key: cord-0696694-k8l0e9j0 authors: Wang, Nan; Zhan, Yan; Zhu, Linyu; Hou, Zhibing; Liu, Feng; Song, Pinhong; Qiu, Feng; Wang, Xiaolin; Zou, Xiafei; Wan, Deyun; Qian, Xiaosong; Wang, Shanshan; Guo, Yabi; Yu, Hao; Cui, Miao; Tong, Gangling; Xu, Yunsheng; Zheng, Zhihua; Lu, Yingying; Hong, Peng title: Retrospective Multicenter Cohort Study Shows that Early Interferon Therapy is Associated with Favorable Clinical Responses in COVID-19 Patients date: 2020-07-18 journal: Cell Host Microbe DOI: 10.1016/j.chom.2020.07.005 sha: 1b890b31d97504c7accbae1c2c25cd70410c6763 doc_id: 696694 cord_uid: k8l0e9j0 Summary Interferons (IFN) are widely used in treating coronavirus disease 2019 (COVID-19) patients. However, recent report of ACE2, the host factor mediating SARS-Cov-2 infection, as interferon-stimulated, raised considerable safety concern. To examine the association between the use and timing of IFN-α2b and clinical outcomes, we analyzed in a retrospective multicenter cohort study 446 COVID-19 patients in Hubei, China. Regression models estimated that early administration (≤5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality compared to no IFN-α2b, while late administration of IFN-α2b was associated with increased mortality. Among survivors, early IFN-α2b was not associated with hospital discharge or CT scan improvement, while late IFN-α2b was associated with delayed recovery. Additionally, early IFN-α2b and umifenovir (UFV) alone or together were associated with reduced mortality and accelerated recovery compared to lopinavir/ritonavir (LPV/r) alone. We concluded that administration of IFN-α2b during the early stage of COVID-19 may induce favorable clinical responses. Center 1 and 2, except that Center 1 has higher prevalence of high-risk exposure, lower 119 prevalence of eosinopenia at admission, and less symptom counts based on fever, cough, fatigue, 120 body or muscle aches, chest pain or short of breath, headache, and diarrhea reported at admission 121 (Table S1 ). Among patients admitted to Center 1, only 25% received IFN-α2b, while 72.2% 122 received LPV/r. In contrast, among patients admitted to Center 2, 73% received IFN-α2b and 123 36.3% received LPV/r. To assess the standard care at the two medical centers, we compared the 124 cumulative event curves for hospital discharge and CT improvement. Among all survivors, 125 patients admitted to Center 1 had longer hospitalization (Log-rank test, p < .001) ( Figure S1A ). 126 However, after excluding patients that received LPV/r, which tended to prolong hospitalization 127 due to various adverse effects, both centers showed comparable rate of hospital discharge cities. Together, we conclude that location of care was not associated with clinical outcomes in 135 this study. 136 Since the timing of IFN therapy may be crucial to its efficacy against SARS-CoV-2 137 infection, we calculated the time from admission to initiation of IFN therapy and found that 68.2% 138 IFN users received the first dose within the first 2 days of hospitalization and 89.3% received the 139 first dose within the first 5 days. Together with the fact that the first CT re-evaluation and 140 adjustment of treatment plans would also be carried out around the 5th day of hospitalization, we 141 empirically determined that initiation of IFN therapy within the first 5 days of hospitalization 142 was deemed early IFN therapy, and vice versa (Figure 2A) (4.9%) groups (Log-rank test, p < .001) ( Figure 2B ). Using logistic regression, we determined 173 that early IFN therapy was univariately associated with lower mortality (odds ratio [OR] = 0.18, p = .029), while late IFN therapy (OR = 3.53, p = .046), age >60 years (OR = 6.87, p < .001), 175 hypertension (OR = 6.87, p < .001), diabetes (OR = 8.96, p < .001), respiratory rate >22/min at 176 admission (OR = 10.1, p < .001), O 2 saturation between 90-93% (OR = 11.8, p < .001) or <93% 177 (OR = 25.2, p < .001) were univariately associated with higher mortality ( Figure S2 ). In the primary analysis, both logistic regression and Cox proportional hazards models were 179 tested and fitted to all patients. Factors associated with mortality were included in the model with Figure 2D ). Using generalized gamma with log link model, we determined that late IFN therapy, 206 age >60 years, hypertension, respiratory rate >22/min at admission, O 2 saturation between 90-93% 207 or <93%, lymphopenia, and eosinopenia were univariately associated with both longer 208 hospitalization and delayed CT improvement, while diabetes and symptom onset to admission >7 209 days was univariately associated with delayed and early CT improvement, respectively ( Figure 210 S3B and C). After adjusting for gender, age, hypertension, diabetes, O 2 saturation at admission, 211 symptom count at admission, and symptom onset to admission >7 days, early IFN therapy was 212 estimated to have adjusted HR of 1.14 (95% CI, 0.93-1.41) for hospital discharge and 1.00 (95% 213 CI, 0.81-1.22) for CT improvement compared to no IFN therapy, while late IFN therapy was estimated to have adjusted HR of 0.69 (95% CI, 0.44-1.08) for hospital discharge and 0.50 (95% Since IFN is regularly used in conjunction with anti-retroviral agents to treat COVID-19 patients, Second, ACE2 has recently been identified as a type Ⅰ and Ⅲ ISG in human airway In summary, we conclude that among severe to critical COVID-19 patients, early treatment 290 with IFN-α2b was associated with reduced in-hospital mortality, while no significant benefit was The authors declare no competing interests. The manuscript includes all datasets generated and analyzed during this study. The primary outcome was in-hospital mortality. • 242 of 446 analyzed COVID-19 patients received interferon-α2b, a type I interferon. • Early initiation of interferon therapy was associated with reduced mortality. • Interferon therapy was not associated with recovery time for COVID-19. • Interferon-α2b was associated with better responses than lopinavir/ritonavir. In a retrospective cohort study of 446 COVID-19 patients, Wang et al. determine that early administration of interferon-α2b was associated with reduced in-hospital mortality. In contrast, late interferon therapy increased mortality and delayed recovery, suggesting the timing of interferon therapy is crucial for favorable responses in COVID-19 patients. 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