Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

Long COVID incidence in adults and children between 2020 and 2023: a real-world data study from the RECOVER Initiative.

Estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) incidence, also known as Long COVID, have varied across studies and changed over time. We estimated PASC incidence among adult and pediatric populations in three nationwide research networks of electronic health records (EHR) participating in the RECOVER Initiative using different classification algorithms (computable phenotypes). Overall, 7% of children and 8.5%-26.4% of adults developed PASC, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 4% in children and ranged from 4-7% among adults, representing a lower-bound incidence estimation based on two control groups - contemporary COVID-19 negative and historical patients (2019). Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants. Our findings indicate that preventing and mitigating Long COVID remains a public health priority. Examining temporal patterns and risk factors of PASC incidence informs our understanding of etiology and can improve prevention and management.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Acute chest syndrome, airway inflammation and lung function in sickle cell disease.

BACKGROUND: Acute chest syndrome (ACS) is an acute complication in SCD but its effects on lung function are not well understood. Inflammation is a key component of SCD pathophysiology but with an unclear association with lung function. We hypothesized that children with ACS had worse lung function than children without ACS and aimed to investigate the association of lung function deficits with inflammatory cytokines. METHODS: Patients enrolled in a previous 2-year randomized clinical trial who had consented to future data use, were enrolled for the present exploratory study. Patients were categorized into ACS and non-ACS groups. Demographic and clinical information were collected. Serum samples were used for quantification of serum cytokines and leukotriene B4 levels and pulmonary function tests (PFTs) were assessed. RESULTS: Children with ACS had lower total lung capacity (TLC) at baseline and at 2 years, with a significant decline in forced expiratory volume in 1 sec (FEV1) and mid-maximal expiratory flow rate (FEF25-75%) in the 2 year period (p = 0.015 and p = 0.039 respectively). For children with ACS, serum cytokines IL-5, and IL-13 were higher at baseline and at 2 years compared to children with no ACS. IP-10 and IL-6 were negatively correlated with PFT markers. In multivariable regression using generalized estimating equation approach for factors predicting lung function, age was significantly associated FEV1 (p = 0.047) and ratio of FEV1 and forced vital capacity (FVC)- FEV1/FVC ratio (p = 0.006); males had lower FEV1/FVC (p = 0.035) and higher TLC (p = 0.031). Asthma status was associated with FEV1 (p = 0.017) and FVC (p = 0.022); history of ACS was significantly associated with TLC (p = 0.027). CONCLUSION: Pulmonary function abnormalities were more common and inflammatory markers were elevated in patients with ACS, compared with those without ACS. These findings suggest airway inflammation is present in children with SCD and ACS, which could be contributing to impaired pulmonary function.

Long-term outcomes of congenital diaphragmatic hernia: A single institution experience.

BACKGROUND/PURPOSE: As survival rates for patients with congenital diaphragmatic hernia (CDH) increase, long-term sequelae become increasingly prevalent. We present the outcomes of patients who underwent CDH repair at our institution and discuss standardization of follow-up care in our long-term multidisciplinary follow-up clinic. METHODS: A retrospective review of patients followed in multidisciplinary clinic after CDH repair at our institution from January 1, 2005 to December 1, 2020. RESULTS: A total of 193 patients met inclusion criteria, 73 females (37.8%) and 120 males (62.2%). Left-sided defects were most common (75.7%), followed by right-sided defects (20.7%). Median age at repair was 4 days (IQR 3-6) and 59.6% of all defects required patch repair. Median length of stay was 29 days (IQR 16.8-50.0). Median length of follow up was 49 months (IQR 17.8-95.3) with 25 patients followed for more than 12 years. Long-term outcomes included gastroesophageal reflux disease (42.0%), diaphragmatic hernia recurrence (10.9%), asthma (23.6%), neurodevelopmental delay (28.6%), attention deficit hyperactivity disorder (7.3%), autism (1.6%), chest wall deformity (15.5%), scoliosis (11.4%), and inguinal hernia (6.7%). CONCLUSION: As survival of patients with CDH improves, long-term care must be continuously studied and fine-tuned to ensure appropriate surveillance and optimization of long-term outcomes.

Cheyne-Stokes Respiration in a 17-Year-Old Boy Awaiting Heart Transplantation.

Cheyne-Stokes respiration is a pattern of alternating central apnea and hyperpnea. It is well described in adults with congestive heart failure, but not in children. We report the case of a 17-year-old boy whose systolic heart failure was complicated by Cheyne-Stokes respiration. He was given supportive therapy until heart transplant, after which his Cheyne-Stokes respiration clinically resolved. Clinicians should be aware of this uncommon condition in pediatric and adolescent patients who have advanced heart failure and irregular breathing.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Trajectories of adiposity indicators and association with asthma and lung function in urban minority children.

BACKGROUND: A relationship between adiposity and asthma has been described in some cohort studies, but little is known about trajectories of adiposity throughout early childhood among children at high risk for developing asthma in urban United States cities. Moreover, early life trajectories of adipokines that have metabolic and immunologic properties have not been comprehensively investigated. OBJECTIVE: Our objective was to characterize trajectories of adiposity in a longitudinal birth cohort of predominately Black and Latinx children (n = 418) using several different repeated measures including body mass index (BMI) z score, bioimpedance analysis, leptin, and adiponectin in the first 10 years of life. METHODS: In a longitudinal birth cohort of predominately Black and Latinx children, we used repeated annual measures of BMI, bioimpedance analysis (ie, percentage of body fat), leptin, and adiponectin to create trajectories across the first 10 years of life. Across those trajectories, we compared asthma diagnosis and multiple lung function outcomes, including spirometry, impulse oscillometry, and methacholine response. RESULTS: Three trajectories were observed for BMI z score, bioimpedance analysis, and leptin and 2 for adiponectin. There was no association between trajectories of BMI, percentage of body fat, leptin, or adipokine and asthma diagnosis or lung function (P > .05). CONCLUSIONS: Trajectories of adiposity were not associated with asthma or lung function in children at high risk for developing asthma. Risk factors related to geography as well as social and demographic factors unique to specific populations could explain the lack of association and should be considered in obesity and asthma studies.

Validation of a Questionnaire to Identify Respiratory Tract Infections in Children With Sickle Cell Disease.

BACKGROUND: No validated questionnaires have been published that are specific for identifying respiratory infections in children with sickle cell disease (SCD). METHODS: A questionnaire was developed that included 6 respiratory symptoms (difficulty breathing, wheezing, fever, cough, runny or stuffy nose, and sore throat) to identify respiratory events for a clinical trial. The questionnaire results were compared with identification of viral respiratory pathogens from nasal samples by reverse transcriptase polymerase chain reaction. RESULTS: Eighty questionnaire responses (40 with symptom/s and 40 without) paired with isolation of viral respiratory pathogen from nasal samples were obtained from 53 children with SCD, ages 4 to 18 years over 2 separate periods in different seasons. The questionnaire yielded a sensitivity of 82%, specificity of 72% with an overall accuracy of 76%. The kappa value was 0.53, indicating moderate agreement, and the Fleiss' kappa test statistic was 4.77 with P<0.001, indicating that agreement between the 2 methods was not by chance. CONCLUSION: These results provide evidence for validity of this 6-symptom respiratory questionnaire in identification of respiratory viral infections for use in SCD-related research.

Atopy and pulmonary function among healthy-weight and overweight/obese children with asthma.

INTRODUCTION: Epidemiologic studies have found low/absence of atopy in obese asthmatic children, but the association or lack thereof of atopy with disease morbidity, including pulmonary function, in obese asthma is not well understood. We sought to define the association of atopy with pulmonary function in overweight/obese minority children with asthma. METHODS: In a retrospective chart review of 200 predominantly minority children evaluated at an academic Pediatric Asthma Center over 5 years, we compared the prevalence of atopy, defined as ≥ 1 positive skin prick test or serum-specific immunoglobulin E quantification to environmental allergens, and its association with pulmonary function in overweight/obese (body mass index [BMI] > 85th percentile) (n = 99) to healthy-weight children (BMI, 5th-85th percentile for age) (n = 101). RESULTS: In a cohort comprised of 47.5% Hispanics and 39.5% African Americans, 81% of overweight/obese and 74% of healthy-weight children were atopic. While atopic healthy-weight children had lower percent-predicted forced expiratory volume in the first second (FEV1 ) (93 ± 13.6 vs 107% ± 33.2%, P = .03) and lower percent-predicted forced vital capacity (FVC) (93% ± 12.2% vs 104% ± 16.1%, P = .01) as compared to nonatopic children, atopy was not associated with FEV1 (P = .7) or FVC (P = .17) in overweight/obese children. Adjusting for demographic and clinical variables, atopy was found to be an independent predictor of FEV1 and FVC in healthy-weight (ß = -2.4, P = .07 and ß = -1.7, P = .04, respectively) but not in overweight/obese children (ß = .6, P = .5 and ß = .8, P = .3). CONCLUSIONS: Atopy is associated with lower lung function in healthy-weight asthmatics but not in overweight/obese asthmatics, supporting the role of nonallergic mechanisms in disease burden in pediatric obesity-related asthma.

Asthma among hospitalized patients with COVID-19 and related outcomes.

BACKGROUND: Several underlying conditions have been associated with severe acute respiratory syndrome coronavirus 2 illness, but it remains unclear whether underlying asthma is associated with worse coronavirus disease 2019 (COVID-19) outcomes. OBJECTIVE: Given the high prevalence of asthma in the New York City area, our objective was to determine whether underlying asthma was associated with poor outcomes among hospitalized patients with severe COVID-19 compared with patients without asthma. METHODS: Electronic heath records were reviewed for 1298 sequential patients 65 years or younger without chronic obstructive pulmonary disease who were admitted to our hospital system with a confirmed positive severe acute respiratory syndrome coronavirus 2 test result. RESULTS: The overall prevalence of asthma among all hospitalized patients with COVID-19 was 12.6%, yet a higher prevalence (23.6%) was observed in the subset of 55 patients younger than 21 years. There was no significant difference in hospital length of stay, need for intubation, length of intubation, tracheostomy tube placement, hospital readmission, or mortality between patients with and without asthma. Observations between patients with and without asthma were similar when stratified by obesity, other comorbid conditions (ie, hypertension, hyperlipidemia, and diabetes), use of controller asthma medication, and absolute eosinophil count. CONCLUSIONS: Among hospitalized patients 65 years or younger with severe COVID-19, asthma diagnosis was not associated with worse outcomes, regardless of age, obesity, or other high-risk comorbidities. Future population-based studies are needed to investigate the risk of developing COVID-19 among patients with asthma once universal testing becomes readily available.

Pulmonary disease burden in Hispanic and non-Hispanic children with sickle cell disease.

RATIONALE: Pulmonary complications are the leading cause of morbidity and mortality in sickle cell disease (SCD) patients. Research in SCD has predominantly been conducted on African-Americans, and the disease burden of SCD in other races and ethnicities, including Hispanic patients, is not well characterized. OBJECTIVE: To compare pulmonary disease burden between Hispanic and non-Hispanic ethnic groups among children with SCD. METHODS: In a retrospective chart review on 566 SCD patients followed at the Children's Hospital at Montefiore, NY, we compared the pulmonary disease burden and disease management in Hispanic patients to their non-Hispanic counterparts. We also compared the contribution of demographic and clinical variables to acute chest syndrome (ACS), vaso-occlusive crisis (VOC), and hospitalizations for SCD related complications between the two ethnic groups. RESULTS: Hispanic patients had a greater proportion of ACS, and had lower forced expiratory volume (FEV1), forced vital capacity, and vital capacity, compared to non-Hispanics. Hispanic patients were more likely to be evaluated in pulmonary clinic and to be on inhaled corticosteroids, short-acting ß agonizts, and leukotriene receptor antagonists. In addition, Hispanic children were more likely to be on hydroxyurea, and receive exchange transfusions. However, the association of asthma with the proportion of ACS did not differ between Hispanics and non-Hispanics. CONCLUSION: Hispanic children with SCD had differences in their pulmonary function profile and received more pulmonary evaluations than non-Hispanic children.

Emergent high fatality lung disease in systemic juvenile arthritis.

OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

Airway Inflammation and Lung Function in Sickle Cell Disease.

Rationale: Asthma is a common comorbid condition in sickle cell disease (SCD). However, obstructive lung disease is prevalent in SCD, independent of a diagnosis of asthma. It is speculated that the heightened state of inflammation in SCD, involving pathways distinct from allergic asthma, may underlie the SCD-specific obstructive disease. Objective: The objective of the study was to compare airway and systemic inflammatory markers between SCD patients with pulmonary manifestations and patients with allergic asthma, and correlate the discriminating inflammatory markers with clinical measures of pulmonary disease. Materials and Methods: In a pilot translational study conducted at the Children's Hospital at Montefiore, 15 patients with SCD, and history of asthma, airway obstruction, or airway hyper-reactivity, and 15 control patients with allergic asthma 6-21 years of age were recruited. Inflammatory markers, including peripheral blood T helper cell subsets, serum and exhaled breath condensate (EBC) cytokines and chemokines of the Th-1/Th-17, Th-2, and monocytic pathways, and serum cysteinyl leukotrienes B4 (LTB4), were quantified, compared between the study groups, and correlated with atopic sensitization, pulmonary function tests, and markers of hemolysis. Results: White blood cells (P < 0.05) and monocytes (P < 0.001) were elevated in the SCD group, while atopic characteristics were higher in the control asthma group. Tumor necrosis factor-alpha (P < 0.01), interferon gamma inducible protein (IP)-10 (P < 0.05), and interleukin-4 (P < 0.01) in serum and monocyte chemotactic protein (MCP)-1 in EBC were higher in the SCD group (P ≤ 0.05). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) in patients with SCD inversely correlated with serum IP-10 and LTB4 levels. Conclusions: Compared with atopic asthmatic patients, inflammatory markers involving Th-1, Th-2, and monocytic pathways were higher in the SCD group, among which Th-1 measures correlated with pulmonary function deficits.

Association of pediatric obesity and asthma, pulmonary physiology, metabolic dysregulation, and atopy; and the role of weight management.

Introduction: Obesity affects about 40% of US adults and 18% of children. Its impact on the pulmonary system is best described for asthma. Areas covered: We reviewed the literature on PubMed and Google Scholar databases and summarize the effect of obesity, its associated metabolic dysregulation and altered systemic immune responses, and that of weight gain and loss on pulmonary mechanics, asthma inception, and disease burden. We include a distinct approach for diagnosing and managing the disease, including pulmonary function deficits inherent to obesity-related asthma, in light of its poor response to current asthma medications. Expert opinion: Given the projected increase in obesity, obesity-related asthma needs to be addressed now. Research on the contribution of metabolic abnormalities and systemic immune responses, intricately linked with truncal adiposity, and that of lack of atopy, to asthma disease burden, and pulmonary function deficits among obese children is fairly consistent. Since current asthma medications are more effective for atopic asthma, investigation for atopy will guide management by distinguishing asthma responsive to current medications from the non-responsive disease. Future research is needed to elucidate mechanisms by which obesity-mediated metabolic abnormalities and immune responses cause medication non-responsive asthma, which will inform repurposing of medications and drug discovery.

A physicians survey assessing management of pulmonary airway involvement in sickle cell disease.

BACKGROUND: Airway involvement in patients with sickle cell disease (SCD) involves recurrent episodes of acute chest syndrome (ACS), co-existent asthma, lower airway obstruction (LAO), or airway hyper-responsiveness/ bronchodilator response (AHR/BDR). With increased recognition that sickle cell (SC) airway inflammation may be distinct from asthma, our aim was to study regional and individual practices among pediatric pulmonologists and elucidate the patient characteristics that determine the diagnosis of asthma or SC airway inflammation. METHODS: A cross-sectional web-based survey including 6 case scenarios on diagnosis and management of pulmonary manifestations of pediatric SC airway disease was conducted. The case scenarios, combined different risk factors for airway inflammation: history of recurrent ACS, atopy, family history of asthma, LAO, or AHR/BDR, with possible responses including - diagnosis of asthma, SC airway inflammation, both or neither. RESULTS: Of the 130 responses, 83 were complete. "Asthma" was diagnosed when LAO (OR, 7.96 [4.28, 14.79]; p < 0.001), family history of asthma (OR 18.88 [5.87, 60.7]; p < 0.001), and atopy (OR 3.19 [1.74, 5.8]; p < 0.001) were present. "SC airway inflammation" was diagnosed when ACS (OR 3.95 [2.08, 7.51]; p < 0.001), and restrictive pattern on PFT (OR 3.75 [2.3, 6.09]; p < 0.001) were present in the scenarios. Regardless of the diagnosis, there was a high likelihood of initiating or stepping up inhaled corticosteroid as compared to prescribing montelukast. CONCLUSION: There is variability in the diagnosis and management of SC airway inflammation among pediatric pulmonologists. This study highlights the need for consensus guidelines to improve management of SC airway inflammation.

A Retrospective Review of Infants Receiving Sildenafil.

OBJECTIVE: The purpose of the study was to assess mortality in an infant population receiving sildenafil. METHODS: A retrospective review of hospitalized infants at Children's Hospital Los Angeles who received sildenafil between 2008 and 2012 was conducted. Patient characteristics, comorbidities, and treatment characteristics were analyzed. Primary outcome was mortality at discharge. Sildenafil dosage ranges were based on the Sildenafil in Treatment-Naïve Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension trial and were categorized as small (<1.5 mg/kg/day), medium (1.5-3.75 mg/kg/day), large (3.76-7.5 mg/kg/day), and very large (>7.5 mg/kg/day). RESULTS: A total of 147 infants were studied. A total of 82% of patients had severe pulmonary hypertension. Our data revealed 29% mortality at discharge. Mortality increased with increasing sildenafil dosage: 14% (small), 19% (medium), 49% (large), and 90% (very large). On multivariate analysis of sildenafil dosage, other pulmonary hypertension therapies, presence of persistent cardiac shunts, and duration of sildenafil, odds of dying were significantly higher with combined high and very high sildenafil dosage groups compared with combined low and medium dosage groups (OR, 13.2; CI, 4.4-39.5; p < 0.0001). CONCLUSION: Sildenafil was given to critically ill infants with multiple risk factors for mortality. Although higher doses cannot be causally related to mortality, there appears to be no added benefit by escalating the sildenafil dose.

Secondary Hypogammaglobulinemia After Rituximab for Neuromyelitis Optica: A Case Report.

A 17-year-old male with history of neuromyelitis optica and seizures presented to the pulmonology clinic for evaluation of recurrent pneumonias. He had received rituximab for the past 6 years. Over the past 2 years, he experienced four episodes of pneumonia. In between these episodes, he would improve briefly but continued to have daily cough that was productive with yellow phlegm. He also had recurrent rhinitis and sinusitis despite multiple antibiotic courses. Review of chest X-rays revealed localized right middle lobe and right lower lobe infiltrates. An extensive workup was performed, including computed tomography (CT) of the chest and bronchoscopy to rule out congenital lesions of the right lung and foreign body aspiration. Chest CT showed right lower lobe bronchiectasis. Flexible bronchoscopy with bronchoalveolar lavage showed normal anatomy with thick mucus secretions in the right lower lobe. Immunologic evaluation was performed and revealed low levels of immunoglobulin (Ig)-G, IgM, and IgA, which had declined since initiation of rituximab. Lymphocyte subset testing was remarkable for low cluster of differentiation (CD)-19. He was referred to allergy and immunology and was initiated on immunoglobulin-replacement therapy (IGRT) for acquired hypogammaglobulinemia secondary to rituximab. There was marked clinical improvement after initiation of IGRT.

Airway inflammation in sickle cell disease-A translational perspective.

Asthma and sickle cell disease (SCD) are common chronic conditions in children of African ancestry that are characterized by cough, wheeze, and obstructive patterns on pulmonary function. Pulmonary function testing in children with SCD has estimated a prevalence of obstructive lung disease ranging from 13% to 57%, and airway hyper-responsiveness of up to 77%, independent of a diagnosis of asthma. Asthma co-existing with SCD is associated with increased risk of acute chest syndrome (ACS), respiratory symptoms, pain episodes, and death. However, there are inherent differences in the pathophysiology of SCD and asthma. While classic allergic asthma in the general population is associated with a T-helper 2 cell (Th-2 cells) pattern of cell inflammation, increased IgE levels and often positive allergy testing, inflammation in SCD is associated with different inflammatory pathways, involving neutrophilic and monocytic pathways, which have been explored to a limited extent in mouse models and with a dearth of human studies. The current review summarizes the existent literature on sickle cell related airway inflammation and its cross roads with allergic asthma-related inflammation, and discusses the importance of further elucidating and understanding these common and divergent inflammatory pathways in human studies to facilitate development of targeted therapy for children with SCD and pulmonary morbidity.