Prophylactic inhaled corticosteroids for the management of recurrent croup.

OBJECTIVES: Croup is characterized by a barky cough, inspiratory stridor, hoarseness and varying degrees of respiratory distress. Acute croup episodes are often treated with oral, inhaled, or intravenous corticosteroids. Recurrent croup, defined as more than 2-3 episodes of acute croup in the same patient, can mimic asthma. We hypothesized that inhaled corticosteroids (ICS) given at the first sign of a respiratory viral prodrome can be a safe treatment to reduce the frequency of recurrent croup episodes in children without fixed airway lesions. METHODS: A retrospective chart review of patients being treated over an 18-month period was performed at a large tertiary care pediatric hospital following Institutional Review Board (IRB) approval. Patients under 21 years old referred to Pediatric Pulmonology, Otolaryngology, or Gastroenterology for recurrent croup were analyzed for their demographics, medical history, evaluation, treatment and clinical improvement. A Fisher's two-tailed exact test was used to compare the number of croup episodes before and after interventions. RESULTS: 124 patients were included in our analysis: 87 male and 34 female with a mean age of 54 months. Of these, 78 had >5 episodes of croup, 45 had 3-5, and 3 had 2 episodes prior to their first visit for recurrent croup. Operative direct laryngoscopy/bronchoscopy was performed in 35 patients (27.8%), with 60% showing a normal exam without fixed lesions. Ninety-two patients (74.2%) were treated with ICS, 24 were lost to follow up. Of the remaining 68 treated patients, 59 (86.7%) saw improvement with reduced severity and overall number of episodes of croup. Additionally, patients with >5 episodes of croup (47) as compared to <5 (12) were more likely to improve with ICS, (p = 0.003). There were no adverse reactions reported with ICS treatment. CONCLUSION: The novel initiation of ICS at the earliest sign of a viral upper respiratory infection shows promise as a safe preventative treatment to mitigate the frequency of recurrent croup episodes.

Cancer incidence after asthma diagnosis: Evidence from a large clinical research network in the United States.

BACKGROUND: Prior studies on the association between asthma and cancer show inconsistent results. This study aimed to generate additional evidence on the association between asthma and cancer, both overall, and by cancer type, in the United States. METHOD: We conducted a retrospective cohort study using 2012-2020 electronic health records and claims data in the OneFlorida+ clinical research network. Our study population included a cohort of adult patients with asthma (n = 90,021) and a matching cohort of adult patients without asthma (n = 270,063). We built Cox proportional hazards models to examine the association between asthma diagnosis and subsequent cancer risk. RESULTS: Our results showed that asthma patients were more likely to develop cancer compared to patients without asthma in multivariable analysis (hazard ratio [HR] = 1.36, 99% confidence interval [CI] = 1.29-1.44). Elevated cancer risk was observed in asthma patients without (HR = 1.60; 99% CI: 1.50-1.71) or with (HR = 1.11; 99% CI: 1.03-1.21) inhaled steroid use. However, in analyses of specific cancer types, cancer risk was elevated for nine of 13 cancers in asthma patients without inhaled steroid use but only for two of 13 cancers in asthma patients with inhaled steroid use, suggesting a protective effect of inhaled steroid use on cancer. CONCLUSION: This is the first study to report a positive association between asthma and overall cancer risk in the US population. More in-depth studies using real-word data are needed to further explore the causal mechanisms of asthma on cancer risk.

Exacerbations of asthma following step-up and step-down inhaled corticosteroid and long acting beta agonist therapy in the managing asthma in pregnancy study.

OBJECTIVE: Guidelines for asthma management contain a consensus recommendation that inhaled corticosteroid (ICS) dose should not be stepped down in pregnancy. However, this is not consistent with consumer preferences and pharmacological principles to minimize medication exposure during pregnancy. We investigated exacerbations after changes to ICS and long acting beta agonist (LABA) therapy in pregnant women with asthma. METHODS: Pregnant women (n = 220) were recruited to a randomized controlled trial (RCT) where maintenance treatment was adjusted monthly based on either symptoms (control group), or fractional exhaled nitric oxide (FeNO, to alter ICS) and symptoms (to alter LABA, FeNO group). Exacerbations were monitored prospectively. RESULTS: ICS were used by 137 (62.3%) women at some time during pregnancy. ICS dose remained unchanged in 16 women (11.7%, 95% confidence interval [CI] 7-18%), increased in 37 women (27%, 95%CI 20-35%), decreased in 34 women (24.8%, 95%CI 18%-33%), or both increased and decreased in 50 women (36.5%, 95%CI 29-45%). Exacerbations occurred within 14 days of ICS step-down in 11 women (13%, 95%CI 7.5%-22%). This was not significantly different from exacerbations occurring within 14 days of step-up, in 7 women (8.1%, 95%CI 4%-16%, P = 0.294). There were no differences between management groups. Exacerbations occurred within 14 days of step-down in 14.7% (95%CI 7%-30%) of women in the control group, and in 12% (95%CI 6%-24%) of women in the FENO group. CONCLUSIONS: ICS step-down could be considered when eosinophilic inflammation or symptoms are low, and may be a useful management approach for women, doctors, and midwives wishing to minimize ICS exposure during pregnancy.

Pharmacoepidemiology of Drug Exposure in Intubated and Non-Intubated Preterm Infants With Severe Bronchopulmonary Dysplasia.

Background: Infants with severe bronchopulmonary dysplasia (BPD) are commonly treated with off-label drugs due to lack of approved therapies. To prioritize drugs for rigorous efficacy and safety testing, it is important to describe exposure patterns in this population. Objective: Our objective was to compare rates of drug exposure between preterm infants with severe bronchopulmonary dysplasia based on respiratory support status at or beyond 36 weeks post-menstrual age. Methods: A cross-sectional cohort study was performed on October 29, 2019. Preterm infants with severe BPD were eligible and details of respiratory support and drug therapy were recorded. Wilcoxon paired signed rank test was used to compare continuous variables between the invasive and non-invasive groups. Fisher's exact test was used to compare binary variables by respiratory support status. Results: 187 infants were eligible for the study at 16 sites. Diuretics were the drug class that most subjects were receiving on the day of study comprising 54% of the entire cohort, followed by inhaled steroids (47%) and short-acting bronchodilators (42%). Infants who were invasively ventilated (verses on non-invasive support) were significantly more likely to be receiving diuretics (p 0.013), short-acting bronchodilators (p < 0.01), long-acting bronchodilators (p < 0.01), systemic steroids (p < 0.01), systemic pulmonary hypertension drugs (p < 0.01), and inhaled nitric oxide (p < 0.01). Conclusion: Infant with severe BPD, especially those who remain on invasive ventilation at 36 weeks, are routinely exposed to multiple drug classes despite insufficient pharmacokinetic, safety, and efficacy evaluations. This study helps prioritize sub-populations, drugs and drug classes for future study.

The Importance of Inhaler Adherence to Prevent COPD Exacerbations.

It has been shown that the better outcomes of chronic obstructive pulmonary disease (COPD) are closely associated with adherence to drug therapy, independent of the treatment administered. The clinical trial Towards a Revolution in COPD Health (TORCH) study clearly showed in a three year follow up that patients with good adherence to their inhaler treatment presented a longer time before the first exacerbation, a lower susceptibility to exacerbation and lower all-cause mortality. The Latin American Study of 24-hour Symptoms in Chronic Obstructive Pulmonary Disease (LASSYC), a real-life study, evaluated the self-reported inhaler adherence in COPD patients in seven countries in a cross-sectional non-interventional study and found that approximately 50% of the patients had good adherence, 30% moderate adherence and 20% poor adherence. Adherence to inhaler may be evaluated by the specific inhaler adherence questionnaire, the Test of Adherence to Inhalers (TAI). Several factors may predict the incorrect use of inhalers or adherence in COPD outpatient, including the number of devices and the daily dosing frequency. Ideally, patient education, simplicity of the device operation, the use of just one device for multiple medications and the best adaptation of the patient to the inhaler should guide the physician in prescribing the device.

Inhaled corticosteroids in ventilated preterm neonates: a non-randomized dose-ranging study.

BACKGROUND: Inhaled corticosteroids (ICS) offer targeted treatment for bronchopulmonary dysplasia (BPD) with minimal systemic effects compared to systemic steroids. However, dosing of ICS in the management of infants at high-risk of developing BPD is not well established. The objective of this study was to determine an effective dose of ICS for the treatment of ventilator-dependent infants to facilitate extubation or reduce fractional inspired oxygen concentration. METHODS: Forty-one infants born at < 32 weeks gestational age (GA) or < 1250 g who were ventilator-dependent at 10-28 days postnatal age were included. A non-randomized dose-ranging trial was performed using aerosolized inhaled beclomethasone with hydrofluoralkane propellant (HFA-BDP). Four dosing groups (200, 400, 600 and 800 µg twice daily for 1 week) with 11, 11, 10 and 9 infants in each group, respectively, were studied. The primary outcome was therapeutic efficacy (successful extubation or reduction in FiO2 of > 75% from baseline) in ≥60% of infants in the group. Oxygen requirements, complications and long-term neurodevelopmental outcomes were also assessed. RESULTS: The median age at enrollment was 22 (10-28) postnatal days. The primary outcome, therapeutic efficacy as defined above, was not achieved in any group. However, there was a significant reduction in post-treatment FiO2 at a dose of 800 µg bid. No obvious trends were seen in long-term neurodevelopmental outcomes. CONCLUSIONS: Therapeutic efficacy was not achieved with all studied doses of ICS. A significant reduction in oxygen requirements was noted in ventilator-dependent preterm infants at 10-28 days of age when given 800 µg of HFA-BDP bid. Larger randomized trials of ICS are required to determine efficacy for the management of infants at high-risk for development of BPD. TRIAL REGISTRATION: This clinical trial was registered retrospectively on clinicaltrials.gov. The registration number is NCT03503994 .

Inhaled steroid inhibits development of total and mite IgE.

Serum levels of total immunoglobulin E (IgE) and allergen-specific IgE are related to asthma severity and risk factors for persistent asthma in childhood wheezing. Inhaled corticosteroids (ICS) have been the most effective therapy in children with asthma, as well as in adults. The serum levels of total and mite specific IgE in children with asthma and the effects on IgE levels of beclomethasone dipropionate (BDP) treatment on IgE levels in asthmatic children were investigated. First, a cross-sectional study of 255 children with asthma was carried out to measure IgE levels. Children under three years of age with asthma who were negative for Df-specific IgE were then treated with BDP or disodium cromoglycate (DSCG) as controls for one year. Serum IgE levels, numbers of eosinophils in peripheral blood and clinical variables were determined before and after treatment. After one-year DSCG treatment, the total IgE levels increased significantly, whereas the levels remained the same during BDP treatment. Five of 22 (23%) patients in the DSCG-treated group became positive for Df-specific IgE; however, only one of 13 (8%) in the BDP-treated group became positive. Taken together, ICS therapy may modulate the levels of total IgE and allergen-specific IgE.

The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: a UK database study.

Chronic obstructive pulmonary disease (COPD), a complex progressive disease, is currently the third leading cause of death worldwide. One recommended treatment option is fixed-dose combination therapy of an inhaled corticosteroid (ICS)/long-acting ß-agonist. Clinical trials suggest pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) show similar efficacy and safety profiles in COPD. Real-world observational studies have shown that combination therapy has significantly greater odds of achieving asthma control when delivered via pMDIs. Our aim was to compare effectiveness, in terms of moderate/severe COPD exacerbations and long-acting muscarinic antagonist (LAMA) prescriptions, for COPD patients initiating fluticasone propionate (FP)/salmeterol xinafoate (SAL) via pMDI versus DPI at two doses of FP (500 and 1,000 µg/d) using a real-life, historical matched cohort study. COPD patients with ≥2 years continuous practice data, ≥2 prescriptions for FP/SAL via pMDI/DPI, and no prescription for ICS were selected from the Optimum Patient Care Research Database. Patients were matched 1:1. Rate of moderate/severe COPD exacerbations and odds of LAMA prescription were analyzed using conditional Poisson and logistic regression, respectively. Of 472 patients on 500 µg/d, we observed fewer moderate/severe exacerbations in patients using pMDI (99 [42%]) versus DPI (115 [49%]) (adjusted rate ratio: 0.71; 95% confidence interval: 0.54, 0.93), an important result since the pMDI is not licensed for COPD in the UK, USA, or China. At 1,000 µg/d, we observed lower LAMA prescription for pMDI (adjusted odds ratio: 0.71; 95% confidence interval: 0.55, 0.91), but no difference in exacerbation rates, potentially due to higher dose of ICS overcoming low lung delivery from the DPI.

Tiotropium may improve asthma symptoms and lung function in asthmatic patients with irreversible airway obstruction: the real-life data.

BACKGROUND AND AIMS: Some patients with asthma have poorly controlled disease despite the use of high-dose inhaled corticosteroids (ICS), long-acting ß2 agonists (LABAs) and antileukotrienes. The aim of the study was to assess the effectiveness of tiotropium as an add-on therapy to the standard treatment with high-dose ICS/LABA on asthma control and lung function in patients with severe asthma. METHODS: Of the 633 asthmatic patients, 64 (10.1%) patients with severe asthma who were add-on treated at least for 3 months were evaluated. Number of exacerbations, emergency department visits, hospitalizations and lung functions of patients belonging to 12 months before starting add-on treatment were compared with those of 12 months after starting add-on treatment. RESULTS: The mean duration of add-on tiotropium treatment was 8.3 ± 0.5 months. For patients with severe asthma that was poorly controlled with standard combination therapy, tiotropium improved asthma control in 42.2%, decreased the number of emergency department visits in 46.9% and decreased the number of hospitalizations in 50.0% of them. The mean baseline forced expiratory volume in 1 s before add-on tiotropium was 57.5 ± 1.9% and forced vital capacity was 74.3 ± 15.6%. However, after 12 months of add-on tiotropium treatment, these rates became 65.5 ± 1.9% and 82.5 ± 15.1%, respectively. The addition of tiotropium significantly improved the percentages of the number of emergency department visits, the number of hospitalizations (P < 0.05). CONCLUSION: Our study has suggested that, for patients with poorly controlled asthma despite of the use of ICS/LABA, the addition of tiotropium to standard care may be beneficial.

Combination corticosteroid/ß-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma?

The recommended treatment of mild asthma is regular maintenance inhaled corticosteroids (ICSs) with a short-acting ß-agonist as a separate inhaler used when needed for symptom relief. However, the benefits of regular ICS use in actual clinical practice are limited by poor adherence and low prescription rates. An alternative strategy would be the symptom-driven (as-required or "prn") use of a combination ICS/short-acting ß-agonist or ICS/long-acting ß-agonist inhaler as a reliever rather than regular maintenance use. The rationale for this approach is to titrate both the ICS and ß-agonist dose according to need and enhance ICS use in otherwise poorly adherent patients who overrely on their reliever ß-agonist inhaler. This strategy will only work if the ß-agonist component has a rapid onset of action for symptom relief. There is evidence to suggest that this regimen has advantages over regular ICS therapy and might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. In this commentary we review this evidence and propose that randomized controlled trials investigating different combination ICS/ß-agonist inhaler products prescribed according to this regimen in intermittent and mild asthma are an important priority.

Perfil de lactentes sibilantes acompanhadosem serviço de referência: avaliação de dez anos / Wheezing infants’ profile from a reference center: 10 year follow-up

Objetivo: Analisar o perfil de lactentes sibilantes que iniciaram e permaneceram em acompanhamento em serviço de referência nos últimos dez anos. Métodos: Estudo descritivo realizado com base na revisão dos prontuários de 195 lactentes sibilantes (sibilância iniciada antes de 36 meses de idade) identificados entre os pacientes de um serviço de referência em alergia, entre 2001 e 2010, que permaneceram em acompanhamento até o momento da pesquisa. Foram avaliados dados clínicos, laboratoriais, tratamentos instituídos e evolução clínica. Resultados: Do total de 195 lactentes avaliados, 129 (66 por cento) eram do gênero masculino e a média de idade no primeiro episódio de sibilância foi 6±6 meses. No início do acompanhamento 44 por cento já haviam sido hospitalizados por problemas respiratórios. Os familiares de 41 por cento dos lactentes relatavam exposição domiciliar à fumaça de cigarro. Cento e vinte e dois pacientes (63 por cento) apresentaram índice preditivo de asma positivo (IPA). Nos exames laboratoriais, 20 por cento apresentavam eosinofilia (> 500/mm3). Do total, 37 por cento eram sensibilizados a algum aeroalérgeno (teste cutâneo de leitura imediata). A rinite foi a comorbidade mais encontrada (57 por cento). O tratamento inicial mais frequentemente instituído foi corticosteroide inalado em dose média (30 por cento), e cerca de 30 por cento dos pacientes não necessitaram introduzir tratamento de controle, no início do acompanhamento. Ao final do seguimento, 69 por cento das crianças com IPA positivo e 57 por cento das com IPA negativo foram classificadas como asmáticas intermitentes. Conclusão: A sibilância recorrente na infância apresenta diferentes fenótipos clínicos e a maior parte dessas crianças apresenta bom prognóstico. A introdução de tratamento de controle deve ser norteada pelos fatores de risco conhecidos para asma. O conhecimento das características clínicas e laboratoriais dos lactentes sibilantes pode auxiliar o diagnóstico de asma e a decisão terapêutica dos casos novos.

Objective: To study the profile of wheezing infants that started and remained medical follow-up in a reference clinic in the last tem years. Methods: It is a descriptive study based on medical records from 195 wheezing infants (wheezing in the first 36 months of age) identified in a reference allergy clinic between 2001 and 2010 that remained being followed until the time of the survey. Clinical and laboratorial data were recorded, as well as treatments and clinical. Results: From the 195 studied infants, 129 (66 percent) were males and the mean age of the first wheezing episode was 6±6 months. At the beginning of the follow-up 44 percent of the infants had been already hospitalized for respiratory disorders. According to the parents’ report, 41 percent were exposed to tobacco smoke at home. Positive predicted index of asthma (IPA) was present in 122 (63 percent) infants. In the initial laboratorial evaluation, 20 percent had eosinophilia (> 500/mm3) and 37 percent were sensitizedto at least one inhaled allergen (skin prick test). Rhinitis was the most frequent comorbidity (57 percent). Medium dose of inhaled steroids was the most common initial treatment (30 percent) and controller medication was not prescribed for 30 of the infants. At the end of the follow-up, asthma was classified as intermittent in 57 percent of those with positive IPA and in 69 percent of those in negative IPA. Conclusions: Children with recurrent wheezing have diferente clinical phenotypes and the majority of them have good prognosis. The introduction of controller medication should be guided by known asthma risk factors. The knowledge of clinical and laboratorial characteristics of wheezing infants may help the asthma diagnosis and the treatment of new cases.

Budesonide/formoterol combination in COPD: a US perspective.

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 µg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.