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.

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.

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.

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.

Expression of immunosuppressive receptor T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain on CD8 + T cells in silicosis patients with Mycobacterium tuberculosis infection / 中华传染病杂志

Objective:To explore the expression and clinical significance of immunosuppressive receptor T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) on the peripheral blood mononuclear cells (PBMC) in silicosis patients with Mycobacterium tuberculosis infection. Methods:August 2018, a total of 78 patients with silicosis (all were quarry workers in Sanmen County, Zhejiang Province) were enrolled and divided into silicosis combined with active pulmonary tuberculosis group (APTB group), silicosis combined with latent tuberculosis infection group (LTBI group), and simple silicosis with non-tuberculosis infection group (non-TB group). Flow cytometry was used to analyze the expressions of TIGIT, programmed death-1 (PD-1) and transcription factor T-bet on PBMC from patients. Mann-Whitney U test and Pearson correlations analysis were used for statistical analysis. Results:Among the 78 patients, eight were in the APTB group, 24 in the LTBI group, and 46 in the non-TB group. The expressions of PD-1 and TIGIT on CD8 + T cells in the APTB group (29.45%(16.78%) and 65.40%(12.12%), respectively) were significantly higher than those in the LTBI group (17.40%(11.17%) and 48.30%(28.75%), respectively; U=23.500 and 43.500, respectively, P=0.000 8 and 0.020 5, respectively) and non-TB group (15.95%(12.46%) and 45.30%(19.75%), respectively; U=64.000 and 69.000, respectively, P=0.002 3 and 0.003 8, respectively), and the differences were all statistically significant. The expression of TIGIT was positively correlated with PD-1 on CD8 + T cells in silicosis patients ( r=0.434 3, P<0.01). The proportion of PD-1 + TIGIT + CD8 + T cells in the APTB group (19.90%(22.67%)) was significantly higher than those in the non-TB group (11.55%(11.29%), U=76.500, P=0.007 1) and LTBI group (11.55%(10.53%), U=41.000, P=0.015 4), while the proportion of PD-1 -TIGIT -CD8 + T cells in the APTB group (30.60%(12.90%)) was significantly lower than non-TB group (48.90%(18.98%), U=58.000, P=0.001 3) and LTBI group (47.20%(24.59%), U=41.000, P=0.015 4). The differences were all statistically significant. The expression of T-bet on the peripheral blood CD8 + T cells in the APTB group (29.45%(16.78%)) was higher than that in the non-TB group (15.95%(12.46%)) and the LTBI group (17.40%(11.17%)), and the differences were both statistically significant ( U=46.500 and 46.000, respectively, P=0.000 3 and 0.028 3, respectively). The expression of T-bet on CD8 + T cells was positively correlated with TIGIT on CD8 + T cells ( r=0.456 7, P<0.01). The expression of T-bet on PD-1 + TIGIT + CD8 + T cells in the APTB group (65.40%(12.12%)) was higher than those in the LTBI group (48.30%(28.75%), U=23.500, P=0.000 8) and non-TB group (45.30%(19.75%), U=65.000, P=0.002 6), and the differences were both statistically significant. Conclusion:The immunosuppressive receptor PD-1 and TIGIT are highly expressed on CD8 + T cells in silicosis patients with active pulmonary tuberculosis, which indicates CD8 + T cells exhaustion in these population, while the highly co-expression of T-bet suggests the exhausted subsets may have reversed potentiality.

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.

Evaluation of clinical utility of a novel method for quantitative detection of hepatitis B virus RNA / 中华传染病杂志

Objective:To evaluate the clinical utility of a novel quantitative assay named hepatitis B virus (HBV) simultaneous amplification and testing (SAT) using a kit for HBV RNA detection (RNA probes).Methods:HBV RNA was detected in 170 serum samples of chronic hepatitis B patients and 30 serum samples of patients without HBV infection collected by simple random sampling method from June 2017 to June 2018 in Huashan Hospital, Fudan University, Shanghai using HBV SAT and reverse transcription polymerase chain reaction (PCR) method. The sensitivity, specificity, kappa value and quantitative correlation of the two methods were analyzed and compared.The detection rates of HBV RNA from samples with different HBV DNA concentrations of the two methods were analyzed and compared. Statistical analysis was performed by chi-square test.Results:Based on the clinical diagnosis, the detection sensitivity, specificity, kappa value of HBV SAT were 97.06%(165/170), 100.00%(30/30) and 0.908, respectively, while the reverse transcription PCR were 92.94%(158/170), 100.00%(30/30) and 0.798, respectively. Among samples with lower concentration of HBV DNA (HBV DNA<100 IU/mL), the detection rates of HBV SAT and reverse transcription PCR were 77.27%(17/22) and 59.09%(13/22), respectively. The linear correlation coefficient of the two methods was r=0.987 8. Conclusions:Quantitation results of HBV RNA by HBV SAT and reverse transcription PCR method are consistent. HBV SAT is a rapid and accurate method for HBV RNA quantitative detection, which has a slightly higher detection rate than reverse transcription PCR in samples with low concentration of HBV DNA.

Analysis of the changes and efficacy of antiviral treatment regimens in patients with chronic hepatitis C from 2014 to 2019 / 中华传染病杂志

Objective:To analyze the changes and efficacy of antiviral treatment regimens in patients with chronic hepatitis C.Methods:This was a single center retrospective study. A total of 157 patients with chronic hepatitis C in Huashan Hospital, Fudan University from January 2014 to February 2019 were included. Clinical informations of antiviral treatment and follow-up were collected. The sustained virologic response (SVR) rate and adverse events in patients receiving different antiviral regimens were compared. Chi-square test was used for statistical analysis.Results:Among the 157 patients, 133 patients had sufficient follow-up data. Seventy-one patients received treatment before 2017, among which 63 patients received interferon regimens and the SVR rate was 74.65%(53/71). Sixty-two patients received treatment after 2017, among which 61 patients received direct-acting antiviral agents (DAA) regimens and the SVR rate was 98.39%(61/62). The difference in SVR rate between the two groups was statistically significant ( χ2=15.230, P<0.01). In 69 patients who received DAA regimens from 2014 to 2019, the SVR at post-treatment week 12 (SVR12) was 95.65%(66/69). Among 43 patients who received DAA regimens containing sofosbuvir, the SVR12 rates of patients with hepatitis C virus genotype 1, 3 and other genotypes were 15/15, 5/6 and 90.91%(20/22), respectively. All the 26 patients who received DAA regimens non-containing sofosbuvir achieved SVR12. The SVR12 rates of patients with different hepatitis C virus genotypes and DAA regimens were not significantly different ( χ2=5.243, P=0.263). The incidences of adverse events in pre-2017 group and post-2017 group were 84.62%(77/91) and 6.06% (4/66), respectively. The difference was statistically significant ( χ2=94.520, P<0.01). The most common adverse events were decreases in neutrophil cell count, decreases in hemoglobin level and decreases in platelet count. Treatment was ceased in six patients due to adverse events. Conclusions:After 2017, the majority of patients with chronic hepatitis C received DAA regimens instead of interferon regimens. The SVR rate increases and the incidence of adverse events decreases along with the changes of leading treatment regimens.The SVR12 rate is higher in patients receiving DAA regimens, regardless of hepatitis C virus genotypes.

Diagnostic values of interleukin-22, interferon-γ and macrophage migration inhibition factor in pleural effusion for tuberculous pleurisy / 中华传染病杂志

Objective:To investigate the diagnostic values of interleukin-22 (IL-22), interferon-γ(IFN-γ)and macrophage migration inhibition factor (MIF) in pleural effusion for tuberculosis pleurisy.Methods:From April 2018 to May 2019, a total of 77 patients including 45 cases of tuberculous pleurisy, 19 cases of malignant pleurisy, 13 cases of parapneumonia and 13 cases of healthy control in Wuxi Fifth People′s Hospital were enrolled. The levels of IL-22, IFN-γ and MIF in plasma and pleural effusion were detected by enzyme linked immunosorbent assay (ELISA). Mann-Whitney U test was used for statistical analysis.The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of IL-22, IFN-γ and MIF for tuberculous pleurisy. Results:The median levels of IL-22, IFN-γ, MIF and adenosine deaminase in 45 cases with pleural effusion in tuberculosis pleurisy group were 396.8 ng/L, 2 200.0 ng/L, 241.3 μg/L and 70.8 U/L, respectively, which were all significantly higher than 32 cases with non-tuberculosis pleurisy group, including 19 cases with malignant pleurisy and 13 cases with parapneumonia (52.8 ng/L, 232.3 ng/L, 179.6 μg/L and 17.0 U/L, respectively). The differences were all statistically significant ( U=179.000, 118.500, 287.000, 162.000, respectively, all P<0.05). The median levels of IL-22 and IFN-γ in plasma of tuberculosis pleurisy group were 20.0 ng/L and 45.9 ng/L, respectively, which were both higher than healthy control group (14.3 ng/L and 33.4 ng/L, respectively). The level of MIF was 96.2 μg/L, which was lower than healthy control (159.5 μg/L). The differences were all statistically significant ( U=74.000, 13.000 and 73.000, respectively, all P<0.05). The areas under ROC curve (AUC) of IL-22, IFN-γ and MIF in pleural effusion for the diagnosis of tuberculosis pleurisy were 0.876, 0.917 and 0.682, respectively.The sensitivities were 93.75%, 100.00% and 63.64%, respectively; the specificities were 82.22%, 91.11% and 65.85%, respectively. The median levels of IL-22 and IFN-γ in plasma in tuberculosis pleurisy group at two months of follow-up after anti-tuberculosis therapy were 16.0 ng/L and 33.9 ng/L, respectively, which were both lower than baseline (20.0 ng/L and 44.7 ng/L, respectively). The differences were both statistically significant ( U=2.156 and 2.221, respectively, both P<0.05). Conclusion:IFN-γ and IL-22 in pleural effusion could be used as effective indicators to identify tuberculous pleurisy, and the dynamic monitoring of IL-22 in patients′plasma could be an important biomarker in evaluating the efficacy of anti-tuberculosis treatment.

Diagnostic approach and management of tuberculous meningitis: a nationwide cross-sectional survey in 49 hospitals in China / 中华传染病杂志

Objective:To take a broad overview of the current allocation of diagnosis and treatment resources and management for patients with tuberculous meningitis (TBM) in 49 hospitals in China.Methods:A cross-sectional survey about TBM was carried out in 49 hospitals from 27 provinces across China, by means of electronic questionnaire.The electronic questionnaire was filled by doctors in charge of the departments where TBM patients were routinely admitted from September to December 2018. The availability of medical resources, diagnosis, evaluation, treatment and surveillance in these hospitals were analyzed from the questionnaire. The count data were expressed as percentage.Results:Among the 49 participating hospitals, 37(75.5%) hospitals had less than 50 admissions of suspected TBM per year. Less than 20 TBM patients were confirmed by etiological diagnosis per year in 42(85.7%) participating hospitals.The availability of conventional medical imaging including computed tomography (CT), magnetic resonance imaging (MRI), enhanced MRI, cerebral angiography and magnetic resonance angiography (MRA) were 100.00%(49/49), 95.92%(47/49), 91.84%(45/49), 61.22%(30/49) and 67.35%(33/49), respectively. The rate of access to classic etiological diagnostic methods including acid-fast bacilli smear, mycobacterial culture and T cell spot test of tuberculosis infection were 77.55%(38/49), 95.92%(47/49) and 83.67%(41/49), respectively. Rifampin (100.0%, 49/49), isoniazid (100.0%, 49/49), pyrazinamide (98.0%, 48/49) and ethambutol (95.9%, 47/49) were most commonly used in initial anti-tuberculosis treatment of non-severe patients with TBM. The course of anti-tuberculosis treatment was 18 months in 25(51.0%) hospitals, and 12 months in 17(34.7%) hospitals. Intrathecal glucocorticoid and isoniazid were used in 39(79.6%) hospitals. Dexamethasone was used as part of treatment in 24(49.0%) hospitals, and the duration of glucocorticoid was about two months in 28(57.1%) hospitals. As for hyponatremia, 32(65.3%) hospitals didn′t investigate the cause, and hypertonic saline (83.7%, 41/49) and oral rehydration salts (71.4%, 35/49) were considered as the most common treatment strategy. Lumbar puncture was most commonly used for intracranial pressure surveillance in 48(98.0%) hospitals.Conclusions:The TBM cases admitted to the investigation hospitals are characterized by scattered sources and few confirmed cases of etiology. There are obvious heterogeneities in the diagnosis and treatment of TBM and the management of complications.The standardized plan for diagnosis and treatment of TBM are needed to improve the management.

Clinical analysis of risk factors for severe patients with corona virus disease 2019 / 中华传染病杂志

Objective:To analyze the clinical features of patients with corona virus disease 2019 (COVID-19) in Shanghai and the risk factors for disease progression to severe cases.Methods:The clinical data of 292 adult patients with COVID-19 hospitalized in Shanghai Public Health Clinical Center from January 20 to February 10, 2020 were retrospectively analyzed, including 21 severe patients and 271 mild patients. The demographic characteristics, epidemiological history, history of underlying diseases and laboratory tests were compared between the two groups. Measurement data were compared using t test or Mann-Whitney U test. The count data were compared using chi-square test. The binary logistic regression equation was used to analyze the risk factors for the progression of patients to severe cases. Results:Among the 292 patients, there were 21 severe cases with the rate of 7.2%. One patient died, and the mortality rate was 4.8% in severe patients. The severe patients aged (65.5±15.7) years old, and 19 (90.5%) were male, 11 (52.4%) had underlying diseases, seven (33.3%) had close relatives diagnosed with COVID-19. The mild patients aged (48.7±15.7) years old, and 135 (49.8%) were male, 74 (27.3%) had underlying diseases, 36 (13.3%) had close relatives diagnosed with COVID-19. The differences between two groups were all significant statistically ( t=-4.730, χ2=12.930, 5.938 and 4.744, respectively, all P<0.05). Compared with the mild patients, the levels of absolute numbers of neutrophils, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatinine, serum cystatin C, C reactive protein (CRP), procalcitonin, D-dimer, pro-B-type natriuretic peptide (proBNP), serum myoglobin, creatine kinase (CK), creatine kinase isoenzyme (CK-MB), serum cardiactroponin I (cTn I) in severe patients were all significantly higher ( U=2 091.5, 1 928.0, 1 215.5, 729.0, 1 580.5, 1 375.5, 947.5, 789.5, 1 209.0, 1 434.0, 638.0, 964.5, 1 747.5 and 1 258.0, respectively, all P<0.05), while the levels of lymphocyte count, albumin, transferrin, CD3 + T lymphocyte count, CD8 + T lymphocyte count and CD4 + T lymphocyte count in severe patients were all significantly lower ( U=1 263.5, t=4.716, U=1 214.0, 962.0, 1 167.5 and 988.0, respectively, all P<0.05). Further logistic regression analysis showed that the albumin (odds ratio ( OR)=0.806, 95% confiderce interval ( CI)0.675-0.961), serum myoglobin ( OR=1.010, 95% CI 1.004-1.016), CRP ( OR=1.016, 95% CI 1.000-1.032), CD3 + T lymphocyte count ( OR=0.996, 95% CI 0.991-1.000) and CD8 + T lymphocyte count ( OR=1.006, 95% CI 1.001-1.010) at admission were independent risk factors for the progression of COVID-19 patients to severe illness (all P<0.05). Conclusions:Severe patients with COVID-19 in Shanghai are predominantly elderly men with underlying diseases. Albumin, CRP, serum myoglobin, CD3 + T lymphocyte count and CD8 + T lymphocyte count could be used as early warning indicators for severe cases, which deserve more clinical attention.

Preliminary study on predictive indicators of disease severity in patients with influenza A (H1N1) / 中华传染病杂志

Objective:To analyze the differences of peripheral blood transcriptome between mild and severe influenza A (H1N1) patients, and to find indicators for the assessment of disease severity.Methods:A total of ten patients (five patients with mild disease and five patients with severe disease) diagnosed with H1N1 infection from January to May 2018 at Huashan Hospital, Fudan University in Shanghai were enrolled, and five healthy people were also enrolled as controls. The peripheral blood of patients was collected for transcriptome sequencing at the time when they were first diagnosed. Measurement data were compared using t test or Mann-Whitney U test. The count data were compared using Fisher exact test when appropriate. Data analysis of transcriptome predictions was performed using bioinformatics methods. Results:The platelet counts were significantly different between mild and severe groups ((163.4±21.5 )×10 9/L vs (255.6±52.5)×10 9/L, t=3.636, P=0.007). There were no differences between the two groups in gender, age, white blood cell counts, neutrophil percentage, lymphocyte percentage and hemoglobin levels (all P>0.05). However, the average expression levels of matrix metalloproteinase (MMP) 8 and MMP9 in severe group (18.41 and 174.00, respectively) were both higher than those in mild group (2.33 and 22.91, respectively) and healthy control (1.43 and 34.65, respectively; all P<0.01). Conclusion:MMP8 and MMP9 could be expected to serve as the molecular biological markers for predicting the disease severity in patients with influenza A (H1N1) infection.