Pediatric pulmonology 2021 year in review: Rare and diffuse lung disease.

The field of rare and diffuse pediatric lung disease is experiencing rapid progress as diagnostic and therapeutic options continue to expand. In this annual review, we discuss manuscripts published in Pediatric Pulmonology in 2021 in (1) children's interstitial and diffuse lung disease, (2) congenital airway and lung malformations, and (3) noncystic fibrosis bronchiectasis including primary ciliary dyskinesia. These include case reports, descriptive cohorts, trials of therapies, animal model studies, and review articles. The results are put into the context of other literature in the field. Each furthers the field in important ways, while also highlighting the continued need for further studies.

Multidisciplinary feeding treatment for a patient with interstitial lung disease.

Children with underlying medical and developmental conditions often present with complications that include feeding difficulties. Severe feeding difficulties may meet the criteria for the psychiatric diagnosis of Avoidant Restrictive Food Intake Disorder (ARFID). ARFID is a disruption in feeding/eating which may include weight loss/faltering growth, nutrient deficiencies, and/or reliance on a nutritionally complete formula to meet caloric needs. Children with interstitial lung disease (ILD), have a higher prevalence of feeding problems than the general population. To date, no published literature exists to provide guidance for treating severe feeding difficulties experienced by children with ILD. In this paper, we present an encounter in which we safely and effectively treated ARFID as evidenced by underweight and dependence on a nutritionally complete formula in a 3-year-old male with ILD using a multidisciplinary approach to treatment. Before the admission, the patient relied primarily on oral nutritional supplementation for most of his nutritional needs and therapeutic efforts to advance food intake were complicated by mealtime behavior problems and concerns regarding swallow safety. Intervention introduced 16 new foods, established consistent caloric intake of target food, and successfully weaned the patient from bottle feeding. We also review special considerations and provide guidelines for adapting treatment at multidisciplinary programs for patients with complex cardiorespiratory disease including modifications to behavior management procedures, medical monitoring, and nutritional consultation.

Pediatric pulmonology 2020 year in review: Rare and diffuse lung disease.

Pediatric Pulmonology publishes original research, review articles, and case reports on topics related to a wide range of children's respiratory disorders. Here we review some of the most notable manuscripts published in 2020 in this journal on (1) children's interstitial lung disease (chILD), (2) congenital airway and lung anomalies, and (3) primary ciliary dyskinesia and other non-cystic fibrosis bronchiectasis. The articles reviewed are discussed in context with published works from other journals.

Care recommendations for the respiratory complications of esophageal atresia-tracheoesophageal fistula.

Tracheoesophageal fistula (TEF) with esophageal atresia (EA) is a common congenital anomaly that is associated with significant respiratory morbidity throughout life. The objective of this document is to provide a framework for the diagnosis and management of the respiratory complications that are associated with the condition. As there are no randomized controlled studies on the subject, a group of experts used a modification of the Rand Appropriateness Method to describe the various aspects of the condition in terms of their relative importance, and to rate the available diagnostic methods and therapeutic interventions on the basis of their appropriateness and necessity. Specific recommendations were formulated and reported as Level A, B, and C based on whether they were based on "strong", "moderate" or "weak" agreement. The tracheomalacia that exists in the site of the fistula was considered the main abnormality that predisposes to all other respiratory complications due to airway collapse and impaired clearance of secretions. Aspiration due to impaired airway protection reflexes is the main underlying contributing mechanism. Flexible bronchoscopy is the main diagnostic modality, aided by imaging modalities, especially CT scans of the chest. Noninvasive positive airway pressure support, surgical techniques such as tracheopexy and rarely tracheostomy are required for the management of severe tracheomalacia. Regular long-term follow-up by a multidisciplinary team was considered imperative. Specific templates outlining the elements of the clinical respiratory evaluation according to the patients' age were also developed.

Novel Application of Aptamer Proteomic Analysis in Cystic Fibrosis Bronchoalveolar Lavage Fluid.

PURPOSE: Biomarkers are needed in cystic fibrosis (CF) to understand disease progression, assess response to therapy, and enrich enrollment for clinical trials. Aptamer-based proteomics have proven useful in blood samples. The aim is to evaluate proteins in bronchoalveolar lavage fluid (BALF) in CF children compared to controls and identify endotypes during CF exacerbations. EXPERIMENTAL DESIGN: BALF is collected clinically from 50 patients with CF and nine disease controls, processed, and stored per protocol. BALF supernatants are analyzed for 1129 proteins by aptamer approach (SOMAscan proteomics platform). Proteins are compared across groups and used for pathway analysis. Endotypes are identified within the CF group. RESULTS: CF BALF has increased concentrations of neutrophil elastase, myeloperoxidase, and decreased concentration of protein folding and host defense proteins. Pathways that distinguished CF subjects included interferon gamma signaling, membrane trafficking, and phospholipid metabolism. In the CF group, unbiased analysis of proteins identified two distinct endotypes that differed based on BALF white blood cell and neutrophil counts and detection of CF pathogens. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic analysis of the CF airway demonstrates a complex environment of proteins and pathways. This work provides evidence that aptamer-based proteomics can differentiate between groups and can determine endotypes within CF.

Analysis of Risk Factors for Abnormal Pulmonary Function in Pediatric Cancer Survivors.

BACKGROUND: Childhood cancer survivors are at increased risk for pulmonary-related morbidity and mortality. The Children's Oncology Group Long-Term Follow-Up (COG-LTFU) guidelines recommend pulmonary function testing after treatment with bleomycin, busulfan, carmustine, lomustine, thoracic radiation, bone marrow transplant, or pulmonary surgery. The aim of this analysis was to determine the prevalence of pulmonary function abnormalities in a pediatric survivor cohort. PROCEDURE: Patients ≥5 years old seen in our survivor clinic with at least one exposure outlined by COG-LFTU Guidelines were included. Original pulmonary function test (PFT) results were obtained and blindly reinterpreted by a single reviewer. Demographic, diagnosis, treatment factors, and clinical and/or patient-reported symptoms of cough, wheeze, and/or dyspnea were abstracted from their medical record. RESULTS: Overall, 143 (63.3%) survivors had PFT results available; 55.2% were male, 49.7% were white, and the mean age was 14.1 ± 4.8 years. Abnormal PFTs were found in 65.0% (n = 93) with 21.0% having multiple abnormalities. Specifically, 41.3% had hyperinflation, 25.9% had obstructive, and 13.3% had restrictive disease. Patients diagnosed at <5 years were more likely to have a pulmonary abnormality (P = 0.04); a majority of those diagnosed <5 years underwent pulmonary surgery or thoracic radiation. Regardless of the presence of a PFT abnormality, more than 80% of survivors were asymptomatic (82.9% vs.81.5%; P-value = 0.54). CONCLUSIONS: Almost two-thirds of survivors screened per the COG-LTFU Guidelines had an abnormal PFT but a majority reported no clinical symptoms. Hyperinflation was the most prevalent abnormality.

Impulse oscillometry: interpretation and practical applications.

Simple spirometry and body plethysmography have been routinely used in children aged > 5 years. New techniques based on physiologic concepts that were first described almost 50 years ago are emerging in research and in clinical practice for measuring pulmonary function in children. These techniques have led to an increased understanding of the pediatric lung and respiratory mechanics. Impulse oscillometry (IOS), a simple, noninvasive method using the forced oscillation technique, requires minimal patient cooperation and is suitable for use in both children and adults. This method can be used to assess obstruction in the large and small peripheral airways and has been used to measure bronchodilator response and bronchoprovocation testing. New data suggest that IOS may be useful in predicting loss of asthma control in the pediatric population. This article reviews the clinical applications of IOS, with an emphasis on the pediatric setting, and discusses appropriate coding practices for the clinician.

Bronchoalveolar lavage fluid cytokine profiles in neuroendocrine cell hyperplasia of infancy and follicular bronchiolitis.

BACKGROUND: Neuroendocrine Cell Hyperplasia of Infancy (NEHI) and Follicular Bronchiolitis (FB) are rare pediatric diffuse lung diseases with poorly understood pathogenesis and similar clinical presentations. We sought to determine if cellular and cytokine profiles in bronchoalveolar lavage fluid (BALF) from subjects with NEHI and FB would differ from pediatric disease controls. METHODS: BALF was obtained from forty-one subjects classified into four disease groups: NEHI, Cystic Fibrosis (CF), other airway disease controls (DC), and FB during clinically indicated procedures. BALF cellular profiles and ten cytokines were measured and values compared across groups using descriptive and nonparametric statistics. RESULTS: Significant BALF cellular and cytokine differences were seen across all groups. NEHI subjects exhibited the lowest total absolute white blood cell (WBC) levels with a higher percentage of BALF alveolar macrophages compared to controls. NEHI also had lower levels of IL-1ß, MIP-1ß and IL-8 and FB had higher levels of IL-1ra, G-CSF and VEGF compared to all groups. IL-6 was elevated in CF and FB. CONCLUSIONS: BALF cytokine and cellular profiles differed between NEHI, FB, CF and DC subjects. This pilot data suggests different and distinguishing inflammatory responses in the airway, with the least inflammatory being NEHI. These data could have diagnostic implications.

Abnormal infant pulmonary function in young children with neuroendocrine cell hyperplasia of infancy.

RATIONALE: Lung function in children with neuroendocrine cell hyperplasia of infancy (NEHI) and correlations with future clinical outcomes are needed to guide clinical management. OBJECTIVE: To compare results of infant pulmonary function tests (IPFTs) in children with NEHI to disease control (DC) subjects and to correlate NEHI IPFTs with future outcomes. METHODS: We performed a retrospective, single center study of IPFT in subjects diagnosed by lung biopsy (NEHI) or clinically (NEHI syndrome) and in DC subjects evaluated for cancer or pre-hematopoietic stem cell transplantation (HSCT). Raised volume rapid thoracoabdominal compression (RVRTC) and plethysmography were performed on all infants and evaluated for quality. Standard spirometry measures, room air oxygen saturations (RA O2 sat), and weight percentiles were collected during follow up. MEASUREMENTS AND MAIN RESULTS: Fifty-seven IPFTs were performed in 15 NEHI, 22 NEHI syndrome, and 20 DC subjects. RVRTC and FRC measurements were obtained in 85% or more of subjects in all groups. Significant airflow limitation (FEV0.5 P-value ≤ 0.01) and air trapping (FRC P-value ≤ 0.01) were seen in NEHI and NEHI syndrome subjects compared to DCs. No significant correlations were found between IPFT, oxygen use, RA O2 sat, and weight at the time of the IPFTs. Initial FEV0.5 and FRC z-scores correlated with RA O2 sat (r = 0.60 and -0.49) at short-term follow up (6-12 months). Most measurements of RVRTC correlated with FEV1 (n = 5) measured 4-5 years later (r > 0.50). CONCLUSIONS: IPFTs in NEHI subjects are feasible, demonstrate significant obstruction and air trapping, and correlate with future RA O2 sat and FEV1 . IPFTs may provide valuable clinical information when caring for NEHI patients. Pediatr Pulmonol. 2013; 48:1008-1015. © 2012 Wiley Periodicals, Inc.

New coding in the International Classification of Diseases, Ninth Revision, for children's interstitial lung disease.

The term "children's interstitial lung disease" (chILD) refers to a heterogeneous group of rare and diffuse lung diseases associated with significant morbidity and mortality. These disorders include neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis, surfactant dysfunction mutations, and alveolar capillary dysplasia with misalignment of pulmonary veins. Diagnosis can be challenging, which may lead to a delay in recognition and treatment of these disorders. Recently, International Classifications of Diseases, Ninth Revision codes have been added for several of the chILD disorders. The purpose of this article is to give an overview of the chILD disorders and appropriate diagnostic coding.

Autoimmune polyendocrine syndrome type 1: Utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab.

Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECD) is a disorder caused by mutations in the autoimmune regulator (AIRE) gene. In some APS-1 patients, significant pulmonary disease is observed. Autoantibodies directed against the potassium channel regulatory protein (KCNRG), found in epithelial cells of terminal bronchioles, have been suggested as a marker for pulmonary disease in APS-1 patients. We report two patients with APS-1; one with and one without lung disease. Patient 1 had multiple admissions for pneumonia and respiratory insufficiency, required non-invasive ventilation, and had findings of bronchiectasis on thoracic imaging and significant lymphocytic infiltrates of the airways on lung biopsy. To verify the autoimmune cause of pulmonary symptoms APS-1 patients, both were tested in a blinded manner for the presence of autoantibodies to KCNRG in serum. We found that only Patient 1 had autoantibodies present. Additionally, Patient 1 had progressive disease despite treatment with several immunomodulating agents, including corticosteroids, azathioprine, and mycophenolate. Patient 1 had a lung biopsy performed which was consistent with B cell lymphocytic aggregates. Rituximab treatment was initiated with apparent good response. This report illustrates the practical use of KCNRG autoantibodies to identify APS-1 patients with pulmonary risk and the successful use of the monoclonal antibody, Rituximab, to treat pulmonary disease in APS-1 patients.

Use of flexible bronchoscopy in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support.

INTRODUCTION: Critically ill children treated with extracorporeal membrane oxygenation (ECMO) support frequently have respiratory complications amenable to evaluation by flexible bronchoscopy (FB). The safety and efficacy of FB in this setting has not been well described in children. METHODS: Retrospective analysis of 153 FBs in 79 children treated with ECMO at a single institution from 2000 to 2008. Demographic data, clinical findings, and complications were obtained. Chest radiographs reports were evaluated prior to and following FB. Physiologic variables were compared prior to and following FB. RESULTS: Seventy-nine patients underwent FB on ECMO [58 veno-venous (VV) and 21 veno-arterial (VA) ECMO], with 153 total FBs performed. Indications for FB included clearance of tenacious airway secretions (n = 118, 77%), or evaluation of suspected secondary infections with bronchoalveolar lavage (n = 26, 17%). Two patients also had surfactant instillation following secretion removal. FB was performed a median 5 days following cannulation for ECMO (range 2-14 days). Most common findings included thick secretions (n = 77, 50.3%), mucoid secretions (n = 15, 9.8%), and mucopurulent secretions (n = 28, 18.3%). No deterioration in radiographic lung findings was described post-FB. FB was not associated with any significant change in heart rate, systemic blood pressure, or temperature. No significant changes in ECMO pump flow rate or sweep gas flow was seen during or after FB. Cannula dislodgement, inadvertent extubation, fever, pneumothorax, or intraprocedural hypoxemia was not reported. Fifty-three FBs (35%) resulted in blood-tinged secretions from the endotracheal tube post-FB, which resolved spontaneously. Three patients received high frequency oscillatory ventilation (HFOV) following FB in association with mild hemorrhage. CONCLUSIONS: FB is a well-tolerated and safe procedure in critically ill pediatric patients on ECMO. FB may have a diagnostic as well as therapeutic benefit in such patients.