Efficacy and safety of Lianhua Qingwen capsules combined with standard of care in the treatment of adult patients with mild to moderate COVID-19 (FLOSAN): protocol for a randomized, double-blind, international multicenter clinical trial.

Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).

Methacholine bronchial provocation test for assessment of bronchial hyperresponsiveness in preschool children.

BACKGROUND: Bronchial hyperresponsiveness (BHR) has not been extensively performed in preschool children, possibly because of the difficulty in cooperating with the tests. We sought to determine the usefulness and safety of methacholine bronchial provocation test (MCh-BPT) for BHR assessment in preschool children. METHODS: We recruited 252 preschool children (190 healthy and 62 with wheezing) who underwent MCh-BPT at baseline. MCh-BPT was re-scheduled in case initial attempts failed. Forced expiratory volumes in 0.5 (FEV0.5), 0.75 (FEV0.75) and one second (FEV1) were measured. We recorded the provocative dose causing 15% (PD15) or 20% reduction (PD20) in FEV0.5, FEV0.75 and FEV1, thus allowing for comparison of the diagnostic value of PD15 and PD20. RESULTS: A total of 209 children [156 (82.1%) healthy, 53 (85.5%) with wheezing] successfully completed MCh-BPT. Compared with healthy children, a significantly greater proportion of children with wheezing had measurable PD15FEV0.5, PD15FEV0.75 and PD15FEV1 (P<0.01), and PD20FEV0.5, PD20FEV0.75 and PD20FEV1 (P<0.05). The sensitivity was 92.5% and 94.3% for PD20FEV1, and PD15FEV1 and the specificity was 93.6% and 93.6% respectively, for discriminating asthmatic from healthy children. CONCLUSIONS: Most preschool children successfully and safely complete MCh-BPT, with higher success rate in larger age group. PD20FEV0.5 and PD20FEV0.75 can be surrogates of PD20FEV1 among children whose expiration lasted for less than one second. PD15 has a good diagnostic value as PD20 for diagnosing of BHR in preschool children, which are also more suitable for children five years old or elder.

Adenosine monophosphate is not superior to histamine for bronchial provocation test for assessment of asthma control and symptoms.

BACKGROUND: Adenosine monophosphate (AMP) may reflect airway inflammation and hyperresponsiveness, but relationship between AMP and histamine (His, a conventional stimulus) bronchial provocation test (BPT) in asthma is not fully elucidated. OBJECTIVES: To compare both BPTs and determine their utility in reflecting changes of asthmatic symptoms. METHODS: BPTs were performed in a cross-over fashion, at 2-4 day intervals. Cumulative doses eliciting 20% FEV1 fall (PD20 FEV1 ), diagnostic performance and adverse events (AEs) were compared. Patients with PD20 FEV1 lower than geometric mean were defined as responders, otherwise poor responders. Patients with uncontrolled and partly controlled asthma, who maintained their original inhaled corticosteroids therapy, underwent reassessment of airway responsiveness and asthmatic symptoms 3 and 6 months after. RESULTS: Nineteen uncontrolled, 22 partly controlled and 19 controlled asthmatic patients and 24 healthy subjects were recruited. Lower PD20 FEV1 geometric means were associated with poorer asthma control in His-BPT (0.424 µmol vs 1.684 µmol vs 3.757 µmol), but not AMP-BPT (11.810 µmol vs 7.781 µmol vs 10.220 µmol). Both BPTs yielded similar overall diagnostic performance in asthma (area under curve: 0.842 in AMP-BPT vs 0.850 in His-BPT). AEs, including wheezing and tachypnea, were similar and mild. Ten patients with uncontrolled and 10 partly controlled asthma were followed-up. At months 3 and 6, we documented an increase in PD20 FEV1 -AMP and PD20 FEV1 -His, which did not correlate with reduction asthmatic symptom scores. This overall applied in responders and poor responders of AMP-BPT and His-BPT. CONCLUSION: Despite higher screening capacity of well-controlled asthma, AMP-BPT confers similar diagnostic performance and safety with His-BPT. AMP-BPT might not preferentially reflect changes asthmatic symptoms.

Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis.

Little is known about the comparative diagnostic value of lung clearance index (LCI) and maximal mid-expiratory flow (MMEF) in bronchiectasis. We compared the diagnostic performance, correlation and concordance with clinical variables, and changes of LCI and MMEF% predicted during bronchiectasis exacerbations (BEs). Patients with stable bronchiectasis underwent history inquiry, chest high-resolution computed tomography (HRCT), multiple-breath nitrogen wash-out test, spirometry and sputum culture. Patients who experienced BEs underwent these measurements during onset of BEs and 1 week following antibiotics therapy. Sensitivity analyses were performed in mild, moderate and severe bronchiectasis. We recruited 110 bronchiectasis patients between March 2014 and September 2015. LCI demonstrated similar diagnostic value with MMEF% predicted in discriminating moderate-to-severe from mild bronchiectasis. LCI negatively correlated with MMEF% predicted. Both parameters had similar concordance in reflecting clinical characteristics of bronchiectasis and correlated significantly with forced expiratory flow in one second, age, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, ventilation heterogeneity and bilateral bronchiectasis. In exacerbation cohort (n = 22), changes in LCI and MMEF% predicted were equally minimal during BEs and following antibiotics therapy. In sensitivity analyses, both parameters had similar diagnostic value and correlation with clinical variables. MMEF% predicted is a surrogate of LCI for assessing bronchiectasis severity.