolution of inflammation, confirmed radiologically (Figure 1.). The patient could be safely extubated and transferred to the wards. No reoccurrence of atelectasis was observed.ConclusionThe treatment of pediatric atelectasis poses a challenge, with limited approaches available and a lack of evidence-based guidelines to guide clinical decision-making. A question that remains to be answered is not only the mode of treatment, but timing. Even with bronchoscopic treatment, different methods exist. In obstructive atelectasis, the approach is simple - to eliminate the obstruction, however, nonobstructive atelectasis remain challenging. Bronchoscopic lung insufflation technique has been explored in adults, with limited cases reported in children3. Several case reports utilized pressure-controlled insufflation with or without surfactant in long standing atelectasis as an add on treatment2; 4.We believe that patients with severe neurological diseases require special attention regarding their susceptibility for developing atelectasis5. Our approach is early bronchoscopic pressure-controlled insufflation in non-obstructive atelectasis. Depending on the duration, we additionally instill surfactant in long standing ones.Ultrasound is recently being used in lung recruitment maneuvers to monitor lung expansion, however, it was only recently reported to be utilized for segmental insufflation monitoring in a spinal muscular atrophy type I patient4. However, to our best knowledge, our case report is the first successful use on a Tay-Sachs patient using real time ultrasound monitoring during pressure-controlled segmental bronchoscopic insufflation. The benefits of ultrasound guidance is the direct visualisation of lung expansion reducing the need for fluoroscopic radiation exposure of visualisation and further monitoring. Besides it increases the safety of the procedure allowing for detection of development of pneumothorax.In conclusion, pressure controlled real-time ultrasound guided bronchoscopic segmental insufflation, with its low-cost, lightweight, and flexible setup, seems to be a safe and promising new modality for treatment of non-obstructive atelectasis, especially in children requiring complex care.FIGURESFigure 1. On the left a large left sided atelectasis can be seen causing the mediastinal shift. On the right complete regression of the atelectasis is observed before extubatingReferences1. Ogake S, Bellinger C. 2020. Role of bronchoscopy in atelectasis. Clinical Pulmonary Medicine. 27(1):30-32.2. Šapina M, Olujic B, Nađ T, Vinkovic H, Dupan ZK, Bartulovic I, Milas K, Kos M, Divkovic D, Zubčić Z. 2023. Bronchoscopic treatment of pediatric atelectasis: A modified segmental insufflation‐surfactant instillation technique. Pediatric Pulmonology.3. Abu‐Hasan MN, Chesrown SE, Jantz MA. 2013. Successful use of bronchoscopic lung insufflation to treat left lung atelectasis. Pediatric Pulmonology. 48(3):306-309.4. Esteban IA, Osona B, Ballestín AS, Rubio CC, de Mendiola JMFP, Gómez VA, López ME, Vicente JCDC. 2024. Bronchoscopic segmental alveolar recruitment in a patient with spinal muscular atrophy and massive atelectasis. Pediatric pulmonology.5. St‐Laurent A, Zysman‐Colman Z, Zielinski D. 2022. Respiratory prehabilitation in pediatric anesthesia in children with muscular and neurologic disease. Pediatric Anesthesia. 32(2):228-236.

Central apneas are a prevalent yet complex phenomenon, particularly among children. This retrospective study, conducted over a decade (from 2012 to 2022), analyzed central apneas in a cohort of 612 pediatric patients who underwent ventilation at the Sleep Medicine and Long-Term Ventilation Unit of the Bambino Gesù Children’s Hospital in Rome, Italy. Among this group, 67 patients met the inclusion criteria for central apneas. Central apneas often arise within the context of various underlying pathologies, including neurological disorders, genetic syndromes, and brain tumors. We categorized patients into three main groups including patients with “exclusively central apneas”, “predominantly central apneas”, and “predominantly obstructive apneas”. Ventilation modes were diverse, with pressure-controlled ventilation and pressure support being commonly used, reflecting the individualized nature of therapy. The choice of ventilation mode has been influenced by the underlying diagnosis and the severity of central apneas, with pressure support ventilation being the most frequently employed mode. Continuous Positive Airway Pressure was also employed in select cases. A statistically significant reduction (p<0.05) in mean cAHI was observed in patients with multimalformation syndromes, hypoxic-ischemic encephalopathy and Prader-Willi Syndrome. The reduction in mean cAHI was not statistically significant in the case of patients with brain tumors. While non-invasive ventilation was commonly used, invasive mechanical ventilation was selectively employed in more severe cases. The study highlights the need for personalized therapeutic strategies when managing central apneas in pediatric patients.

Deterioration of lung diffusion capacity during childhood in sickle cell diseaseWord count: 1500To the Editor,The American Society of Hematology guidelines, 2019, recommended obtaining pulmonary function tests (PFTs) in patients with sickle cell disease (SCD) with various respiratory symptoms even if they are at their steady state.1 These guidelines acknowledged that the usefulness of routine PFT is unknown because of the lack of research. However, this society further suggested that if the PFTs are obtained, it should be a comprehensive study including lung volumes and lung-diffusing capacity for carbon monoxyde (DLCO), in addition to spirometry.1 A large study in adult patients (n=310) with SCD showed that pulmonary function is abnormal in 90% of adult patients with Hb-SS.2 Common abnormalities included restrictive physiology and decreased DLCO. In this study, decreased DLCO indicated more severe sickle vasculopathy characterized by impaired hepatic and renal function, and a negative linear correlation existed between DLCO and age, suggesting that in adults with Hb-SS, disruption of alveolar–capillary gas exchange progressively deteriorated with time.2 Two recent cross-sectional studies of children with SCD showed that pulmonary function, including DLCO, worsened with age and showed correlations with biological markers of inflammation (induced sputum IL‐6 levels or blood neutrophilia).3,4Overall, these studies highlight the potential interest of DLCO measurement in SCD. The DLCO is the product of KCO (carbon monoxide coefficient of transfer) and alveolar volume (VA) and these two latter indices need to be interpreted separately since the decrease in DLCO is often mitigated by a preserved KCO or even increased KCO in SCD. It has been demonstrated that when corrected for hemoglobin levels, the children with SCD compared to controls of similar age had elevated KCOcorrected. The determination of alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) from the lung diffusing capacity for carbon monoxide (DLCO) or for nitric oxide (DLNO) has been done in SCD since the seventies, demonstrating an increase in Vc in SCD. KCO is mathematically linked to both Dm and Vc (1/KCO = VA/Dm + VA/θVc); thus, the increase in KCO is related to Vc increase, but since DLCO has been shown to worsen with age, the changes of DLCO, VA and KCO over time in children with SCD deserve to be studied.The objectives of our study were to describe the evolution of DLCO and its determinants, KCO and VA, and to further assess the initial risk factors of the decrease in DLCO in children/adolescents with SCD. To this end, we retrospectively recorded the routine follow-up PFTs of children with SCD who were included in a prospective cross-sectional study that included the measurement of both DLCO and DLNO with the calculation of Dm and Vc.5

Title: Major aortopulmonary collateral artery aneurysms- a rare cause of airway narrowing

Background and Aims: The long-term respiratory sequelae of COVID-19 infection in children remain poorly understood and may differ across countries. This study aims to investigate the respiratory sequelae, including residual respiratory symptoms and pulmonary function in Thai children. The secondary aim is to identify factors associated with the respiratory sequelae. Materials and Methods: This is an observational study involving 56 healthy children, aged between 7-18 years, who were diagnosed with COVID-19 infection from July 2021 to February 2023. Clinical data relating to COVID-19 infection and persistent symptoms after the infection were assessed after the infection up to six months. Spirometry was performed to assess pulmonary function. Results: Post COVID-19 symptoms were identified in 14 patients (25%), with fatigue, cough, and dyspnea being common symptoms (28-35%). A significant correlation was found between post COVID-19 symptoms and pneumonia (OR = 6.00, 95%CI [1.54,23.33], p=0.01). Abnormal pulmonary function was identified in 10 patients (17.8%) with obstructive impairment being the most common. However, there were no significant association between clinical factors and pulmonary function impairment. Conclusion: Prolonged respiratory symptoms and abnormal pulmonary function following COVID-19 infection are not uncommon in children. The post COVID-19 symptoms are possibly associated with COVID-19 pneumonia.

TITLE: CLINICAL EVIDENCE OF PANCREATIC RECOVERY IN CHILDREN WITH CYSTIC FIBROSIS ON IVACAFTORTo the Editor,Pediatric research has shown that young children with cystic fibrosis (CF) and treated with ivacaftor have seen improvements in pancreatic function. KIWI was a 24-week safety and efficacy trial of ivacaftor in children aged 2-5 years with CF (1). KLIMB was an 84-week open label extension of KIWI (2). Patients enrolled in KIWI revealed an average increase of 99.8 ug/g in fecal elastase (FE). Before beginning ivacaftor, 26 of 27 patients were pancreatic insufficient. After 24 weeks, 25% of these 26 patients had FE results demonstrating pancreatic sufficiency (>200 ug/g) (1). These improvements in FE were maintained during the 84-week KLIMB extension (2).In the ARRIVAL Study, a younger population was studied. Infants aged 12-24 months previously diagnosed with pancreatic insufficiency were assessed (3). After 24 weeks post ivacaftor initiation, six of nine, or 67%, of the infants had repeat FE values of >200 ug/g, consistent with pancreatic sufficiency, as well as evidence of decreased pancreatic inflammation noted with reduction in immunoreactive trypsinogen.Based on this data we instituted a new protocol for repeat FE monitoring in all patients with pancreatic insufficiency who started on ivacaftor by the age of two years. If FE is normal (>200 ug/g), discontinuation of pancreatic enzyme replacement therapy (PERT) is considered along with ongoing monitoring of clinical symptoms and adjustments to vitamin and diet recommendations as indicated.Below is a review of our cohort of pediatric patients who were currently, had been consistently treated with ivacaftor, and were assessed for current pancreatic function by repeat FE testing. All FE values were collected prior to initiation of elexacaftor/tezacaftor/ivacaftor (ETI) in those newly eligible. Nine patients at our CF center who were on PERT have started ivacaftor in the last 6 years with a mean current age of 4.9 years (SD 1.7). The median age of ivacaftor initiation was 1.1 years (range 0.4 - 2). The mean duration of treatment is 3.9 years (SD 1.3).Seven patients had a repeat FE result >200 ug/g. Six of the seven pancreatic insufficient patients presented as newly pancreatic sufficient as evidenced by a FE result of >200 ug/g compared to previous result of <200 ug/g. Patient I was included in this cohort as he was treated with PERT for clinical symptoms of pancreatic insufficiency even though his baseline FE values were above 200 ug/g.The six newly pancreatic sufficient patients started ivacaftor between 0.4 and 1.1 years of age. Our recovery data of 75% is close to the rate seen in the ARRIVAL study. We calculated binomial probability for pancreatic recovery in this small case control series using 0.67 factor based on previous data in ARRIVAL (4). This resulted in a 28% favorability of success.Unsurprisingly, the rate of recovery was higher in the younger age of initiation of ivacaftor than that seen in the older 2–5 year-old cohort in KIWI. A correlation between pancreatic recovery and younger age of initiation was also noted in a recently published multi-center retrospective study of all available CFTR modulators and PE recovery (5). In this study, of the 15 patients with FE results of 200 or greater, 10 had been treated with ivacaftor as their initial modulator therapy. Based on the demographic data, 62.5% of those treated with ivacaftor had pancreatic recovery, which is similar to our cohort data.We urge CF Centers to institute clinical protocols to recheck pancreatic elastase to assess for restoration of pancreatic function in all pediatric patients treated with PERT on ivacaftor. Subsequently, CF Centers should establish processes for discontinuing PERT, monitoring fat soluble vitamins, and adjusting diet as indicated. Resulting medication adjustments will significantly impact the treatment burden and cost for these children and their families. Those with pancreatic restoration should be monitored for symptoms of pancreatic insufficiency as well as growth trends at routine intervals and pursue repeat FE as indicated based on clinical assessment.This study was approved by the Oregon Health and Science University Institutional Review Board (IRB#26442).

Purpose: Predicting Bronchopulmonary dysplasia (BPD) to assess the risk-benefit of the therapy is necessary due to the side effects of medications. We developed and validated an instrument for predicting BDP and compared it with an instrument currently used in neonates born in a Brazilian hospital. Methods: Retrospective cohort of patients born between 2016 and 2020, with gestational ages (GA) between 23 and 30 weeks. Predictive equations were elaborated using methods of selection of component variables: stepwise, conditional inference tree, Fisher’s exact test and all the collected variables; 70% of the sample was randomly selected for the construction of risk prediction equations, and the remaining 30% were used for their validation, application and comparison with the National Institute of Child Health and Human Development (NICHD) instrument published in 2011, currently used in that institution. Sensitivity, specificity, and predictive values of the equations were calculated. Results: The equation that used variables whose p-value was lower than 5% in Fisher’s exact test (clinical chorioamnionitis, GA, birth weight, sex, need for surfactant, patent ductus arteriosus, late-onset sepsis, inspired fraction of oxygen, and respiratory support) presented the best results: specificity of 98% and positive predictive value of 93%. Our instrument allowed applying the prediction to small-for-gestational-age (SGA). The currently used calculator applied to our population had a specificity of 93% and a positive predictive value of 75% and could not be applied to SGA patients. Conclusion: Our tool has a higher specificity and positive predictive value than the foreign instrument and is suited for SGA.

Introduction: Pseudomonas aeruginosa AUST-03 (ST242) has been reported to cause epidemics in cystic fibrosis (CF) patients from Tasmania and Australia and has been associated with multidrug resistance and increased morbidity and mortality. Here, we report epidemic P. aeruginosa (AUST-03) strains in South African CF patients at a public academic hospital detected during a previous study and characterise the resistomes. Methods: The P. aeruginosa AUST-03 (ST242) strains were analysed with whole genome sequencing using the Illumina NextSeq2000 platform. Raw sequencing reads were processed using the Jekesa pipeline and multi-locus sequence typing and resistome characterisation was performed using public databases. Core single nucleotide polymorphism phylogenies were performed on P. aeruginosa ST242 strains from the study and from public databases. Antibiotic susceptibility testing was performed using the disk diffusion and broth microdilution techniques. Results: A total of 11 P. aeruginosa AUST-03 strains were isolated from two children with CF who had pulmonary exacerbations. The majority of the P. aeruginosa AUST-03 strains (8/11) were multidrug resistant (MDR) or extensively drug resistant; and the multidrug efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXY-OprM were the most clinically relevant antibiotic resistance determinants and were detected in all of the strains. The P. aeruginosa AUST-03 (ST242) study strains were most closely related to strains from Canada, China, Denmark and Slovenia. Conclusion: Epidemic MDR P. aeruginosa strains are present at South African public CF clinics and need to be considered when implementing patient segregation and infection control strategies to prevent further spread and outbreaks.