COVID-19 severity and corticosteroid treatment have minimal effect on specific antibody production (preprint)

Background Dexamethasone is currently administered for Coronavirus disease 2019(COVID-19); however, there are concerns about its effect on specific antibodies’ production. The aim of this study was to evaluate whether specific antibodies were affected by COVID-19 severity and corticosteroid treatment.Methods Of 251 confirmed COVID-19 patients admitted to our hospital between January 26 and August 10, 2020, the early period of the pandemic, 75 patients with sera within 1 month of onset and 1month or longer were included in the research. A total of 253 serum samples from these patients were collected. The levels of specific antibodies for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), immunoglobulin G (IgG) and M (IgM), were measured retrospectively. The results were compared separately of each COVID-19 severity, and with or without corticosteroid treatment.Results Among the 75 patients, 47, 18, and 10 had mild, moderate, and severe disease, respectively. The median age was 53.0 years and 22 (29%) were women. The most common comorbidities were hypertension and dyslipidemia. Corticosteroids were administered to 20 (27%) and 10 (53%), patients with moderate and severe disease, respectively. The positivity rates IgM increased first, and IgG was almost always positive after day 16, regardless of the severity of COVID-19. On days 6–10, both IgG and IgM positivity rates were higher in patients with moderate disease than in those with mild or severe disease. In patients with moderate disease, IgG positivity was similar over time, regardless of corticosteroid treatment.Conclusions In COVID-19 patients, specific IgG is positive and maintained for a long period of time, even after corticosteroid treatment. The effect of corticosteroid treatment in a COVID-19 epidemiological study using specific IgG antibodies was considered minor. COVID-19 patients were more likely to receive oxygen if IgM was positive 1 week after onset, but not mechanical ventilation. IgM measurement 1 week after onset may predict COVID-19 severity.

Comparative Effectiveness of Tocilizumab vs Standard Care in Patients with severe COVID-19–related Pneumonia: A retrospective cohort study utilizing registry data as a synthetic control (preprint)

Background The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. Therefore, this study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan.Methods This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP) data, with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study’s primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge.Results For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% CI: 0.565 to 2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596 to 2.075), 0.628 (95% CI: 0.202 to 1.953), and 1.019 (95% CI: 0.555 to 1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582 to 1.230).Conclusions Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistical differences, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups in other clinical outcomes.

Post COVID-19 condition of the Omicron variant of SARS-CoV-2 (preprint)

BackgroundNo epidemiological data on post coronavirus disease (COVID-19) condition due to Omicron variant has been reported yet. MethodsThis was as a single-center, cross-sectional study, that interviewed via telephone the patients who recovered from Omicron COVID-19 infection (Omicron group), and surveyed via self-reporting questionnaire those patients infected with other strains (control group). Data on patients characteristics, information regarding the acute-phase COVID-19, as well as presence and duration of COVID-19-related symptoms were obtained. Post COVID-19 condition in this study was defined as a symptom that lasted at least 2 months within 3 months since the onset of COVID-19. We investigated and compared the prevalence of post COVID-19 condition in both groups after performing propensity score matching. ResultsWe conducted interviews for 53 out of 128 patients with Omicron, and obtained 502 responses in the control group. After matching, 18 patients each in Omicron and control group had improved covariate balance of the older adult, female sex, obese patients, and vaccination status. There were no significant differences in the prevalence of each post-acute COVID-19 symptoms between the two groups. The numbers of patients with at least one post-acute COVID-19 symptom in the Omicron and the control group were 1 (5.6%) and 10 (55.6%) (p=0.003), respectively. ConclusionThe prevalence of post Omicron COVID-19 conditions was less than that of the other strains. Further research with more participants is needed to investigate the precise epidemiology of post COVID-19 condition of Omicron, and its impact on health-related quality of life and social productivity.

Predictive Model of Risk Factors of High Flow Nasal Cannula Using Machine Learning in COVID-19 (preprint)

Background: With the rapid increase in the number of COVID-19 patients in Japan, the number of patients receiving oxygen at home has also increased rapidly, and some of these patients have died. An efficient approach to identify high-risk patients with slowly progressing and rapidly worsening COVID-19, and to avoid missing the timing of therapeutic intervention will improve patient prognosis and prevent medical complications. Methods: Patients admitted to medical institutions in Japan from November 14, 2020 to April 11, 2021 and registered in the COVID-19 Registry Japan were included. Risk factors for patients with High Flow Nasal Cannula invasive respiratory management or higher were comprehensively explored using machine learning. Age-specific cohorts were created, and severity prediction was performed for the patient surge period and normal times, respectively. Results: We were able to obtain a model that was able to predict severe disease with a sensitivity of 57% when the specificity was set at 90% for those aged 40-59 years, and with a specificity of 50% and 43% when the sensitivity was set at 90% for those aged 60-79 years and 80 years and older, respectively. We were able to identify lactate dehydrogenase level (LDH) as an important factor in predicting the severity of illness in all age groups. Discussion: Using machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. Using machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. We plan to develop a tool that will be useful in determining the indications for hospitalisation for patients undergoing home care and early hospitalisation.

Risk Factors Associated with Development and Persistence of Long COVID: A Cross-Sectional Study (preprint)

Background: Long coronavirus disease (COVID) has been a social concern. Though patient characteristics associated with the development of long COVID are partially known, those associated with its persistence have not been identified. Methods: We conducted a cross-sectional questionnaire survey of patients after COVID-19 recovery who visited the National Center for Global Health and Medicine between February 2020 and March 2021. Demographic and clinical data and data regarding the presence and duration of long COVID were obtained. We identified factors associated with the development and persistence of long COVID using multivariate logistic and linear regression analysis, respectively. Results: We analyzed 457 of 526 responses (response rate, 86.9%). The median age was 47 years, and 378 patients (84.4%) had mild disease in the acute phase. The number of patients with any symptoms after 6 and 12 months after onset or diagnosis were 120 (26.3%) and 40 (8.8%), respectively. Women were at risk for development of fatigue (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.31-3.14), dysosmia (OR: 1.91, 95% CI: 1.24-2.93), dysgeusia (OR: 1.56, 95% CI: 1.02-2.39), and hair loss (OR: 3.00, 95% CI: 1.77-5.09) and for persistence of any symptoms (coefficient: 38.0, 95% CI: 13.3-62.8). Younger age and low body mass index were risk factors for developing dysosmia (OR: 0.96, 95% CI: 0.94-0.98 and OR: 0.94, 95% CI: 0.89-0.99, respectively) and dysgeusia (OR: 0.98, 95% CI: 0.96-1.00 and OR: 0.93, 95% CI: 0.88-0.98, respectively). Conclusion: We identified risk factors for the development and persistence of long COVID. Many patients suffer from long-term residual symptoms, even in mild cases.

Risk factors associated with development and persistence of long COVID (preprint)

BackgroundLong COVID has been a social concern. Though patient characteristics associated with developing long COVID are partially known, those associated with persisting it have not been identified. MethodsWe conducted a cross-sectional questionnaire survey of patients after COVID-19 recovery who visited the National Center for Global Health and Medicine between February 2020 and March 2021. Demographic and clinical data, and the presence and duration of long COVID were obtained. We identified factors associated with development and persistence of long COVID using multivariate logistic and linear regression analysis, respectively. ResultsWe analyzed 457 of 526 responses (response rate, 86.9%). The median age was 47 years, and 378 patients (84.4%) had mild disease in acute phase. The number of patients with any symptoms after 6 and 12 months after onset or diagnosis were 120 (26.3%) and 40 (8.8%), respectively. Women were at risk for development of fatigue (OR 2.03, 95% CI 1.31-3.14), dysosmia (OR 1.91, 95% CI 1.24-2.93), dysgeusia (OR 1.56, 95% CI 1.02-2.39), and hair loss (OR 3.00, 95% CI 1.77-5.09), and were at risk for persistence of any symptoms (coefficient 38.0, 95% CI 13.3-62.8). Younger age and low body mass index were risk factors for developing dysosmia (OR 0.96, 95% CI 0.94-0.98, and OR 0.94, 95% CI 0.89-0.99, respectively) and dysgeusia (OR 0.98, 95% CI 0.96-1.00, and OR 0.93, 95% CI 0.88-0.98, respectively). ConclusionWe identified risk factors for the persistence as well as development of long COVID. Many patients suffer from long-term residual symptoms, even in mild cases. SummaryOur cross-sectional questionnaire survey of patients recovering from COVID-19 revealed that women, young age, and low body mass index were risk factors for the development of multiple symptoms, and that even mild cases of COVID-19 suffered from long-term residual symptoms.

Smoking, Comorbidities, and Severity of Disease in Hospitalized COVID-19 Patients in Japan (preprint)

Background: The aim of this study was to identify associations between smoking status and the severity of COVID-19 using a large-scale data registry of hospitalized COVID-19 patients in Japan (COVIREGI-JP) and to explore the reasons for the inconsistent results previously reported on this subject. Methods: The analysis included 17,702 COVID-19 inpatients aged 20-89 years (10,279 men and 7,423 women). We graded the severity of COVID-19 (grade 0 to 5) according to the most intensive treatment required during hospitalization. Associations of smoking status with severe grade 3/4/5 (invasive mechanical ventilation/extracorporeal membrane oxygenation/death) and separately with grade 5 (death) were analyzed using multiple logistic regression with grade 0 (no oxygen) as the control group. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and other factors considering the potential intermediate effects of comorbidities.Findings: Among men, former smoking significantly increased the risk of grade 3/4/5 and grade 5, with age-adjusted ORs (95% CI) of 1·50 (1·18-1·90) and 1·65 (1·23-2·21), respectively. An additional adjustment for comorbidities weakened these ORs to 1·29 (1·00-1·66) and 1.41 (1·01-1·95), respectively. Similar results were seen for women. Current smoking did not significantly increase the risk of grade 3/4/5 and grade 5 in either sex.Interpretation: Smoking cessation should be recommended even if the observed relationship between current smoking and the severity of COVID-19 is null because current smoking increases the risks of future comorbidities due to different diseases that increase the risk of severe COVID-19.Funding Information: This research was funded by the Health and Labour Sciences Research grant (19HA1003, 20CA2031) and the National Center for Global Health and Medicine (20A-3002).Declaration of Interests: All authors report no conflict of interest.Ethics Approval Statement: This study was approved by the National Center for Global Health and Medicine (NCGM) ethics review (NCGM-G-003494-0).

Risk factors for severity on admission and the disease progression during hospitalization in a large cohort of COVID-19 patients in Japan (preprint)

Objectives: To investigate the risk factors contributing to severity on admission. Additionally, risk factors on worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity, and fatality. Design: A observational cohort study utilizing data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP. Setting: As of August 31, 2020, 7,546 cases from 780 facilities have been registered. Participating facilities cover a wide range of hospitals where COVID-19 patients are admitted in Japan. Participants: Participants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests, and were admitted to participating healthcare facilities. A total of 3,829 cases were identified from January 16 to May 31, 2020, of which 3,376 cases were included in this study. Primary and secondary outcoe measures: Primary outcome was severe or non-severe on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2, or respiratory rate. Secondary outcome was the worst severity during hospitalization, judged by the requirement of oxygen and/or IMV/ECMO. Results: Risk factors for severity on admission were older age, male, cardiovascular disease, chronic respiratory disease, diabetes, obesity, and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumor, and hyperlipidemia did not influence severity on admission ; however it influenced worst severity. Fatality rates for obesity, hypertension, and hyperlipidemia were relatively lower. Conclusions: This study segregated the comorbidities driving severity and death. It is possible that risk factors for severity on admission, worst severity, and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidemia, and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation. Trial registration: UMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453

Evaluation of serum antibodies against SARS-CoV-2 in healthcare workers who participated in the operation of charter flights for the evacuation of Japanese residents from Hubei Province (preprint)

There are several recommendations for the use of personal protective equipment (PPE) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the selection of appropriate PPE for the current situation remains controversial. We measured serum antibody titers for SARS-CoV-2 in 10 participants who were engaged in the operation of charter flights for the evacuation of Japanese residents from Hubei Province. All participants wore PPE in accordance with Centers for Disease Control and Prevention guidelines. A total of 17 samples were tested, and all were seronegative. Hence, we conclude that the current PPE recommendation is effective to protect healthcare workers from SARS-CoV-2 infection.

Efficacy of remdesivir in hospitalised COVID-19 patients in Japan: A large observational study using the COVID-19 Registry Japan (preprint)

Objectives Although several randomised controlled trials have compared the efficacy of remdesivir with that of placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. Methods We evaluated the efficacy of remdesivir on the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalised COVID-19 patients in Japan. Two regimens (start remdesivir therapy within 4 days from admission vs. no remdesivir during hospitalisation) among patients without the need for supplementary oxygen therapy were compared by a three-step processing (cloning, censoring, and weighting) method. The primary outcome was supplementary oxygen requirement during hospitalisation. Secondary outcomes were 30-day fatality risk and risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). Results The data of 12,657 cases met our inclusion criteria. The ‘start remdesivir’ regimen showed a lower risk of supplementary oxygen requirement (hazard ratio: 0.861, p < 0.001). Both 30-day fatality risk and risk of IMV/ECMO introduction were not significantly different between the two regimens (hazard ratios: 1.05 and 0.886, p values: 0.070 and 0.440, respectively). Conclusions Remdesivir might reduce the risk of oxygen requirement during hospitalisation in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction of IMV/ECMO requirement.

An open-label, randomized, controlled trial to evaluate the efficacy of convalescent plasma therapy for COVID-19.