Prevalence and distribution of hepatitis C among high-risk populations in Pudong New Area, Shanghai City / 中华传染病杂志

Objective:To investigate the prevalence of positive hepatitis C virus (HCV) antibody, HCV RNA and genotype distribution of HCV in high-risk populations in Pudong New Area, Shanghai City, so that to provide evidence for making "hepatitis C micro elimination" strategies in Shanghai area.Methods:A survey with proportional sampling method was conducted among the high-risk populations, including people who inject drugs (PWID), voluntarily or compulsorily accepted drug detoxification or methadone treatment, human immunodeficiency virus voluntary counseling and testing (HIV VCT) outpatients, sexually transmitted disease (STD) outpatients, and commercial sex workers, who participated in the routine physical examination activities held by the community health service centers and public hospitals of Pudong New Area from July 2021 to November 2022. The residual plasma samples were collected from medical examinations. HCV antibody was tested in all samples. HCV RNA and HCV genotype were tested in samples with positive HCV antibody results.Results:A total of 1 000 HCV high-risk people were screened, including 453 PWID, 166 human immunodeficiency virus (HIV) infectors, 245 STD outpatients, and 136 commercial sex workers. The positive rates of HCV antibody in the four categories of personnel were 21.85%(99/453), 1.81%(3/166), 1.22%(3/245) and 0(0/136), respectively. The positive rate of HCV RNA was 42.68%(35/82) among HCV antibody positive people in high-risk populations. As much as 74.29%(26/35) of HCV RNA positive people had junior high school education or less, and 77.14%(27/35) of them were not married. Among the 12 samples tested for HCV genotype, five were genotype 3, five were genotype 6, and two were subtype 1b.Conclusions:PWID is the main high-risk HCV infection population, who should be the target of the following "hepatitis C micro elimination" strategies. The proportions of genotype 3 and genotype 6 are high in the high-risk HCV infection populations, and the pan-genotype direct-acting antiviral agent treatment may be more suitable in this situation. HCV infected persons in high-risk groups have low education level and marriage rate, which indicates that education and care in community are needed.

Diagnostic value of neutrophil CD64 index in disseminated nontuberculous mycobacteria infection / 中华传染病杂志

Objective:To investigate the diagnostic value of neutrophil CD64 index (nCD64) in disseminated nontuberculous mycobacteria (NTM) infection.Methods:Thirty-six patients with NTM infection from January 2020 to June 2021 in Huashan Hospital, Fudan University were included. Patients were classified into groups of disseminated infection and focal infection according to their medical history and discharge diagnosis. The expressions of nCD64 in patients with focal infection and disseminated infection before treatment were collected and analyzed. Statistical analysis was performed using the Mann-Whitney U test, and the diagnostic value of nCD64 for disseminated NTM infection was analyzed using the receiver operator characteristic curve (ROC curve). Results:Among the 36 patients with NTM infection, 18 cases were focal infection (due to the low white blood cell count of the patient with myelodysplastic syndrome, the detection results were biased, which were excluded from the subsequent analysis) and 18 cases were disseminated infection. The expression of nCD64 in focal infection was 0.72(0.50, 1.55), and that in disseminated infection was 13.63(6.77, 32.31). The difference was statistically significant ( U=15.50, P<0.001). Using focal infection as a control, the area under the ROC curve for the operational characteristics of the subjects was 0.949 3 for disseminated NTM infection. The diagnostic cut-off value of nCD64 was 3.06, with the sensitivity and specificity of the disseminated NTM infection were 88.89% and 100.00%, respectively. Conclusions:In patients with NTM infection before effective treatment, the diagnostic cut-off value of nCD64 of 3.06 has high sensitivity and specificity, which is useful for the aided diagnosis of disseminated NTM infection.

Prognostic value of systemic immune-inflammation index in patients with hepatitis B virus-related acute-on-chronic liver failure / 中华传染病杂志

Objective:To investigate the prognostic value of systemic immune-inflammation index (SII) in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).Methods:The clinical data, including age, gender, complications, laboratory examination results post-admission, SII, model for end-stage liver disease (MELD) score, MELD-Na score, Child-Turcotte Pugh (CTP) score of HBV-ACLF patients treated in Huashan Hospital, Fudan University from January 2016 to August 2021 were retrospectively analyzed. The patients were divided into survival group and death group according to the outcome at 90 days of follow-up.Paired sample t test, Mann-Whitney U test and chi-square test were used for statistical analysis.Pearson correlation was used to analyze the correlation between SII and the prognosis prediction model of HBV-ACLF. The area under the curve (AUC) was used to analyze the clinical efficacies of SII, MELD score, MELD-Na score and CTP score in predicting the prognosis of HBV-ACLF patients, and the optimal cut-off value of SII for predicting the prognosis of HBV-ACLF was calculated. Kaplan-Meier method was used for survival analysis. Results:A total of 140 patients with HBV-ACLF were included. There were 88 patients in the survival group, including 65 males and 23 females, with the age of (47.69±11.96) years. There were 52 cases in the death group, including 40 males and 12 females, with the age of (52.73±12.22) years. The age, aspartate aminotransferase, total bilirubin, serum creatinine, international normalized ratio, neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, SII, MELD score, MELD-Na score, CTP score and the incidence of infection in the death group were all significantly higher than those in the survival group, and albumin, lymphocyte count, platelet count, prognostic nutritional index in the death group were all significantly lower than those in the survival group, and the differences were all statistically significant ( t=-2.39, Z=-2.84, t=-4.81, Z=-2.15, Z=-4.91, Z=-3.47, Z=-3.36, Z=-3.83, Z=-4.69, Z=-4.56, Z=-6.31, χ2=24.96, t=3.06, t=3.03, Z=-7.57 and t=4.12, respectively, all P<0.05). Pearson correlation analysis showed that SII was positively correlated with CTP score ( r=0.272 7, P=0.001), MELD score ( r=0.365 8, P<0.001) and MELD-Na score ( r=0.381 1, P<0.001). The AUC of SII was the largest of 0.80, and 0.76 for MELD score, 0.74 for MELD-Na score and 0.73 for CTP score. The optimal cut-off value of SII was 447.49. Kaplan-Meier analysis showed that the 90 days survival rate of patients with SII≥447.49(38.60%(22/57)) was lower than that of SII<447.49 group (79.52%(66/83)), and the difference between the two groups was significant ( χ2=23.80, P<0.001). Conclusions:SII can be used to assess the severity and prognosis of HBV-ACLF patients. SII ≥447.49 indicates poor prognosis.

The past, present and future of tuberculosis treatment / 浙江大学学报·医学版

Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.

Neutralization of Omicron BA.4/BA.5 and BA.2.75 by Booster Vaccination or BA.2 Breakthrough Infection Sera

Many new Omicron sub-lineages have been reported to evade neutralizing antibody response, including BA.2, BA.2.12.1, BA.4 and BA.5. Most recently, another emerging sub-lineage BA.2.75 has been reported in multiple countries. In this study, we constructed a comprehensive panel of pseudoviruses (PsVs), including wild-type, Delta, BA.1, BA.1.1, BA.2, BA.3, BA.2.3.1, BA.2.10.1, BA.2.12.1, BA.2.13, BA.2.75 and BA.4/BA.5, with accumulate coverage reached 91% according to the proportion of sequences deposited in GISAID database since Jan 1st, 2022. We collected serum samples from healthy adults at day14 post homologous booster with BBIBP-CorV, or heterologous booster with ZF2001, primed with two doses of BBIBP-CorV, or from convalescents immunized with three-dose inactivated vaccines prior to infection with Omicron BA.2, and tested their neutralization activity on this panel of PsVs. Our results demonstrated that all Omicron sub-lineages showed substantial evasion of neutralizing antibodies induced by vaccination and infection, although BA.2.75 accumulated the largest number of mutations in its spike, BA.4 and BA.5 showed the strongest serum escape. However, BA.2 breakthrough infection could remarkably elevated neutralization titers against all different variants, especially titers against BA.2 and its derivative sub-lineages.

Comprehensive analyses reveal the impacts of vaccination status and physiological variables in early infection on viral persistence in COVID-19 patients: a retrospective single-center cohort study

BACKGROUNDViral persistence is a crucial factor that influences the communicability of SARS-CoV-2 infection. However, the impacts of vaccination status and physiological variables on viral RNA shedding have not been adequately clarified. METHODSIn this study, we retrospectively collected the clinical records of 377 hospitalized COVID-19 patients, which contained unvaccinated patients and patients received two doses of an inactivated vaccine or an mRNA vaccine. Firstly, we analyzed the impacts of vaccination on disease severity and viral RNA persistence. Next, to clarify the impacts of physiological variables on viral RNA shedding in COVID-19 patients, we retrieved 49 laboratory variables and analyzed their correlations with the duration of viral RNA shedding. Finally, we established a multivariate regression model to predict the duration of viral RNA shedding. RESULTSOur results showed that both inactivated and mRNA vaccines significantly reduced the rate of moderate cases, while the vaccine related shortening of viral RNA shedding were only observed in moderate patients. Correlation analysis showed that 10 significant laboratory variables were shared by the unvaccinated mild patients and mild patients inoculated with an inactivated vaccine, but not by the mild patients inoculated with an mRNA vaccine. Moreover, we demonstrated that a multivariate regression model established based on the variables correlating with viral persistence in unvaccinated mild patients could predict the duration of viral shedding for all groups of patients. CONCLUSIONSVaccination contributed limitedly to the clearance viral RNA in COVID-19 patients. While, laboratory variables in early infection could predict the persistence of viral RNA.

Antibody Resistance of SARS-CoV-2 Omicron BA.1, BA.1.1, BA.2 and BA.3 Sub-lineages

The SARS-CoV-2 Omicron variant has been partitioned into four sub-lineages designated BA.1, BA.1.1, BA.2 and BA.3, with BA.2 becoming dominant worldwide recently by outcompeting BA.1 and BA.1.1. We and others have reported the striking antibody evasion of BA.1 and BA.2, but side-by-side comparison of susceptibility of all the major Omicron sub-lineages to vaccine-elicited or monoclonal antibody (mAb)-mediated neutralization are urgently needed. Using VSV-based pseudovirus, we found that sera from individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV) showed very weak to no neutralization activity, while a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) markedly improved the neutralization titers against all Omicron variants. The comparison between sub-lineages indicated that BA.1.1, BA.2 and BA.3 had comparable or even greater antibody resistance than BA.1. We further evaluated the neutralization profile of a panel of 20 mAbs, including 10 already authorized or approved, against these Omicron sub-lineages as well as viruses with different Omicron spike single or combined mutations. Most mAbs lost their neutralizing activity completely or substantially, while some demonstrated distinct neutralization patterns among Omicron sub-lineages, reflecting their antigenic difference. Taken together, our results suggest all four Omicron sub-lineages threaten the efficacies of current vaccines and antibody therapeutics, highlighting the importance of vaccine boosters to combat the emerging SARS-CoV-2 variants.

Omicron booster in ancestral strain vaccinated mouse augments protective immunities against both the Delta and Omicron variants

A booster vaccination is called for constraining the evolving epidemic of SARS-CoV-2. However, the necessity of a new COVID-19 vaccine is currently unclear. To compare the effect of an Omicron-matched S DNA vaccine and an ancestral S DNA vaccine in boosting cross-reactive immunities, we firstly immunized mice with two-dose of a DNA vaccine encoding the spike protein of the ancestral Wuhan strain. Then the mice were boosted with DNA vaccines encoding spike proteins of either the Wuhan strain or the Omicron variant. Specific antibody and T cell responses were measured at 4 weeks post boost. Our data showed that the Omicron-matched vaccine efficiently boosted RBD binding antibody and neutralizing antibody responses against both the Delta and the Omicron variants. Of note, antibody responses against the Omicron variant elicited by the Omicron-matched vaccine were much stronger than those induced by the ancestral S DNA vaccine. Meanwhile, CD8+ T cell responses against both the ancestral Wuhan strain and the Omicron strain also tended to be higher in mice boosted by the Omicron-matched vaccine than those in mice boosted with the ancestral S DNA vaccine, albeit no significant difference was observed. Our findings suggest that an Omicron-matched vaccine is preferred for boosting cross-reactive immunities.

Global research hotspots and trends of hepatitis B from 2016 to 2021 based on analysis using bibliometric methods / 中华传染病杂志

Objective:To analyze the hotspots and trends of global researches in the field of hepatitis B from 2016 to 2021.Methods:Based on the Web of Science Core Collection Database, the indexed "article" and "review" related to hepatitis B from January 1, 2016 to November 22, 2021 were collected. Using InCites and VOSviewer 1.6.8 to cluster the published features, highly cited papers, key research directions and subject headings.And combined with the specific content of the literature, a summary of research hotspots was formed and analyzed.Results:As of November 22, 2021, a total of 12 299 articles were retrieved. From 2016 to 2021, the numbers of global hepatitis B-related research publications were 2 045, 1 996, 2 039, 2 118, 2 186 and 1 915, respectively. China′s mainland published the most papers (4 422 pieces, 35.95%), with the average citation frequency of only 7.46, and the United States ranked second in terms of the number of papers published (1 949 pieces, 15.85%), with the average citation frequency of 13.78. The hotspots obtained after the clustering of keyword topics were hepatitis B virus (HBV) infection, coinfections of HBV and hepatitis C virus/human immunodeficiency virus, primary hepatocellular carcinoma, antiviral therapy and hepatitis B cure, HBV virology, HBV and immunology, HBV reactivation, HBV vaccine, etc.Conclusions:In the past six years, global researches in the field of hepatitis B have focused on hepatitis B epidemiology and management, prediction and prevention of hepatitis B-related liver cancer, hepatitis B cure and treatment optimization, HBV virology and host immune mechanism in the development of hepatitis B, etc.The number of published papers in the field of hepatitis B keeps relatively stable. The number of researches in China′s mainland is at the international leading level, but the influence of researches needs to be further improved.

SARS-CoV-2 variants, immune escape, and countermeasures / 医学前沿

Coronavirus disease 2019 (COVID-19) has become a global pandemic disease. SARS-CoV-2 variants have aroused great concern and are expected to continue spreading. Although many countries have promoted roll-out vaccination, the immune barrier has not yet been fully established, indicating that populations remain susceptible to infection. In this review, we summarize the literature on variants of concern and focus on the changes in their transmissibility, pathogenicity, and resistance to the immunity constructed by current vaccines. Furthermore, we analyzed relationships between variants and breakthrough infections, as well as the paradigm of new variants in countries with high vaccination rates. Terminating transmission, continuing to strengthen variant surveillance, and combining nonpharmaceutical intervention measures and vaccines are necessary to control these variants.

CD8 + T cell exhaustion statuses in patients with human immunodeficiency virus infection, Mycobacterium tuberculosis infection and co-infection / 中华传染病杂志

Objective:To analyze the statuses of CD8 + T cell exhaustion in patients with human immunodeficiency virus (HIV) infection, Mycobacterium tuberculosis (MTB) infection and co-infection. Methods:A total of 87 patients infected with HIV and/or MTB in Wuxi Fifth People′s Hospital and Taicang First People′s Hospital from August 2019 to January 2020 were enrolled, including 18 cases of HIV infection, 34 cases of active tuberculosis (ATB), 19 cases of latent tuberculosis infection (LTB), seven cases of HIV coinfected with ATB, and nine cases of HIV coinfected with LTB. Another 11 healthy controls were also included. The peripheral blood of all subjects was collected for cell surface staining and intracellular cytokine staining, and flow cytometry was used to detect the expressions of activation molecules including CD62 ligand, CD44 and CD127, the transcription factor like eomesodermin (EOMES), T cell factor 1 (TCF-1), T-box expressed in T cells (T-bet), B lymphocyte-induced maturation protein 1 (Blimp-1), inhibitory receptors including programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain 3 (Tim-3) on CD8 + T cells. Mann-Whitney U test was used for statistical analysis. Results:The mean fluorescence intensities (MFIs) of the activation molecules CD62 ligand and CD44 in the HIV group were lower than those in the healthy control group, while the inhibitory receptor Tim-3 was higher than that in the healthy control group. The differences were all statistically significant ( U=31.00, 1.00 and 0.00, respectively, all P<0.010). The MFIs of CD62 ligand and CD44 in HIV coinfected with LTB group were lower than those in LTB group, while PD-1 and Tim-3 were higher than those in LTB group. The differences were all statistically significant ( U=4.00, 26.00, 6.00 and 3.00, respectively, all P<0.010). The MFIs of CD62 ligand, CD44 and CD127 in HIV coinfected with ATB group were lower than those in ATB group, while PD-1 and Tim-3 were higher than those in ATB group. The differences were all statistically significant ( U=9.00, 40.00, 45.50, 28.00 and 7.00, respectively, all P<0.010). The proportion of terminal effector CD8 + T cells in the HIV group was higher than that in the healthy control group, while the proportion of central memory CD8 + T cells was lower than that in the healthy control group. The differences were both statistically significant ( U=15.00 and 33.00, respectively, both P<0.010). The proportion of terminal effector CD8 + T cells in the HIV coinfected with LTB group was higher than the LTB group, while the proportion of central memory CD8 + T cells was lower than that in the LTB group. The differences were both statistically significant ( U=7.00 and 20.00, respectively, both P<0.010). The proportion of terminal effector CD8 + T cells in the HIV coinfected with ATB group was higher than that in ATB group, while the proportion of central memory CD8 + T cells was lower than that in ATB group. The differences were statistically significant (both U=7.00, P<0.001). The expression level of PD-1 + Tim-3 + T cells in HIV group was higher than that in healthy control group, that in HIV coinfected with LTB group was higher than that in LTB group, and that in HIV coinfected with ATB group was higher than that in ATB group. The differences were all statistically significant ( U=21.00, 6.00 and 5.50, respectively, all P<0.001). The MFI of transcription factors EOMES and TCF-1 in HIV coinfected with LTB group were lower than those in HIV group, while the MFI of T-bet was higher than that in HIV group. The differences were all statistically significant ( U=3.00, 4.00 and 9.00, respectively, all P<0.001). The MFI of EOMES and TCF-1 in HIV coinfected with ATB group were lower than those in HIV group, while the MFI of T-bet and Blimp-1 were higher than those in the HIV group. The differences were all statistically significant ( U=11.00, 14.00, 7.00 and 22.00, respectively, all P<0.050). Conclusions:MTB co-infected with HIV patients present lower immune function and a higher degree of CD8 + T cell exhaustion. In addition, HIV patients co-infected with LTB and ATB have a higher degree of CD8 + T cell exhaustion than HIV infected patients.

Clinical characteristics of the 2019 novel coronavirus Omicron variant infected cases / 中华传染病杂志

Objective:To investigate the clinical characteristics and prognostic factors of 2019 novel coronavirus (2019-nCoV) Omicron variant infected cases.Methods:A total of 987 coronavirus disease 2019 (COVID-19) adult imported cases admitted to Shanghai Public Health Clinical Center, Fudan University from July 1, 2021 to January 6, 2022 were recruited. The cases were divided into Omicron group (193 cases) and non-Omicron group (794 cases) according to the genotype of the virus. The clinical data, imaging examination and laboratory results of two groups were collected and compared. Chi-square test and Mann-Whitney U test were used as statistical methods. Multiple linear regression analysis was used for multiple linear regression analysis. Results:The majority of patients in Omicron group were 18 to 30 years old, accounting for 51.3%(99/193), which was higher than 31.4%(249/794) in non-Omicron group. The difference was statistically significant ( χ2=52.75, P<0.001). The proportion of mild cases in Omicron group was 88.6%(171/193), which was higher than 81.6%(648/794) in non-Omicron group. The difference was statistically significant ( χ2=5.37, P=0.021). Cases with symptoms were more common in Omicron group than those in non-Omicron group (60.1%(116/193) vs 29.1%(231/794)), and the difference was statistically significant ( χ2=65.49, P<0.001), with the main clinical manifestations of sore/itchy throat, fever and cough/expectoration. The proportion of cases with pulmonary computed tomography (CT) imaging manifestations at admission in Omicron group was 13.0%(25/193), which was lower than that in non-Omicron group (215/794, 27.1%). The difference was statistically significant ( χ2=16.83, P<0.001). The proportion of cases with 2019-nCoV IgG positive at admission was 47.7%(92/193) in Omicron group, which was lower than 61.1%(485/794) in non-Omicron group, and the difference was statistically significant ( χ2=11.51, P<0.001). The hospitalization time of Omicron group was 20.0 (16.0, 23.0) d, which was longer than that of non-Omicron group (14.0 (10.0, 22.0) d), and the difference was statistically significant ( Z=-7.42, P<0.001). Multiple linear regression analysis showed that the time of hospitalization of cases with 2019-nCoV IgG positive at admission was shorter, while that of the cases with fever in Omicron group was longer (both P<0.050). Conclusions:The main clinical characteristics of cases with Omicron variant are fever and upper respiratory symptoms. Their pulmonary CT imaging manifestations are less, and the time of hospitalization is slightly longer. The time of hospitalization and the virus clearance time in Omicron variant infected cases with 2019-nCoV IgG positive at admission and not presented with fever are both shorter.

Clinical characteristics and prognosis of central nervous system tuberculosis in adults / 中华传染病杂志

Objective:To investigate the clinical characteristics of central nervous system tuberculosis in adults and the possible factors affecting the mortality and disability of the patients.Methods:The clinical data of patients diagnosed as "tuberculous meningitis" "tuberculous meningoencephalitis" "tuberculous cerebrospinal meningitis" or "tuberculous brain ubscess" in Huashan Hospital, Fudan University and Jing′an Branch, Huashan Hospital, Fudan University in Shanghai from January 1, 2010 to December 31, 2017 were collected, and a retrospective cohort was established. The clinical characteristics were analyzed, Medical Research Council (MRC) grade system was used to assess the severity of meningitis, and the modified Rankin Scale was used to assess the impairment of self-care. Survival rate and disability rate of the cohort were analyzed. Binary logistic regression was used for multivariate analysis. Kaplan-Meier survival curve was used for survival analysis.Results:A total of 161 patients with central nervous system tuberculosis were enrolled. Among the 161 patients, 55 cases (34.2%) were confirmed, 72 cases (44.7%) were highly suspected and 34 cases (21.1%) were suspected diagnosis. There were 56 cases (34.8%) with MRC grade Ⅰ, 76 cases (47.2%) with MRC grade Ⅱ and 29 cases (18.0%) patients with MRC grade Ⅲ before treatment. Up to January 1, 2019, ten (6.2%) patients died, 32 (19.9%) patients lost to follow-up, 119 (73.9%) patients survived. The five-year survival rate was 92.83%. There were 72 patients with no impact on life, 34 patients with moderate impact and 13 patients with severe impact. The disability rate was 39.5% (47/119). Binary logistic regression analysis showed that increasing age (odds ratio ( OR)=1.06, 95%confidence interval ( CI) 1.00 to 1.13, P=0.032) and deterioration of MRC grade during anti-tuberculosis treatment ( OR=89.00, 95% CI4.46 to 1 779.00, P=0.003) were independent risk factors for death. When severe disability and death were used as adverse outcomes, logistic regression analysis showed increasing age ( OR=1.07, 95% CI 1.01 to 1.13, P=0.035) and deterioration of MRC grade during anti-tuberculosis treatment ( OR=77.17, 95% CI4.45 to 1 337.00, P=0.003) were still independent risk factors for adverse outcomes. Conclusions:The mortality of central nervous system tuberculosis in adults in this cohort is relatively low, but the disability rate is still high. Increasing age and deterioration of MRC grade during anti-tuberculosis treatment are independent risk factors for death and disability.

Expert statement on the construction criteria of critical care department in municipal and district designated hospitals under the pandemic prevention and control / 中华危重病急救医学

The global coronavirus disease 2019 epidemic is still in a pandemic state. Aging population with underlying diseases is prone to become severe, and have a higher mortality. The treatment capacity of the critical care department directly determines the treatment success rate of critical illness. At present, there is still a certain gap between domestic and foreign countries in intensive care unit (ICU), which is not only in the allocation of medical staff, but also in the beds and settings. The current medical model cannot fully meet the needs of development. The experience and lessons of many major public health emergencies suggested that " dual track of peace and war" approach in discipline construction of critical care is the best medical model. Following the concept of "combination of peace and war", strengthening the discipline construction of critical care department in municipal and district designated hospitals, allocating reasonable standard ICU, step-down ICU and combat readiness ICU, establishing rapid response team, and strengthening regular training and scientific management may be the key measures to deal with the epidemic.

Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in people living with HIV-1

BackgroundIt has been proven that inactivated COVID-19 vaccines are safe and effective in general population with intact immunity. However, their safety and immunogenicity have not been demonstrated in people living with HIV (PLWH). Methods42 HIV-1 infected individuals who were stable on cART and 28 healthy individuals were enrolled in this study. Two doses of an inactivated COVID-19 vaccine (BIBP-CorV) were given 4 weeks apart. The safety and reactogenicity of the vaccine were evaluated by observing clinical adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and surrogate neutralization assays. Cell-mediated immune responses and vaccine induced T cell activation were measured by flow cytometry. FindingsAll the HIV-1 infected participants had a CD4+ T cell count of above 200 cells/L both at baseline and 4 weeks after vaccination. No solicited adverse reaction was observed among all participants. Similar binding antibody, neutralizing antibody and S protein specific T cell responses were elicited in PLWH and healthy individuals. Further analyses showed that PLWH with low baseline CD4+/CD8+ T cell ratios (<0{middle dot}6) generated lower antibody responses after vaccination than PLWH with medium (0{middle dot}6[~]1{middle dot}0) or high ([≥]1{middle dot}0) baseline CD4+/CD8+ T cell ratios (P<0{middle dot}01). The CD3+, CD4+ and CD8+ T cell counts of PLWH decreased significantly after vaccination, but it did not lead to any adverse clinical manifestation. Moreover, we found that the general burden of HIV-1 among the PLWH cohort decreased significantly (P=0{middle dot}0192) after vaccination. And the alteration of HIV-1 viral load was not significantly associated with the vaccine induced CD4+ T cell activation. InterpretationOur data demonstrate that the inactivated COVID-19 vaccine is safe and immunogenic in PLWH who are stable on cART with unsuppressed CD4 counts. FundingThis work was funded by the National Natural Science Foundation of China (Grant No. 81971559, 82041010). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe safety and efficacy of inactivated COVID-19 vaccines have been validated in general population with intact immunity. However, their safety and immunogenicity have not been demonstrated in people living with HIV (PLWH). Added value of this studyOur study provides the first evidence to show humoral and cellular immune responses to an inactivated vaccine in PLWH who have been stable on cART with good CD4 cell counts. We found that participants with HIV-1 generated antibody and T cell responses comparable with those of healthy individuals after two-dose vaccination. The baseline CD4/CD8 ratios while not the absolute CD4+ T cell counts were shown to be associated with the magnitudes of vaccine induced antibody responses. Moreover, we showed that the vaccine induced T cell activation did not increase the viral burden in PLWH on cART. On the contrary, the levels of plasma HIV-1 RNA decreased among a significant percentage of PLWH. Implications of all the available evidenceOur data demonstrate that the inactivated COVID-19 vaccine is safe and immunogenic in PLWH who are stable on cART with unsuppressed CD4 counts and indicate that this vaccine might be protective and efficacious against COVID-19 for people with HIV.

Herd immunity induced by COVID-19 vaccination programs to suppress epidemics caused by SARS-CoV-2 wild type and variants in China

BackgroundTo allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission. However, it remains to be seen whether herd immunity will be within reach of these programs. MethodsWe developed a data-driven model of SARS-CoV-2 transmission for China, a population with low prior immunity from natural infection. The model is calibrated considering COVID-19 natural history and the estimated transmissibility of the Delta variant. Three vaccination programs are tested, including the one currently enacted in China and model-based estimates of the herd immunity level are provided. ResultsWe found that it is unlike to reach herd immunity for the Delta variant given the relatively low efficacy of the vaccines used in China throughout 2021, the exclusion of underage individuals from the targeted population, and the lack of prior natural immunity. We estimate that, assuming a vaccine efficacy of 90% against the infection, vaccine-induced herd immunity would require a coverage of 93% or higher of the Chinese population. However, even when vaccine-induced herd immunity is not reached, we estimated that vaccination programs can reduce SARS-CoV-2 infections by 53-58% in case of an epidemic starts to unfold in the fall of 2021. ConclusionsEfforts should be taken to increase populations confidence and willingness to be vaccinated and to guarantee highly efficacious vaccines for a wider age range.

Pre-existing antibodies targeting a dominant linear antibody epitope on SARS-CoV-2 S2 cross-reacted with commensal gut bacteria and shaped immune responses elicited by a candidate vaccine

The origins of pre-existing SARS-CoV-2 cross-reactive antibodies and their potential impacts on vaccine efficacy have not been fully clarified. In this study, we demonstrated that S2 was the prevailing target of the pre-existing S protein cross-reactive antibodies in both healthy human and SPF mice. A dominant antibody epitope was identified on the connector domain of S2 (1147-SFKEELDKYFKNHT-1160, P144), which could be recognized by pre-existing antibodies in both human and mouse. Through metagenomic sequencing and fecal bacteria transplant, we proved that the generation of S2 cross-reactive antibodies was associated with commensal gut bacteria. Furthermore, six P144 specific monoclonal antibodies were isolated from naive SPF mice and proved to cross-react with commensal gut bacteria collected from both human and mouse. Mice with high levels of pre-existing S2 cross-reactive antibodies mounted higher S protein specific binding antibodies, especially against S2, after being immunized with a SARS-CoV-2 S DNA vaccine. Similarly, we found that levels of pre-existing S2 and P144 reactive antibodies correlated positively with RBD specific binding antibody titers after two doses of inactivated SARS-CoV-2 vaccination in human. Finally, we provided data demonstrating that immunization of a SARS-CoV-2 S DNA vaccine could alter the gut microbiota compositions of mice.

Analysis of clinical characteristics and prognosis of Epstein-Barr virus-related diseases in adults / 中华传染病杂志

Objective:To investigate the clinical characteristics and prognosis of Epstein-Barr virus-related diseases in adults.Methods:The clinical data of 59 patients with Epstein-Barr virus-related diseases in Huashan Hospital, Fudan University, Shanghai from January 2017 to August 2019 were analyzed retrospectively. The clinical manifestations of patients with infectious mononucleosis (IM), chronic active Epstein-Barr virus infection (CAEBV) and lymphoma in patients were compared. Patients were divided into acute course group (IM) and chronic course group (CAEBV+ lymphoma), and the results of labratory indications (blood rontine, liver function, imflammatory indications, Epstein-Barr virus DNA, Epstein-Barr virus antibody and T lymphocyte) were compared between two groups. Statistical analysis was performed by Mann-Whitney U test, chi-square test or Fisher exact probability test. Results:Among the 59 patients, 23 cases (39.0%) were diagnosed with IM, 23 cases (39.0%) were lymphoma and 13 cases (22.0%) were CAEBV. The clinical manifestations of patients with Epstein-Barr virus-related diseases were fever (57/59, 96.6%), lymphadenopathy (37/59, 62.7%) and splenomegaly (36/59, 61.0%). There were 17 patients in the chronic course group experienced hemophagocytic lymphohistiocytosis (HLH). The white blood cell counts, hemoglobin levels and platelet counts of patients in the chronic course group (4.07(1.94, 8.35)×10 9/L, 89.5(74.5, 108.0) g/L and 100(37, 161)×10 9/L, respectively) were all lower than those in the acute course group (9.91(6.75, 17.38)×10 9/L, 132.5(118.2, 152.0) g/L and 197(129, 233)×10 9/L, respectively), with statistically significant differences ( U=3.69, 5.22 and 3.61, respectively, all P<0.01). The levels of procalcitonin, C-reactive protein and serum ferritin in the chronic course group (0.45(0.15, 1.13) μg/L, 47.75(17.57, 84.67) mg/L and 2 000(682, 2 002) μg/L, respectively) were all higher than those in the acute course group (0.12(0.07, 0.28) μg/L, 6.39(3.13, 11.38) mg/L and 482(159, 1 271) μg/L, respectively), with statistically significant differences ( U=-2.95, -3.77 and -4.16, respectively, all P<0.01). The counts of CD4 + T lymphocytes, CD8 + T lymphocytes, CD19 + B lymphocytes and natural killer cells in the chronic course group (259.15(101.98, 509.26), 214.69(119.31, 529.47), 46.14(4.44, 135.87) and 81.09(41.53, 118.46)/μL, respectively) were all lower than those in the acute course group (738.88(592.20, 893.94), 1 609.17(920.88, 3 952.34), 144.52(83.65, 215.14) and 309.82(123.78, 590.68)/μL, respectively), with statistically significant differences ( U=3.66, 3.80, 2.90 and 3.40, respectively, all P<0.01), while the CD4 + /CD8 + T lymphocytes ratio in the chronic course group was higher (0.90(0.60, 1.70) vs 0.45(0.10, 1.28))( U=-2.29, P=0.02). Twenty-three patients with IM were all cured, while 10 patients with lymphoma died and 13 received chemotherapy. Seven patients with CAEBV died and six improved. Conclusions:The clinical characteristics of Epstein-Barr virus-related diseases in adults are fever, lymphadenectasis, splenomegaly.Chronic Epstein-Barr virus infection may be associated with HLH. The prognosis of adults with acute Epstein-Barr virus infection is good, while that of long-term chronic Epstein-Barr virus infection is poor.

Clinical characteristics and prognosis analysis of cytomegalovirus reactivation in patients with liver failure / 中华传染病杂志

Objective:To investigate the clinical characteristics and prognosis of cytomegalovirus (CMV) reactivation in patients with liver failure.Methods:A total of 75 patients diagnosed with liver failure and tested for serum CMV DNA between January 2016 and June 2019 in Huashan Hospital, Fudan University were retrospectively analyzed. According to the CMV DNA test results, the patients were divided into CMV DNA positive group and CMV DNA negative group. The classification of liver failure, the use of glucocorticoids, the proportions of T lymphocyte subsets of the two groups were compared and the prognosis was evaluated. Mann-Whitney U test and chi-square test were used to analyze the data. Results:Of the 75 patients with liver failure, 17 were CMV DNA positive and 58 were CMV DNA negative. Among the 17 CMV DNA positive patients, nine were acute (subacute) liver failure, and 13 were treated with glucocorticoids, which were all significantly higher than those in the CMV negative group (20.7%(12/58) and 20.7%(12/58), respectively). The differences were both statistically significant ( χ2=6.70 and 18.40, respectively, both P<0.05). The proportions of CD3 + T lymphocytes and CD8 + T lymphocytes in the CMV DNA positive group were both higher than those in the CMV DNA negative group, and the proportions of CD4 + T lymphocytes, the ratio of CD4 + /CD8 + T lymphocytes and the proportion of B lymphocytes were all lower than those in the CMV DNA negative group. The differences were all statistically significant ( U=274.50, 165.50, 273.00, 185.00 and 189.00, respectively, all P<0.05). Acute (subacute) liver failure (odds ratio ( OR)=4.3, 95% confidence interval ( CI) 1.3-12.6) and glucocorticoid use ( OR=12.5, 95% CI 3.4-38.3) were risk factors for CMV reactivation in patients with liver failure. The disease improvement rate in the CMV DNA negative group was 56.9% (33/58), and five out of 17 patients improved in the CMV DNA positive group, with a statistically significant difference ( χ2=1.99, P=0.04). Conclusions:The use of glucocorticoids increases the risk of CMV reactivation in patients with liver failure, and CMV reactivation in patients with liver failure presents immune disorders which seriously affect their prognosis. Therefore, it is important to pay attention to CMV DNA monitoring in patients with liver failure using glucocorticoids.

Clinical characteristics and prognosis of 44 patients with Nocardia infection / 中华传染病杂志

Objective:To investigate the clinical characteristics and prognosis of the patients with nocardiosis.Methods:From January 2013 to July 2019, 44 patients with nocardiosis in Department of Infectious Diseases, Huashan Hospital, Fudan University in Shanghai were enrolled, and their clinical data were retrospectively analyzed, including baseline characteristics, clinical manifestations, underlying diseases history of glucocorticoid therapy, laboratory data (blood routine examination, procalcitonin, C-reactive protein, lymphocytes subsets, etc.), imaging changes, bacterial strain identification, treatment regimens and outcomes. According to the locations of infection, patients were divided into pulmonary nocardiosis, extrapulmonary single-organ nocardiosis and disseminated nocardiosis. The Mann-Whitney U test was used for comparison between two groups, and the Kruskal-Wallis H test was used for comparison among multiple groups. Results:Among the 44 cases of nocardiosis, 14 cases were pulmonary nocardiosis, 17 cases were extrapulmonary single-organ nocardiosis (including nine cases with central nervous system infection, six cases with skin and soft tissue infection, one case with abdominal abscess and one case with urinary tract infection) and 13 cases were disseminated nocardiosis (including four cases with bloodstream infection, six cases with central nervous system and lung or skin and soft tissue infection, three cases of lung and skin and soft tissue infection). Thirty-four cases had underlying diseases, and 27 cases received glucocorticoid or immunosuppressant treatment. The main symptom of 11 patients in pulmonary nocardiosis group was productive cough, while that of the patients in other two groups was fever. Nocardia species were mainly Nocardia brasiliensis, Nocardia nova and Nocardia farcinicaia. The white blood cell counts and neutrophils proportion were normal or slightly increased in 42 cases, and the platelets were normal or slightly decreased in 41 cases. Erythrocyte sedimentation rate increased in 19 cases, procalcitonin increased in 21 cases, C-reactive protein increased in 34 cases, and ferritin increased in 18 cases. A total of 34 patients were tested for lymphocyte subsets, of which 15 had CD4 + T lymphocytes decreased, 14 had CD8 + T lymphocytes increased, seven had B lymphocytes increased, seven had B lymphocytes decreased, and eight had natural killer cells decreased. The hemoglobin of patients with pulmonary nocardiosis was higher than that of patients with extrapulmonary infection, and the difference was statistically significant ( U=0.095, P=0.025). The imaging manifestations were mainly abscess and inflammatory exudation. Forty cases were cured or improved, one case was still on treatment, and three cases died. Conclusions:The clinical manifestations of nocardiosis involving various organs are non-specific. Standardized treatment could reduce the mortality of nocardiosis.