Expectations versus reality: Understanding the accuracy of impressions made during virtual interviews of pediatric pulmonary fellowship programs.

RATIONALE: As a result of the SARS-CoV-2 pandemic, all pediatric pulmonary fellowship programs conducted virtual interviews for the first time in the Fall of 2020. This study aimed to understand the accuracy of virtual-interview derived-impressions of fellowship programs, as well as applicant preference for future fellowship interview cycles. METHODS: A group of pediatric pulmonary fellows and Program Directors designed a REDCap survey. The survey was distributed to all first-year pediatric pulmonary fellows who participated in the 2020-2021 virtual interview season. RESULTS: 23/52 (44%) of first-year pediatric pulmonary fellows completed the survey. 96% were able to form general impressions about fellowship programs during their virtual interviews. 96% reported that generally their fellowship experience matched their virtual-interview derived-impressions. 17 of the 19 factors applicants use to rank programs had no statistically significant change (p > 0.05) in impression from virtual interview to fellowship experience. The two factors with a statistically significant (p < 0.05) change in impression were patient care related-volume of "bread and butter" pediatric pulmonary patients and volume of tertiary care pediatric pulmonary patients. 87% prefer some form of in-person interview option in future application cycles. A tiered interview format in which applicants are first invited to a virtual interview day followed by an optional in-person second look day was the most popular preference for future interview cycles (48%). CONCLUSIONS: Virtual interviews may provide accurate representations of pediatric pulmonary fellowship programs and applicants prefer some type of in-person interview option in future application cycles.

Pediatric EVALI in the Age of COVID-19/MIS-C: Diagnostic Considerations.

OBJECTIVES: Multisystem inflammatory syndrome in children (MIS-C) and e-cigarette or vaping product use-associated lung injury (EVALI) have significant overlap in clinical features, which can contribute to delay in identification and treatment. The objectives of this report were to identify and describe features that are common in both diagnoses and those that may help distinguish EVALI from MIS-C, and to highlight the diagnostic challenges observed at our tertiary medical center. METHODS: We identified adolescents diagnosed with MIS-C who had respiratory or gastrointestinal symptoms and patients diagnosed with EVALI during the same time period. We compared demographics, history, clinical manifestations, laboratory findings, and features of the hospital course to determine areas of overlap between MIS-C and EVALI, as well as distinct features of each diagnosis. Mann-Whitney U test was used to compare continuous variables and Fisher's exact test was used to compare categorical variables. RESULTS: We found that cardiovascular and mucocutaneous findings and thrombocytopenia were more common in MIS-C. EVALI patients had a higher degree of inflammation and history of antecedent weight loss. Providers at our institution were more likely to consider MIS-C than EVALI on the differential diagnosis, including in patients with vaping history and no evidence of previous severe acute respiratory syndrome coronavirus 2 infection. CONCLUSIONS: This study emphasizes the need for a thorough collection of substance use history for all patients and consideration of EVALI in adolescents who present with respiratory compromise or gastrointestinal symptoms and systemic inflammation, particularly in the absence of severe acute respiratory syndrome coronavirus 2 exposure or cardiac findings characteristic of MIS-C.

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Vaping and e-cigarette use. Mysterious lung manifestations and an epidemic.

Electronic (e)-cigarette use and the practice of vaping has rapidly expanded both in adult smokers and previously nicotine naïve youths. Research has focused on harm reduction in adults using e-cigarettes to stop or reduce traditional cigarette use, but the short and long-term safety of these products has not been established. Vaping has more recently been associated with a growing list of pulmonary complications with the most urgent being the e-cigarette or vaping product use-associated lung injury (EVALI) epidemic. This review details the inhalant toxicology of vaping products, the described lung diseases associated with vaping with a focus on EVALI, and the predicted long-term consequences of e-cigarette use, including increased asthma severity.

MRSA septic pulmonary emboli presenting as isolated focal chest pain in an adolescent.

This case demonstrates the importance of considering septic pulmonary embolism (SPE) on the differential for chest pain in the pediatric population, especially in patients with a history of skin and soft tissue infection. The adolescent patient in this report, with a history of axillary hidradenitis suppurativa complicated by methicillin-resistant Staphylococcus aureus (MRSA) superinfection and recent completion of a 3-month course of doxycycline, presented with isolated focal chest pain in the absence of other infectious or respiratory signs or symptoms. Initial pulmonary imaging revealed multiple bilateral wedge-shaped nodules. Three specialty teams were consulted in the patient's evaluation, resulting in biopsy of a suspicious lesion that confirmed the diagnosis of MRSA SPE. Following a course of targeted antibiotic therapy, the patient's chest pain resolved and imaging findings improved. Insights gleaned from the workup of this patient are useful in formulating a framework for recognition of SPE in children presenting with chest pain, and also highlight the importance of considering insidious SPE presentation in the setting of antibiotic pretreatment.

A review of toxic effects of electronic cigarettes/vaping in adolescents and young adults.

In this review, we examine the known and suspected toxicity of electronic cigarettes (e-cigarettes) in adolescents and young adults, to improve awareness of risks and identification of complications of their use. The use of e-cigarettes, or "vaping," is exploding among the pediatric population. E-cigarettes heat a solution containing a psychoactive compound, most commonly nicotine or tetrahydrocannabinol (THC), along with flavorings and other additives to a vapor, which users inhale. Since their introduction in the early 2000s, e-cigarette use is now prolific among youth, per the Monitoring the Future survey, with over 40% of high school seniors reporting use within the past year. Adolescents are vulnerable to the risks of e-cigarettes, as they are targeted as new consumers with advertisements and flavoring compounds, and are not utilizing them as a means to smoking cessation. The pulmonary risks of vaping are rapidly emerging, with the most immediately alarming being the condition electronic-cigarette/vaping associated lung injury (EVALI). Additionally, there have been more recent studies showing extrapulmonary effects including cardiovascular, immunologic and neuro-developmental effects. Many of these effects are likely dose-dependent. Public health efforts are urgently needed to decrease or eliminate new e-cigarette initiation, and support should be established to assist current e-cigarette users with cessation. We strongly advocate for the elimination of e-cigarette flavorings and advertising directed at adolescents, and call for physicians to be cognizant of this expanding epidemic.

Overview of the ChILD Research Network: A roadmap for progress and success in defining rare diseases.

Children's interstitial and diffuse lung diseases are a diverse group of rare lung disorders that present in childhood with diffuse pulmonary infiltrates and respiratory signs and symptoms. Children with these disorders face high morbidity and mortality and their families must cope with overwhelming uncertainty. Physicians caring for these patients are challenged by a paucity of directed therapies, or even understanding of natural history. Through the establishment of the Children's Interstitial Lung Disease Foundation Research Network and the Children's Interstitial Lung Disease Foundation significant progress has been made through collaboration and research. This review outlines the past and current successes in the new and rapidly growing field of Children's Interstitial and Diffuse Lung Disease.

Case series: Adolescent victims of the vaping public health crisis with pulmonary complications.

Alongside the epidemic use of electronic cigarettes (e-cigarettes) across the country, evidence of multiple pulmonary complications has emerged, with the most immediately life-threatening being the new clinical condition of e-cigarette/vaping-associated lung injury (EVALI), with investigation actively underway to further define this entity and determine the cause or causes. We present a series of cases of respiratory illnesses associated with e-cigarette use, many of which meet criteria for suspected or confirmed EVALI, managed at a pediatric tertiary care center, demonstrating notable variation in presenting symptoms and severity. Most cases improved with supportive respiratory care and the administration of corticosteroids and antibiotics, although generally no infection was found. The cases also tend to show improvement with discontinuation of the use of e-cigarettes. We discuss challenges in determining the contribution of e-cigarettes to the case pathology and review possible diagnostic and treatment options. In patients suffering from e-cigarette-related respiratory illness including EVALI, the primary treatment goal should be the cessation of e-cigarette use and avoidance of other possible pulmonary toxins, including conventional cigarettes. Prevention of e-cigarette use is critical in the youth population, as these patients are typically nicotine naïve and do not engage in smoking conventional cigarettes before initiation of vaping.

Pulmonary hemorrhage in infancy: A 10-year single-center experience.

AIM: Pulmonary hemorrhage in infancy is rare, with challenges in determining its incidence, causes, and outcomes across diverse groups. Our aim was to better understand the incidence and identified causes. We further analyzed the subgroup of patients meeting criteria for acute idiopathic pulmonary hemorrhage of infancy (AIPHI) to determine recurrence, mortality, and treatment. METHODS: We performed a 10-year retrospective cohort study of infants with pulmonary hemorrhage in a large tertiary care center. One-hundred fifty-seven patients overall were identified. RESULTS: The most common diagnoses in infants with pulmonary hemorrhage were congenital heart disease (36.6%), prematurity/premature lung disease (34.6%), congenital or acquired lung disorders (15.0%), and congenital or acquired coagulopathies (13.7%). Nonaccidental trauma (NAT; n = 3) was also an important cause of pulmonary hemorrhage. All patients diagnosed with NAT had normal retinal examinations and skeletal surveys. Only four patients were identified with AIPHI. There was no mortality in this group of infants. One of four patients with AIPHI had a recurrence. Steroids were the consistent treatment for AIPHI, with a large range of treatment duration. CONCLUSION: Diagnostic studies should focus on identifying non-pulmonary sources of bleeding, infection, underlying lung disease, congenital heart defects, coagulopathies, infection, and NAT, as these were the most frequently identified causes of bleeding. NAT is not adequately identified with ophthalmology exam and skeletal survey. Overall, we found AIPHI to be a rare diagnosis. All of the patients with idiopathic hemorrhage received systemic steroids with varying doses and lengths of treatment.

Current Update on Interstitial Lung Disease of Infancy: New Classification System, Diagnostic Evaluation, Imaging Algorithms, Imaging Findings, and Prognosis.

Childhood interstitial lung disease represents a rare and heterogeneous group of diseases that can result in significant morbidity and mortality, some leading to death during infancy. CT is the imaging test of choice. Although many CT findings are nonspecific and a definitive diagnosis usually cannot be reached by CT alone, the interpreting radiologist is instrumental in defining disease extent and refining the diagnosis. Chest CTs are of key importance in guiding site selection for lung biopsy and for following disease progression and response to treatment. Thus, from the radiologist's perspective, ensuring maximal quality of CT imaging and interpretation is paramount.

Lung Pathology in Pediatric Pulmonary Vein Stenosis.

Pulmonary vein stenosis is a rare progressive narrowing of the extrapulmonary pulmonary veins, presenting predominantly in infancy and virtually always lethal. It typically arises following repair of congenital heart disease, particularly anomalous pulmonary venous return. Histologic characterization of pediatric pulmonary vein stenosis, not previously well described, may provide insight into the disease pathobiology. We retrieved archival lung specimens (biopsy, explant, or autopsy) from patients with pediatric pulmonary vein stenosis. Medical records were reviewed. Microscopic examination included hematoxylin and eosin (H&E)-stained slides, and for a subset of patients, elastic, trichrome, smooth-muscle actin, and D2-40. Groups with different clinical disease features were compared using Fisher's exact test. A total of 33 patients (median age, 7 months) had available tissue and 52% had congenital heart disease; 18% were premature. Within the lungs, interlobular septal veins showed thickened muscular coats (in 58%), proliferation/tortuosity (in 6%), and fibromyxoid intimal proliferation (in 3%). Associated arterial hypertensive changes were seen in 30 (91%). The one patient with intrapulmonary venous fibromyxoid intimal proliferation was the only patient with apparent primary familial disease. Lymphangiectasia and arterial medial hypertrophy were histologic features that correlated with clinical grouping. We conclude that in pediatric pulmonary vein stenosis, intrapulmonary pulmonary veins commonly show muscular thickening, best interpreted as venous hypertensive remodeling. Fibromyxoid intimal proliferation resembling that of the extrapulmonary pulmonary veins is uncommon. Awareness of intrapulmonary features in various clinical subtypes of pulmonary vein stenosis may be diagnostically and therapeutically informative considering that current catheter-based and surgical therapy is directed at the extrapulmonary component of pulmonary vein stenosis.

Genotype-phenotype correlations for infants and children with ABCA3 deficiency.

RATIONALE: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private. OBJECTIVES: To determine genotype-phenotype correlations for recessive ABCA3 mutations. METHODS: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. MEASUREMENTS AND MAIN RESULTS: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001). CONCLUSIONS: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.

Chest radiographic and CT evaluation of lung abnormalities in pediatric patients with laryngeal cleft.

BACKGROUND: The purpose of this study was to (1) evaluate chest radiography (CR) and computed tomography (CT) findings in pediatric patients with laryngoscopically confirmed laryngeal cleft and (2) determine whether CT provided additional information over CR in evaluating lung abnormalities in pediatric patients with laryngeal cleft. METHODS: Two pediatric radiologists performed a retrospective review of CRs and CTs in pediatric patients with laryngoscopically confirmed laryngeal cleft from January, 2002 to January, 2010. Lungs were evaluated for pattern (airspace or interstitial), distribution (upper, middle, or lower lung zones), and extent (<25% or >25%) of abnormalities on CRs and CTs. In patients who had both CR and CT, CT findings were compared with concurrent CRs to determine whether CT provided additional information and resulted in alterations in patient management. RESULTS: The final study cohort consisted of 67 pediatric patients (37 males and 30 females; mean age 3.0 years ± 3.5 years; range 25 days to 17.5 years) who had CR. Sixteen (24%) of these 67 patients had both CR and CT. Chest radiographs were abnormal in 47 patients (70%) which included consolidation (n = 35; 74%) and reticular opacities in 12 patients (26%). Lung parenchymal abnormalities were observed in the upper (n = 10; 21%), middle (n = 2; 4%), or lower (n = 35; 75%) lung zones on CR. The extent of lung parenchymal abnormalities was >25% in 30 patients (64%) and <25% in 17 patients (36%). Chest CT examinations were abnormal in all 16 patients (100%) who had available chest CT examinations, which included consolidation (n = 9; 56%) and reticular opacities (n = 7; 44%). Lung parenchymal abnormalities were observed in the upper (n = 2; 12.5%) or lower (n = 14; 87.5%) lung zones on CT. The extent of lung abnormalities was >25% in 10 patients (60%) and <25% in six patients (40%). CT provided major additional findings in 12 patients (75%) and minor findings in four patients (25%). Additionally, CT improved the evaluation of the distribution and extent of lung abnormalities in 11 patients (69%). The additional information provided by CT resulted in alteration of patient management in seven patients (43.8%). CONCLUSIONS: Among pediatric patients with laryngeal cleft, CR and CT often show lung abnormalities such as consolidation and reticular opacities. CT frequently provides additional information, which may change patient management.

Expiratory volumetric MDCT evaluation of air trapping in pediatric patients with and without tracheomalacia.

OBJECTIVE: The purpose of this study was to use paired inspiratory-expiratory volumetric MDCT to compare the frequency, severity, and pattern of air trapping in pediatric patients with tracheomalacia with the findings in children without tracheomalacia. MATERIALS AND METHODS: The study group consisted of 15 consecutively registered pediatric patients (younger than 18 years) who had tracheomalacia, defined as 50% or greater reduction in tracheal cross-sectional luminal area between end inspiration and end expiration, diagnosed with MDCT and confirmed with bronchoscopy. The comparison group consisted of 15 consecutively registered pediatric patients without evidence of tracheomalacia at MDCT and bronchoscopy. Two blinded pediatric radiologists working in consensus interpreted the randomly viewed end-expiratory thin-section CT images of both groups of children for the presence, severity, and pattern of air trapping at three anatomic levels (upper, middle, and lower lung zones). The severity of air trapping was graded visually on a 5-point scale. The total air trapping scores, obtained by summing the values for the three anatomic levels for the study and comparison groups, were compared by Wilcoxon's rank sum test. The pattern of air trapping was categorized as lobular, segmental, lobar, diffuse, or mixed, and the patterns in the two study groups were compared by Pearson's chi-square test. RESULTS: The study cohort with tracheomalacia consisted of 15 patients (10 boys, five girls; mean age, 2.4 +/- 2.8 years; range, 1 month-11.8 years). The comparison group without tracheomalacia consisted of 15 patients (nine boys, six girls; mean age, 2.7 +/- 2.4 years; range, 1 month-8.1 years). Air trapping was identified in all 15 patients with tracheomalacia (median score, 5.0; range, 3-11) and in 10 of 15 children (67%) in the comparison group (median score, 3.0; range, 1-4). The median total air trapping score was significantly higher in the study cohort than in the comparison group (p = 0.002), but there were no significant differences in the air trapping patterns between the study groups (p = 0.53). CONCLUSION: Pediatric patients with tracheomalacia have a higher frequency and greater severity of air trapping than do children without tracheomalacia.