Identification of priority pathogens for aetiological diagnosis in adults with community-acquired pneumonia in China: a multicentre prospective study.

BACKGROUND: Community-acquired pneumonia (CAP) is a major public health challenge worldwide. However, the aetiological and disease severity-related pathogens associated with CAP in adults in China are not well established based on the detection of both viral and bacterial agents. METHODS: A multicentre, prospective study was conducted involving 10 hospitals located in nine geographical regions in China from 2014 to 2019. Sputum or bronchoalveolar lavage fluid (BALF) samples were collected from each recruited CAP patient. Multiplex real-time PCR and bacteria culture methods were used to detect respiratory pathogens. The association between detected pathogens and CAP severity was evaluated. RESULTS: Among the 3,403 recruited eligible patients, 462 (13.58%) had severe CAP, and the in-hospital mortality rate was 1.94% (66/3,403). At least one pathogen was detected in 2,054 (60.36%) patients, with two or more pathogens were co-detected in 725 patients. The ten major pathogens detected were Mycoplasma pneumoniae (11.05%), Haemophilus influenzae (10.67%), Klebsiella pneumoniae (10.43%), influenza A virus (9.49%), human rhinovirus (9.02%), Streptococcus pneumoniae (7.43%), Staphylococcus aureus (4.50%), adenovirus (2.94%), respiratory syncytial viruses (2.35%), and Legionella pneumophila (1.03%), which accounted for 76.06-92.52% of all positive detection results across sampling sites. Klebsiella pneumoniae (p < 0.001) and influenza viruses (p = 0.005) were more frequently detected in older patients, whereas Mycoplasma pneumoniae was more frequently detected in younger patients (p < 0.001). Infections with Klebsiella pneumoniae, Staphylococcus aureus, influenza viruses and respiratory syncytial viruses were risk factors for severe CAP. CONCLUSIONS: The major respiratory pathogens causing CAP in adults in China were different from those in USA and European countries, which were consistent across different geographical regions over study years. Given the detection rate of pathogens and their association with severe CAP, we propose to include the ten major pathogens as priorities for clinical pathogen screening in China.

Corrigendum to "Comprehensive Humoral and Cellular Immune Responses to SARS-CoV-2 Variants in Diverse Chinese Population".

[This corrects the article DOI: 10.34133/2022/9873831.].

Comprehensive Humoral and Cellular Immune Responses to SARS-CoV-2 Variants in Diverse Chinese Population.

The SARS-CoV-2 variants have been emerging and have made great challenges to current vaccine and pandemic control strategies. It is urgent to understand the current immune status of various Chinese populations given that the preexisting immunity has been established by national vaccination or exposure to past variants. Using sera from 85 individuals (including 21 convalescents of natural infection, 15 cases which suffered a breakthrough infection after being fully vaccinated, and 49 healthy vaccinees), we showed significantly enhanced neutralizing activities against SRAS-CoV-2 variants in convalescent sera, especially those who had been fully vaccinated. The neutralizing antibodies against Omicron were detectable in 75% of convalescents and 44.9% of healthy vaccinees (p = 0.006), with a GMT of 289.5, 180.9-463.3, and 42.6, 31.3-59, respectively. However, the neutralizing activities were weaker in young convalescents (aged < 18 y), with a detectable rate of 50% and a GMT of 46.4 against Omicron. We also examined and found no pan-sarbecovirus neutralizing activities in vaccinated SARS-CoV-1 survivors. A booster dose could further increase the breadth and magnitude of neutralization against WT and variants of concern (VOCs) to different degrees. In addition, we showed that COVID-19-inactivated vaccines can elicit Omicron-specific T-cell responses. The positive rates of ELISpot reactions were 26.7% (4/15) and 43.8% (7/16) in the full vaccination group and the booster vaccination group, respectively, although without statistically significant difference. The neutralizing antibody titers declined while T-cell responses remain consistent over 6 months. These findings will inform the optimization of public health vaccination and intervention strategies to protect diverse populations against SARS-CoV-2 variants. Advances. Breakthrough infection significantly boosted neutralizing activities against SARS-CoV-2 variants as compared to booster immunization with inactivated vaccine. Vaccine-induced virus-specific T-cell immunity, on the other hand, may compensate for the shortfall. Furthermore, the public health system should target the most vulnerable group due to a poorer protective serological response in both infected and vaccinated adolescents.

[Advances in SARS-CoV-2 diagnostic strategies during the later COVID-19 era].

Based on natural infection or vaccination, the protective barrier for population has been preliminarily established. However, with constant appearances of SARS-CoV-2 variants, breakthrough infection events cannot be completely avoided, and thus the diagnostic strategy is still the key to discovering epidemic sources and blocking the transmission chain. Currently, SARS-CoV-2 diagnosis technologies based on nucleic acid, antigen and antibody detections have developed and extended in diversity. Under the background of work resumption and epidemic-prevention normalization during the later COVID-19 era, it is necessary for us to choose appropriate detection methods to satisfy the need of epidemic prevention and control in various scenarios. We summarized the principles and applicable characteristics of existing SARS-CoV-2 detection technologies in this paper, aimed to provide guidance for clinical and public health personnel to make targeted decisions.

Prognostic Value of Histidine-Rich Glycoprotein for Community-Acquired Pneumonia.

PURPOSE: Histidine-rich glycoprotein (HRG) is abundant in serum and has been implicated in several processes including blood coagulation and immune response. This prospective study is aimed at exploring HRG as a biomarker in patients hospitalized for community-acquired pneumonia (CAP). METHODS: A total of 160 patients (73 severe CAP, 57 nonsevere CAP), and 30 healthy controls were enrolled in 2019. Demographic and clinical data were recorded for all patients. Serum HRG concentration was measured upon admission using ELISA. RESULTS: HRG levels were significantly lower in severe CAP patients compared with other groups, regardless of etiology, and were negatively correlated with serum interleukin-6 and disease severity index scores. Combination of CURB-65, PSI, and APACHE II scores with HRG values significantly improved the accuracy of predicting 30-day mortality in these patients. Cox regression analysis showed that HRG could serve as an independent risk factor for 30-day mortality. Notably, patients with HRG ≤ 16.92 µg/mL had significantly lower cumulative survival than those with HRG > 16.92 µg/mL. CONCLUSION: Serum HRG levels are lower in patients with severe CAP and are negatively correlated with disease severity scores. Measurement of HRG upon admission can provide valuable prognostic information for patients with CAP.

Investigation of the impact of SARS-CoV infection on the immunologic status and lung function after 15 years.

BACKGROUND: We investigate the long-term effects of SARS-CoV on patients' lung and immune systems 15 years post-infection. SARS-CoV-2 pandemic is ongoing however, another genetically related beta-coronavirus SARS-CoV caused an epidemic in 2003-2004. METHODS: We enrolled 58 healthcare workers from Peking University People's Hospital who were infected with SARS-CoV in 2003. We evaluated lung damage by mMRC score, pulmonary function tests, and chest CT. Immune function was assessed by their serum levels of globin, complete components, and peripheral T cell subsets. ELISA was used to detect SARS-CoV-specific IgG antibodies in sera. RESULTS: After 15 years of disease onset, 19 (36.5%), 8 (34.6%), and 19 (36.5%) subjects had impaired DL (CO), RV, and FEF25-75, respectively. 17 (30.4%) subjects had an mMRC score ≥ 2. Fourteen (25.5%) cases had residual CT abnormalities. T regulatory cells were a bit higher in the SARS survivors. IgG antibodies against SARS S-RBD protein and N protein were detected in 11 (18.97%) and 12 (20.69%) subjects, respectively. Subgroup analysis revealed that small airway dysfunction and CT abnormalities were more common in the severe group than in the non-severe group (57.1% vs 22.6%, 54.5% vs 6.1%, respectively, p < 0.05). CONCLUSIONS: SARS-CoV could cause permanent damage to the lung, which requires early pulmonary rehabilitation. The long-lived immune memory response against coronavirus requires further studies to assess the potential benefit. Trial registration ClinicalTrials.gov, NCT03443102. Registered prospectively on 25 January 2018.

Detection of Antibodies Against the SARS-CoV-2 Spike Protein and Analysis of the Peripheral Blood Mononuclear Cell Transcriptomic Profile, 15 Years After Recovery From SARS.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shows a high degree of homology with SARS-CoV. They share genes, protein sequences, clinical manifestations, and cellular entry patterns. Thus, SARS research may serve helpful in gaining a better understanding of the current coronavirus disease 2019 (COVID-19) pandemic. Serum antibodies from convalescent patients with SARS collected in 2018 were used to target the recombinant SARS-CoV-2 spike protein via a chemiluminescence microsphere immunoassay. Antibodies of convalescent patients with SARS exhibited serous immune cross-reactivity with the SARS-CoV-2 spike protein. The serous antibodies, excluding S22 of convalescent patients with SARS, did not competitively inhibit the binding of SARS-CoV-2 spike protein to ACE2. T cellular immunity research was conducted in vitro using peripheral blood mononuclear cells (PBMCs) stimulated by pooled peptide epitopes 15 years post-infection. Interferon gamma was detected and the PBMC transcriptomic profile was obtained. The heatmap of the transcriptomic profile showed that mRNAs and circRNAs of the SARS group clustered together after being stimulated by the peptide epitope pool. Differentially expressed mRNAs were most significantly enriched in immunity and signal transduction (P < 0.01). SARS elicits cytokine and chemokine responses, partially consistent with previously published data about COVID-19. Overall, our results indicate that antibodies from convalescent patients with SARS persisted for 15 years and displayed immune cross-reactivity with the SARS-CoV-2 spike protein. The immune status of patients with SARS 15 years post-infection may provide a better understanding of the future immune status of patients with COVID-19.

The Implementation of Patient-Centered Humanistic Care for COVID-19 Closely Contacted Hemodialysis Patients Under the Hospital-Based Group Medical Quarantine: A Brief Research Report.

In February 2020, an inpatient in Peking University People's Hospital (PKUPH), China, was confirmed positive for the novel coronavirus. In this case, 143 hemodialysis patients were labeled as close contacts and required to be placed under the hospital-based group medical quarantine (HB-GMQ) for 2 weeks by the authorities. After the case was reported, false or misleading information about the case flourished on social media platforms, which led to infodemic. Under this context, PKUPH adopted patient-centered humanistic care to implement the HB-GMQ, through the synergy of administrative, healthcare, logistical, and other measures under the model of patient-centered care of the Massachusetts Medical Society (MMS). As a result, all the patients tided over the HB-GMQ with no COVID-19 infection and no unanticipated adverse events, and all met the criteria for lifting the HB-GMQ. According to the questionnaires taken during the HB-GMQ, a high level of satisfaction was found among the quarantined and no symptomatic increase of anxiety and depression in the patients before and during the HB-GMQ, by comparing the Zung self-rating anxiety scale (SAS) and self-rating depression scale (SDS) conducted in December 2019 and on the 12th day of the HB-GMQ. This article is to brief on PKUPH's experience in implementing patient-centered humanistic care tailored to hemodialysis patients under the HB-GMQ, and to validate the hypothesis that patient-centered humanistic care is effective and helpful to help them tide over the HB-GMQ, so as to shed light on how to implement the HB-GMQ and cope with the HB-GMQ-induced problems in other hospitals.

Correction: Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study.

[This corrects the article DOI: 10.1038/s41413-020-0084-5.].

Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study.

The most severe sequelae after rehabilitation from SARS are femoral head necrosis and pulmonary fibrosis. We performed a 15-year follow-up on the lung and bone conditions of SARS patients. We evaluated the recovery from lung damage and femoral head necrosis in an observational cohort study of SARS patients using pulmonary CT scans, hip joint MRI examinations, pulmonary function tests and hip joint function questionnaires. Eighty medical staff contracted SARS in 2003. Two patients died of SARS, and 78 were enrolled in this study from August 2003 to March 2018. Seventy-one patients completed the 15-year follow-up. The percentage of pulmonary lesions on CT scans diminished from 2003 (9.40 ± 7.83)% to 2004 (3.20 ± 4.78)% (P < 0.001) and remained stable thereafter until 2018 (4.60 ± 6.37)%. Between 2006 and 2018, the proportion of patients with interstitial changes who had improved pulmonary function was lower than that of patients without lesions, as demonstrated by the one-second ratio (FEV1/FVC%, t = 2.21, P = 0.04) and mid-flow of maximum expiration (FEF25%-75%, t = 2.76, P = 0.01). The volume of femoral head necrosis decreased significantly from 2003 (38.83 ± 21.01)% to 2005 (30.38 ± 20.23)% (P = 0.000 2), then declined slowly from 2005 to 2013 (28.99 ± 20.59)% and plateaued until 2018 (25.52 ± 15.51)%. Pulmonary interstitial damage and functional decline caused by SARS mostly recovered, with a greater extent of recovery within 2 years after rehabilitation. Femoral head necrosis induced by large doses of steroid pulse therapy in SARS patients was not progressive and was partially reversible.

Follow-Ups on Persistent Symptoms and Pulmonary Function Among Post-Acute COVID-19 Patients: A Systematic Review and Meta-Analysis.

Objective: As the number of recovering COVID-19 patients increases worldwide, the persistence of symptoms and signs through the post-acute phase indicates an urgent need for prolonged follow-up care. To explore existing data about post-acute COVID-19 syndrome, this meta-analysis assesses the prevalence of persistent manifestations in multiple systems and abnormalities in lung function, as well as their related risks in patients with various severities. Methods: Articles about discharged COVID-19 patients (published from January 1, 2020 to February 23, 2021) were obtained by searching four databases. Cohort studies with follow-up periods >1 month post-discharge or >2 months post-admission were included. Results: A total of 4,478 COVID-19 patients from 16 cohort studies were included in this meta-analysis. Fatigue or weakness (47%) were the most prevalent physical effects of post-acute COVID-19 syndrome, while psychosocial (28%) symptoms were the most common manifestations among several systems. Abnormalities in lung function of recovering patients, i.e., DLCO <80% (47%, 95% CI: 32-61%) persisted for long periods. Severe patients were more likely to present joint pain (OR 1.84, 95% CI: 1.11-3.04) and decreased lung functions compared with non-severe patients, with pooled ORs for abnormal TLC, FEV1, FVC, and DLCO of 3.05 (95% CI: 1.88-4.96), 2.72 (95% CI: 1.31-5.63), 2.52 (95% CI: 1.28-4.98), and 1.82 (95% CI: 1.32-2.50), respectively. Conclusions: Our research indicates that patients recovering from COVID-19 manifest long-term, multi-system symptoms, and the adverse effects on psychosocial health and lung functions were the most extensive and persistent. These findings together may facilitate much needed in-depth study of clinical treatments for long-term, post-acute phase symptoms that affect a great number of recovering COVID-19 patients.

Roles of host small RNAs in the evolution and host tropism of coronaviruses.

Human coronaviruses (CoVs) can cause respiratory infection epidemics that sometimes expand into globally relevant pandemics. All human CoVs have sister strains isolated from animal hosts and seem to have an animal origin, yet the process of host jumping is largely unknown. RNA interference (RNAi) is an ancient mechanism in many eukaryotes to defend against viral infections through the hybridization of host endogenous small RNAs (miRNAs) with target sites in invading RNAs. Here, we developed a method to identify potential RNAi-sensitive sites in the viral genome and discovered that human-adapted coronavirus strains had deleted some of their sites targeted by miRNAs in human lungs when compared to their close zoonic relatives. We further confirmed using a phylogenetic analysis that the loss of RNAi-sensitive target sites could be a major driver of the host-jumping process, and adaptive mutations that lead to the loss-of-target might be as simple as point mutation. Up-to-date genomic data of severe acute respiratory syndrome coronavirus 2 and Middle-East respiratory syndromes-CoV strains demonstrate that the stress from host miRNA milieus sustained even after their epidemics in humans. Thus, this study illustrates a new mechanism about coronavirus to explain its host-jumping process and provides a novel avenue for pathogenesis research, epidemiological modeling, and development of drugs and vaccines against coronavirus, taking into consideration these findings.

Clinical features and risk factors associated with severe COVID-19 patients in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout the world. In this study, we aimed to identify the risk factors for severe COVID-19 to improve treatment guidelines. METHODS: A multicenter, cross-sectional study was conducted on 313 patients hospitalized with COVID-19. Patients were classified into two groups based on disease severity (nonsevere and severe) according to initial clinical presentation. Laboratory test results and epidemiological and clinical characteristics were analyzed using descriptive statistics. Univariate and multivariate logistic regression models were used to detect potential risk factors associated with severe COVID-19. RESULTS: A total of 289 patients (197 nonsevere and 92 severe cases) with a median age of 45.0 (33.0, 61.0) years were included in this study, and 53.3% (154/289) were male. Fever (192/286, 67.1%) and cough (170/289, 58.8%) were commonly observed, followed by sore throat (49/289, 17.0%). Multivariate logistic regression analysis suggested that patients who were aged ≥ 65 years (OR: 2.725, 95% confidence interval [CI]: 1.317-5.636; P = 0.007), were male (OR: 1.878, 95% CI: 1.002-3.520, P = 0.049), had comorbid diabetes (OR: 3.314, 95% CI: 1.126-9.758, P = 0.030), cough (OR: 3.427, 95% CI: 1.752-6.706, P < 0.001), and/or diarrhea (OR: 2.629, 95% CI: 1.109-6.231, P = 0.028) on admission had a higher risk of severe disease. Moreover, stratification analysis indicated that male patients with diabetes were more likely to have severe COVID-19 (71.4% vs. 28.6%, χ2 = 8.183, P = 0.004). CONCLUSIONS: The clinical characteristics of those with severe and nonsevere COVID-19 were significantly different. The elderly, male patients with COVID-19, diabetes, and presenting with cough and/or diarrhea on admission may require close monitoring to prevent deterioration.

Predictive and Prognostic Utility of the Serum Level of Resistin-Like Molecule Beta for Risk Stratification in Patients with Community-Acquired Pneumonia.

Despite progress in intensive care, the morbidity and mortality of patients with community-acquired pneumonia (CAP) remains high. Furthermore, the predictive and prognostic utility of resistin-like molecule beta (RELM-ß) in patients with CAP is uncertain. This study investigated the role of RELM-ß in patients with CAP and evaluated its correlation with disease severity and the risk of death. A prospective, multicenter study was conducted in 2017, and admission serum levels of RELM-ß were detected using quantitative enzyme-linked immunosorbent assay. A total of 114 and 112 patients with severe CAP (SCAP) and non-severe CAP (NSCAP) were enrolled, respectively, with 15 healthy controls. Patients with SCAP, especially non-survivors, had significantly higher levels of serum RELM-ß than patients with NSCAP. RELM-ß levels positively correlated with severity scores and consistently predicted SCAP in patients with CAP (area under the curve = 0.794). Increased levels of RELM-ß were closely related to the severity and prognosis of patients with CAP. The accuracy of 30-day mortality predictions of CURB-65 (confusion, urea, respiratory rate, blood pressure, and age ≥ 65 years) can be significantly improved when combined with RELM-ß levels. The level of RELM-ß can assist clinicians in risk stratification of patients with CAP in early stages.

Genomic Diversity of Severe Acute Respiratory Syndrome-Coronavirus 2 in Patients With Coronavirus Disease 2019.

BACKGROUND: A novel coronavirus (CoV), severe acute respiratory syndrome (SARS)-CoV-2, has infected >75 000 individuals and spread to >20 countries. It is still unclear how fast the virus evolved and how it interacts with other microorganisms in the lung. METHODS: We have conducted metatranscriptome sequencing for bronchoalveolar lavage fluid samples from 8 patients with SARS-CoV-2, and also analyzed data from 25 patients with community-acquired pneumonia (CAP), and 20 healthy controls for comparison. RESULTS: The median number of intrahost variants was 1-4 in SARS-CoV-2-infected patients, ranged from 0 to 51 in different samples. The distribution of variants on genes was similar to those observed in the population data. However, very few intrahost variants were observed in the population as polymorphisms, implying either a bottleneck or purifying selection involved in the transmission of the virus, or a consequence of the limited diversity represented in the current polymorphism data. Although current evidence did not support the transmission of intrahost variants in a possible person-to-person spread, the risk should not be overlooked. Microbiotas in SARS-CoV-2-infected patients were similar to those in CAP, either dominated by the pathogens or with elevated levels of oral and upper respiratory commensal bacteria. CONCLUSION: SARS-CoV-2 evolves in vivo after infection, which may affect its virulence, infectivity, and transmissibility. Although how the intrahost variant spreads in the population is still elusive, it is necessary to strengthen the surveillance of the viral evolution in the population and associated clinical changes.

Development and validation of a prediction model for early identification of critically ill elderly COVID-19 patients.

In this study, we established a simple and practical tool for early identification of potentially high-risk individuals among elderly COVID-19 patients. Included were 2106 laboratory-confirmed COVID-19 patients aged 60 years and above in 30 provinces of mainland China. Using discrimination (the area under the receiver-operator characteristic curve [AUC]) and calibration (Hosmer-Lemeshow goodness-of-fit test and calibration plots), a nomogram for predicting critically ill cases was developed, and its performance was examined using an internal validation cohort (444 patients) and external cohort (770 patients). The proportion of critically ill patients was 11.8% (248/2106). The most common symptoms at the onset of illness were fever (66.6%), cough (34.1%), fatigue (23.3%), and expectoration (23.6%). Older age, history of chronic obstructive pulmonary disease, fever, fatigue, shortness of breath, and lymphocyte percentage lower than 20% at admission were associated with increased risk of becoming critically ill. The AUCs for the six-variable-based nomogram were 0.77 (95% CI: 0.73-0.82), 0.73 (95% CI: 0.67-0.79), and 0.77 (95% CI: 0.71-0.83) in the development, internal validation, and external validation cohorts, respectively. This six-variable-based nomogram could potentially serve as a practical and reliable tool for early identification of elderly COVID-19 patients at high risk of becoming critically ill.