key: cord-0050353-485m3w78 authors: Cao, Yang; Wei, Jia; Wang, Gaoxiang; Chen, Liting; Luo, Hui; Zhou, Jianfeng title: Reply date: 2020-09-18 journal: J Allergy Clin Immunol DOI: 10.1016/j.jaci.2020.07.037 sha: 087fed5c06e72d5a27202a89756bb77aa337057b doc_id: 50353 cord_uid: 485m3w78 nan Reply Q 1 To the Editor: We appreciate Li and Liu 1 for their interests in and comments on our article. 2 Although most patients with severe coronavirus disease 2019 (COVID-19) have a self-limited disease course, about 10% to 15% subsequently developed critical illness and experienced a high mortality. 3, 4 In our randomized controlled trial, we evaluated whether the use of ruxolitinib was safe and superior in shortening the time to recovery and in preventing severe COVID-19 from progression. Given below are our point-to-point responses to each of the comments. The median interval of time from illness onset to discharge in our study was 39 days, which was substantially longer than the time in previously reported results. 5 All enrolled patients were transferred from other designated hospitals and had substantially high comorbidities. To better describe the baseline characteristics of our cohort, a risk scoring system (COVID-GRAM, an online calculator, http://118.126.104.170) was used to rate the risk of the subsequent occurrence of critical illness on the basis of 10 variables determined at hospital admission. 6 Nine patients in the control group and 7 patients in the ruxolitinib group were estimated to have a high risk of progressing to critical illness. In fact, 4 highrisk patients in the control group experienced subsequent clinical deterioration, and 3 of them eventually died of respiratory failure, whereas all high-risk patients in the ruxolitinib group showed clinical improvement. These results justified the use of investigational therapeutic intervention in our study cohort. The demographic and clinical characteristics of the patients were balanced between the 2 groups at enrollment. The use of corticosteroids and antivirals was comparable in the control and ruxolitinib groups. Therefore, it was unlikely that the significantly accelerated improvement in computed tomography imaging of disease with ruxolitinib recipients was the result of natural disease course. The delicate nature of dysregulated immune responses in COVID-19 is poorly understood so far, and it is unknown what is the appropriate timing to administer ruxolitinib. However, several reports showed that the escalation in COVID-19 went through 3 phases, that is, early infection, pulmonary phase, and hyperinflammatory phase. 7 The use of ruxolitinib for COVID-19 during middle-to-late stage in our randomized controlled trial study is reasonable based on its therapeutic rationale. Wilcoxon rank-sum test, also called Mann-Whitney-Wilcoxon test, was used for evaluating the CT improvement at day 14 because the CT improvement was measured on an ordered scale (''Improvement,'' ''Stable,'' and ''Progression'') and a P value indicating statistical significance (P 5 .0495) was obtained. Mann-Whitney-Wilcoxon test is appropriate for the analysis of an ordered table when the outcomes fall into 2 or more ordered categories and it could use the information of the ordering. 8 We also recalculated the P value adjusted with tied values in Mann-Whitney-Wilcoxon test and a P value indicating statistical significance (P 5 .0475) was obtained. The P value proposed by Li and Liu 1 is derived from chisquare test. Chi-square test is more appropriate when the response (CT improvement) is a nominal variable and it is designed to test whether 2 distributions are from the same population, and hence may not be appropriate for checking whether a distribution shifts to higher values compared with another distribution. Therefore, Mann-Whitney-Wilcoxon test is more suitable here and our conclusion was valid. In conclusion, the comments made by readers further underline the great importance of randomized controlled trials for evaluating the efficacy and safety of novel treatments for COVID-19. Future trials involving larger populations to assess with ruxolitinib or other JAK1/2 inhibitors in patients with COVID-19 are needed . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Regarding ''Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial Clinical characteristics of coronavirus disease 2019 in China Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei (epicentre) and outside Hubei (non-epicentre): a nationwide analysis of China China Medical Treatment Expert Group for COVID-19. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19 COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal A note on the Wilcoxon-Mann-Whitney test for 2 X kappa ordered tables