Early-life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite-induced asthma.

INTRODUCTION: Early-life exposure to antibiotics (ABX) has been linked to increases in asthma severity and prevalence in both children and laboratory animals. We explored the immunologic mechanisms behind this association using a mouse model of house dust mite (HDM)-induced asthma and early-life ABX exposure. METHODS: Mice were exposed to three short courses of ABX following weaning and experimental asthma was thereafter induced. Airway cell counts and differentials; serum immunoglobulin E (IgE); pulmonary function; lung histopathology; pulmonary regulatory T cells (Tregs); and the fecal microbiome were characterized following ABX exposure and induction of experimental asthma. RESULTS: Asthma severity was increased in mice exposed to ABX, including: airway eosinophilia, airway hyper-reactivity, serum HDM-specific IgE, and lung histopathology. ABX treatment led to sharp reduction in fecal microbiome diversity, including the loss of pro-regulatory organisms such as Lachnospira. Pulmonary Tregs were reduced with ABX treatment, and this reduction was directly proportional to diminished microbiome diversity. CONCLUSION: Intermittent exposure to ABX early in life worsened the severity of experimental asthma and reduced pulmonary Tregs; the latter change correlated with decreased microbiome diversity. These data may suggest targets for immunologic or probiotic therapy to counteract the harmful effects of childhood ABX.

Regulation of IgE activity in inhalational tolerance via formation of IgG anti-IgE/IgE immune complexes.

BACKGROUND: Allergic asthma is an inflammatory disorder of the airways that results from inappropriate production of IgE against harmless, environmental antigens. Sequestration of free IgE using humanized IgG anti-IgE is an effective therapy for asthma and other atopic disorders. However, the status of free IgE in subjects who have naturally developed immune tolerance to inhaled antigens has not been well studied. METHODS: C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) for 7 days to induce allergic airway disease (AAD) or 6 weeks to induce a state of local inhalational tolerance (LIT). Serum from AAD or LIT mice, diluted to achieve equivalent levels of total OVA-specific IgE, was used to sensitize rat basophil leukemia cells for allergen-mediated degranulation. Levels of degranulation were measured in relation to serum concentrations of free IgE and IgG anti-IgE/IgE immune complexes. RESULTS: Serum from AAD animals induced a greater degree of basophil degranulation than serum from LIT animals. These results correlated with higher levels of free IgE in AAD animals, whereas LIT mice demonstrated a significant increase in IgG anti-IgE/IgE immune complexes relative to their diseased counterparts. CONCLUSIONS: Sequestration of free IgE by naturally occurring IgG anti-IgE may aid in the development of immune tolerance against inhaled allergens. The decrease in bioavailability of free IgE may, in turn, contribute to the overall reduction of asthma symptoms via a mechanism that mimics the therapeutic effects of humanized IgG anti-IgE.

Clinical Examination Does Not Predict Response to Albuterol in Ventilated Infants With Bronchiolitis.

OBJECTIVE: Bronchiolitis is a common respiratory infection in infants that is sometimes treated with albuterol. Response to albuterol is determined by clinical assessment, but this subjective determination is potentially unreliable. In this study, we compared providers' clinical assessment of response to albuterol with the measurement of response by pulmonary mechanics in intubated, sedated, and ventilated infants. DESIGN: Before and 20 minutes following racemic albuterol therapy, a nurse, respiratory therapist, and physician performed simultaneous examinations and assessed response to albuterol in a population of intubated infants with bronchiolitis. Measurements of ventilator-derived pulmonary mechanics were obtained at these same times. SETTING: This study was conducted in a PICU of a children's hospital. PATIENTS: Seventy-five paired clinical assessments were made in 25 infants who were intubated and mechanically ventilated for severe bronchiolitis. INTERVENTIONS: Pulmonary function measurements and clinical assessments before and after administration of albuterol. MEASUREMENTS AND MAIN RESULTS: Response to albuterol was defined using a threshold of improvement in respiratory system resistance from baseline. Nine children (36%) had greater than 20% change and were deemed responders. Providers' discrimination of response was poor. The positive predictive values of nurses, respiratory therapists, and physicians were 38%, 25%, and 25%, respectively, and the negative predictive values were 67%, 54%, and 59%, respectively. Overall accuracy was 44% for nurses, 40% for respiratory therapists, and 48% for physicians. When comparing separate assessments of wheezing, aeration, and expiratory time, there was poor agreement between groups of providers in all variables (κ < 0.4 for each). CONCLUSIONS: A provider's clinical assessment was not a reliable method for determining response to albuterol in children with bronchiolitis. Without assessment of pulmonary mechanics, caution should be used in classifying children with bronchiolitis as responders to albuterol.

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation.

BACKGROUND: Allergic asthma is a major cause of worldwide morbidity and results from inadequate immune regulation in response to innocuous, environmental antigens. The need exists to understand the mechanisms that promote nonreactivity to human-relevant allergens such as house dust mite (HDM) in order to develop curative therapies for asthma. The aim of our study was to compare the effects of short-, intermediate- and long-term HDM administration in a murine asthma model and determine the ability of long-term HDM exposure to suppress allergic inflammation. METHODS: C57BL/6 mice were intranasally instilled with HDM for short-term (2 weeks), intermediate-term (5 weeks) and long-term (11 weeks) periods to induce allergic airway disease (AAD). The severity of AAD was compared across all stages of the model via both immunological and pulmonary parameters. RESULTS: Short- and intermediate-term HDM exposure stimulated the development of AAD that included eosinophilia in the bronchoalveolar lavage fluid (BALF), pronounced airway hyperreactivity (AHR) and evidence of lung inflammation. Long-term HDM exposure promoted the suppression of AAD, with a loss of BALF eosinophilia and AHR despite persistent mononuclear inflammation in the lungs. Suppression of AAD with long-term HDM exposure was associated with an increase in both Foxp3+ regulatory T cells and IL-10-positive alveolar macrophages at the site of inflammation. CONCLUSIONS: This model recapitulates the key features of human asthma and may facilitate investigation into the mechanisms that promote immunological tolerance against clinically relevant aeroallergens.

An adolescent with Wolfram syndrome and central sleep apnea.

Wolfram syndrome is a rare autosomal recessive disorder affecting approximately 1 in 500,000 individuals. The disorder is most commonly caused by mutations in the WFS1 gene, which encodes an endoplasmic reticulum protein, wolframin, which is thought to protect against endoplasmic reticulum stress-related apoptosis. The major clinical findings of Wolfram syndrome are diabetes mellitus and optic atrophy, both of which usually appear before 16 years of age. Common additional findings include sensorineural hearing impairment, central diabetes insipidus, nonautoimmune hypothyroidism, delayed puberty, neurogenic bladder, cerebellar ataxia, and psychiatric disorders. Central sleep apnea is an uncommon but serious feature of Wolfram syndrome. However, the clinical details of this manifestation have not been documented. Herein, we report an adolescent with recently diagnosed Wolfram syndrome who demonstrated severe central sleep apnea on polysomnography testing. CITATION: Harris JC, Kenkare JD, Schramm CM. An adolescent with Wolfram syndrome and central sleep apnea. J Clin Sleep Med. 2024;20(7):1205-1208.

A Survey of Cystic Fibrosis Center Recommendations for Nebulizer Cleaning and Disinfection.

BACKGROUND: Despite advancements in cystic fibrosis (CF) therapeutics, the persistence of chronic infections necessitates continued use of nebulized therapies. Though the Cystic Fibrosis Foundation recommends well-defined cleaning and disinfection of nebulizers to mitigate pathogen exposure risks, discrepancies between Cystic Fibrosis Foundation guidelines, manufacturers' instructions, and variability in center recommendations contribute to confusion and non-standardized practices. METHODS: A digital survey was distributed to directors, associate directors, and care coordinators of CF centers across the United States to investigate the methods, frequency, and educational practices surrounding nebulizer care they provide patients. Responses were analyzed using descriptive techniques and chi-square analyses. RESULTS: Of 855 distributed surveys, 129 respondents provided insights into nebulizer care recommendations. Discrepancies in disinfection frequency were notable, with 18% of respondents recommending disinfecting nebulizers less than daily. Approximately 20% of respondents were unsure if their recommendations aligned with Cystic Fibrosis Foundation guidelines while 73% reported that their recommendations strictly adhered to the published guidelines. Of this 73%, all recommended at least daily cleaning, with 69% specifying cleaning before reuse; and 88% recommended disinfection at least daily, with 36% specifying disinfection before reuse. Only 10% recommended both cleaning and disinfection after every use. Disinfection less than daily was recommended by 11% of the respondents who felt they were strictly following the guidelines. We also highlight respondents who cited barriers to strict adhesion to the published guidelines. CONCLUSIONS: The highlighted variations in CF centers' recommendations for nebulizer care with deviations from Cystic Fibrosis Foundation guidelines underscore the necessity for developing clear and practical guidelines that consider both efficacy and the realities of patient adherence. Collaboration among CF care centers, patients, guideline committees, and other stakeholders is essential to develop recommendations that effectively address the challenges faced by the CF community, ensuring the safe and effective nebulizer use.

Phenotypic changes to the endogenous antigen-specific CD8+ T cell response correlates with the development and resolution of allergic airway disease.

The role of CD8(+) T cells in the pathogenesis of asthma remains controversial, as both pro- and anti-inflammatory functions have been suggested. This study was designed to examine the endogenous CD8(+) T cell response in a biphasic ovalbumin (OVA)-induced model of allergic airway disease (AAD) and its subsequent resolution with the development of local inhalational tolerance (LIT). We observed increases in OVA-specific CD8(+) T cell numbers in the local lung compartments (bronchoalveolar lavage, lung tissue, hilar lymph node) at AAD and LIT; systemic compartments (spleen, inguinal lymph node) displayed no such increases in CD8(+) T cell numbers. OVA-specific CD8(+) T cells appeared to exhibit plasticity both phenotypically and functionally. They possessed pro-inflammatory characteristics at AAD, with high phenotypic expression of CD11a and increased functional expression of granzyme B and interferon-γ. In contrast, at LIT they showed increased phenotypic expression of the inhibitory marker NKG2A and functionally did not produce granzyme B or interferon-γ. In addition, in a discontinuous model the OVA-specific CD8(+) T cells could be recalled on re-exposure to OVA, demonstrating memory. Finally, confocal microscopy results showed that OVA-specific CD8(+) T cells at AAD are associated with B cell aggregates in lung tissue. These B cell aggregates resembled tertiary ectopic lymphoid tissue and may thus provide a local environment for the salient cellular interactions that contribute to the development of LIT.

Clinical features cannot distinguish allergic from non-allergic asthma in children.

OBJECTIVE: Environmental allergens are a major trigger of asthma, but not all asthmatics are allergic. This study was designed to review clinical characteristics in children with allergic and non-allergic asthma, based on responsiveness to allergy skin tests, in order to identify a combination of features that could distinguish allergic from non-allergic asthma in children. METHODS: Medical records of 321 children who had allergy skin testing were reviewed, and demographic and clinical data were compared between allergic and non-allergic patients. RESULTS: Approximately two-thirds of the asthmatic children had at least one positive skin test. These allergic patients were more likely to have a history of eczema or Medicaid insurance, but these findings had poor predictive value. There was no difference between allergic patients and non-allergic patients in terms of family history of atopy or asthma, home tobacco smoke exposure, age of onset of asthma, gender, rate of obesity, or asthma severity. Among the allergic asthma patients, neither the number of positive skin tests nor specific individual allergic sensitivities correlated with age of onset of asthma or asthma severity. CONCLUSIONS: This study failed to identify any combination of features that could reliably distinguish allergic from non-allergic asthma in children. Thus, all children with asthma should undergo allergy testing in order to identify potential allergic triggers in allergic patients and to avoid the institution of unnecessary environmental control measures in non-allergic patients.

Pulmonary mechanics following albuterol therapy in mechanically ventilated infants with bronchiolitis.

BACKGROUND AND AIMS: Bronchiolitis is a common cause of critical illness in infants. Inhaled ß(2)-agonist bronchodilators are frequently used as part of treatment, despite unproven effectiveness. The purpose of this study was to describe the physiologic response to these medications in infants intubated and mechanically ventilated for bronchiolitis. MATERIALS AND METHODS: We conducted a prospective trial of albuterol treatment in infants intubated and mechanically ventilated for bronchiolitis. Before and for 30 minutes following inhaled albuterol treatment, sequential assessments of pulmonary mechanics were determined using the interrupter technique on repeated consecutive breaths. RESULTS: Fifty-four infants were enrolled. The median age was 44 days (25-75%; interquartile range (IQR) 29-74 days), mean hospital length of stay (LOS) was 18.3 ± 13.3 days, mean ICU LOS was 11.3 ± 6.4 days, and mean duration of mechanical ventilation was 8.5 ± 3.5 days. Fifty percent (n = 27) of the infants were male, 81% (n = 44) had public insurance, 80% (n = 41) were Caucasian, and 39% (n = 21) were Hispanic. Fourteen of the 54 (26%) had reduction in respiratory system resistance (Rrs) that was more than 30% below baseline, and were defined as responders to albuterol. Response to albuterol was not associated with demographic factors or hospitalization outcomes such as LOS or duration of mechanical ventilation. However, increased Rrs, prematurity, and non-Hispanic ethnicity were associated with increased LOS. CONCLUSIONS: In this population of mechanically ventilated infants with bronchiolitis, relatively few had a reduction in pulmonary resistance in response to inhaled albuterol therapy. This response was not associated with improvements in outcomes.

ß2-adrenergic receptor haplotype linked to intubation and mechanical ventilation in children with asthma.

BACKGROUND AND AIMS: Children with asthma and respiratory failure comprise a small but significant subset of children with acute asthma. In addition to clinical and historical factors that have been associated with respiratory failure, there may also be genetic factors that predispose some asthmatic children to intubation and mechanical ventilation. However, this has not previously been assessed in this population. We hypothesized that genetic polymorphisms of the ß(2)-adrenergic receptor (ADRß(2)) are associated with intubation and mechanical ventilation in children with asthma. MATERIALS AND METHODS: We performed genotyping of the ADRß(2) in a pooled cohort of 104 children admitted to the intensive care unit (ICU) with a severe asthma exacerbation between 2002 and 2008. Genotype of the ADRß(2) was compared with intubation for respiratory failure. RESULTS: At amino acid position 16, 33% (n = 34) of children were homozygous for the glycine allele (Gly16Gly), 15% (n = 16) were homozygous for the arginine allele (Arg16Arg), and 52% (n = 54) were heterozygous (Arg16Gly). At amino acid position 27, 54% (n = 56) of children were homozygous for the glutamine allele (Gln27Gln), 8% (n = 8) were homozygous for the glutamic acid allele (Glu27Glu), and 38% (n = 40) were heterozygous (Gln27Glu). The haplotypes at these positions were Arg16Gly-Gln27Gln (29%, n = 30), Arg16Gly-Gln27Glu (22%, n = 23), Gly16Gly-Gln27Glu (16%, n = 17), Arg16Arg-Gln27Gln (16%, n = 17), Gly16Gly-Gln27Gln (9%, n = 9), and Gly16Gly-Glu27Glu (8%, n = 8). Twelve children in this cohort were intubated for respiratory failure. Intubation was not associated with age, obesity, race/ethnicity, or NHBLI asthma classification. However, children with the Arg16Gly-Gln27Gln haplotype were significantly more likely to be intubated and mechanical ventilated (OR = 4.2; 95% CI = 1.2-14.5; p = .036) than children with other haplotypes of the ADRß(2). When examining the subset of intubated children, those with the Arg16Gly-Gln27Gln haplotype trended towards longer ICU length of stay (329 ± 270 vs. 124 ± 57 hours; p = .09), but this was not statistically significant. CONCLUSIONS: Children with the Arg16Gly-Gln27Gln haplotype of the ADRß(2) were four times more likely to be intubated and mechanically ventilated during severe asthma exacerbations. Genetic factors may influence the development of a more severe asthma phenotype during acute exacerbations.

Bromelain limits airway inflammation in an ovalbumin-induced murine model of established asthma.

CONTEXT: Allergic asthma continues to increase despite new pharmacological advances for both acute treatment and chronic-disease management. Asthma is a multifactorial disease process with genetic, allergic, infectious, environmental, and dietary origins. Researchers are investigating the benefits of lifestyle changes and alternative asthma treatments, including the ability of bromelain to inhibit inflammation. Bromelain is a commonly used, proteolytically active pineapple extract. OBJECTIVE: The present study intended to determine the ability of bromelain to reduce the inflammation of preexisting asthma via an ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). DESIGN: The research team designed a study examining the effects of bromelain in a control group of mice that received phosphate buffered saline (PBS) only and in an intervention group that received bromelain in PBS. Setting The study took place in the Department of Immunology at the University of Connecticut's School of Medicine, Farmington. Intervention The research team sensitized female C57BL/6J mice with intraperitoneal OVA/alum and then challenged them with OVA aerosolization for 10 consecutive days. On day 4, the team began administering daily doses of PBS to the control group (n = 10) and bromelain (6mg/kg) in PBS to the bromelain (intervention) group (n = 10). OUTCOME MEASURES: The primary measures included bronchoalveolar lavage (BAL) cellular differential, cellular phenotype via flow cytometry, and lung histology. Additional outcomes included testing for serum cytokines and immunoglobulin. RESULTS: Bromelain treatment of AAD mice (bromelain group) resulted in significant anti-inflammatory activity as indicated by reduced BAL total leukocytes (P < .05), eosinophils (P < .05), and cellular infiltrates via lung pathology (P < .005), as compared to the control group. In addition, bromelain significantly reduced BAL CD4+ and CD8+ T cells without affecting cell numbers in the spleen or hilar lymph node. The study found decreased interleukins IL-4, IL-12, IL-17, as well as IFN-α in the serum of bromelain-treated animals. CONCLUSIONS: The results suggest that bromelain has a therapeutic effect in established AAD, which may translate into an effective adjunctive therapy in patients with similar conditions, such as allergic asthma, who have chosen to initiate treatment after the onset of symptoms.

Bacterial Surface Detachment during Nebulization with Contaminated Reusable Home Nebulizers.

Patients with chronic respiratory diseases use home nebulizers that are often contaminated with pathogenic microbes to deliver aerosolized medications. The conditions under which these microbes leave the surface as bioaerosols during nebulization are not well characterized. The objectives of this study were to (i) determine whether different pathogens detach and disperse from the nebulizer surface during aerosolization and (ii) measure the effects of relative humidity and drying times on bacterial surface detachment and aerosolization. Bacteria were cultured from bioaerosols after Pari LC Plus albuterol nebulization using two different sources, as follows: (i) previously used nebulizers donated by anonymous patients with cystic fibrosis (CF) and (ii) nebulizers inoculated with bacteria isolated from the lungs of CF patients. Fractionated bioaerosols were collected with a Next-Generation Impactor. For a subset of bacteria, surface adherence during rewetting was measured with fluorescence microscopy. Bacteria dispersed from the surface of used CF patient nebulizers during albuterol nebulization. Eighty percent (16/20) of clinical isolates inoculated on the nebulizer in the laboratory formed bioaerosols. Detachment from the plastic surface into the chamber solution predicted bioaerosol production. Increased relative humidity and decreased drying times after inoculation favored bacterial dispersion on aerosols during nebulized therapy. Pathogenic bacteria contaminating nebulizer surfaces detached from the surface as bioaerosols during nebulized therapies, especially under environmental conditions when contaminated nebulizers were dried or stored at high relative humidity. This finding emphasizes the need for appropriate nebulizer cleaning, disinfection, and complete drying during storage and informs environmental conditions that favor bacterial surface detachment during nebulization. IMPORTANCE Studies from around the world have demonstrated that many patients use contaminated nebulizers to deliver medication into their lungs. While it is known that using contaminated medications in a nebulizer can lead to a lung infection, whether bacteria on the surface of a contaminated nebulizer detach as bioaerosols capable of reaching the lung has not been studied. This work demonstrates that a subset of clinical bacteria enter solution from the surface during nebulization and are aerosolized. Environmental conditions of high relative humidity during storage favor dispersion from the surface. We also provide results of an in vitro assay conducted to monitor bacterial surface detachment during multiple cycles of rewetting that correlate with the results of nebulizer/bacterial surface interactions. These studies demonstrate for the first time that pathogenic bacteria on the nebulizer surface pose a risk of bacterial inhalation to patients who use contaminated nebulizers.

Factors associated with the development of severe asthma exacerbations in children.

BACKGROUND: Asthma exacerbations are one of the most common causes of hospitalization in children and account for approximately 10,000 intensive care unit (ICU) admissions per year in the United States. Despite the prevalence of this disease in children, the factors associated with the development of these severe exacerbations are largely unknown. METHODS: A retrospective case-control study was conducted involving all eligible children admitted to the hospital with asthma for a 1-year period. Potential associated factors and outcomes of children admitted to the ICU with a severe exacerbation (cases) were compared to those of children with acute asthma admitted to the ward (controls). RESULTS: A total of 188 children were hospitalized with asthma during the study period, 57 (30%) of whom required admission to the ICU. There were no differences in age, gender, or race between cases and controls. Children admitted to the ICU were significantly more likely to have an allergy or irritant-triggered exacerbation than children admitted to the ward (OR 3.9; 95% CI 1.9-8.2; p = .0003). Additionally, children in the ICU had a significantly shorter duration of illness before being admitted to the hospital compared to those admitted to the ward (1.7 ± 2.3 vs. 3.4 ± 4.8 days; p = .002). CONCLUSIONS: In this retrospective review, severe asthma exacerbations in children are associated with a more rapid onset of symptoms and are more likely to be associated with allergens or irritants, supporting the importance of atopy in this population.

Identifying an at-risk population of children with recurrent near-fatal asthma exacerbations.

BACKGROUND: Children are frequently admitted to hospitals for treatment of severe asthma exacerbations. Anecdotally, a cohort of these children are thought to have multiple readmissions to the intensive care unit (ICU), yet this group of children has not been characterized. The purpose of this study was to examine the factors related to recurrent ICU admissions in children with asthma. METHODS: The authors conducted a retrospective study of all children admitted to the pediatric ICU for asthma between April 1997 and December 2007. Children with more than one ICU admission were defined as having recurrent near-fatal asthma exacerbations. RESULTS: During this period, 306 children with asthma were admitted to the ICU on 350 occasions; 269 children had only one ICU admission and 33 children (11%) had two or more ICU admissions. To predict who might require readmission, the authors compared the first hospitalization of all children. When compared with children admitted to the ICU only once, children admitted to the ICU more than once were more likely to be overweight (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.1, 4.9), to have public insurance (OR 3.6; 95% CI 1.5, 8.5), and less likely to be Caucasian (OR 0.34; 95% CI 0.14, 0.86). There was no difference in Nation Heart, Lung and Blood Institute (NHLBI) asthma classification, admission illness severity, durations of therapy, or length of stay (LOS) that might identify those who would require readmission. To determine the effect of readmission analysis on subsequent hospitalization, the authors used multiple logistic regression to identify factors associated with increased LOS in all hospitalizations of the subset of children with recurrent near-fatal asthma exacerbations. In this analysis, LOS was most closely associated with admission severity of illness (p = .002), but not with number of hospitalizations. CONCLUSIONS: In this single hospital cohort, there were identifiable factors in children admitted to the ICU that are associated with an increased risk of developing recurrent near-fatal asthma exacerbations. Specifically, overweight children with public insurance were more likely and Caucasian children less likely to be readmitted to the ICU for asthma. These children may represent a group to which specific interventions should be targeted prospectively to prevent readmission.

Advances in treating acute asthma exacerbations in children.

PURPOSE OF REVIEW: Asthma continues to be a major chronic disease in children, and acute asthma exacerbations are common. Although the basic therapy of asthma exacerbations has not changed, recent studies have demonstrated improved outcomes with different modes of delivery of medications, improved patients' self-management of their asthma, and recognition of risk factors for severe exacerbations. RECENT FINDINGS: Recent studies in children have shown that written action plans based on symptom recognition are more effective than action plans based on peak expiratory flows. Bronchodilator administration by metered-dose inhaler is becoming the preferred therapy for treating mild-to-moderate asthma exacerbations in the emergency department, but nebulizers may still have a role in home and inpatient asthma management. High-dose inhaled corticosteroids may be as effective as oral corticosteroids for acute asthma exacerbations. A novel treatment strategy has titrated combination therapy with budesonide and formoterol for both maintenance and relief of symptoms. Lastly, the contributions of obesity and genetic variation to severe asthma exacerbations are becoming known, and noninvasive positive pressure ventilation has become an option for patients in severe asthma exacerbations. SUMMARY: Improvements in management strategies can significantly improve outcomes in children with asthma.

Two vs four puffs of albuterol: does dose change bronchodilator response?

BACKGROUND: Reversible obstruction on spirometry may be used to diagnose asthma. As per 2005 American Thoracic Society (ATS) guidelines, our pulmonary center began using 360 µg (four puffs) of albuterol rather than 180 µg (two puffs) to determine reversibility on spirometry starting in 2009. HYPOTHESIS: We hypothesized that fewer patients would respond to two puffs of albuterol than four puffs during spirometric testing. METHODS: We retrospectively reviewed records from new asthmatics seen in Pediatric Pulmonary Clinic from March 2002 to April 2014 who performed reproducible spirometry. Patients were divided into two groups based on whether they had received two or four puffs of albuterol for bronchodilator assessment. A positive bronchodilator response was defined as an increase of ≥12% in forced expiratory volume in one second (FEV1) or ≥25% in forced expiratory flow (FEF25-75%). Data were expressed as percentages and mean ± standard error of the mean values. Chi-squared test and Student's t-test were utilized. RESULTS: Data were collected for 240 patients; 115 patients received two puffs of albuterol and 125 patients received four puffs. There were no significant differences in baseline characteristics between the two groups. There were no differences following two puffs or four puffs in changes in FEV1 (10.0±1.1% vs 10.5±1.1% predicted) or FEF25-75% (30.2±2.9% vs 33.5±2.9% predicted). Moreover, there was no difference in ATS-defined bronchodilator response between the two groups. CONCLUSION: Based on the mean change in FEV1 and overall bronchodilator responsiveness, two puffs of albuterol were not inferior to four puffs in the determination of bronchodilator responsiveness in our pediatric asthmatic patients.

Repeated hot water and steam disinfection of Pari LC Plus® nebulizers alter nebulizer output.

Currently, cystic fibrosis patients require daily nebulized treatments to achieve optimal lung health. Growth of pathogenic bacteria in patient nebulizers is well known, and disinfection guidelines have been established. In this short communication, we sought to discover what effect, if any, repeated nebulization/disinfection cycles had on nebulizer output. We nebulized saline repeatedly after exposure to boiling water, steam, and alcohol disinfection methods. While alcohol disinfection did not affect nebulizer output, boiling water and steam significantly decreased nebulizer output from baseline, 74.1 ±â€¯5.9% (p = 0.022) and steam 63.6 ±â€¯6.5% (p = 0.0048) after 60 cycles respectively. This decrease in nebulizer output could significantly increase the duration of nebulizer treatment time and negatively impact the burden of care on patients with cystic fibrosis.

Accumulation of regulatory T cells in local draining lymph nodes of the lung correlates with spontaneous resolution of chronic asthma in a murine model.

BACKGROUND: Mice sensitized to ovalbumin develop allergic airway disease (AAD) with short-term aerosol challenge; however, airway inflammation resolves with long-term aerosol challenge, referred to as local inhalational tolerance (LIT). METHODS: We sought to determine if resolution of airway inflammation correlated with increases in lymphocyte subsets in local lung compartments, including putative regulatory T cells. RESULTS: At the AAD stage, total numbers of T and B lymphocytes in bronchoalveolar lavage (BAL) were significantly increased above controls; however, at LIT, T and B lymphocytes were significantly reduced compared to AAD. In the lung tissue, the only alteration was a significant increase in CD4+ CD25+ T cells at AAD. In the hilar lymph node (HLN), CD4+ and CD4+ CD25+ T cells were significantly increased at AAD and LIT. In addition, CD8+ T cells were significantly elevated in the HLN at LIT, and CD19+ B cells were significantly increased at AAD. Adoptive transfer of HLN lymphocytes to lymphopenic mice confirmed that AAD lymphocytes could induce airway inflammation in response to aerosol challenge, whereas LIT lymphocytes were unable to do so. Depletion of CD4+ CD25+ T cells in vivo resulted in exacerbation of inflammation at AAD and LIT. CD4+ CD25+ T cells in the HLN also displayed suppressive activity in vitro. Additionally, T cells expressing Foxp3 were increased in the BAL and HLN during LIT. CONCLUSIONS: These results indicate that lymphocytes with regulatory functions are increased and sustained in local lung compartments at LIT and that their appearance correlates with the resolution of lung inflammation.

Severe exacerbations in children with mild asthma: characterizing a pediatric phenotype.

BACKGROUND: NHLBI guidelines classify asthma in children as intermittent, mild persistent, moderate persistent, and severe persistent asthma based on baseline symptoms and pulmonary function. However, this may not capture the spectrum of asthma in children, since even mild baseline disease can have significant effects on quality of life. Our objective was to describe a population of children with mild asthma admitted to the ICU with severe exacerbations. METHODS: We examined data from all children with asthma who were admitted to the ICU with an acute exacerbation between April 1997, and December 2006. Children were defined as having mild asthma if their disease was classified as intermittent or mild persistent according to NHLBI criteria. RESULTS: Of the 298 children admitted to the ICU with asthma, 164 (55%) were classified as having mild baseline asthma. Compared with children with more severe baseline asthma, mild asthmatic children were younger and less likely to have been previously admitted to the hospital for asthma. Other demographics, including admission severity of illness, gender, and prevalence of overweight, were similar in the two groups. There were no differences between the groups in ICU length of stay, hospital length of stay or types of therapies received. Thirteen children with mild asthma were intubated, although less frequently than those with more severe disease. CONCLUSIONS: Children with mild asthma have severe exacerbations. This suggests that chronic asthma severity does not necessarily predict asthma phenotypes during acute exacerbations.

Endotracheal intubation and pediatric status asthmaticus: site of original care affects treatment.

OBJECTIVES: Status asthmaticus is a common cause of admission to a pediatric intensive care unit (PICU). Children unresponsive to medical therapies may require endotracheal intubation; however, this treatment carries significant risk, and thresholds for intubation vary. Our hypothesis was that children who sought care at community hospitals received less aggressive treatment and more frequent intubation than children who sought care at a children's hospital. DESIGN: Retrospective cohort study. SETTING: A university-affiliated children's hospital PICU. PATIENTS: We retrospectively examined data from all children older than 2 yrs admitted to the PICU with status asthmaticus between April 1997 and July 2005. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 251 children admitted to the PICU with status asthmaticus, 130 initially presented to the emergency department of a children's hospital and 116 presented to the emergency department of a community hospital. Despite similar illness severity, children presenting to a community hospital were significantly more likely to be intubated than those presenting to a children's hospital (17% vs. 5%; p = .004). In addition, those children intubated at community hospitals were intubated sooner after presentation (2.4 +/- 5.2 vs. 7.5 +/- 5.8 hrs; p = .009), had shorter durations of intubation (71 +/- 73 vs. 151 +/- 81 hrs; p = .02), and had shorter PICU length of stays (129 +/- 82 vs. 230 +/- 84 hrs; p = .01). CONCLUSIONS: Children with status asthmaticus are more likely to be intubated, and intubated sooner, at a community hospital. The shorter duration of intubation suggests that some children may not have been intubated had they presented to a children's hospital or received more aggressive therapy at their community hospital.