The Effect of Long-Term Azithromycin on Objective and Subjective Cough in Chronic Respiratory Disease: A Systematic Review and Meta-analysis of Randomised Controlled Trials and Noncomparative Studies.

INTRODUCTION: Azithromycin is an effective treatment for various respiratory conditions but its effect on cough is poorly understood. We synthesised data from randomised controlled trials (RCTs) and noncomparative studies (NCT) examining its effect on objective and subjective cough. METHODS: After prospective registration on PROSPERO, we searched MEDLINE, EMBASE, and CENTRAL for both RCTs and NCT trials examining the effect azithromycin on cough in respiratory disease. RESULTS: We identified 1240 studies of which 6 (4 RCTs and 2 NCT studies) were included in the meta-analysis, with a total of 275 patients. Azithromycin was associated with significant improvement in Leicester Cough Questionnaire scores at follow-up when compared to baseline scores (SMD = 0.62 [95% CI 0.12 to 1.12], p = 0.01). However, when only RCTs were synthesised, no significant effect was observed (SMD = 0.12 [95% CI - 0.36 to 0.60], p = 0.62). There was no significant reduction in cough severity VAS score (SMD = - 0.39 [95% CI - 0.92 to 0.14], p = 0.15). There was no significant reduction in objective cough count (SMD = - 0.41 [95% CI - 1.04 to 0.32], p = 0.09). CONCLUSION: Azithromycin therapy improves cough-related quality of life in various chronic respiratory diseases; however, there was no significant effect on cough outcomes when only data from RCTs were synthesised. We believe that to accurately identify which patients whose cough would benefit from azithromycin a large-scale clinical trial of patients with a broad spectrum of respiratory diseases, with sufficiently severe cough, should be undertaken with subgroup analysis of individual disease areas.

ERS International Congress 2023: highlights from the Respiratory Intensive Care Assembly.

Early career members of Assembly 2 (Respiratory Intensive Care) attended the 2023 European Respiratory Society International Congress in Milan, Italy. The conference covered acute and chronic respiratory failure. Sessions of interest to our assembly members and to those interested in respiratory critical care are summarised in this article and include the latest updates in respiratory intensive care, in particular acute respiratory distress syndrome and mechanical ventilation.

Digitally monitored inhaled therapy: a 'smart' way to manage severe asthma?

INTRODUCTION: One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a 'smart' inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. METHODS: Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics. RESULTS: 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). CONCLUSIONS: In severe asthma patients, 'smart' inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Examining the relationship between inflammatory biomarkers during COVID-19 hospitalization and subsequent long-COVID symptoms: A longitudinal and retrospective study.

INTRODUCTION: Long-COVID is a heterogeneous condition with a litany of physical and neuropsychiatric presentations and its pathophysiology remains unclear. Little is known about the association between inflammatory biomarkers, such as interleukin-6 (IL-6) and C-reactive protein (CRP) in the acute phase, and persistent symptoms after hospitalization in COVID-19 patients. METHODS: IL-6, CRP, troponin-T, and ferritin were analyzed at admission for all patients with COVID-19 between September 1, 2020 to January 10, 2021. Survivors were followed up 3-months following hospital discharge and were asked to report persistent symptoms they experienced. Admission data were retrospectively collected. Independent t-tests and Mann-Whitney U tests were performed. RESULTS: In a sample of 144 patients (62.5% male, mean Age 62 years [SD = 13.6]) followed up 3 months after hospital discharge, the commonest symptoms reported were fatigue (54.2%), breathlessness (52.8%), and sleep disturbance (37.5%). In this sample, admission levels of IL-6, CRP and ferritin were elevated. However, those reporting myalgia, low mood, and anxiety at follow-up had lower admission levels of IL-6 (34.9 vs. 52.0 pg/mL, p = .043), CRP (83 vs. 105 mg/L, p = .048), and ferritin (357 vs. 568 ug/L, p = .01) respectively, compared with those who did not report these symptoms. Multivariate regression analysis showed that these associations were confounded by gender, as female patients had significantly lower levels of IL-6 and ferritin on admission (29.5 vs. 56.1, p = .03 and 421.5 vs. 589, p = .001, respectively) and were more likely to report myalgia, low mood and anxiety, when compared to males. CONCLUSIONS: Our data demonstrate that female patients present more often with lower levels of inflammatory biomarkers on admission which are subsequently associated with long-term post-COVID symptoms, such as myalgia and anxiety, in those discharged from hospital with severe COVID-19. Further research is needed into the role of serum biomarkers in post-COVID prognostication.

Investigating the diagnostic utility of high-resolution oesophageal manometry in patients with refractory respiratory symptoms.

BACKGROUND: The interaction between the respiratory and gastrointestinal systems, and the role of the latter in the development of respiratory pathology, has been examined with a focus on gastro-oesophageal reflux disease (GORD). However, little data exists examining the link between oesophageal motility and respiratory disease. AIMS AND OBJECTIVES: In this study, we examined patterns in oesophageal motility using high-resolution oesophageal manometry (HROM) in patients with refractory respiratory symptoms. METHODS: Data were collected retrospectively for all patients that were investigated using HROM at a single centre for refractory respiratory symptoms between January 1st, 2011-December 1st, 2021. Patients were selected for investigation based on airway reflux symptoms, measured by the Hull Airways Reflux Questionnaire (HARQ). RESULTS: 441 patients were investigated with HROM (64% female, mean age = 56.5 [SD = 13.9]). The commonest diagnoses of these patients were Chronic Cough (77%, n = 339), Asthma (10%, n = 44), and Interstitial Lung Disease (7%, n = 29). The prevalence of oesophageal dysmotility was 66% in our cohort. Those with oesophageal dysmotility had significantly higher HARQ scores than those with normal motility (40.6 vs 35.3, p < 0.001) and there was a significant inverse correlation between HARQ scores and distal contractile integral (DCI), a measure of oesophageal contractility. CONCLUSIONS: Two-thirds of patients with refractory respiratory symptoms were found to have oesophageal dysmotility on HROM. These findings suggest motility disorders of the oesophagus may contribute to the development and progression of respiratory disease. This study highlights the need for further prospective study of the relationship between oesophageal dysmotility and respiratory disease.

ATP, an attractive target for the treatment of refractory chronic cough.

Chronic cough is the most common complaint in respiratory clinics. Most of them have identifiable causes and some may respond to common disease-modifying therapies. However, there are many patients whose cough lacks effective aetiologically targeted treatments or remains unexplained after thorough assessments, which have been described as refractory chronic cough. Current treatments for refractory chronic cough are limited and often accompanied by intolerable side effects such as sedation. In recent years, various in-depth researches into the pathogenesis of chronic cough have led to an explosion in the development of drugs for the treatment of refractory chronic cough. There has been considerable progress in the underlying mechanisms of chronic cough targeting ATP, and ongoing or completed clinical studies have confirmed the promising antitussive efficacy of P2X3 antagonists for refractory cough. Herein, we review the foundation on which ATP target was developed as potential antitussive medications and provide an update on current clinical progresses.

Treatment of chronic cough: P2X3 receptor antagonists and beyond.

For years chronic cough (CC) has presented an enormous physical, psychological, and social burden on those who experience it, with no approved pharmacological therapies to assuage their symptoms. With our improved understanding of the pathophysiological mechanisms of CC, primarily the recognition of neuronal dysregulation in its aetiology, there appears to be a new hope for such patients. In this review we discuss the multitude of proposed pharmacological targets in CC, including the promising results produced by the antagonism of P2X3 receptors. We also assess the evidence of other peripherally acting pharmacolgical agents still in development.

Chronic cough-the limitation and advances in assessment techniques.

Accurate and consistent assessments of cough are essential to advance the understanding of the mechanisms of cough and individualised the management of patients. Considerable progress has been made in this work. Here we reviewed the currently available tools for subjectively and objectively measuring both cough sensitivity and severity. We also provided some opinions on the new techniques and future directions. The simple and practical Visual Analogue Scale (VAS), the Leicester Cough Questionnaire (LCQ), and the Cough Specific Quality of Life Questionnaire (CQLQ) are the most widely used self-reported questionnaires for evaluating and quantifying cough severity. The Hull Airway Reflux Questionnaire (HARQ) is a tool to elucidate the constellation of symptoms underlying the diagnosis of chronic cough. Chemical excitation tests are widely used to explore the pathophysiological mechanisms of the cough reflex, such as capsaicin, citric acid and adenosine triphosphate (ATP) challenge test. Cough frequency is an ideal primary endpoint for clinical research, but the application of cough counters has been limited in clinical practice by the high cost and reliance on aural validation. The ongoing development of cough detection technology for smartphone apps and wearable devices will hopefully simplify cough counting, thus transitioning it from niche research to a widely available clinical application.

Outcomes and characteristics of COVID-19 patients treated with continuous positive airway pressure/high-flow nasal oxygen outside the intensive care setting.

BACKGROUND: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been used to manage hypoxaemic respiratory failure secondary to coronavirus disease 2019 (COVID-19) pneumonia. Limited data are available for patients treated with noninvasive respiratory support outside of the intensive care setting. METHODS: In this single-centre observational study we observed the characteristics, physiological observations, laboratory tests and outcomes of all consecutive patients with COVID-19 pneumonia between April 2020 and March 2021 treated with noninvasive respiratory support outside of the intensive care setting. RESULTS: We report the outcomes of 140 patients (mean±sd age: 71.2±11.1, 65% male (n=91)) treated with CPAP/HFNO outside of the intensive care setting. Overall mortality was 59% and was higher in those deemed unsuitable for mechanical ventilation (72%). The mean age of survivors was significantly lower than those who died (66.1 versus 74.4 years, p<0.001). Those who survived their admission also had a significantly lower median Clinical Frailty Score than the non-survivor group (2 versus 4, p<0.001). We report no significant difference in mortality between those treated with CPAP (n=92, mortality: 60%) or HFNO (n=48, mortality: 56%). Treatment was well tolerated in 86% of patients receiving either CPAP or HFNO. CONCLUSIONS: CPAP and HFNO delivered outside of the intensive care setting are viable treatment options for patients with hypoxaemic respiratory failure secondary to COVID-19 pneumonia, including those considered unsuitable for invasive mechanical ventilation. This provides an opportunity to safeguard intensive care capacity for COVID-19 patients requiring invasive mechanical ventilation.

The Cough Reflex: The Janus of Respiratory Medicine.

In clinical practice, we commonly face adversity when encountering dysfunction of the cough reflex. Similar to ancient Roman deity Janus, it often presents with one of two opposing "faces". Continual aberrant activation of the cough reflex, also known as chronic cough, can cause great detriment to quality of life and many of these patients are left misdiagnosed and undertreated. In contrast, loss of normal functioning of the cough reflex is the cause of a significant proportion of mortality in the elderly, primarily through the development of aspiration pneumonia. In this review we discuss both hyper- and hypo-activation of the cough reflex and how airway reflux and chronic aspiration may be involved in the aetiology and sequalae of both disease states. We detail the physiological and pharmacological mechanisms involved in cough, and how the recent development of P2X3 receptor antagonists may lead to the first pharmaceutical agent licensed for chronic cough. The treatment and prevention of loss of the cough reflex, which has been largely neglected, is also discussed as novel low-cost interventions could help prevent a number of hospital and domiciliary deaths from both acute and chronic aspiration.

COVID-19 progression, frailty, and use of prolonged continuous positive airway pressure as a ward-based treatment: Lessons to be learnt from a case.

Coronavirus disease 19 (COVID-19) poses the greatest public health threat in 100 years, with cases rising rapidly in many countries around the world. We report a case of a 78-year-old female who exhibited a biphasic course of COVID-19; showing initial clinical improvement followed by deterioration before making a full recovery. The patient was managed with prolonged continuous positive airway pressure (CPAP) and supportive care. In total, 24 days of treatment with CPAP was administered. We emphasize the role of CPAP in the management of severely hypoxemic patients who are inappropriate for mechanical ventilation and describe the role of adequate nutrition and hydration for such patients.

Post-COVID-19 Symptom Burden: What is Long-COVID and How Should We Manage It?

The enduring impact of COVID-19 on patients has been examined in recent studies, leading to the description of Long-COVID. We report the lasting symptom burden of COVID-19 patients from the first wave of the pandemic. All patients with COVID-19 pneumonia discharged from a large teaching hospital trust were offered follow-up. We assessed symptom burden at follow-up using a standardised data collection technique during virtual outpatient clinic appointments. Eighty-six percent of patients reported at least one residual symptom at follow-up. No patients had persistent radiographic abnormalities. The presence of symptoms at follow-up was not associated with the severity of the acute COVID-19 illness. Females were significantly more likely to report residual symptoms including anxiety (p = 0.001), fatigue (p = 0.004), and myalgia (p = 0.022). The presence of long-lasting symptoms is common in COVID-19 patients. We suggest that the phenomenon of Long-COVID may not be directly attributable to the effect of SARS-CoV-2, and believe the biopsychosocial effects of COVID-19 may play a greater role in its aetiology.

Impact of COVID-19 on COPD and asthma admissions, and the pandemic from a patient's perspective.

There has been a significant reduction in all-cause and exacerbation-related #asthma and #COPD admissions during the #COVID19 pandemic. Patients also report a subjective decline in disease control and describe a negative impact on their mental health. https://bit.ly/2Kv0O0H.

Objective Assessment of Cough: An Early Marker of Response to Biological Therapies in Asthma?

Cough is an important symptom of asthma. The objective assessment of chronic cough has been enhanced by the development of ambulatory cough monitoring systems. Mepolizumab has been demonstrated to reduce exacerbations in eosinophilic asthmatics long-term. We evaluate the utility of objective cough count as an outcome measure in severe eosinophilic asthma treated with mepolizumab. Consecutive, consenting patients initiated on treatment with mepolizumab had a 24-h cough count recorded at baseline; this was repeated at 1, 3 and 6 months. Asthma control questionnaire (ACQ) scores and exacerbation frequency were also recorded. The mean 24-h cough count in 11 subjects (8 females, mean age 53.6 years) was 172.4 at baseline; at 1, 3 and 6 months following initiation of treatment this decreased to 101.4, 92 and 70.8, respectively (p < 0.02). Significant improvements were also observed in mean ACQ score (3-1.6, p < 0.01) and exacerbation frequency (5.5 per year - 1.3, p < 0.01). Objective cough measurement could be used as an early, precise and clinically relevant endpoint in assessing response to asthma therapy.