The effects of vaccination on the disease severity and factors for viral clearance and hospitalization in Omicron-infected patients :A retrospective observational cohort study from recent regional outbreaks in China (preprint)

ABSTRACT Object It remains unelucidated regarding the effects of vaccination on disease severity and factors for viral clearance and hospitalization in omicron-infected patients. Methods The clinical manifestations of 3,265 Omicron-infected patients (BA.2 variant; the Omicron group) were compared with those of 226 Delta-infected patients (the Delta group).A Multi-class logistic regression model was employed to analyze the impacts of vaccination doses and intervals on disease severity; a logistic regression model to evaluate the risk factors for hospitalization; R 4.1.2 data analysis to investigate the factors for time for nucleic acid negativization (NAN). Results Compared with the Delta group, the Omicron group reported a fast transmission, mild symptoms, and lower severity incidence, and a significant inverse correlation of vaccination dose with clinical severity (OR: 0.803, 95%CI: 0.742-0.868, p<0.001). Of the 7 or 5 categories of vaccination status, the risk of severity significantly decreased only at ≥21 days after three doses (OR: 0.618, 95% CI: 0.475-0.803, p<0.001; OR: 0.627, 95% CI: 0.482-0.815, p<0.001, respectively). The Omicron group also reported underlying illness as an independent factor for hospitalization, sore throat as a protective factor, and much shorter time for NAN [15 (12,19) vs. 16 (12,22), p<0.05]. NAN was associated positively with age, female gender, fever, cough, and disease severity, but negatively with vaccination doses. Conclusion Booster vaccination should be advocated for COVID-19 pandemic-related control and prevention policies and adequate precautions should be taken for patients with underlying conditions.

The effects of altered PK/PD parameters on efficacy and toxicity of therapeutic drugs in critically ill patients with COVID-19 (preprint)

Although many therapies have been proposed, there is no evidence of any effective treatment for COVID-19 to date. Currently, the main therapies being used to treat the critically patients with COVID-19 are antiviral drugs, chloroquine/hydroxychloroquine and respiratory therapy. Pharmacokinetics (PK) and pharmacodynamics (PD) play an important role in different clinical situations, and are keys to balance the effect (reduction of SARS-CoV-2 virus and symptom improvement) and toxicity (adverse effects). Critically ill patients always have altered PK and PD due to multiple factors such as hypoproteinemia, organ dysfunction, and organ support treatment including continuous renal replacement therapy (CRRT), and extracorporeal membrane oxygenation (ECMO). Here we provide an overview of the effects of the clinical treatments for critically COVID-19 patients and the pathological state of patients on pharmacokinetics and pharmacodynamics parameters of therapeutic drugs in detail. However, current evidence is insufficient to speculate the changes of drug concentration of antimicrobials, therapeutic drug monitoring (TDM) is a useful tool used in severe patients since many suspected factors were exist to influence the clinical responses and adverse drug reactions of drugs.

A need of COVID19 vaccination for children aged <12 years: Comparative evidence from the clinical characteristics in patients during a recent Delta surge (B.1.617.2) (preprint)

Objective: To evaluate the necessity of Covid-19 vaccination in children aged < 12 y by comparing the clinical characteristics in unvaccinated children aged < 12 y with vaccinated patients aged > 12y during the Delta surge (B.1.617.2) in Putian, Fujian, China. Methods: A total of 226 patients with SARS-Cov-2 Delta variant (B.1.167.2; confirmed by Realtime PCR positive and sequencing) were enrolled from Sep 10th to Oct 20th, 2021, including 77 unvaccinated children (aged < 12y) and 149 people aged > 12y, mostly vaccinated. The transmission route was explored and the clinical data of two groups were compared;the effect factors for the time of the nucleic acid negativization (NAN) were examined by R statistical analysis. Results: The Delta surge in Putian spread from children in schools to factories, mostly through family contact. Compared with those aged; 12y, patients aged < 12y accounted for 34.07% of the total and showed milder fever, less cough and fatigue; they reported higher peripheral blood lymphocyte counts [1.84(1.32,2.71)x 10^9/L vs. 1.31(0.94,1.85)x 10^9/L; p<0.05), higher normal CRP rate (92.21% vs. 57.72%), lower IL-6 levels [5.28(3.31,8.13) vs. 9.10(4.37,15.14); p<0.05]. Upon admission, their COVID19 antibodies (IgM and IgG) and IgG in convalescence were lower [0.13(0.00,0.09) vs. 0.12(0.03,0.41), p<0.05; 0.02(0.00,0.14) vs. 1.94(0.54,6.40), p <0.05; 5.46(2.41,9.26) vs. 73.63 (54.63,86.55), p<0.05, respectively], but longer NAN time (18 days vs. 16 days, p=0.13). Conclusion: Children aged < 12y may be critical hidden spreaders, which indicates an urgent need of vaccination for this particular population.

CD4+ T cell lymphopenia and dysfunction in severe COVID-19 disease is autocrine TNF-α/TNFRI-dependent (preprint)

Lymphopenia is common in severe COVID-19 disease, yet the mechanisms are poorly understood. In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared to recovered, mild disease (p<0.0001). In severe disease, immunodominant CD4+ T cell responses to Spike-1(S1) produced increased in vitro TNF-, but impaired proliferation and increased susceptibility to activation-induced cell death (AICD). CD4+TNF-+ T cell responses inversely correlated with absolute CD4+ counts from severe COVID-19 patients (n=76; R=-0.744, P<0.0001). TNF- blockade including infliximab or anti-TNFRI antibodies strikingly rescued S1-specific CD4+ proliferation and abrogated S1-AICD in severe COVID-19 patients (P<0.001). Single-cell RNAseq demonstrated downregulation of Type-1 cytokines and NF{kappa}B signaling in S1-stimulated CD4+ cells with infliximab treatment. Lung CD4+ T cells in severe COVID-19 were reduced and produced higher TNF- versus PBMC. Together, our findings show COVID-19-associated CD4+ lymphopenia and dysfunction is autocrine TNF-/TNFRI-dependent and therapies targeting TNF- may be beneficial in severe COVID-19.

Role of Darunavir/cobicisitat in the Treatment of COVID-19: Initial Virological and Clinical Findings (preprint)

Background: COVID-19 still become a common threat to public health.In this study, we evaluated the antiviral effects and safety of darunavir/cobicisitat (DRV/c) in patients with confirmed COVID-19. Patients and Methods: Totally 66 patients with COVID-19 infection who were admitted to Zhongnan Hospital of Wuhan University between February 3 and March 11, 2020 were collected. The patients were divided into the DRV/c group and the control group. The Primary endpoints was the time of SARS-CoV-2 nucleic acid conversion detected in respiratory specimens.Results: A total of 66 subjects with confirmed SARS-CoV-2 infection were enrolled in this study, 32 subjects were enrolled in the DRV/c group and 34 in the control group. The mean time to nucleic acid conversion (NAC) was shorter in DRV/c group. The cumulative nucleic acid conversion rate (CNACR) in the DRV/C group was higher during the first 2 weeks, but the difference was not statistically significant. The proportion of fever during hospitalization in the DRV/C group was significantly lower than that in the control group (P value 0.01). It was found that in DRV/c group NAC of patients with duration from symptom onset to admission within 3 days was significantly shorter (7.9 ± 6.7 days) than that of and above 3 days (15.9 ± 7.1 days)( P = 0.01). Conclusion: Although the combination of DRV/c and routine treatment for patients with non-severe COVID-19 can significantly reduce the proportion of fever after admission, but no significant differences were observed between the DRV/c group and the conventional therapy group, including overall time to nucleic acid conversion, safety and tolerability. 

Detection of SARS-CoV-2 nucleic acid in CSF by ultrahigh depth sequencing in a patient with COVID-19 and neurological dysfunction: a case report (preprint)

Background: SARS-Coronavirus-2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), not only infects the respiratory tract, but also other organs. About a third of the inpatients of COVID-19 have neurological symptoms and in vitro experiments revealed that SARS-CoV-2 could infect human neural progenitor cells and brain organoids. However, the traditional test often reports negative owing to the low number of virus in the cerebrospinal fluid. To date, timely diagnosis of central nervous system infection of SARS-CoV-2 remains a challenge.Case presentation: On day 14 of COVID-19, seizures, maxillofacial convulsions, intractable hiccups and significant increase in intracranial pressure developed in a 56-year-old man. The RT-PCR of SARS-CoV-2 was negative. SARS-CoV-2 nucleic acid were detected in cerebrospinal fluid (CSF) by ultrahigh depth sequencing. The patient was successfully treated after 14 days of mechanical ventilation and treatment of pneumonia and neurological dysfunction.Conclusions: This case suggests SARS-CoV-2 can invade the central nervous system and relevant examinations with CSF including ultrahigh depth sequencing of SARS-CoV-2 are needed among COVID-19 patients with neurological dysfunction.

Clinical Characteristics Hospitalized Patients with SARS-Cov-2 and HBV Co-infection (preprint)

Background & Aims The coronavirus disease 2019 (COIVD-19) caused by SARS-CoV-2 has been characterized as a pandemic, which causes a serious public health challenge in the world. A very large group of patients infected by HBV has been reported worldwide, especially in China. In order to answer whether specific treatment strategy on the patients coinfected with HBV and SARS-CoV-2, it requires profound understanding of the clinical characteristics on those patients. However, the impacts of SARS-CoV-2 infection on HBV patients remain largely unknown. Approach & Results In this retrospective investigation, we included 123 COVID-19 patients admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from January 5 to March 7, 2020. All enrolled patients are the laboratory confirmed COVID-19 pneumonia cases according to the criteria reported previously. A total of 123 patients were analyzed for their Clinical records, laboratory results including the diagnosis of HBV infection and liver function. Among 123 confirmed COVID-19 patients, the mean age was 51 years old and 59.3% were females (73/123). Fifteen were previously HBV infected patients, 66.7% of them were males (10/15), patients with HBV infection appeared to have a higher incidence of liver cirrhosis and an increased level of total bilirubin. Seven (46.7%) patients with HBV infection were defined as severe cases, while the severity rate was 24.1% for the patients without HBV infection (26/108). The mortality of patients with HBV infection was 13.3% (2/15) compared to 2.8% (3/108) for the patients without HBV infection. Conclusions SARS-CoV-2 infection may cause liver function damage in COVID-19 cases and the patients with HBV infection are likely to have more severe disease outcome.

Hypertension and Diabetes Delay the Viral Clearance in COVID-19 Patients (preprint)

Objectives: Comorbidities have significant indications for the disease outcome of COVID-19, however which underlying diseases that contribute the most to aggravate the conditions of COVID-19 patients is still largely unknown. SARS-CoV-2 viral clearance is a golden standard for defining the recovery of COVID-19 infections. To dissect the underlying diseases that could impact on viral clearance, we enrolled 106 COVID-19 patients who were hospitalized in the Zhongnan Hospital of Wuhan University, Wuhan, China between Jan 5 and Feb 25, 2020. Methodology: We comprehensively analyzed demographic, clinical and laboratory data, as well as patient treatment records. Survival analyses with Kaplan-Meier and Cox regression modelling were employed to identify factors influencing the viral clearance negatively. Results: We found that increasing age, male gender, and angiotensin-converting enzyme 2 (ACE2) associated factors (including hypertension, diabetes, and cardiovascular diseases) adversely affected the viral clearance. Furthermore, analysis by a random forest survival model pointed out hypertension, cortisone treatment, gender, and age as the four most important variables. Conclusions: We conclude that patients at old age, males, and/or having diseases associated with high expression of ACE2 will have worse prognosis during a COVID-19 infections.

Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients (preprint)

Background: Viral clearance is one important indicator for the recovery of SARS-CoV-2 infected patients. Suboptimal T and B cell responses can delay viral clearance in MERS and SARS patients. The role of leukomonocytes in viral clearance of COVID-19 patients is not yet well defined.Methods: From January 26 to February 28, 2020, an observational study was launched at Zhongnan Hospital of Wuhan University, Wuhan, China. We enrolled 25 laboratory-confirmed COVID-19 patients, whose throat-swab specimens were tested positive for SARS-CoV-2 infection by qRT-PCR. We comprehensively analyzed clinical records, counts of lymphocyte subsets including CD3+, CD4+, CD8+ T cells, B cells and NK cells in the patients who successfully cleared SARS-CoV-2, and compared to those that failed to, after a standardized treatment of 8-14 days. Findings: In 25 enrolled COVID-19 patients, lymphopeniawas a common feature. After the treatment, 14 patients were tested negative for SARS-CoV-2. The patients that cleared the infection had restored the numbers of CD3+, CD4+, CD8+ T cellsand B cells as compared to the still viral RNA positive patients, while the recovered patients had a higher count of leukomonocytes. Conclusions: By comparison of leukomonocytes counts in COVID-19 patients at different stages of the disease, we found that CD3+, CD4+, CD8+ T cells and B cells appear to play important roles in viral clearance. The restoration of leukomonocytes counts from peripheral blood can be used as prognosis for the recovery of an COVID-19 infection. We propose that restoration of leukomonocytes counts can be added to the COVID-19 diagnostic guidanceas a criterion for releasing and discharging patients.

Highly ACE2 Expression in Pancreas May Cause Pancreas Damage After SARS-CoV-2 Infection (preprint)

The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in the end of 2019 in China has triggered a global public health crisis. Previous studies have shown that SARS-CoV-2 infects cells by binding angiotensin-converting enzyme 2 (ACE2), which is the same as SARS-CoV. The expression and distribution of ACE2 in the pancreas are unknown. At the same time, the injury of pancreas after SARS-CoV-2 infection has not been concerned. Here, we collected public datasets (bulk RNA-seq and single-cell RNA-seq) to indicate the expression and the distribution of ACE2 in pancreas (in both exocrine glands and islets). And further, clinical data including mild and severe patients with COVID-19 demonstrated there existed mild pancreatitis. In the 67 severe cases, 11 patients (16.41%) showed elevated levels of both amylase and lipase, and 5 patients (7.46%) showed imaging alterations. Only one patient (1.85%) showed elevated levels of both amylase and lipase in 54 mild cases, without imaging changes. Our study revealed the phenomenon and possible cause of mild pancreatic injury in patients with COVID-19. This suggests that pancreatitis after SARS-CoV-2 infection should also be paid attention in clinical work.

Prediction of the Epidemic of COVID-19 Based on Quarantined Surveillance in China (preprint)

Background and Objective: To predict the epidemic of COVID-19 based on quarantined surveillance from real world in China by modified SEIR model different from the previous simply mathematical model. Design and Methods: We forecasted the epidemic of COVID-19 based on current clinical and epidemiological data and built a modified SEIR model to consider both the infectivity during incubation period and the influence on the epidemic from strict quarantined measures. Results: The peak time of the curve for the infected newly diagnosed as COVID-19 should substantially present on Feb.5,2020(in non-Hubei areas) and Feb.19,2020(in Hubei. It is estimated that the peak of the curve of the cumulative confirmed cases will appear in non-Hubei areas on Mar.3,2020 and in Hubei province on Mar.10,2020,and the total number of the patients diagnosed as COVID-19 is 18,000 in non-Hubei areas and 78,000-96,000 in Hubei.The Chinese COVID-19 epidemic can be completely controlled in May,2020. Conclusions: COVID-19 is only a local outbreak in Hubei Province,China.It can be probably avoided the pandemic of global SARS-CoV-2 cases rise with the great efforts by Chinese government and its people.

Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China ;Clinical Infectious Diseases ;Oxford Academic

Background Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China. This study aimed to clarify the characteristics of patients with refractory COVID-19. Methods In this retrospective single-center study, we included 155 consecutive patients with confirmed COVID-19 in Zhongnan Hospital of Wuhan University from January 1st to February 5th. The cases were divided into general and refractory COVID-19 groups according to the clinical efficacy after hospitalization, and the difference between groups were compared. Results Compared with general COVID-19 patients (45.2%), refractory patients had an older age, male sex, more underlying comorbidities, lower incidence of fever, higher levels of maximum temperature among fever cases, higher incidence of breath shortness and anorexia, severer disease assessment on admission, high levels of neutrophil, aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and C-reactive protein, lower levels of platelets and albumin, and higher incidence of bilateral pneumonia and pleural effusion (P<0.05). Refractory COVID-19 patients were more likely to receive oxygen, mechanical ventilation, expectorant, and adjunctive treatment including corticosteroid, antiviral drugs and immune enhancer (P<0.05). After adjustment, those with refractory COVID-19 were also more likely to have a male sex and manifestations of anorexia and fever on admission, and receive oxygen, expectorant and adjunctive agents (P<0.05) when considering the factors of disease severity on admission, mechanical ventilation, and ICU transfer. Conclusion Nearly 50% COVID-19 patients could not reach obvious clinical and radiological remission within 10 days after hospitalization. The patients with male sex, anorexia and no fever on admission predicted poor efficacy.