Associations of COVID-19 Symptoms with Omicron Subvariants BA.2 and BA.5, Host Status, and Clinical Outcomes: A Registry-Based Observational Study in Sapporo, Japan (preprint)

Background: Previous SARS-CoV-2 infection and vaccination, coupled to rapid evolution of SARS-CoV-2 variants, have modified COVID-19 clinical manifestations. We characterized clinical symptoms of COVID-19 individuals in omicron BA.2 and BA.5 Japanese pandemic periods to identify omicron and subvariant associations between symptoms, immune status, and clinical outcomes. Methods: Individuals registered in Sapporo's web-based COVID-19 information system entered 12 pre-selected symptoms, days since symptom onset, vaccination history, SARS-CoV-2 infection history, and background. Symptom frequencies, variables associated with symptoms, and symptoms associated with progression to severe disease were analysed. Results: For all omicron-infected individuals, cough was the most common symptom (62.7%), followed by sore throat (60.7%), nasal discharge (44.3%), and fever (38.8%). Omicron BA.5 infection was associated with a higher symptom burden than BA.2 in vaccinated and unvaccinated individuals. Omicron breakthrough-infected individuals with 3 or more vaccinations or previous infection were less likely to exhibit systemic symptoms, but more likely to exhibit upper respiratory symptoms. Infected elderly individuals had lower odds for all symptoms, but, when symptoms were manifest, systemic symptoms were associated with an increased risk, whereas upper respiratory symptoms with a decreased risk, of severe disease. Conclusion: Host immunological status, omicron subvariant, and age were associated with a spectrum of COVID-19 symptoms and outcomes. BA.5 produced a greater symptom burden than BA.2. Vaccination and prior infection mitigated systemic symptoms and improved outcomes, but increased upper respiratory tract symptom burden. Systemic, but not upper respiratory, symptoms in the elderly heralded severe disease.

Incidence, Risk Factors, and Clinical Impact of Major Bleeding in Hospitalized Patients with COVID-19: A Sub-analysis of the CLOT-COVID Study (preprint)

Background: The coronavirus disease 2019 (COVID-19) causes extensive coagulopathy and a potential benefit of anticoagulation therapy has been documented for prevention of thromboembolic events. Bleeding events has also been reported as a notable complication; whereas, the incidence, risks, and clinical impact of bleeding remain unclear.Method: The CLOT-COVID Study was a nationwide, retrospective, multicenter cohort study on consecutive hospitalized patients with COVID-19 in Japan between April 2021 and September 2021. In this sub-analysis, we compared the characteristics of patients with and without major bleeding; moreover, we examined the risk factors for and clinical impact of bleeding events.Results: Among 2882 patients with COVID-19, 57 (2.0%) had major bleeding. The incidence of major bleeding increased with COVID-19 severity as follows: 0.5%, 2.3%, and 12.3% in patients with mild, moderate, and severe COVID-19, respectively. COVID-19 severity, history of major bleeding, and anticoagulant type/dose were independently and additively associated with the bleeding incidence. Compared with patients without major bleeding, those with major bleeding exhibited a longer duration of hospitalization (9 [6-14] vs 28 [19-43] days, P<0.001) and higher mortality during hospitalization (4.9% vs. 35.1%, P<0.001).Conclusions: In the real-world clinical practice, the incidence of major bleeding was not uncommon, especially in patients with severe COVID-19. Independent risk factors for major bleeding included history of major bleeding, COVID-19 severity, and anticoagulant use, which could be associated with poor clinical outcomes including higher mortality. Precise recognition of the risks for bleeding may be helpful for an optimal use of anticoagulants and for better outcomes in patients with COVID-19. 

Remdesivir in combination with immunomodulators improves respiratory status in COVID-19: A retrospective study (preprint)

Background: Although immunomodulators (tocilizumab or baricitinib) have been shown to improve outcomes in patients with coronavirus disease (COVID-19), the additive effect of remdesivir is unknown. We retrospectively tested the effect of remdesivir in combination with immunomodulators and standard treatments in COVID-19 patients.Methods: A retrospective, single-center study was conducted on patients with COVID-19 admitted to the Hokkaido University Hospital between April 2020 and September 2021, who were treated with either tocilizumab or baricitinib. The duration to achievement of oxygen-free in both groups was compared, and the effect of remdesivir use on respiratory status was examined through multivariate analysis. The severity of respiratory status in the two groups on day 14 and day 28 was compared. A sensitivity analysis using propensity score was also performed.Results: We enrolled 98 patients who received either tocilizumab or baricitinib. Of these, 72 patients used remdesivir (remdesivir group) and 26 did not (control group). Most cases were severe and treated with concomitant steroids. The remdesivir group had faster recovery of respiratory status compared to the control group (11 days vs. 26 days, P=0.033). Multivariate analysis showed that remdesivir use contributed to shorter time to being oxygen-free (hazard ratio [HR] = 2.33, 95 % confidence interval [CI] 1.17 – 4.46, P=0.016). Age, body mass index, diabetes mellitus, and time from onset to oxygen administration were independent prognostic factors. The remdesivir group achieved higher rate of oxygen free than the control group at days 14 and 28 after treatment (P=0.033, P=0.003, respectively). The degree of improvement from baseline severity was also higher in the remdesivir group (day 14; P=0.047, day 28; P=0.018). The survival time between two groups was not significantly different (HR = 0.55, 95 %CI 0.10 – 2.99, P=0.49). Similarly, the propensity score-matched patient groups showed the efficacy of remdesivir. Conclusions: Among patients with COVID-19 who used immunomodulator containing tocilizumab or baricitiib, remdesivir contributed to shorter respiratory recovery time and better respiratory status at days 14 and 28. Concomitant use of remdesivir may contribute to improved respiratory status in patients on immunomodulator and standard treatment.

Comparative efficacy of tocilizumab and baricitinib in COVID-19 treatment: a retrospective cohort study (preprint)

Background: Although the biological agents tocilizumab and baricitinib have been shown to improve the outcomes of patients with COVID-19, a comparative evaluation has not been performed. The aim of our study was to evaluate the comparative effect of the use of tocilizumab and baricitinib on patient outcomes in COVID-19. Methods A retrospective, single-center study was conducted using the data of patients with COVID-19 admitted to Hokkaido University hospital between April 2020 and September 2021 and were treated with tocilizumab or baricitinib. The clinical characteristics of the patients who received each drug were compared. Univariate and multivariate logistic regression analyses were performed against the outcomes of all-cause mortality and the improvement in respiratory status. The development of secondary infection events was analyzed using the Kaplan–Meier method and the log-rank test. Results Among the 459 patients hospitalized with COVID-19 during the study, 64 received tocilizumab and 34 received baricitinib, and they were included in the study. Most patients were treated with concomitant steroids, and the severity of the disease at the time of initiation of biological agents was similar. The use of tocilizumab or baricitinib was not associated with all-cause mortality or the improvement in respiratory status within 28 days of drug administration. Age, chronic renal disease, and comorbid respiratory disease were independent prognostic factors for all-cause mortality, whereas anti-viral drug use and severity of COVID-19 at baseline were associated with the improvement in respiratory status. There was no significant difference in the infection-free survival rate between patients treated with tocilizumab and those with baricitinib. Conclusion There were no differences in efficacy and safety between tocilizumab and baricitinib in the treatment of COVID-19. Both these biological agents are expected to be equally safe and clinically effective.

Comparative efficacy of tocilizumab and baricitinib in COVID-19 treatment: a retrospective cohort study (preprint)

Summary Background Although biological agents, tocilizumab and baricitinib, have been shown to improve the outcomes of patients with COVID-19, a comparative evaluation has not been performed. Methods A retrospective, single-center study was conducted using the data of patients with COVID-19 admitted to the Hokkaido University hospital between April 2020 and September 2021, who were treated with tocilizumab or baricitinib. The clinical characteristics of patients who received each drug were compared. Univariate and multivariate logistic regression models were performed against the outcomes of all-cause mortality and the improvement in respiratory status. The development of secondary infection events was analyzed using the Kaplan–Meier analysis and the log-rank test. Results The use of tocilizumab or baricitinib was not associated with all-cause mortality and the improvement in respiratory status within 28 days of drug administration. Age, chronic renal disease, and comorbid respiratory disease were independent prognostic factors for all-cause mortality, while anti-viral drug use and severity of COVID-19 at baseline were associated with the improvement in respiratory status. There was no significant difference in the infection-free survival between patients treated with tocilizumab and those with baricitinib. Conclusion There were no differences in efficacy and safety between tocilizumab and baricitinib for the treatment of COVID-19.

C-Reactive Protein Level Predicts Need For Medical Intervention In Pregnant Women With SARS-CoV2 Infection: A Retrospective Study (preprint)

Background: During the Coronavirus disease 2019 (COVID-19) pandemic, many hospitals experienced a shortage of hospital beds. To make effective use of the limited available hospital space during the pandemic, we conducted this study to investigate the laboratory indices that identify pregnant women with SARS-CoV2 infection who require medical intervention. Methods: We carried out a retrospective analysis of pregnant women positive for COVID-19 who were admitted to Hokkaido University Hospital from September 2020 to June 2021. Medical interventions included oxygen supplementation, systemic corticosteroids, or supplemental liquids to treat infection-related symptoms. Results: Forty-two infected pregnant patients were admitted to the hospital, half of whom required medical intervention (n = 21). Fever, C-reactive protein , and platelet count are all associated with need for medical intervention. Of the 32 patients with a fever of ≥37.5℃ on days 0–3 after onset of syndromes, 22 (69%) continued to have a fever on days 4–6, of which 19 (86.4%) required medical intervention. C-reactive protein level and platelet count on days 4–6 predicted the presence or absence of medical intervention (area under the receiver operating characteristic curve = 0.913, and 0.856, respectively), with a sensitivity of 81% and specificity of 100% at a C-reactive protein cutoff of 1.28 mg/dL, with a sensitivity of 75% and specificity of 87% at a platelet count cutoff of 16.3 × 10⁴/μL. Conclusions: The need for medical intervention in pregnant patients can be predicted with high accuracy using a C-reactive protein cutoff of 1.28 mg/dL on days 4–6 after onset of syndromes. The presence of fever also may be an easy marker for selecting subjects who need or will need therapeutic intervention. These could be an effective triage method to determine appropriate indications for the hospitalization of pregnant women in future outbreaks.

Performance of qualitative and quantitative antigen tests for SARS-CoV-2 in early symptomatic patients using saliva (preprint)

Background: The rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an urgent need for the prevention and containment of disease outbreaks in communities. Although the gold standard is polymerase chain reaction (PCR), antigen tests such as immunochromatographic assay (ICA) and chemiluminescent enzyme immunoassay (CLEIA) that can yield results within 30 minutes. Methods: We evaluated performance of ICA and CLEIA using 34 frozen PCR-positive specimens (17 saliva and 17 nasopharyngeal swab) and 307 PCR-negative samples. Results: ICA detected SARS-CoV-2 in only 14 (41%) samples, with positivity of 24% in saliva and 59% in NPS. Notably, ICA detected SARS-CoV-2 in 5 (83%) of 6 samples collected within 4 days after symptom onset. CLEIA detected SARS-CoV-2 in 31 (91%) samples, with positivity of 82% in saliva and 100% in NPS. CLEIA was negative in 3 samples with low viral load by PCR. Conclusions: These results suggest that use of ICA should be limited to earlier time after symptom onset and CLEIA is more sensitive and can be used in situations where quick results are required.

Equivalent SARS-CoV-2 viral loads between nasopharyngeal swab and saliva in symptomatic patients (preprint)

COVID-19 is diagnosed by detecting SARS-CoV-2 by nasopharyngeal swab (NPS) using real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Emerging evidences have shown the utility of saliva, although conflicting results have been reported regarding viral loads between NPS and saliva. We conducted a study to compare the viral loads in 42 patients with COVID-19. Both NPS and saliva specimens were simultaneously obtained at a median of 6 days (range, 1-12) after symptom onset. SARS-CoV-2 was detected in 34 (81%) using NPS (median Ct value [IQR]=27.4 [21.3, 35.6]) and 38 (90%) using saliva (median Ct value [IQR]= 28.9 [23.1, 33.6]). There was no significance difference between them (Wilcoxon signed rank test: P=0.79) and Kendalls W was 0.82, showing a high degree of agreement, indicating equivalent viral loads in NPS and saliva. After symptom onset, the Ct values of both NPS and saliva continued to increase over time, with no substantial difference. Self-collected saliva has a detection sensitivity comparable to that of NPS and is a useful diagnostic tool with mitigating uncomfortable process and the risk of aerosol transmission to healthcare workers.

Proposal of COVID-19 Clinical Risk Score for the management of suspected COVID-19 cases: a case control study (preprint)

BackgroundNo clinical scoring system has yet been established to estimate the likelihood of COVID-19 and to determine the suitability of diagnostic testing in suspected COVID-19 patients.MethodsThis was a single-center, retrospective, observational study of patients with suspected COVID-19 and confirmed COVID-19. Patient background, clinical course, laboratory and CT findings, and the presence of alternative diagnoses were evaluated. Clinical risk scores were developed based on clinical differences between patients with and those without COVID-19.ResultsAmong 110 patients suspected of COVID-19, 60.9% underwent PCR testing based on the judgment of physicians. Two patients were found to have COVID-19. The clinical characteristics of 108 non-COVID-19 patients were compared with those of 23 confirmed COVID-19 patients. Patients with COVID-19 were more likely to have a history of high-risk exposures and abnormal sense of taste and smell. Significantly higher rates of subnormal white blood cell count, lower eosinophil count, and lower procalcitonin level were observed in the COVID-19 group than in the non-COVID-19 group. When blood tests, CT findings, and the presence of alternative diagnoses were scored on an 11-point scale, i.e., “COVID-19 Clinical Risk Score”, the COVID-19 group scored significantly higher than the non-COVID-19 group, with more than four points in the COVID-19 group. All non-COVID cases that did not undergo PCR had a score of 4 or less.ConclusionsThe COVID-19 Clinical Risk Score enables risk classification of patients suspected of having COVID-19 and can help in decision-making in clinical practice, including appropriateness of diagnostic testing. 

Older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples (preprint)

PCR testing of nasopharyngeal swab samples is used for the diagnosis of coronavirus disease 2019 (COVID-19) and for determining timing of discharge. The viral load usually declines at convalescent phase, but sometimes remained positive for a long time even after relief of symptoms. In this study, we identified older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples.

Efficacy of a novel SARS-CoV-2 detection kit without RNA extraction and purification (preprint)

Rapid detection of SARS-CoV-2 is critical for the diagnosis of coronavirus disease 2019 (COVID-19) and preventing the spread of the virus. A novel "2019 Novel Coronavirus Detection Kit (nCoV-DK)" halves detection time by eliminating the steps of RNA extraction and purification. We evaluated concordance between the nCoV-DK and direct PCR. The virus was detected in 53/71 fresh samples by the direct method and 55/71 corresponding frozen samples by the nCoV-DK. The overall concordance rate of the virus detection between the two methods was 94.4% (95% CI, 86.2-98.4). Concordance rates were 95.2% (95% CI, 83.8-99.4), 95.5% (95% CI, 77.2-99.9), 85.7% (95% CI, 42.1-99.6) in nasopharyngeal swab, saliva, and sputum samples, respectively. These results indicate that the nCoV-DK effectively detects SARS-CoV-2 in all types of the samples including saliva, while reducing time required for detection, labor, and risk of human error.

Comparison of SARS-CoV-2 detection in nasopharyngeal swab and saliva (preprint)

We prospectively compared the efficacy of PCR detection of SARS-CoV-2 between paired nasopharyngeal and saliva samples in 76 patients including ten COVID-19 patients. The overall concordance rate of the virus detection between the two samples was 97.4% (95%CI, 90.8-99.7). Viral load was equivalent in COVID-19 patients, but the virus tended to disappear earlier in saliva at convalescent phase compared to nasopharyngeal samples. These results suggest that saliva is a reliable noninvasive alternative to nasopharyngeal swabs and facilitate widespread PCR testing in the face of shortages of swabs and protective equipment without posing a risk to healthcare workers.