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. 2021 Aug 31;8(9):ofab448.
doi: 10.1093/ofid/ofab448. eCollection 2021 Sep.

Sex and Gender Differences in Testing, Hospital Admission, Clinical Presentation, and Drivers of Severe Outcomes From COVID-19

Eileen P Scully  1 , Grant Schumock  2 , Martina Fu  2 , Guido Massaccesi  1 , John Muschelli  2 , Joshua Betz  2 , Eili Y Klein  3 , Natalie E West  4 , Matthew Robinson  1 , Brian T Garibaldi  4 , Karen Bandeen-Roche  2 , Scott Zeger  2 , Sabra L Klein  5   6 , Amita Gupta  1   7
Affiliations

Sex and Gender Differences in Testing, Hospital Admission, Clinical Presentation, and Drivers of Severe Outcomes From COVID-19

Eileen P Scully et al. Open Forum Infect Dis. .

Abstract

Background: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear.

Methods: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5-8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect.

Results: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males (P < .001). Among 18-49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18-49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness.

Conclusions: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes.

Keywords: BMI; COVID-19; CRP; inflammation.

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Figures

Figure 1.
Figure 1.
A comparison of males and females stratified by age for (A) number of COVID-19 tests and proportion positive by age group and (B) proportion of those testing positive who required hospital admission. *P < .0001 and **P < .001, by chi-square; asterisk is on the side with the higher value. C, Test positivity rates by sex among individuals considered asymptomatic at the time of testing: ***P = .03, by chi-square. D, Seven-day moving average of test positivity rates for males and females in different race/ethnicity groups. Abbreviation: COVID-19, coronavirus disease 2019.
Figure 2.
Figure 2.
Frequency of comorbid conditions at baseline for males and females, with several comorbidities presenting with a sex imbalance. A, *P < .05 and **P < .001, by chi-square. Distribution of BMI categories (B), alcohol use (C), and smoking status (D) by sex and age. Overall chi-square for (B), (C), and (D): P < .001. Abbreviations: BMI, body mass index; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus.
Figure 3.
Figure 3.
Median lab values at the time of admission (–48 hours to +48 hours) by sex and age. Red represents females, and blue represents males; total numbers of observations for each lab are indicated below the column, and the right-most column is the overall sex comparison. Statistics on the overall comparison: *P < .001, by Wilcoxon rank test. Abbreviations: ALC, absolute lymphocyte count; CRP, C-reactive protein; IL-6, interleukin-6; NLR, neutrophil:lymphocyte ratio.
Figure 4.
Figure 4.
Odds ratio of increased risk for severe or death outcomes in males stratified by age. The risk of male sex is represented for the baseline model (open gray symbol in each graph) and then after addition of each block of variables (black-filled symbol) for a model of outcomes at 24 hours and at peak status during hospitalization. The numbers indicate the point estimate for the OR and the 95% CI. Abbreviations: BMI, body mass index; OR, odds ratio.
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