Sex differences in mortality in the intensive care unit patients with severe COVID-19.

Dear Sir,

The available evidence suggests that mortality from coronavirus disease 2019 (COVID-19) in males is higher than in females. In a recent cross-sectional study, de Lusignan et al. evaluated the absolute excess risk (AER) of mortality and excess mortality rate (EMR) in the UK from a COVID-19 sentinel surveillance network in people aged 45 years and above. The AER in mortality was calculated by comparing mortality for weeks 2–20 this year with mortality data from the Office for National Statistics (ONS) from 2018 for the same weeks. The absolute excess mortality was approximately 2 deaths per 100 person years in the first wave of COVID-19, whereas the EMR for male gender, compared with female, was 1.4 (95% confidence interval [CI] 1.35–1.44, p<0.00).

We investigated the sex-related differences in the occurrence of comorbidities and mortality rates in a nationwide study in 1522 consecutive patients with severe SARS-CoV-2 pneumonia who were admitted to intensive care unit (ICU) for respiratory support. Medical records of patients were submitted by the COVID-19 hospitals located in 70 regions across Russia to the Federal Center at the Sechenov University (Moscow) that provided advice on critical care of patients. In 995 patients (65.4%), diagnosis of SARS-CoV-2 pneumonia was confirmed by polymerase chain reaction (PCR), whereas in the other cases SARS-CoV-2 pneumonia was defined as severe acute respiratory infection with typical CT findings and no other obvious etiology. Most patients were older than 40 years of age and had various comorbidities. Among 1522 patients enrolled in this study, 995 patients (65.4%) died, and 527 patients (34.6%) recovered. Most patients (93.2%) died from progressive respiratory failure.

In the total cohort, the requirement for mechanical ventilation and mortality rates were similar in males and females (Table 1 ). However, female patients were older and had a higher occurrence of various chronic illnesses, that is, arterial hypertension, obesity and type 2 diabetes, that impair prognosis in patients with COVID-19. , Coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD) were more frequent in males than in females, although their occurrence was lower compared to that of the other significant comorbidities. The mortality rates increased with age both in males and females. In patients aged 50 years or younger, the mortality rates were similar in males and females (odds ratio [OR] 0.975; 95% CI 0.596–1.596; p=0.92) despite a higher requirement for mechanical ventilation in male patients. In the other age groups, the mortality rates were significantly higher in males than in females (51–60 years: OR 1.796; 95% CI 1.192–2.705; p=0.005; 61–70 years: OR 1.952; 95% CI 1.290–2.952; p=0.002; ≥71 years: OR 2.006; 95% CI 1.109–3.629; p=0.021), whereas the requirement for mechanical ventilation did not differ between sexes. In all age groups, the occurrence of arterial hypertension, type 2 diabetes and obesity was higher in females than in males, although these differences reached statistical significance only in a proportion of cases (Table 1). On the contrary, CAD occurred significantly more frequently in males aged 51–60 and 61–70 years than in females of similar age, whereas the frequency of COPD was increased in males aged 61–70 and ≥70 years.

Table 1

Demographic and clinical characteristics and the mortality rates in the different age groups of the ICU patients with severe SARS-CoV-2 pneumonia requiring respiratory support

	All			Age ≤50 years		Age 51-60 years		Age 61-70 years		Age ≥71 years
Parameters	All(n=1522)	Males(n=864)	Females(n=658)	Males(n=226)	Females(n=88)	Males(n=237)	Females(n=156)	Males(n=230)	Females(n=194)	Males(n=171)	Females(n=220)
Age, years; Me (IQR)	62 (53; 71)	59 (50; 68)d	64 (56; 74)	–	–	–	–	–	–-	–	–
Death, n (%)	995 (65.4)	582 (67.4)	413 (62.8)	109 (48.2)	43 (48.9)	148 (62.4)b	75 (48.1)	172 (74.8)b	117 (60.3)	153 (89.5)a	178 (80.9)
Oxygen supplementation, n (%)	199 (13.1)	102 (11.8)	97 (14.7)	32 (14.2)a	22 (25.0)	34 (14.3)	28 (17.9)	25 (10.9)	24 (12.4)	11 (6.4)	23 (10.5)
Non-invasive ventilation, n (%)	95 (6,2)	53 (6.1)	42 (6.4)	19 (8.4)	9 (10.2)	18 (7.6)	9 (5.8)	10 (4.3)	12 (6.2)	6 (3.5)	12 (5.5)
Mechanical ventilation, n (%)	944 (62,0)	709 (82.1)	519 (78.9)	175 (77.4)a	57 (64.8)	185 (78.1)	119 (76.3)	195 (84.8)	158 (81.4)	154 (90.1)	185 (84.1)
ECMO, n (%)	7 (0,5)	1 (0.1)a	6 (0.9)	1 (0.4)	3 (3.4)	0	2 (1.3)	0	0	0	1 (0.5)
CVD, n (%)	976 (64,1)	508 (58.8)d	468 (71.7)	52 (23.0)	28 (31.8)	131 (55.3)	97 (62.2)	175 (76.1)	149 (76.8)	150 (87.7)	194 (88.2)
Hypertension, n (%)	905 (59,5)	452 (52.3)d	453 (68.8)	49 (21.7)	27 (30.7)	121 (51.1)	94 (60.3)	153 (66.5)	143 (73.7)	129 (75.4)b	189 (85.9)
CAD, n (%)	234 (15,4)	151 (17.5)b	83 (12.6)	7 (3.1)	2 (2.3)	26 (11.0)a	7 (4.5)	65 (28.3)d	24 (12.4)	53 (31.0)	50 (22.7)
Stroke, n (%)	113 (7,4)	61 (7.1)	52 (7.9)	2 (0.9)	0	9 (3.8)	8 (5.1)	26 (11.3)	12 (6.2)	24 (14.0)	32 (14.5)
AF, n (%)	161 (10,6)	98 (11.3)	63 (9.6)	3 (1.3)	1 (1.1)	13 (5.5)	5 (3.2)	32 (13.9)	17 (8.8)	50 (29.2)a	40 (18.2)
Diabetes mellitus, n (%)	406 (26,7)	191 (22.1)d	215 (32.7)	24 (10.6)	15 (17.0)	57 (24.1)	45 (28.8)	65 (28.3)a	76 (39.2)	45 (26.3)a	79 (35.9)
Obesity, n (%)	396 (26,0)	183 (21.2)d	213 (32.4)	51 (22.6)	32 (36.4)	61 (25.7)b	60 (38.5)	51 (22.2)d	74 (38.1)	20 (11.7)a	47 (21.4)
Asthma, n (%)	35 (2,3)	13 (1.5)a	22 (3.3)	5 (2.2)	3 (3.4)	1 (0.4)	4 (2.6)	3 (1.3)	9 (4.6)	4 (2.3)	6 (2.7)
COPD, n (%)	78 (5,1)	58 (6.7)c	20 (3.0)	10 (4.4)	1 (1.1)	9 (3.8)	4 (2.6)	22 (9.6)a	8 (4.1)	17 (9.9)b	7 (3.2)

p<0.05.

p ≤ 0.01.

p ≤ 0.001.

p ≤ 0.0001; characteristics were compared using a Pearson chi-square test for categorical variables and Mann-Whitney U test for continuous variables; Me(IQR) = median (interquartile range); ECMO = extracorporeal membrane oxygenation; CVD = cardiovascular disease; CAD = coronary artery disease (a history of myocardial infarction or interventions on the coronary arteries); AF = atrial fibrillation

jObesity was defined as body mass index ≥30 kg/m2; COPD = chronic obstructive pulmonary disease.

In summary, the mortality rate in the ICU patients with severe SARS-CoV-2 pneumonia was higher in males aged >50 years than in females of similar age. Our findings are in line with de Lusignan et al. data, who reported a higher EMR in males during the COVID-19 pandemic in the English population. The differences between mortality rates in males and females cannot be explained by comorbidities, given the divergent trends in the occurrence of chronic illnesses that may worsen survival in COVID-19 patients. Al-Lami et al. suggested that low levels of testosterone, as can occur in normally aging men, may account for more severe lung damage since testosterone deficiency has been linked with autoimmune disease and increases in inflammatory markers. Moreover, anti-inflammatory effects of estrogens may protect females from progression of SARS-CoV-2 induced lung disease. Our data indirectly support that sex steroid hormones underlie sex-related differences in COVID-19 mortality.

Declaration of Competing Interest

The authors report no competing interests.