IL-36 receptor agonist and antagonist imbalance drives neutrophilic inflammation in COPD.

Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and is further induced by a viral mimetic, whereas IL-36Ra is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ, thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, which was inhibited by exogenous IL-36Ra. The use of a therapeutic antibody that inhibits binding to the IL-36R attenuated IL-36γ-driven inflammation and cellular crosstalk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and have shown that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising therapeutic strategy in the treatment of COPD.

An online breathing and wellbeing programme (ENO Breathe) for people with persistent symptoms following COVID-19: a parallel-group, single-blind, randomised controlled trial.

BACKGROUND: There are few evidence-based interventions for long COVID; however, holistic approaches supporting recovery are advocated. We assessed whether an online breathing and wellbeing programme improves health related quality-of-life (HRQoL) in people with persisting breathlessness following COVID-19. METHODS: We conducted a parallel-group, single-blind, randomised controlled trial in patients who had been referred from one of 51 UK-based collaborating long COVID clinics. Eligible participants were aged 18 years or older; were recovering from COVID-19 with ongoing breathlessness, with or without anxiety, at least 4 weeks after symptom onset; had internet access with an appropriate device; and were deemed clinically suitable for participation by one of the collaborating COVID-19 clinics. Following clinical assessment, potential participants were given a unique online portal code. Participants were randomly assigned (1:1) to either immediate participation in the English National Opera (ENO) Breathe programme or to usual care. Randomisation was done by the research team using computer-generated block randomisation lists, with block size 10. The researcher responsible for randomisation was masked to responses. Participants in the ENO Breathe group participated in a 6-week online breathing and wellbeing programme, developed for people with long COVID experiencing breathlessness, focusing on breathing retraining using singing techniques. Those in the deferred group received usual care until they exited the trial. The primary outcome, assessed in the intention-to-treat population, was change in HRQoL, assessed using the RAND 36-item short form survey instrument mental health composite (MHC) and physical health composite (PHC) scores. Secondary outcome measures were the chronic obstructive pulmonary disease assessment test score, visual analogue scales (VAS) for breathlessness, and scores on the dyspnoea-12, the generalised anxiety disorder 7-item scale, and the short form-6D. A thematic analysis exploring participant experience was also conducted using qualitative data from focus groups, survey responses, and email correspondence. This trial is registered with ClinicalTrials.gov, NCT04830033. FINDINGS: Between April 22 and May 25, 2021, 158 participants were recruited and randomly assigned. Of these, eight (5%) individuals were excluded and 150 participants were allocated to a treatment group (74 in the ENO Breathe group and 76 in the usual care group). Compared with usual care, ENO Breathe was associated with an improvement in MHC score (regression coefficient 2·42 [95% CI 0·03 to 4·80]; p=0·047), but not PHC score (0·60 [-1·33 to 2·52]; p=0·54). VAS for breathlessness (running) favoured ENO Breathe participation (-10·48 [-17·23 to -3·73]; p=0·0026). No other statistically significant between-group differences in secondary outcomes were observed. One minor self-limiting adverse event was reported by a participant in the ENO Breathe group who felt dizzy using a computer for extended periods. Thematic analysis of ENO Breathe participant experience identified three key themes: (1) improvements in symptoms; (2) feeling that the programme was complementary to standard care; and (3) the particular suitability of singing and music to address their needs. INTERPRETATION: Our findings suggest that an online breathing and wellbeing programme can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. Mind-body and music-based approaches, including practical, enjoyable, symptom-management techniques might have a role supporting recovery. FUNDING: Imperial College London.

Symptomatic, biochemical and radiographic recovery in patients with COVID-19.

BACKGROUND: The symptoms, radiography, biochemistry and healthcare utilisation of patients with COVID-19 following discharge from hospital have not been well described. METHODS: Retrospective analysis of 401 adult patients attending a clinic following an index hospital admission or emergency department attendance with COVID-19. Regression models were used to assess the association between characteristics and persistent abnormal chest radiographs or breathlessness. RESULTS: 75.1% of patients were symptomatic at a median of 53 days post discharge and 72 days after symptom onset and chest radiographs were abnormal in 47.4%. Symptoms and radiographic abnormalities were similar in PCR-positive and PCR-negative patients. Severity of COVID-19 was significantly associated with persistent radiographic abnormalities and breathlessness. 18.5% of patients had unscheduled healthcare visits in the 30 days post discharge. CONCLUSIONS: Patients with COVID-19 experience persistent symptoms and abnormal blood biomarkers with a gradual resolution of radiological abnormalities over time. These findings can inform patients and clinicians about expected recovery times and plan services for follow-up of patients with COVID-19.

Pediatric Endobronchial Ultrasound-Transbronchial Needle Aspiration Under Conscious Sedation for Suspected Tuberculosis in London.

Tuberculosis (TB) is an important cause of childhood death and morbidity worldwide. The diagnosis in the pediatric population remains challenging due to the paucibacillary nature of the disease. Intrathoracic lymphadenopathy is one of the most common manifestations of primary disease but is often difficult to sample. A retrospective case review was performed of children (younger than 16 years) suspected with intrathoracic TB lymphadenopathy who underwent an endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) between January 2010 and 2020 in a London TB center. Ten children between 11 years 4 months and 15 years 9 months, with weights ranging from 48 to 95 kg, underwent EBUS-TBNA. All procedures were performed under conscious sedation with no reported complications. Six of 10 cases showed granulomas on rapid onsite histologic evaluation. Nine of 10 cases were confirmed to have Mycobacterium tuberculosis. Seven of 10 cases were culture positive with a mean turn-around time of 13.7 days; of these, 4 of 7 were smear positive. Six of 7 culture positive cases were also TB polymerase chain reaction (PCR) positive. TB PCR identified 2 further cases where microscopy and culture remained negative. One case had multidrug-resistant TB identified on TB PCR allowing early initiation of correct drug therapy. In our cohort, we show EBUS-TBNA is a safe and effective way of investigating intrathoracic TB lymphadenitis in children and a high diagnostic rate can be achieved. In high-resource settings, we should approach childhood TB with a standardized diagnostic approach and utilize EBUS-TBNA as a diagnostic modality. Samples should be sent for culture but also for molecular assays to timely identify TB and drug-resistant disease.