Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

INTRODUCTION: Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. METHODS: Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. RESULTS: There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. CONCLUSION: This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

A Comparison of State-Specific Pediatric Emergency Medical Facility Recognition Programs, 2020.

OBJECTIVES: Prior research suggests that the presence of state-specific pediatric emergency medical facility recognition programs (PFRPs) is associated with high emergency department (ED) pediatric readiness. The PFRPs aim to improve the quality of pediatric emergency care, but individual state programs differ. We aimed to describe the variation in PFRP characteristics and verification requirements and to describe the availability of pediatric emergency care coordinators (PECCs) in states with PFRPs. METHODS: In mid-2020, we collected information about each PFRP from 3 sources: the state Emergency Medical Services for Children (EMSC) website, the EMSC Innovation and Improvement Center website, or via communication with the state's EMSC program manager. For each state with a PFRP, we documented program characteristics, including program start date, number of tiers, whether participation was required/optional, and requirements for verification. RESULTS: Overall, we identified 17 states with active PFRPs. Five states had only 1 tier or level of recognition whereas the others had multiple. All programs did require presence of a PECC for verification. However, some PRFPs with multiple verification tiers did not require presence of a PECC to achieve each level of verification. In states with PFRPs, EDs with higher total visit volumes, a separate pediatric ED area, located in the Northeast, and earlier program start date were all more likely to have a PECC. CONCLUSIONS: There is variation in state PFRPs, although all prioritize the presence of a PECC. We encourage further research on the effect of different aspects of PFRPs on patient outcomes.

Emergency Department and Health Care System Factors Associated with Telehealth Innovation During the COVID-19 Pandemic.

Objective: Telehealth capacity may be an important component of pandemic response infrastructure. We aimed to examine changes in the telehealth use by the US emergency departments (EDs) during COVID-19, and to determine whether existing telehealth infrastructure or increased system integration were associated with increased likelihood of use. Methods: We analyzed 2016-2020 National ED Inventory (NEDI)-USA data, including ED characteristics and nature of telehealth use for all US EDs. American Hospital Association data characterized EDs' system integration. An ordinary least-squares regression model obtained one-step-ahead forecast of the expected proportion of EDs using telehealth in 2020 based on growth observed from 2016 to 2019. Among EDs without telehealth in 2019, we used logistic regression models to examine whether system membership or existing telehealth infrastructure were associated with odds of innovation in telehealth use in 2020, accounting for ED characteristics. Results: Of 4,038 EDs responding to telehealth questions in 2019 and 2020 (73% response rate), 3,015 used telehealth in 2020. Telehealth use by US EDs increased more than expected in 2020 (2016: 58%, 2017: 61%, 2018: 65%, 2019: 67%, 2020: 74%, greater than predicted 71%, p = 0.004). Existing telehealth infrastructure was associated with increased telehealth innovation (OR = 1.88, 95% CI: 1.49-2.36), whereas hospital system membership was not (odds ratio [OR] = 1.00, 95% confidence interval [CI]: 0.80-1.25). Conclusions: Telehealth use by US EDs in 2020 grew more than expected and preexisting telehealth infrastructure was associated with increased innovation in its use. Preparation for future pandemic responses may benefit from considering strategies to invest in local infrastructure to facilitate technology adoption and innovation.

Association between household cleaning product exposure in infancy and development of recurrent wheeze and asthma.

OBJECTIVE: Household chemicals may act as irritants in the lungs; however, their association with recurrent wheeze and asthma in children remains controversial. We aimed to investigate if household cleaning product exposure in infancy is associated with recurrent wheezing and asthma development in children. METHODS: We analyzed data from two cohorts: MARC-35 consisting of 815 children with history of severe bronchiolitis in infancy, and MARC-43 consisting of 525 healthy children in infancy. Frequency of use of cleaning product at the child's home during infancy was collected via telephone interview with parents. Outcomes were recurrent wheezing by age 3 years and asthma diagnosis at age 6 years. RESULTS: In MARC-35, there was no association between cleaning product exposure in infancy and recurrent wheeze (adjusted HR = 1.01 [95% CI 0.66-1.54] for 4-7 days/week exposure frequency), nor asthma (adjusted OR = 0.91 [95% CI 0.51-1.63]). In MARC-43, there was also no association between cleaning product exposure in infancy and recurrent wheeze (adjusted HR = 0.69 [95% CI 0.29-1.67] for 4-7 days/week exposure frequency). CONCLUSION: We found no association between household cleaning product exposure in infancy and later development of recurrent wheeze or asthma, even among children who are at high risk for asthma due to history of severe bronchiolitis.

Recurrent wheezing phenotypes after severe bronchiolitis and progression to asthma.

Background: Recurrent wheezing, a common diagnosis after severe bronchiolitis, has multiple phenotypes of uncertain relation to childhood asthma. Objective: Among infants hospitalized for bronchiolitis, we investigated the relation of three 2020 recurrent wheezing phenotypes by age 4 years to asthma by age 6 years. Methods: In a 17-center cohort study of infants hospitalized with bronchiolitis, we investigated the National Heart, Lung, and Blood Institute (NHLBI) 2020-defined recurrent wheezing phenotype and 2 additional phenotypes based on this definition: multitrigger and severe. As a sensitivity analysis, we examined the NHLBI 2007 recurrent wheezing phenotype. We calculated the proportion of study subjects who developed asthma by age 6 years and used multivariable logistic regression to examine characteristics associated with the highest-risk 2020 phenotype. Results: Of 921 infants, 632 (69%) developed NHLBI 2020 recurrent wheezing, 734 (80%) developed multitrigger wheezing, and 165 (18%) developed severe wheezing by age 4 years; in addition, 296 (32%) developed NHLBI 2007-defined recurrent wheezing by age 3 years. Of 862 children with sufficient data (94%), 239 (28%) developed asthma by age 6 years. The proportions of children who progressed to asthma were as follows: 33% of those with NHLBI 2020-defined wheezing, 33% of those with multitrigger wheezing, 54% of those with severe wheezing, and 52% of those with NHLBI 2007-defined recurrent wheezing. The children with the severe phenotype who developed asthma had the associated characteristics preterm birth, child eczema, maternal asthma, and non-respiratory syncytial virus infection. Conclusion: Most infants with severe bronchiolitis developed the NHLBI 2020-defined recurrent wheezing phenotype by age 4 years. Depending on the phenotype, 33% to 54% will develop asthma by age 6 years. Future research will examine whether earlier treatment of high-risk phenotypes will improve wheezing symptoms and potentially prevent childhood asthma. (J Allergy Clin Immunol Global 2023;2:84-7.).

Availability of Pediatric Emergency Care Coordinators in US Emergency Departments in 2018.

OBJECTIVES: In 2007, the US Institute of Medicine recommended that every emergency department (ED) appoint pediatric emergency care coordinators (PECCs). Despite this recommendation, our national surveys showed that few (17%) US EDs reported at least 1 PECC in 2015. This number increased slightly to 19% in 2016 and 20% in 2017. The current study objectives were to determine the following: percent of US EDs with at least 1 PECC in 2018, factors associated with availability of at least 1 PECC in 2018, and factors associated with addition of at least 1 PECC between 2015 and 2018. METHODS: In 2019, we conducted a survey of all US EDs to characterize emergency care in 2018. Using the National ED Inventory-USA database, we identified 5514 EDs open in 2018. This survey collected availability of at least 1 PECC in 2018. A similar survey was administered in 2016 and identified availability of at least 1 PECC in 2015. RESULTS: Overall, 4781 (87%) EDs responded to the 2018 survey. Among 4764 EDs with PECC data, 1037 (22%) reported having at least 1 PECC. Three states (Connecticut, Massachusetts, and Rhode Island) had PECCs in 100% of EDs. The EDs in the Northeast and with higher visit volumes were more likely to have at least 1 PECC in 2018 (all P < 0.001). Similarly, EDs in the Northeast and with higher visit volumes were more likely to add a PECC between 2015 and 2018 (all P < 0.05). CONCLUSIONS: The availability of PECCs in EDs remains low (22%), with a small increase in national prevalence between 2015 and 2018. Northeast states report a high PECC prevalence, but more work is needed to appoint PECCs in all other regions.

Impact of Airway Virus in Severe Asthmatic Patients: A Pilot Study.

The lungs have their own microbiota which seems to be altered in disease processes such as asthma. Viral infection accounts for many asthma exacerbations. Little is known about the lung virome, and the role that viruses play in non-exacerbating asthmatics. We aimed to assess if detection of virus in bronchoscopy samples of asthmatic patients in a non-exacerbating state influences their asthma control and modulates airway cytokine composition. Patients were recruited from a specialist asthma clinic and underwent bronchoscopy with standardised bronchoalveolar lavage (BAL). Viral analysis was performed; cell differential and cytokine levels were measured. Forty-six samples were obtained of which 10.8% demonstrated evidence of airway virus, and 91.3% of patients in the cohort were classed as severe asthmatics. Oral steroid use was significantly higher in severe asthmatic patients with virus detected, and the forced expiratory volume in one second tended to be lower in the virus-detected group. It was also found that BAL interleukin-13 and tumor necrosis factor-α levels were significantly higher in severe asthmatic patients with virus detected. Our results suggest that in severe asthmatics in a non-exacerbating state, the presence of virus resulted in overall poorer asthma control. The pattern of cytokine elevation seen in asthmatic patients with virus detected may provide insight to the pathophysiology involved.

Case-control study of exclusive breast feeding and severe bronchiolitis in the United States.

BACKGROUND: Bronchiolitis is a major cause of infant illness, with few known modifiable risk factors. Breast feeding may reduce risk of severe bronchiolitis, but the association of exclusive vs. partial breast feeding with severe bronchiolitis is unclear. OBJECTIVE: To estimate the association of exclusive vs. partial breast feeding during ages 0-2.9 months with bronchiolitis hospitalisation during infancy. METHODS: We conducted a case-control study as a secondary analysis of two prospective US cohorts in the Multicenter Airway Research Collaboration. Cases were enrolled in a 17-centre study of infants hospitalised for bronchiolitis during 2011-2014 (n = 921). Controls were enrolled in a five-centre study of healthy infants during 2013-2014 and 2017 (n = 719). Breast feeding history during ages 0-2.9 months was collected by parent interview. Among breastfed infants, the association of exclusive vs. partial breast feeding with odds of bronchiolitis hospitalisation was estimated using a multivariable logistic regression model adjusted for demographic variables, parental asthma history, and early-life exposures. As a secondary analysis, we estimated the associations of exclusive, predominant, and occasional breast feeding vs. no breast feeding with the odds of bronchiolitis hospitalisation. RESULTS: Among 1640 infants, the prevalence of exclusive breast feeding was 187/921 (20.3%) among cases and 275/719 (38.3%) among controls. Exclusive vs. partial breast feeding was associated with 48% reduced odds of bronchiolitis hospitalisation (adjusted odds ratio [OR] 0.52, 95% confidence interval [CI] 0.39, 0.69). In the secondary analysis, exclusive vs. no breast feeding was associated with 58% reduced odds of bronchiolitis hospitalisation (OR 0.42, 95% CI 0.23, 0.77), whereas predominant breast feeding (OR 0.77, 95% CI 0.37, 1.57) and occasional breast feeding (OR 0.98, 95% CI 0.57, 1.69) were not associated with meaningfully reduced odds of bronchiolitis hospitalisation. CONCLUSION: Exclusive breast feeding had a strong protective association against bronchiolitis hospitalisation.

An E1-E2 fusion protein primes antiviral immune signalling in bacteria.

In all organisms, innate immune pathways sense infection and rapidly activate potent immune responses while avoiding inappropriate activation (autoimmunity). In humans, the innate immune receptor cyclic GMP-AMP synthase (cGAS) detects viral infection to produce the nucleotide second messenger cyclic GMP-AMP (cGAMP), which initiates stimulator of interferon genes (STING)-dependent antiviral signalling1. Bacteria encode evolutionary predecessors of cGAS called cGAS/DncV-like nucleotidyltransferases2 (CD-NTases), which detect bacteriophage infection and produce diverse nucleotide second messengers3. How bacterial CD-NTase activation is controlled remains unknown. Here we show that CD-NTase-associated protein 2 (Cap2) primes bacterial CD-NTases for activation through a ubiquitin transferase-like mechanism. A cryo-electron microscopy structure of the Cap2-CD-NTase complex reveals Cap2 as an all-in-one ubiquitin transferase-like protein, with distinct domains resembling eukaryotic E1 and E2 proteins. The structure captures a reactive-intermediate state with the CD-NTase C terminus positioned in the Cap2 E1 active site and conjugated to AMP. Cap2 conjugates the CD-NTase C terminus to a target molecule that primes the CD-NTase for increased cGAMP production. We further demonstrate that a specific endopeptidase, Cap3, balances Cap2 activity by cleaving CD-NTase-target conjugates. Our data demonstrate that bacteria control immune signalling using an ancient, minimized ubiquitin transferase-like system and provide insight into the evolution of the E1 and E2 machinery across domains of life.

Parental Mental Health and Childhood Respiratory Outcomes in a Severe Bronchiolitis Cohort.

Parental mental health conditions appear to contribute to the development of childhood respiratory illness. We investigated the relationship between parental mental health and childhood respiratory illness using data from a 17-center prospective cohort study of infants hospitalized with bronchiolitis between 2011 and 2014 (n = 921). Among 779 (84.6%) participants with self-reported parental mental health history data, 184 (23.6%) had parental history of depression and 155 (19.9%) had anxiety. Multivariable analyses found that both parental history of depression (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.01-1.99) and anxiety (HR 1.28, 95% CI 1.08-1.52) were associated with an increased risk of recurrent wheezing by age 3 years. However, only parental history of anxiety was associated with asthma by age 5 years (odds ratio 1.79, 95% CI 1.25-2.55). Further research on exposure severity, other early life stressors, and effective methods of parental psychosocial support is needed to develop targeted risk factor prevention strategies to reduce the burden of childhood respiratory illness.

Pediatric Telehealth Use in U.S. Emergency Departments in 2019.

Objectives: Little is known about the recent usage of pediatric telehealth across all emergency departments (EDs) in the United States. Building upon our prior work, we aimed to characterize the usage of ED pediatric telehealth in the pre-COVID-19 era. Methods: The 2019 National ED Inventory-USA survey characterized all U.S. EDs open in 2019. Among EDs reporting receipt of pediatric telehealth services, we selected a random sample (n = 130) for a second survey on pediatric telehealth usage (2019 ED Pediatric Telehealth Survey). We also recontacted a random sample of EDs that responded to a prior, similar 2017 ED Pediatric Telehealth Survey (n = 107), for a total of 237 EDs in the 2019 ED Pediatric Telehealth Survey sample. Results: Overall, 193 (81%) of the 237 EDs responded to the 2019 Pediatric Telehealth Survey. There were 149 responding EDs that confirmed pediatric telehealth receipt in 2019. Among these, few reported ever having a pediatric emergency medicine (PEM) physician (10%) or pediatrician (9%) available for emergency care. Although 96% of EDs reported availability of pediatric telehealth services 24 h per day, 7 days per week, the majority (60%) reported using services less than once per month and 20% reported using services every 3-4 weeks. EDs most frequently used pediatric telehealth to assist with placement and transfer coordination (91%). Conclusions: Most EDs receiving pediatric telehealth in 2019 had no PEM physician or pediatrician available. Most EDs used pediatric telehealth services infrequently. Understanding barriers to assimilation of telehealth once adopted may be important to enable improved access to pediatric emergency care expertise.

Development of a unified national trauma center database, 2018.

OBJECTIVE: Trauma center certifications across the United States (U.S.) are not unified. Participation in the national trauma certification program established through the American College of Surgeons (ACS) is not universal, and many states maintain unique trauma certification systems with varying criteria. We investigated degree of similarity between the ACS national trauma certification program and state trauma certifications, then combined these distinct certifications into a unified national trauma center database. METHODS: We performed a cross-sectional study of all non-specialty, non-federal emergency U.S. departments (EDs) open in 2018 to determine availability and levels of trauma centers. We created a "Standard" definition of trauma levels using ACS criteria as a benchmark. ACS similar trauma levels were then assigned to state levels I-III by comparing trauma receiving protocol, maximum response times, and general surgical coverage; through this process, levels across distinct systems established through different criteria were standardized. RESULTS: In 2018, ACS certifications spanned 47 states and DC; 3 states did not participate in ACS (Mississippi, Pennsylvania, and Washington). A distinct, non-ACS state certification system was present in 47 states and DC; 3 states had no ongoing state certification system in 2018 (Maine, Rhode Island, and Vermont). Among 5,514 US EDs open in 2018, we identified 2,132 associated with adult and pediatric trauma centers (39%) holding certification (ACS, state, or both); 1,083 (51%) were certified levels I-III, and the rest (1,049, 49%) were levels IV-V. Of the 1,083 centers with any level I-III certification, 498 (46%) held ACS certification, and 1,059 (98%) held state certification. Applying ACS-similar criteria to centers with state levels I-III (n=1,059) resulted in a level change for 124 centers (12%). Using our "Standard" definition of a trauma level based on ACS criteria, our unified level I-III database included 959 (89%) adult and pediatric centers, with 24 (3%) ACS-certified only, 461 (48%) state-certified only, and 474 (49%) certified by both. CONCLUSIONS: Discrepancies exist between ACS and state trauma certification systems. The differences in level I-III state criteria confirm discrepant standards for a given trauma "level" across the U.S. We combined these certifications into a unified national trauma center database available to researchers and the public.

U.S. Emergency Department Telepsychiatry Use in 2019.

Introduction: Although many emergency departments (EDs) receive telehealth services for psychiatry, or telepsychiatry, to manage acute psychiatric emergencies, national research on the usage of ED telepsychiatry is limited. To investigate ED telepsychiatry usage in the pre-COVID-19 era, we surveyed a sample of EDs receiving telepsychiatry in 2019, as a follow-up to a survey targeted to similar EDs in 2017. Methods: All U.S. EDs open in 2019 (n = 5,563) were surveyed to characterize emergency care. A more in-depth second survey on telepsychiatry use (2019 ED Telepsychiatry Survey) was then sent to 235 EDs. Of these EDs, 130 were randomly selected from those that reported telepsychiatry receipt in 2019, and 105 were selected based on their participation in a similar survey in 2017 (2017 ED Telepsychiatry Survey). Results: Of the 235 EDs receiving the 2019 Telepsychiatry Survey, 192 (82%) responded and 172 (90% of responding EDs) confirmed 2019 telepsychiatry receipt. Of these, five were excluded for missing data (analytic samplen = 167). Telepsychiatry was the only form of emergency psychiatric services for 92 (55%) EDs. The most common usage of telepsychiatry was for admission or discharge decisions (82%) and transfer coordination (70%). The most commonly reported telepsychiatry mental health consultants were psychiatrists or other physician-level mental health professionals (74%). Discussion: With telepsychiatry as the only form of psychiatric services for most telepsychiatry-receiving EDs, this innovation fills a critical gap in access to emergency psychiatric care. Further research is needed to investigate the impact of the COVID-19 pandemic on usage of ED telepsychiatry.

A Geographical Analysis of Access to Trauma Centers from US National Parks in 2018.

INTRODUCTION: Millions of people visit US national parks annually to engage in recreational wilderness activities, which can occasionally result in traumatic injuries that require timely, high-level care. However, no study to date has specifically examined timely access to trauma centers from national parks. This study aimed to examine the accessibility of trauma care from national parks by calculating the travel time by ground and air from each park to its nearest trauma center. Using these calculations, the percentage of parks by census region with timely access to a trauma center was determined. METHODS: This was a cross-sectional study analyzing travel times by ground and air transport between national parks and their closest adult advanced trauma center (ATC) in 2018. A list of parks was compiled from the National Parks Service (NPS) website, and the location of trauma centers from the 2018 National Emergency Department Inventory (NEDI)-USA database. Ground and air transport times were calculated using Google Maps and ArcGIS, with medians and interquartile ranges reported by US census region. Percentage of parks by region with timely trauma center access-defined as access within 60 minutes of travel time-were determined based on these calculated travel times. RESULTS: In 2018, 83% of national parks had access to an adult ATC within 60 minutes of air travel, while only 26% had timely access by ground. Trauma center access varied by region, with median travel times highest in the West for both air and ground transport. At a national level, national parks were unequally distributed, with the West housing the most parks of all regions. CONCLUSION: While most national parks had timely access to a trauma center by air travel, significant gaps in access remain for ground, the extent of which varies greatly by region. To improve the accessibility of trauma center expertise from national parks, the study highlights the potential that increased implementation of trauma telehealth in emergency departments (EDs) may have in bridging these gaps.

Development of a unified national database of primary percutaneous coronary intervention centers with co-located emergency departments, 2020.

BACKGROUND: Although primary percutaneous coronary intervention (pPCI) is the preferred intervention for ST-elevation myocardial infarction (STEMI), not all patients are admitted directly to an emergency department (ED) with 24/7/365 pPCI capabilities. This is partly due to a lack of a national system of known pPCI-capable EDs. Our objective was to create a unified, national database of confirmed 24/7/365 pPCI centers co-located in hospitals with EDs. METHODS: We compiled all hospitals designated as Chest Pain Centers with Primary PCI by the American College of Cardiology's (ACC) National Clinical Data Registry (NCDR), all STEMI Receiving Centers designated by the American Heart Association's (AHA) Mission: Lifeline registry, and all state-designated pPCI-capable hospitals and designation criteria from state departments of health. We matched ACC, AHA, and state-designated facilities to those in the 2019 National ED Inventory (NEDI)-USA database to identify all EDs in pPCI-capable hospitals. RESULTS: Overall, 467 hospitals were recognized as Chest Pain Centers with Primary PCI by ACC, 293 hospitals were recognized as being STEMI Receiving Centers by AHA, and 827 hospitals were confirmed to be pPCI-capable by state designations and operated 24/7/365. Together, there were 1,178 EDs (21% of 5,587 total) co-located in pPCI-capable hospitals operating 24/7/365. CONCLUSIONS: There is substantial heterogeneity in cardiac systems of care, with large regional systems existing alongside local state-led initiatives. We created a unified national database of confirmed 24/7/365 pPCI centers co-located in hospitals with EDs. This data set will be valuable for future cardiac systems research and improving access to pPCI.