key: cord-0909310-idn4ivdg
authors: Liu, Dan; Li, Ruyuan; Yu, Ruidi; Wang, Ya; Feng, Xinxia; Yuan, Yuan; Wang, Siyuan; Zeng, Shaoqing; Gao, Yue; Xu, Sen; Li, Huayi; Jiao, Xiaofei; Chi, Jianhua; Yu, Yang; Song, Chunyan; Jin, Ning; Cui, Pengfei; Liu, Jiahao; Zheng, Xu; Gong, Wenjian; Liu, Xingyu; Cai, Guangyao; Song, Jianming; Kwan, Susan Yuk‐Lin; Desai, Aakash; Li, Chunrui; Gao, Qinglei
title: Alteration of serum markers in COVID‐19 and implications on mortality
date: 2020-07-21
journal: Clin Transl Med
DOI: 10.1002/ctm2.119
sha: c4a61e14f4a307dce04d255d22d0ba907bb64cf4
doc_id: 909310
cord_uid: idn4ivdg

nan

and tumor necrosis factor-α (TNF-α) occurred in 651 (56.17%) and 762 (46.15%) patients, respectively. Elevation of cytokines such as IL-2R and IL-6 occurred in 589 (35.61%) and 547 (32.89%) patients, respectively. Patients who died had significantly higher median levels of CRP (103. Table S3 .

To depict the dynamic course of COVID-19 and further explore the risk factors associated with poor prognosis, cytokines and other significant indices were tracked over 6 weeks (shown in Figures S2 and S3 ). The mortality reached its peak approximately around the third week of illness from the onset. Similarly, elevations of D-dimer and cTnI were also observed around 3 weeks from the illness onset among patients with higher mortality. Lastly, in week 5-6, elevated levels of cytokines (including IL-2R, IL-6, IL-8, and IL-10, Ferritin, and TNF-α) were seen among non-survivors compared with patients who recovered. Other laboratory indices, such as LDH, procalcitonin (PCT), and NT-proBNP, also peaked in the corresponding period.

To further understand the role of cytokine storm and other risk factors in COVID-19-related mortality, univariable logistic regression was performed as summarized in Table 1 . Older patients were associated with increased odds of death than the younger. The risk of death increased proportionately with the number of comorbidities. The presence of severe respiratory symptoms and unstable vital signs on admission also predicted poor outcomes.

Surprisingly, we found that some risk factors of mortality disproportionately affected males compared to females. Hypertension (OR 2.88, 95% CI 2.02 to 4.11, P < .001) and coronary heart disease (CHD) (2.96, 1.88 to 4.67, P < .001) increased the odds of death in males but had no 

Abbreviations: CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; CLD, chronic liver disease; HBV, hepatitis B virus; CKD, chronic kidney disease; SOFA, Sequential Organ Failure Assessment;

WBC, white blood cell; BUN, blood urea nitrogen; PT, prothrombin time; APTT, activated partial thromboplastin time; IL-2R, interleukin-2R; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α. † P < .05 was considered statistically significant. ‡

The statistical significance of effect modification between gender and other factors were tested using logistic regression models containing the interaction terms (gender and hypertension, gender, CHD, etc.). § Upper limit of normal value (ULN) for males and females, separately. ¶ Two times of upper limit of normal value (ULN) for males and females, separately.

. Different strategies of risk management in different periods of COVID-19. Leukocytosis was defined as white blood cells count greater than 10 × 10 9 /L. Lymphocytopenia was defined as lymphocyte count less than 0.8 × 10 9 /L. Risk factors for male: age ≥ 50 years, with hypertension, D-dimer > 1 μg/mL, PCT ≥ 0.25 ng/mL, CRP > 10 mg/L, leukocytosis, lymphocytopenia, and IL-6 ≥ 14 pg/mL. Risk factors for female: IL-8 ≥ 62 pg/mL, IL-2R > 710 U/mL, cTnI > 15.6 pg/mL, leukocytosis, lymphocytopenia, and IL-6 ≥ 14 pg/mL. a Time from illness onset adverse influence on females ( Figures S4 and S5 ). However, women with cancer and COPD had a higher risk of death compared to men. Females were also found to have increased odds of death in the cases of cytokine storm, cardiac injury, and coagulopathy compared to their male counterparts.

In the multivariable logistic regression model, we analyzed the factors with significant impact on mortality separately for males and females. Overall, IL-6 ≥ 14 pg/mL, leukocytosis, and lymphocytopenia were independent risk factors of death for both sexes. For male patients, advanced age (≥50 years), hypertension, the elevated PCT, CRP, and D-dimer were associated with increased odds of mortality. Meanwhile, IL-2R, IL-8, and cTnI were independent risks for higher mortality in females.

To further investigate the influence of risk factors, we plotted Kaplan-Meier curves to study the prognoses of patients based on the numbers of independent risk factors they had ( Figure S4C,D) . Males (females) who had 0-3 (0-2), 4-6 (3), and 7-8 (4-6) factors were regarded as lowrisk, moderate-risk, and high-risk patients, respectively, and had diverse prognoses. 67.00% (75.93%) of the high-risk male (female) patients died while only 0.82% (0.77%) of the low-risk ones had fatal outcome. A summary of these findings is shown in Figure 1 .

In conclusions, IL-6 ≥ 14 pg/mL, leukocytosis, and lymphocytopenia were found to be risk factors for mortality in both sexes. Advanced age, presence of hypertension, elevated D-dimer, CRP, and PCT were independent risk factors of death only in males, while elevated IL-2R, IL-8, and cTnI increased the risk of mortality in females. Increase in D-dimer and cTnI were observed in the second and third weeks of illness onset while multiple cytokines were found to be increased in the fifth and sixth weeks among those with high mortality. Cytokine storm was a major concern throughout the clinical course, especially in later stages of COVID-19 and among females. Whether early intervention with potential anti-inflammatory or anti-cytokine agents can improve the prognosis in COVID-19 remains to be seen. Risk stratification based on cytokine profile and other risk factors might be considerable in the management of COVID-19. 

The novel coronavirus originating in Wuhan, China: challenges for global health governance

COVID-19: consider cytokine storm syndromes and immunosuppression

On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatology

The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical and immunological features of severe and moderate coronavirus disease 2019

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

The authors have no conflicts of interest to declare.

QG had full access to all data in the study and take responsibility for the integrity of data and the accuracy of the data analysis. SZ, SW, YG, SX, RY, YW, and YY collected the clinical data. XJ, JC, YaY, CS, NJ, PC, JL, XZ, WG, XL, and GC double-checked and entered the data into database. DL, RL, XF, CL, and QG analyzed the clinical records. RL, RY, YW, XF, YY, HL, and AD drafted the manuscript. DL, QG, RL, RY, YW, XF, and YY analyzed and interpreted the data. CL, JS, and SK advised on the conception and design of the study. DL, CL, QG, and AD conceptualized and designed the study, supervised the project, and revised the manuscript. All authors vouch for the respective data and analysis, revised, approved the final version, and agreed to publish the manuscript. DL, RL, RY, YW, XF, and YY share first authorship, the order in which they are listed was determined by workload.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.