key: cord-0820950-c3dxfet9 authors: Yang, Yang; Shen, Chenguang; Li, Jinxiu; Yuan, Jing; Yang, Minghui; Wang, Fuxiang; Li, Guobao; Li, Yanjie; Xing, Li; Peng, Ling; Wei, Jinli; Cao, Mengli; Zheng, Haixia; Wu, Weibo; Zou, Rongrong; Li, Delin; Xu, Zhixiang; Wang, Haiyan; Zhang, Mingxia; Zhang, Zheng; Liu, Lei; Liu, Yingxia title: Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome date: 2020-03-06 journal: nan DOI: 10.1101/2020.03.02.20029975 sha: ebed882da10cbf669cbb86802e9fa07a4a33ef91 doc_id: 820950 cord_uid: c3dxfet9 The outbreak of Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, December 2019, and continuously poses a serious threat to public health. Our previous study has shown that cytokine storm occurred during SARS-CoV-2 infection, while the detailed role of cytokines in the disease severity and progression remained unclear due to the limited case number. In this study, we examined 48 cytokines in the plasma samples from 53 COVID-19 cases, among whom 34 were severe cases, and the others moderate. Results showed that 14 cytokines were significantly elevated upon admission in COVID-19 cases. Moreover, IP-10, MCP-3, and IL-1ra were significantly higher in severe cases, and highly associated with the PaO2/FaO2 and Murray score. Furthermore, the three cytokines were independent predictors for the progression of COVID-19, and the combination of IP-10, MCP-3 and IL-1ra showed the biggest area under the curve (AUC) of the receiver-operating characteristics (ROC) calculations. Serial detection of IP-10, MCP-3 and IL-1ra in 14 severe cases showed that the continuous high levels of these cytokines were associated with disease deterioration and fatal outcome. In conclusion, we report three cytokines that closely associated with disease severity and outcome of COVID-19. These findings add to our understanding of the immunopathologic mechanisms of SARS-CoV-2 infection, which suggested novel therapeutic targets and strategy. and Murray scores ( Figure S2 ). Our previous study has found that the viral shedding infections correlated with severe diseases 28-30 , while not for all of them 31 . These results suggested that the production of specific cytokines while not the viral burden We further analyzed whether these cytokines could be used as predictors for the 1 1 0 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi. org/10.1101 org/10. /2020 disease severity and progression of COVID-19. Firstly, we calculated the receiver we tested the different combination of these cytokines for the prediction of disease 1 1 5 progression. Combinations of the three cytokines showed the highest AUC of 0.943, of IP-10 and IL-1ra (0.923) ( Figure 3 ). Furthermore, we analyzed the serial change of improvement of the disease, and became moderate cases (cases 4, 10, 12 and 14) or 1 2 5 discharged from hospital (cases 3, 5, 6 and 10). These results indicated that these 1 2 6 three cytokines could be considered as biomarkers to predict disease progression and 1 2 7 outcome of SARS-CoV-2 infections. Cytokine storm with uncontrolled proinflammatory responses induce significant 1 2 9 immunopathology and severe disease outcomes during some viral infections, indicating an important role in the pathogenesis of these viruses 2,32 . Accordingly, not 1 3 1 only the pathogens but also the pathogen induced cytokine storm should be 1 3 2 considered during the treatment. Therapy strategy with a combination of antimicrobial 1 3 3 and immunotherapy may produce a more favorable outcome 9 . Corticosteroids which 1 3 4 could downregulate proinflammatory cytokine transcription and subsequently inhibit 1 3 5 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.02.20029975 doi: medRxiv preprint the cytokine storm 33 , and the antiviral cytokine interferon-α were widely used during shown to be associated with an increase in mortality and significantly longer 1 3 8 durations of viral shedding in H7N9 infected patients 35 , which is of concern. The 1 3 9 results of our study suggested a crucial role of IP-10 in the pathogenesis of 1 4 0 SARS-CoV-2, which has also been shown to be associated with disease severity of In summary, we compared the differences of cytokines profiles between severe and 1 4 7 moderate COVID-19 cases, and found that IP-10, MCP-3 and IL-1ra were antibodies against theses cytokines, especially IP-10. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the Commission Guidelines for Diagnosis and Treatment of 2019-nCoV infection. Healthy controls (N=8) were also included. Clinical information and laboratory result 1 5 8 were collected at the earliest time-point after hospitalization. The study protocol was Declaration of Helsinki and institutional ethics guidelines. qRT-PCR were done as previously reported 26, 34 . In brief, throat swabs, nasal swabs, Food and Drug Administration (CDFA) approved commercially kit (GeneoDX Co., Shanghai, China) were used for the detection of SARS-CoV-2 specific RNAs. Samples whose Ct was higher than 37 were re-tested and considered positive if Ct Disease severity classification 1 7 5 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10. 1101 /2020 Disease severity classification and Murray Score calculation were evaluated as The partial pressure of oxygen (PaO 2 ) in arterial blood taken from the patients at 1 8 9 various time-points after hospitalization is measured by the ABL90 blood gas FiO 2 value. A PaO 2 /FiO 2 ratio less than or equal to 100 mmHg is considered one of were calculated as reported 39 . Cytokine and chemokine measurements 1 9 7 The plasma of patients with laboratory-confirmed COVID-19 cases (N=53) were 1 9 8 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10. 1101 /2020 collected at the earliest possible time-point after hospitalization and thereafter. The author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the Nature 499, 500-503, doi:10.1038/nature12379 (2013). patients. J Med Virol 75, 185-194, doi:10.1002/jmv.20255 (2005 author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https: //doi.org/10.1101 //doi.org/10. /2020 2019-nCoV infections. medRxiv (2020). represents not significant. values of all AUC for the three cytokines were less than 0.05. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10. 1101 /2020 † Values shown represent the mean and inter-quartile range (IQR) All rights reserved. No reuse allowed without permission.author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The authors declare no competing interests. All rights reserved. No reuse allowed without permission.author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.02.20029975 doi: medRxiv preprint were marked in red. Cases in critical condition were marked in blue, and the others 3 6 6were cases with moderate disease or discharged at present. (***), respectively, whereas ns represents not significant. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which was not peer-reviewed) is the . https: //doi.org/10.1101 //doi.org/10. /2020 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which was not peer-reviewed) is the . https: //doi.org/10.1101 //doi.org/10. /2020 author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10. 1101 /2020