Compile in full! Nature paper published in China reveals viral and host factors associated with clinical outcomes in PATIENTs with COVID-19

May 24, 2020 /PRNewswire/ -- Biovalley BIOON/--- the COVID-19 outbreak in Wuhan city is closely related to the South China Seafood Wholesale Market (HSWM) in WuhanThe pathogen that caused the outbreak, SARS-CoV-2, is closely related to the bat coronavirus RaTG13, but its receptor binding domain is more similar to the pangolin coronavirusAt present, there are several questions about the origin, evolution and interaction of SARS-CoV-2 with the hostFirst, although the HSWM market is widely considered to be the site of the original outbreak of SARS-CoV-2, a significant number of cases did not come into contact with the market in the first series of casesThis raises doubts about the single event in which zoonotic diseases spill edire into humans during the initial outbreakSecond, whether the toxicity of SARS-CoV-2 has changed as a result of the evolution of genome sequences during the spread of the disease, and more data remain to be answeredThird, although SARS-CoV-2 infection can cause life-threatening respiratory diseases, most cases are characterized by mild pneumoniaTo date, the factors associated with the clinical outcomes of the disease have not been fully describedFigure 1Systematic developmental analysis of the assembled SARS-CoV-2 genomeIn a new study, researchers from Fudan University in China, Shanghai Jiaotong University School of Medicine and Shanghai Institute of Life Sciences of the Chinese Academy of Sciences systematically analyzed key immunological parameters throughout the infection process, obtained the viral genome directly from clinical samples, and identified factors associated with clinical outcomes and epidemiological characteristics of the diseaseThe findings were published online May 20, 2020 in the journal Nature with the title "Viral and host factors to the clinical life of COVID-19"A total of 326 patients were recruited from January 20 to February 25 in ShanghaiThese infections fall into four categories5 people asymptomatic, i.eno obvious fever, respiratory symptoms and radiological manifestationsMost patients (293 cases) had mild eras and had radiological manifestations of fever and pneumonia In 12 patients, patients developed symptoms of breathing difficulties and pulmonary grinding glass-like shadow expansion within 24 to 48 hours, and were therefore defined as severe Another 16 patients were classified as critically ill because they deteriorated into acute respiratory distress syndrome (ARDS) and required mechanical ventilation or in vitro membrane oxygen absorption (ECMO) As of 1 April, 315 (96.63%) patients had been discharged from hospital and 6 (1.84%) had died Nucleotide variation in the viral genome quality control of the sequencing data of 112 samples (sputum, mouth-swallow swab) and used for nucleotide variation called (nucleo tide dro called) A total of 66 synonymous and 103 non-synonymous variants were identified in nine protein coding regions, compared to the first-published SARS-CoV-2 genome (Wuhan-Hu-1) THE REPLACEMENT RATES OF ORF1AB, S, ORF3A, E, M, AND ORF7A ARE SIMILAR (APPROXIMATELY 3.5 X 10-4/BIT/YEAR), WHILE ORF8 (9.51 X 10-4/YEAR) AND N (1.05 X 10-3/POINT/YEAR) ARE HIGHER These Shanghai samples have similar repetition rates of viral genome variation between the GISAID data set Next, the authors used the viral genome sins of 94 cases (90% complete) to perform systematic development almost in conjunction with 221 SARS-CoV-2 sequences in the GISAID database The two main branches (clade) were identified (Figure 1), both of which include cases diagnosed in early December 2019 Branch I consists of several sub-branches, such as sub-branch V described by ORF3a: p.251G and V, or sub-branch G as described by S: p.614D G The difference between branch II and branch I is two connected variations: ORF8: p.84L S (28144T(C) and ORF1ab: p.2839S (8782C) (Figure 1) The sequence of these patients runs through the two main branches and their sub-branches, suggesting that there are multiple sources of transmission to Shanghai No significant branch/sub-branch expansion was observed in Shanghai In addition, six cases with a clear history of exposure to the HSWM market (the suspected site of the initial outbreak) were classified as sub-line I, while the three cases diagnosed during the same period without a history of exposure to the HSWM market were classified as subline II (Figure 1) In HSWM/non-HSWM-related samples and bat coronavirus bat-SARS-CoV-RaTG13, the sequence near nt8782 and nt28144 bit stakes of SARS-CoV-2 was analyzed The authors note that the non-HSWM sequence is the same as Bat-SARS-CoV-RaTG13 at both points The authors compared the clinical performance of patients infected with branch I or branch II virus They found no statistical differences in the severity of the disease (p-0.88), lymphocyte count (p-0.79), CD3-T cell count (p-0.21), C-reactive protein (p-0.83), or D-dipolymer (p-0.19) and post-onset virus shedding time (p-0.79) As a result, viruses in both branches exhibit similar pathogenic effects, although their genome sequences differ Similarly, no significant association was found between the severity of the disease and the 13 most common variants (the synonym and non-synonyms) A notable feature of host factors associated with the severity of the disease is that some infected people (5 cases, 1.53%) can detect significant virus shedding, but do not show obvious symptoms Asymptomatic patients were admitted to hospital for 5 days after no apparent lung lesions were found In contrast, one-sided and two-sided grinding of the lungs was observed in mild and severe cases, and the condition rapidly deteriorated in just two days Figure 2 Time changes in the cell count of CD3 plus (a), CD4 plus (b), CD8 plus (c), CD16 plus CD56 (d), CD19 plus (e) cells during hospitalization in each group The authors further analyzed the immunological and biochemical indicators of these patients A prominent feature of COVID-19 is the reduction of sexual lymphocytes, especially in patients with severe and critical conditions (initial test results after admission, P is 6 x 10-6) A detailed analysis of lymphocyte subtypes found that the most significant effects on CD3-T cells (P 10-6), CD4 plus T cells and CD8-T cells had similar trends (CD4 plus T cells, P 10-6; CD8 plus T cells, P x 1 x 10-5) It is worth noting that these changes in T-cells are not only statistically significant in critical cases, but also statistically significant in three other types of cases (asymptomatic, mild, and severe) (CD3 plus T cells, p-0.013; CD8-T cells, p-0.004) In contrast, in the case of CD19 plus B cells, although a significant decrease in CD19 plus B cells was found in critical cases (p-1 x 10-5), there was no significant change in asymptomatic, mild, and severe cases (p-0.47) They further studied longitudinal cell count data for each group of cases It is clear that as the disease worsens, there is a gradient decline in CD3-T cells (7, 8, 11, 14 to 18, 22 to 25, 28, 29 days, Cruzcarr-Wallis test, P 0.05), CD4 plus T cells and CD8-T cells also have a downward trend (Figure 2b-c) However, this trend was not found in natural killer cells (CD16 plus, CD56 plus) or B cells (CD19 plus) (Figure 2d-e) The authors then compared the clinical parameters grouped by comorbidity (co-morbidity) and found that if comorbidities were taken into account, the risk of disease progression increased significantly (p-0.01), although the median age of the comorbidity group was also higher (p-0.02) Indeed, single-factor logical regression analysis showed that age (p 0.0001), number of lymphocytes at the time of admission (p.0001), comorbidities (p.01) and sex (p-0.014) were the main factors associated with the severity of the disease Multifactoric analysis showed that age (p-0.002) and lymphocyte reduction (p-0.002) were the two main independent factors, while comorbidities did not reach statistical significance The correlation between inflammatory cytokines and lymphocyte count. Levels of 11 cytokines (IFN-alpha, IFN-sic, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-17) were measured during admission and treatment Among them, IL-6 (p 10-6) and IL-8 (p-1 x 10-5) show the most significant changes It is worth noting that these two cytokines are inversely proportional to lymphocyte counts (Figure 3a-b) In addition, the authors combined longitudinal cytokine data for each group of cases to map their patterns of fluctuations with the point in time after onset of the disease They compiled the highest IL-6 data for each patient between the 6th and 10th days after the onset of the disease and compared critically ill patients with non-critical patients It was found that the IL-6 level in the critically ill patient group was significantly higher than that of the non-critical patient group (p-0.001, two-sided Mann-Whitney U test, Figure 3c) A similar significant difference in IL-8 levels was observed when data from the 16th to 20th days after the onset of the disease were summarized (p-0.006, Figure 3d) These data show a close link between inflammatory cytokines and the pathogenesis of SARS-CoV-2 infection The discussion of the authors' analysis of some recently treated patients provides further evidence that the SARS-CoV-2 virus genome is basically stable Consistent with a recent study, the authors found that the observed smaller sequence variation divided the viral genome into two major subtypes They noted that the six sequences obtained from patients with a history of HSWM exposure were all in branch I, while the three genomes from patients diagnosed during the same period were classified as branch II As a result, the two main haplotype strains are likely to represent two viral lineages from a common ancestor that evolved independently in Wuhan in early December 2019, one of which was created in the HSWM market, where high-density vendors, vendors and customers may have facilitated the spread of human-to-human transmission Consistent with this view, an epidemiological survey of the earliest cases in Wuhan before December 18 found that two patients were linked to the HSWM market, but five patients were not associated with the HSWM market The authors' time-resolution system developmental analysis suggests that the earliest zoonotic overflows may have occurred in late November 2019, consistent with the analysis by Andersen et al Nevertheless, patients infected with branch I or subline TYPE II did not show significant differences in a range of clinical characteristics, mutation rates, or transmission These data are consistent with the lack of selectivity of any of the branches suggested by others, but are inconsistent with tang et al.'s conclusion--- that their L/S type classification is based on the same two connected polymorphism--- Since the early upload sequences in the GISAID database were obtained in a limited number of critically ill patients, and repeated assembly from the same patient was not uncommon, the presumed propagation differences may be due to sampling deviations Recently, Guan et al analyzed 1,099 cases of COVID-19 patients in China and found that lymphocyte reduction was one of the most common characteristics in laboratory tests In the new study, the authors confirmed this observation and further found that CD3 plus T cells were the main type of inhibition in infected patients, while CD19 plus B cells and CD16-CD56 plus natural killer cells showed less inhibition In fact, reduced lymphocytes, especially CD4/CD8 cell counts, are also major manifestations of SARS-CoV-2 infection In addition, the authors' longitudinal monitoring of the main cytokines showed that IL-6 and IL-8 were negatively correlated with lymphocyte count, and that IL-6 dynamics were highly correlated with disease severity At present, the relationship between viral activity, cytokine release and lymphocyte reduction remains unclear They speculate that the immunopathological response to SARS-CoV-2, including "cytokine storms" and cd3 plus T lymphocyte splylothers, can at least form the basic mechanisms of disease progression and death As observed in infected patients and macaques, lung macrophages may be the first driver of the "cytokine storm" in the early stages of COVID-19 pneumonia, and subsequent cytokine mobilization of lymphocyte immersion may explain lymphocyte decline, although possible cytokine-induced T-cell failure cannot be ruled out In summary, by closely monitoring molecular and immunological data in 326 patients with COVID-19, the authors suggested that adverse clinical results were associated with CD3 plus T lymphocyte failure, which was closely related to the sharp increase in cytokines such as IL-6 and IL-8 Targeted sequencing of 94 cases infected between late January and February found that limited variation in the virus's genome suggested steady evolution Two major viral lineages from the same ancestor may have evolved independently in Wuhan in December 2019, although no significant differences have been found between them in clinical manifestations or transmission These data provide further evidence to shed light on the respective roles of viruses and host factors in disease mechanisms and highlight the importance of early intervention in treatment (BioValley Bioon.com) References: Xiaonan Zhang et al Viral and Viral host factor s the sthes the clinical the outcome of THE COVID-19 Nature, 2020, doi:10.1038/s41586-020-2355-0.