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To the Editor: The analysis of safety trials of long-acting β 2 -agonists (LABAs) by Busse et al. (June 28 issue) 1 concluded that adding a LABA to an inhaled glucocorticoid was safe. However, patients with previous life-threatening reactions were excluded from the analysis. My colleague and I had previously reported on two boys, 10 and 15 years of age, who received a LABA with an inhaled glucocorticoid and who had life-threatening bronchospasm not prevented with a short-acting β 2 -agonist (SABA) until the LABA was discontinued. 2 Loss of the bronchoprotective effect of a SABA from regular use of a LABA has been reported previously 3,4 . . .

DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0–68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0–66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4–7·1) in cohort 1 and 5·5 months (1·4–8·7) in cohort 1A, and median follow-up was 12·0 months (5·4–22·4) in cohort 1 and 10·6 months (4·5–13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0–41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1–50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. Daiichi Sankyo and AstraZeneca.

This multicenter, randomized trial showed significant benefit of propranolol for the treatment of infantile hemangiomas. Infantile hemangiomas are the most common soft-tissue tumors of childhood, occurring in 3 to 10% of infants. 1 – 4 Lesions are usually not developed at birth and are generally diagnosed during the first 4 to 6 weeks of life, with most growth during the first 5 months. 5 The characteristic evolution of nearly all infantile hemangiomas is proliferation, stabilization, and slow, spontaneous involution. Although most lesions follow an uncomplicated clinical course, approximately 12% result in complications requiring referral to a specialist. 6 , 7 Many infantile hemangiomas leave permanent sequelae, with potential psychological effects in the children and their parents. 8 , 9 Historically, systemic glucocorticoids . . .

Bronchospasm is caused by reversible constriction of the smooth muscles of the bronchial tree. This causes obstruction of the lower airways, which is commonly seen at the emergency department (ED) in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease. Ventilation may be difficult in mechanically intubated patients with severe bronchospasm due to airflow limitation, air trapping, and high airway resistance. The beneficial effects of volatile inhaled anesthetic gas had been reported due to its bronchodilation properties. In this case series, we would like to share our experience delivering inhaled volatile anesthetic gas via a conserving device for three patients with refractory bronchospasm at the ED. Inhaled anesthetic gas is safe, feasible and should be considered as an alternative rescue therapy for ventilated patients with severe lower airway obstruction.

Opioid-induced respiratory depression is potentially life-threatening and often regarded as the main hazard of opioid use. Main cause of death is cardiorespiratory arrest with hypoxia and hypercapnia. Respiratory depression is mediated by opioid μ receptors expressed on respiratory neurons in the CNS. Studies on the major sites in the brainstem mediating respiratory rate suppression, the pre-Bӧtzinger complex and parabrachial complex (including the Kӧlliker Fuse nucleus), have yielded conflicting findings and interpretations but recent investigations involving deletion of μ receptors from neurons have led to greater consensus. Some opioid analgesic drugs are histamine releasers. The range of clinical effects of released histamine include increased cardiac output due to an increase in heart rate, increased force of myocardial contraction, and a dilatatory effect on small blood vessels leading to flushing, decreased vascular resistance and hypotension. Resultant hemodynamic changes do not necessarily relate directly to the concentration of histamine in plasma due to a range of variables including functional differences between mast cells and histamine-induced anaphylactoid reactions may occur less often than commonly believed. Opioid-induced histamine release rarely if ever provokes bronchospasm and histamine released by opioids in normal doses does not lead to anaphylactoid reactions or result in IgE-mediated reactions in normal patients. Hypersensitivities to opioids, mainly some skin reactions and occasional type I hypersensitivities, chiefly anaphylaxis and urticaria, are uncommon. Hypersensitivities to morphine, codeine, heroin, methadone, meperidine, fentanyl, remifentanil, buprenorphine, tramadol, and dextromethorphan are summarized. In 2016, the FDA issued a Drug Safety Communication concerning the association of opioids with serotonin syndrome, a toxicity associated with raised intra-synaptic concentrations of serotonin in the CNS, inhibition of serotonin reuptake, and activation of 5-HT receptors. Opioids may provoke serotonin toxicity especially if administered in conjunction with other serotonergic medications. The increasing use of opioid analgesics and widespread prescribing of antidepressants and psychiatric medicines, indicates the likelihood of an increased incidence of serotonin toxicity in opioid-treated patients.

Objective The aim of this study was to analyze whether physical exercise can contribute to improving the control and severity of exercise‐induced bronchospasm (EIB) in children and adolescents. Method This is a systematic review that used PubMed/Medline and Scopus databases as a search source, and using descriptors indexed to DeCS/Mesh. The articles were analyzed in three stages in the selection process. Methodological quality was assessed using the TESTEX scale. Result and discussion A total of 5867 articles were filtered in the initial search; however, only eight of these were included after the eligibility criteria. All presented improvements in cardiorespiratory fitness. Only two followed the international EIB diagnostic guidelines. Of these, only one described a reduction in FEV1 and considered that this improvement may influence the EIB response in children and adolescent athletes with a non‐asthmatic sample. Conclusion The studies analyzed in this review did not enable drawing a conclusion regarding the influence of physical exercise on EIB in asthmatics. The lack of clinical trials on EIB and physical exercise, as well as the difficulty in methodological standardization for EIB diagnosis evidence the lack of scientific knowledge in this area, serving as a stimulus for researchers to find more consolidated answers. Understanding the benefits of physical exercise in adolescents with EIB can provide treatment evolutions by changing the course of the disease status. There are reports of these benefits in the literature; however, due to the small number of trials, we cannot reach a concrete conclusion.

PurposeAsthma is a heterogeneous disease with a wide range of symptoms. Severe asthma exacerbations (SAEs) are characterized by worsening symptoms and bronchospasm requiring emergency department visits. In addition to conventional strategies for SAEs (inhaled β-agonists, anticholinergics, and systemic corticosteroids), another pharmacological option is represented by ketamine. We performed a systematic review to explore the role of ketamine in refractory SAEs.MethodsWe performed a systematic search on PubMed and EMBASE up to August 12th, 2021. We selected prospective studies only, and outcomes of interest were oxygenation/respiratory parameters, clinical status, need for invasive ventilation and effects on weaning.ResultsWe included a total of seven studies, five being randomized controlled trials (RCTs, population range 44–92 patients). The two small prospective studies (n = 10 and n = 11) did not have a control group. Four studies focused on adults, and three enrolled a pediatric population. We found a large heterogeneity regarding sample size, age and gender distribution, inclusion criteria (different severity scores, if any) and ketamine dosing (bolus and/or continuous infusion). Of the five RCTs, three compared ketamine to placebo, while one used fentanyl and the other aminophylline. The outcomes evaluated by the included studies were highly variable. Despite paucity of data and large heterogeneity, an overview of the included studies suggests absence of clear benefit produced by ketamine in patients with refractory SAE, and some signals towards side effects.ConclusionOur systematic review does not support the use of ketamine in refractory SAE. A limited number of prospective studies with large heterogeneity was found. Well-designed multicenter RCTs are desirable.

European Respiratory Society (ERS), British Thoracic Society/ Scottish Intercollegiate Guideline Network (BTS/SIGN), National Institute for Health and Care Excellence (NICE), and Global Initiative for Asthma (GINA) Guideline (date published) ERS (March 2021) BTS/SIGN (July 2019) NICE (March 2021) GINA (June 2022) Number of objective tests required for diagnosis 2 1 - 2 † 2 2 Suggested order in which objective tests should be done 1 Spirometry 2 BDR (if spirometry abnormal) 3 FeNO 4 Diurnal PEF × 2 weeks/ challenge test 1 Spirometry + BDR 2 Variability tests/ tests for eosinophilic inflammation or atopy 1 Spirometry 2 BDR (if spirometry obstructed) 3 FeNO 4 PEF variability 1 Spirometry/ PEF with BDR 2 Diurnal PEF × 2 weeks/ exercise challenge test Age range covered by diagnostic algorithm 5-16 years ≤18 years ≤ 17 years 5-≤ 16 years What do the guidelines say about under 5s? “We did not include children aged <5 years in these guidelines, because diagnostic tests for asthma on young children are rarely performed” “Consider monitored initiation of treatment or watchful waiting according to the assessed probability of asthma” “Treat symptoms based on observation and clinical judgment, and review the child on a regular basis” “A probability-based approach using symptom pattern during and between respiratory infections may be helpful” Sensitivity Specificity of algorithm ‡ Not available Not available Sensitivity (69%) Specificity (67%) Sensitivity (42%) Specificity (90%) † Where there is a high probability of asthma (based on symptoms) spirometry before and after starting preventer treatment is recommended ‡ From a Swiss study of children referred to outpatient clinic.9 A second study, which used an epidemiological definition for asthma, concluded that the NICE diagnostic algorithm should not be used in children9 BDR=bronchodilator response. Box 1 Diagnosing asthma History taking Asthma includes recurrent episodes of cough and wheeze and difficulty in breathing A history of only cough or wheeze or difficulty in breathing is not consistent with asthma In children with asthma, their cough is typically dry and especially noted on exercise and a few hours after the child has gone to sleep Features suggesting an alternative diagnosis in children include: daily symptoms, symptoms present since birth, and a persistent wet cough6 Personal history of eczema, hayfever, or food allergies marginally increase the likelihood of asthma A first degree family history of asthma modestly increases the likelihood of asthma Exposures that cause symptoms (eg, exposure to second hand smoke) can be sought but these exposures are common in all children and typically increase the odds of asthma by twofold, and so should not carry much weight when making a diagnosis.10 Examination Examination is usually normal (unless the child is having an asthma exacerbation). Tests All four guidelines (and NHS England’s 2021 National Bundle of Care for Children and Young People with Asthma) recommend that a clinical diagnosis should be supported by objective testing, ideally before starting preventer treatment because this may affect test results. Usually done twice daily over a two week period Airway calibre variability Other tests Bronchodilator response Spirometry before and after inhaling a short acting beta agonist Level of reversible airway obstruction Airway challenge, eg, with methacholine Spirometry before and after inhaling increasing concentrations or doses of a chemical known to induce bronchospasm Level of airway reactiveness Exercise test Spirometry before, during, and after exercise Level of airway reactiveness to exercise These tests can be carried out in children under 5 but usually only in centres with expertise Spirometry Guidelines recommend spirometry as the primary diagnostic test for children.

Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature.

The prevalence of asthma has been rising steadily for several decades, and continues to be a major public health and global economic burden due to both direct and indirect costs. Asthma is defined as chronic heterogeneous inflammatory diseases characterized by airway obstruction, mucus production and bronchospasm. Different endotypes of asthma are being recognized based on the distinct pathophysiology, genetic predisposition, age, prognosis, and response to remedies. Mucosal innate response to environmental triggers such as pollen, cigarette smoke, fragrances, viral infection, and house dust mite (HDM) are now recognized to play an important role in allergic asthma. HDM are the most pervasive allergens that co-habitat with us, as they are ubiquitous in-house dusts, mattress and bedsheets, and feed on a diet of exfoliated human skin flakes. Dermatophagoides pteronyssinus , is one among several HDM identified up to date. During the last decade, extensive studies have been fundamental in elucidating the interactions between HDM allergens, the host immune systems and airways. Moreover, the paradigm in the field of HDM-mediated allergy has been shifted away from being solely a Th2-geared to a complex response orchestrated via extensive crosstalk between the epithelium, professional antigen presenting cells (APCs) and components of the adaptive immunity. In fact, HDM have several lessons to teach us about their allergenicity, the complex interactions that stimulate innate immunity in initiating and perpetuating the lung inflammation. Herein, we review main allergens of Dermatophagoides pteronyssinus and their interactions with immunological sentinels that promote allergic sensitization and activation of innate immunity, which is critical for the development of the Th2 biased adaptive immunity to HDM allergens and development of allergic asthma.