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Preprint in English | medRxiv | ID: ppmedrxiv-22269723


BackgroundAcute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of viral load has passed; however, its underlying mechanisms remain unclear. Alveolar epithelial injury is reported to be a very early event in ARDS with COVID-19. Herein, we assessed whether necrosis of alveolar epithelial cells and subsequent releases of damage associated molecular patterns (DAMPs) at an early disease stage aggravates ARDS with COVID-19 MethodsWe analyzed the levels of cytokeratin18-M65, an epithelial total cell death marker; CK18-M30, an epithelial apoptosis-specific marker; and HMGB-1, one of the DAMPs released from necrotic cells, in patients with COVID-19 with and without ARDS and healthy adults, in addition to the circulating alveolar epithelial and endothelial injury markers, namely sRAGE, angiopoietin-2, and surfactant protein-D. Molecular mechanisms of alveolar epithelial cell death and effects of neutralization on alveolar tissue injury were assessed using a mouse model mimicking COVID-19-induced ARDS. ResultsCOVID-19-induced ARDS was characterized by the elevation of sRAGE, an epithelial injury marker, at a very early disease stage. Although both serum levels of CK18-M65 and CK18-M30 were elevated in COVID-19-induced ARDS, the median CK18-M30/M65 ratio, an indicator of the fraction of apoptosis among total epithelial cell death, was 31.5% in serum from COVID-19 patients with ARDS, a value significantly lower than that of non-ARDS patients or healthy subjects. Moreover, the median M30/M65 ratio in bronchoalveolar lavage fluid (BALF) in COVID-19-induced ARDS was 27.8%, indicating that alveolar epithelial cell death is mainly caused by necrosis. Serum levels of HMGB-1 were also significantly elevated in ARDS versus non-ARDS patients. In a mouse model mimicking COVID-19-induced ARDS, the ratio of CK18-M30 to a total epithelial cell death marker in BALF was also lower than that in control subjects. Moreover, the alveolar epithelial cell necrosis involved two forms of programmed necrosis: necroptosis and pyroptosis. Finally, neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. ConclusionsNecrosis, including necroptosis and pyroptosis, seems to be the primary form of alveolar epithelial cell death and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

Preprint in English | medRxiv | ID: ppmedrxiv-21264013


SARS-CoV-2 infection elicits varying degrees of protective immunity conferred by neutralizing antibodies (nAbs). Here we report the persistence of nAb responses over 12 months after infection despite its decreasing trend noticed from 6 months. The study included sera from 358 individuals who had been infected with SARS-CoV-2 between January and May 2020. Samples were collected at 6 and 12 months after onset. The titers of IgG to the viral nucleocapsid protein (NP) and receptor-binding domain of the spike protein (RBD) were measured by CLEIA. The nAb titer was determined using lentivirus-based pseudovirus or authentic virus. Antibody titers of NP-IgG, RBD-IgG, and nAbs were higher in severe and moderate cases than in mild cases at 12 months after onset. While the nAb levels were likely to confer adequate protection against wild-type viral infection, the neutralization activity to recently circulating variants in some of the mild cases ([~]30%) was undermined, implying the susceptibility of reinfection to the variants of concerns (VOCs). COVID-19 convalescent individuals have robust humoral immunity even at 12 months after infection albeit that the medical history and background of patients could affect the function and dynamics of antibody response to the VOCs.

Preprint in English | medRxiv | ID: ppmedrxiv-21255109


ImportancePersistent symptoms are reported in patients who survive the initial stage of COVID-19, often referred to as "long COVID" or "post-acute sequelae of SARS-CoV-2 infection" (PASC); however, evidence on incidence is still lacking, and symptoms relevant to pain are yet to be assessed. ObjectiveTo determine long-term symptoms in COVID-19 survivors after infection. Data SourcesA literature search was performed using the electronic databases PubMed, EMBASE, Scopus, and CHINAL and preprint servers MedR{chi}iv and BioR{chi}iv through January 15, 2021. Study SelectionEligible studies were those reporting patients with a confirmed diagnosis of SARS-CoV-2 and who showed any symptoms persisting beyond the acute phase. Data Extraction and SynthesisIncidence rate of symptoms were pooled using inverse variance methods with a DerSimonian-Laird random-effects model. Main Outcomes and MeasuresThe primary outcome was pain-related symptoms such as headache or myalgia. Secondary outcomes were symptoms relevant to pain (depression or muscle weakness) and symptoms frequently reported (anosmia and dyspnea). Heterogeneity among studies and publication bias for each symptom were estimated. The source of heterogeneity was explored using meta-regression, with follow-up period, age and sex as covariates. ResultsIn total, 35 studies including 18,711 patients were eligible. Eight pain-related symptoms and 26 other symptoms were identified. The highest pooled incidence among pain-related symptoms was chest pain (17%, 95% CI, 12%-25%), followed by headache (16%, 95% CI, 9%-27%), arthralgia (13%, 95% CI, 7%-24%), neuralgia (12%, 95% CI, 3%-38%) and abdominal pain (11%, 95% CI, 7%-16%). The highest pooled incidence among other symptoms was fatigue (45%, 95% CI, 32%-59%), followed by insomnia (26%, 95% CI, 9%-57%), dyspnea (25%, 95% CI, 15%-38%), weakness (25%, 95% CI, 8%-56%) and anosmia (19%, 95% CI, 13%-27%). Substantial heterogeneity was identified (I2, 50-100%). Meta-regression analyses partially accounted for the source of heterogeneity, and yet, 53% of the symptoms remained unexplained. Conclusions and RelevanceThe current meta-analysis may provide a complete picture of incidence in PASC. It remains unclear, however, whether post-COVID symptoms progress or regress over time or to what extent PASC are associated with age or sex. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the incidence rate of long-term post-acute sequelae of SARS-Cov-2 infection related to pain and other symptoms? FindingsIn the current meta-analysis of 35 studies with 18,711 patients, the highest estimated incidence among pain-related symptoms was chest pain (17%), followed by headache (16%), arthralgia (13%), neuralgia (12%) and abdominal pain (11%). That among other symptoms was fatigue (45%), followed by insomnia (26%), dyspnea (25%), weakness (25%) and anosmia (19%). MeaningThese findings suggest that long-term post-acute sequelae of SARS-Cov-2 infection must not be overlooked or underestimated especially when vaccination has become the focus.

Preprint in English | medRxiv | ID: ppmedrxiv-21249528


The time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of acute respiratory distress syndrome (ARDS) with coronavirus disease (COVID-19) remain unclear. Here, we evaluated the characteristics of circulating markers of alveolar epithelial and endothelial injury in serum samples from eleven ARDS patients and ten non-ARDS patients, all with COVID-19. Our results indicates that the alveolar epithelial injury at the very early disease stage and the endothelial injury which continues to exacerbate during the later disease stage seem to be the hallmarks of ARDS with COVID-19.

Preprint in English | medRxiv | ID: ppmedrxiv-20225805


ObjectiveSerological tests for COVID-19 have been instrumental in studying the epidemiology of the disease. However, the performance of the currently available tests is plagued by the problem of variability. We have developed a high-throughput serological test capable of simultaneously detecting total immunoglobulins (Ig) and immunoglobulin G (IgG) against two of the most immunologically relevant SARS-CoV-2 antigens, nucleocapsid protein (NP) and spike protein (SP) and report its performance in detecting COVID-19 in clinical samples. MethodsWe designed and prepared reagents for measuring NP-IgG, NP-Total Ig, SP-IgG, and SP-Total Ig (using N-terminally truncated NP ({Delta}N-NP) or receptor-binding domain (RBD) antigen) on the advanced chemiluminescence enzyme immunoassay system TOSOH AIA-CL. After determining the basal thresholds based on 17 sera obtained from confirmed COVID-19 patients and 600 negative sera. Subsequently, the clinical validity of the assay was evaluated using independent 202 positive samples and 1,000 negative samples from healthy donors. ResultsAll of the four test parameters showed 100% specificity individually (1,000/1,000; 95%CI, 99.63-100). The sensitivity of the assay increased proportionally to the elapsed time from symptoms onset, and all the tests achieved 100% sensitivity (153/153; 95%CI, 97.63-100) after 13 days from symptoms onset. NP-Total Ig was the earliest to attain maximal sensitivity among the other antibodies tested. ConclusionOur newly developed serological testing exhibited 100% sensitivity and specificity after 13 days from symptoms onset. Hence, it could be used as a reliable method for accurate detection of COVID-19 patients and to evaluate seroprevalence and possibly for surrogate assessment of herd immunity.