Heme oxygenase-1 as an important predictor of the severity of COVID-19.

BACKGROUND AND OBJECTIVE: A cytokine storm is caused by inflammatory cells, including pro-inflammatory macrophage phenotype (M1), and play a critical role in the pathogenesis of COVID-19, in which diffuse alveolar damage occurs in the lungs due to oxidative stress exposure. Heme oxygenase (HO)-1 is a stress-induced protein produced by the anti-inflammatory / anti-oxidative macrophage phenotype (M2), which also produces soluble CD163 (sCD163). In our study, we investigated and determined that serum HO-1 can be a predictive biomarker for assessing both the severity and the outcome of COVID-19 patients. METHOD: The serum concentrations of HO-1 and sCD163 of COVID-19 patients were measured on admission. The relationship between these biomarkers and other clinical parameters and outcomes were evaluated. RESULTS: Sixty-four COVID-19 patients (11 mild, 38 moderate, and 15 severe cases) were assessed. The serum HO-1 tended to increase (11.0 ng/mL vs. 24.3 ng/mL vs. 59.6 ng/mL with severity). Serum HO-1 correlated with serum lactate dehydrogenase (R = 0.422), C-reactive protein (R = 0.463), and the ground glass opacity (GGO) and consolidation score (R = 0.625) of chest computed tomography. The serum HO-1 showed a better area under the curve (AUC) for predicting ICU admission than the serum sCD163 (HO-1; 0.816 and sCD163; 0.743). In addition, composite parameters including serum HO-1 and the GGO and consolidation score showed a higher AUC for predicting ICU admission than the AUC of a single parameter. CONCLUSION: Clinically, serum HO-1, reflecting the activation of M2, could be a very useful marker for evaluating disease severity and predicting prognoses for COVID-19 patients. In addition, controlling activated M2 might be a preventative COVID-19 therapeutic target.

Clinical importance of serum heme oxygenase-1 measurement in patients with acute exacerbation of idiopathic pulmonary fibrosis triggered by coronavirus disease 2019.

A 70-year-old man diagnosed with idiopathic pulmonary fibrosis (IPF) one year earlier developed progressive exertional dyspnea 3 weeks after onset of coronavirus disease 2019 (COVID-19). High-resolution computed tomography showed new extensive ground-glass opacities with rapidly progressive honeycombing. Although he was diagnosed with acute exacerbation (AE) of IPF triggered by COVID-19 and received methylprednisolone pulse therapy twice within one month, there was no improvement of oxygenation and lung involvement. Three months after COVID-19 onset, it was decided to provide best supportive care. An AE of IPF as a sequela of COVID-19, which is recognized as macrophage activation syndrome, is fatal, and in this case, the measurement of serum heme oxygenase-1, which is a macrophage activation biomarker involved in pulmonary cellular protection against oxidative stress, was useful for tracking disease activity.

Persistence of Robust Humoral Immune Response in Coronavirus Disease 2019 Convalescent Individuals Over 12 Months After Infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits varying degrees of protective immunity conferred by neutralizing antibodies (nAbs). In this study, we report the persistence of nAb responses over 12 months after infection despite their decreasing trend noticed from 6 months. METHODS: The study included sera from 497 individuals who had been infected with SARS-CoV-2 between January and August 2020. Samples were collected at 6 and 12 months after onset. The titers of immunoglobulin (Ig)G to the viral nucleocapsid protein (NP) and receptor-binding domain (RBD) of the spike protein were measured by chemiluminescence enzyme immunoassay. The nAb titer was determined using lentivirus-based pseudovirus or authentic virus. RESULTS: Antibody titers of NP-IgG, RBD-IgG, and nAbs were higher in severe and moderate cases than in mild cases at 12 months after onset. Although the nAb levels were likely to confer adequate protection against wild-type viral infection, the neutralization activity to recently circulating variants in some of the mild cases (~30%) was undermined, implying the susceptibility to reinfection with the variants of concerns (VOCs). CONCLUSIONS: Coronavirus disease 2019 convalescent individuals have robust humoral immunity even at 12 months after infection albeit that the medical history and background of patients could affect the function and dynamics of antibody response to the VOCs.

Identification of serum prognostic biomarkers of severe COVID-19 using a quantitative proteomic approach.

The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.

The effect of the outbreak of COVID-19 on respiratory physicians and healthcare in Japan: Serial nationwide surveys by the Japanese Respiratory Society.

BACKGROUND: The impact of the outbreak of COVID-19 on the work of respiratory physicians in Japan has not yet been evaluated. The study investigates the impact of the outbreak on respiratory physicians' work over time and identifies problems to be addressed in the future. METHODS: We conducted a web-based survey of respiratory physicians in 848 institutions. The survey comprised 32 questions and four sections: Survey 1 (April 20, 2020), Survey 2 (May 27, 2020), Survey 3 (August 31, 2020), and Survey 4 (December 4, 2020). RESULTS: The mean survey response rate was 24.9%, and 502 facilities (59.2%) participated in at least one survey. The proportion of facilities that could perform PCR tests for diagnosis and more than 20 tests per day gradually increased. The percentage capable of managing extracorporeal membrane oxygenation (ECMO) or more than five ventilators did not increase over time. The proportion that reported work overload of 150% or more, stress associated with lack of personal protective equipment (PPE), and harassment or stigma in the surrounding community did not sufficiently improve. CONCLUSION: While there was an improvement in expanding the examination system and medical cooperation in the community, there was no indication of enhancement of the critical care management system. The overwork of respiratory physicians, lack of PPE, and harassment and stigma related to COVID-19 did not sufficiently improve and need to be addressed urgently.

Real-world evaluation of a computed tomography-first triage strategy for suspected Coronavirus disease 2019 in outpatients in Japan: An observational cohort study.

ABSTRACT: The Coronavirus disease 2019 pandemic continues to spread worldwide. Because of the absence of reliable rapid diagnostic systems, patients with symptoms of Coronavirus disease 2019 are treated as suspected of the disease. Use of computed tomography findings in Coronavirus disease 2019 are expected to be a reasonable method for triaging patients, and computed tomography-first triage strategies have been proposed. However, clinical evaluation of a computed tomography-first triage protocol is lacking.The aim of this study is to investigate the real-world efficacy and limitations of a computed tomography-first triage strategy in patients with suspected Coronavirus disease 2019.This was a single-center cohort study evaluating outpatients with fever who received medical examination at Yokohama City University Hospital, prospectively registered between 9 February and 5 May 2020. We treated according to the computed tomography-first triage protocol. The primary outcome was efficacy of the computed tomography-first triage protocol for patients with fever in an outpatient clinic. Efficacy of the computed tomography-first triage protocol for outpatients with fever was evaluated using sensitivity, specificity, positive predictive value, and negative predictive value. We conducted additional analyses of the isolation time of feverish outpatients and final diagnoses.In total, 108 consecutive outpatients with fever were examined at our hospital. Using the computed tomography-first triage protocol, 48 (44.9%) patients were classified as suspected Coronavirus disease 2019. Nine patients (18.8%) in this group were positive for severe acute respiratory syndrome coronavirus 2 using polymerase chain reaction; no patients in the group considered less likely to have Coronavirus disease 2019 tested positive for the virus. The protocol significantly shortened the duration of isolation for the not-suspected versus the suspected group (70.5 vs 1037.0 minutes, P < .001).Our computed tomography-first triage protocol was acceptable for screening patients with suspected Coronavirus disease 2019. This protocol will be helpful for appropriate triage, especially in areas where polymerase chain reaction is inadequate.

Hydroxychloroquine and chloroquine for treatment of coronavirus disease 19 (COVID-19): a systematic review and meta-analysis of randomized and non-randomized controlled trials.

BACKGROUND: Although the US government approved hydroxychloroquine (HCQ) and chloroquine (CQ) for hospitalized coronavirus disease 19 (COVID-19) patients, some studies denied efficacy of HCQ and CQ. We aimed to evaluate HCQ/CQ treatment for COVID-19. METHODS: Five databases were searched on April 15, 2020, without publication date restriction. We followed both Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology statement reporting recommendations. A random-model meta-analysis was conducted to pool odds ratio (OR) and hazard ratio (HR). The quality of evidence for each outcome and the final recommendation was assessed using the GRADE guidelines of the American College of Chest Physicians. RESULTS: We identified four randomized controlled trials (RCTs) and four observational studies with 2,063 COVID-19 cases. All-cause mortality was not affected by the administration of HCQ/CQ [OR: 1.05, 95% confidence interval (CI): 0.53-2.09, P=0.89]. No improvement of viral clearance was found neither by time-to-event analysis (HR: 1.19, 95% CI: 0.74-1.94, P=0.47) nor frequency on day 7 (OR: 1.47, 95% CI: 0.33-6.63, P=0.62). HCQ/CQ treatment increased the risk of the any adverse event with OR of 3.56 (95% CI: 1.62-7.83, P=0.002). CONCLUSIONS: HCQ/CQ failed to decrease the all-cause mortality (very low quality evidence) and did not improve viral clearance (low or very low quality evidence) but increased the risk of any adverse event (moderate quality evidence). Routine administration of HCQ/CQ for COVID-19 patients is not recommended (weak recommendation, Grade 2C).

Development of an Automated Chemiluminescence Assay System for Quantitative Measurement of Multiple Anti-SARS-CoV-2 Antibodies.

OBJECTIVES: Serological tests for COVID-19 have been instrumental in studying the epidemiology of the disease. However, the performance of the currently available tests is plagued by the problem of variability. We have developed a high-throughput serological test capable of simultaneously detecting total immunoglobulins (Ig) and immunoglobulin G (IgG) against nucleocapsid protein (NP) and spike protein (SP) and report its performance in detecting COVID-19 in clinical samples. METHODS: We designed and prepared reagents for measuring NP-IgG, NP-Total Ig, SP-IgG, and SP-Total Ig (using N-terminally truncated NP (ΔN-NP) or receptor-binding domain (RBD) antigen) dedicated automated chemiluminescent enzyme immunoassay analyzer AIA-CL1200. After determining the basal thresholds based on 17 sera obtained from confirmed COVID-19 patients and 600 negative sera, the clinical validity of the assay was evaluated using independent 202 positive samples and 1,000 negative samples from healthy donors. RESULTS: All of the four test parameters showed 100% specificity individually (1,000/1,000; 95%CI, 99.63-100). The sensitivity of the assay increased proportionally to the elapsed time from symptoms onset, and all the tests achieved 100% sensitivity (153/153; 95%CI, 97.63-100) after 13 days from symptoms onset. NP-Total Ig was the earliest to attain maximal sensitivity among the other antibodies tested. CONCLUSION: Our newly developed serological testing exhibited 100% sensitivity and specificity after 13 days from symptoms onset. Hence, it could be used as a reliable method for accurate detection of COVID-19 patients and to evaluate seroprevalence and possibly for surrogate assessment of herd immunity.

Current national policies for infant universal bacille Calmette-Guérin vaccination were associated with lower mortality from coronavirus disease 2019.

An exciting debate has emerged whether bacille Calmette-Guérin (BCG) vaccination is effective for the coronavirus disease 2019 (COVID-19) pandemic. Some advocated that BCG-vaccinated people are less suffered from the virus because BCG vaccination is recommendedin COVID-19 high burden countries. However, the others objected because this seemingly attractive relationship is explainable with confounding factors. In a multiple regression with 171 countries adjusting socioeconomical and climatic covariates, countries with current universal pediatric BCG policy were associated with 30-fold (95% confidence interval, 17-52) decrease of COVID-19 mortality per population compared to countries without the policy.

Outcome of early-stage combination treatment with favipiravir and methylprednisolone for severe COVID-19 pneumonia: A report of 11 cases.

Although the use of corticosteroids is not recommended in the World Health Organization statement for the treatment of coronavirus disease 2019 (COVID-19), steroid therapy may be indicated for critical cases in specific situations. Here, we report the successful treatment of 11 cases of severe COVID-19 pneumonia with favipiravir and methylprednisolone. All cases were severe and patients required oxygen administration or had a blood oxygen saturation ≤93% on room air. All were treated with favipiravir and methylprednisolone, and 10 of 11 patients responded well and required no further oxygen supplementation or ventilator management. This study shows the importance of the early-stage use of a combination of favipiravir and methylprednisolone in severe cases to achieve a favorable clinical outcome.