Efficacy of clarithromycin in patients with mild COVID-19 pneumonia not receiving oxygen administration: protocol for an exploratory, multicentre, open-label, randomised controlled trial (CAME COVID-19 study)

Introduction: The COVID-19 pandemic has emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, very few treatment strategy has been established for patients with mild COVID-19 who do not require oxygen administration. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza. In this study, we aim to evaluate the efficacy of clarithromycin in patients with mild COVID-19.Methods and analysis: This is an exploratory, multicentre, open-label, randomised controlled trial. This study was initiated in May 2021 and will end in July 2022. Patients with mild COVID-19 pneumonia who do not require oxygen administration will be enrolled and randomly assigned in a 1:1:1 ratio to group A (administration of clarithromycin 800 mg/day), group B (administration of clarithromycin 400 mg/day) or group C (standard treatment without clarithromycin). The planned number of enrolled patients is 60 (20 patients × three groups). The primary endpoint is the number of days required to improve the clinical symptoms as measured by the severity score. Secondary endpoints include days for recovery of the body temperature, proportion of patients with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers and pneumonia infiltrations.Ethics and dissemination: The study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported as journal publications.Trial registration number: jRCTs071210011

Infectious Pneumonia and Lower Airway Microorganisms in Patients with Rheumatoid Arthritis

The relationship between microorganisms present in the lower respiratory tract and the subsequent incidence of pneumonia in patients with rheumatoid arthritis is unclear. A retrospective cohort study was designed to include a total of 121 patients with rheumatoid arthritis who underwent bronchoscopy at three hospitals between January 2008 and December 2017. Data on patient characteristics, microorganisms detected by bronchoscopy, and subsequent incidences of pneumonia were obtained from electronic medical records. Patients were divided into groups based on the microorganisms isolated from the lower respiratory tract. The cumulative incidence of pneumonia was assessed using the Kaplan–Meier method, and decision tree analysis was performed to analyze the relation between the presence of microorganisms and the occurrence of pneumonia. The most frequently isolated microbes were Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae. Patients whose samples tested negative for bacteria or positive for normal oral flora were included in the control group. The rate of the subsequent incidence of pneumonia was higher in the P. aeruginosa group than in the control group (p = 0.026), and decision tree analysis suggested that P. aeruginosa and patient performance status were two important factors for predicting the incidence of pneumonia. In patients with rheumatoid arthritis, the presence of P. aeruginosa in the lower respiratory tract was associated with the subsequent incidence of pneumonia

A multicenter randomized controlled trial to evaluate the efficacy and safety of nelfinavir in patients with mild COVID-19

Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms

Multicenter, single-blind, randomized controlled study of the efficacy and safety of favipiravir and nafamostat mesilate in patients with COVID-19 pneumonia

Objectives: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19. Methods: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO2). Results: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO2 were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group. Conclusion: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO2 were observed in the combination group

The Impact of Ambient Environmental and Occupational Pollution on Respiratory Diseases

Ambient pollutants and occupational pollutants may cause and exacerbate various lung and respiratory diseases. This review describes lung and respiratory diseases in relation to ambient pollutants, particularly particulate matter (PM2.5), and occupational air pollutants, excluding communicable diseases and indoor pollutants, including tobacco smoke exposure. PM2.5 produced by combustion is an important ambient pollutant. PM2.5 can cause asthma attacks and exacerbations of chronic obstructive pulmonary disease in the short term. Further, it not only carries a risk of lung cancer and death, but also hinders the development of lung function in children in the long term. It has recently been suggested that air pollution, such as PM2.5, is a risk factor for severe coronavirus disease (COVID-19). Asbestos, which causes asbestosis, lung cancer, and malignant mesothelioma, and crystalline silica, which cause silicosis, are well-known traditional occupational pollutants leading to pneumoconiosis. While work-related asthma (WRA) is the most common occupational lung disease in recent years, many different agents cause WRA, including natural and synthetic chemicals and irritant gases. Primary preventive interventions that increase awareness of pollutants and reduce the development and exacerbation of diseases caused by air pollutants are paramount to addressing ambient and occupational pollution