Gender Disparities in COVID-19 Survivors with Impaired Quality of Life, Effort Intolerance, and Cardiopulmonary Symptoms: A Prospective Cohort Study

TL;DR

This study finds that while male COVID-19 patients face higher risks during hospitalization, female survivors experience worse long-term physical function and fatigue despite better heart function.

Contribution

The study reveals gender-specific differences in both acute and post-acute outcomes of hospitalized COVID-19 patients.

Findings

Males were more likely to require ICU and oxygen during hospitalization and had higher inflammatory markers.

Females reported worse physical function and fatigue one year post-hospitalization and walked shorter distances.

Females had higher ejection fractions and smaller infarct sizes on CMR despite worse functional outcomes.

Abstract

Prior studies have suggested gender differences in COVID-related outcomes that have the potential to impact cardiovascular risk. We aimed to investigate gender differences on short- and long-term effects of COVID-19 infection.

Patients hospitalized with COVID-19 infection were enrolled in an ongoing prospective registry across NY-Presbyterian networks, which encompassed same-day echocardiogram, cardiac magnetic resonance (CMR), 6-minute walk test, and quality of life assessment 1 year following acute COVID hospitalization.

In this prospective cohort of 213 hospitalized patients with COVID-19 infection, males were more likely to require intensive care unit (ICU) stay (13.6 vs. 3.6%; p = 0.009) and oxygen supplementation (40.8 vs. 26.4%; p = 0.026), paralleling higher rates of elevated troponin, C-reactive protein, ferritin, and D-dimer (p < 0.05 for all). In contrast, 1 year following COVID hospitalization, females reported worse physical function and fatigue on Patient-Reported Outcomes Measurement Information System (PROMIS) scale (p < 0.05 for all). Additionally, 6-minute walk distance was less in females than males (383.0 ± 98.0 vs. 428.6 ± 78.6 m; p = 0.006), and Borg dyspnea score was nearly twofold higher in females vs. males (2.0 ± 2.3 vs. 1.0 ± 1.5; p < 0.001). With respect to imaging parameters, females had higher left ventricle and right ventricle ejection fraction (p < 0.05 for all) with smaller infarct size (p = 0.042) on CMR.

Whereas males have greater morbidity during acute COVID hospitalization, females are disproportionately impacted by post-COVID impaired functional status despite higher biventricular ejection fraction and smaller infarct size.

Tables

Table 1.. Acute COVID Hospitalization of COVID-19 Survivors with Cardiac Sequalae Stratified by Gender

	All (n = 213)	Male (n = 103)	Female (n = 110)	Odds ratioa	p
Hospitalization characteristics
ICU stay	18 (8.5)	14 (13.6)	4 (3.6)	4.2	0.009
ICU length of stay (days)	5.3 ± 14.7	8.1 ± 20.1	2.7 ± 5.1		0.009
Oxygenation support	71 (33.3)	42 (40.8)	29 (26.4)	1.9	0.026
Nasal cannula use	61 (28.6)	37 (35.9)	24 (21.8)	2.0	0.023
Mechanical ventilation	9 (4.2)	7 (6.8)	2 (1.8)	3.9	0.093
Acute kidney injury	19 (8.9)	15 (14.6)	4 (3.6)	4.5	0.005
Cardiac arrest	1 (0.5)	1 (1.0)	0 (0.0)	0.5	0.484
Vasopressor use	5 (2.3)	3 (2.9)	2 (1.8)	1.6	0.675
Steroid use	72 (33.8)	37 (35.9)	35 (31.8)	1.2	0.527
Remdesivir	52 (24.4)	26 (25.2)	26 (23.6)	1.1	0.785
Tocilizumab	7 (3.3)	6 (5.8)	1 (0.9)	6.7	0.058
Paxlovid	21 (9.9)	9 (8.7)	12 (10.9)	0.8	0.595
Plaquenil	28 (13.1)	17 (16.5)	11 (10.0)	1.8	0.160
Monoclonal antibodies	14 (6.6)	6 (5.8)	8 (7.3)	0.8	0.670
Readmission	27 (12.7)	11 (10.7)	16 (14.5)	0.7	0.397
Vaccination	201 (94.4)	98 (95.1)	103 (93.6)	1.3	0.633
Laboratory values
Troponin (ng/L)	0.5 ± 2.8	0.9 ± 3.7	0.1 ± 0.3		0.123
ULN troponin, n = 131	17 (13.0)	13 (20.0)	4 (6.1)	3.9	0.018
BNP (pg/mL)	137.7 ± 450.3	149.1 ± 503.0	121.9 ± 372.5		0.800
ULN BNP, n = 89	12 (13.5)	7 (14.9)	5 (11.9)	1.3	0.680
CRP (mg/dL)	14.2 ± 33.8	14.7 ± 15.7	13.4 ± 48.7		0.859
ULN CRP, n = 109	86 (78.9)	52 (88.1)	34 (68.0)	3.5	0.010
ESR (mm/hour)	58.4 ± 36.3	61.4 ± 40.4	54.3 ± 30.3		0.373
ULN ESR, n = 85	66 (77.6)	38 (82.6)	28 (71.8)	1.9	0.233
WBC (103/uL)	8.9 ± 5.5	10.1 ± 5.8	7.8 ± 5.0		0.006
ULN WBC, n = 181	61 (33.7)	35 (38.9)	26 (28.6)	1.6	0.142
Platelet (103/uL)	281.0 ± 138.0	290.1 ± 151.1	272.0 ± 123.9		0.379
ULN platelet, n = 180	37 (20.6)	22 (24.4)	15 (16.7)	1.6	0.197
Hematocrit (%)	40.1 ± 5.7	41.8 ± 4.9	38.4 ± 6.0		<0.001
ULN hematocrit, n = 179	57 (31.8)	39 (43.8)	18 (20.0)	3.1	<0.001
Ferritin (ng/mL)	773.5 ± 905.9	972.7 ± 942.0	526.6 ± 801.9		0.011
ULN ferritin, n = 90	61 (67.8)	38 (79.2)	23 (54.8)	3.1	0.013
D-dimer (ng/L)	1185.7 ± 2771.1	1815.7 ± 3569.8	370.5 ± 313.4		0.011
ULN D-dimer, n = 108	58 (53.7)	34 (64.2)	24 (43.6)	2.3	0.033
LDH (U/L)	392.3 ± 449.7	442.5 ± 555.8	318.4 ± 200.1		0.203
ULN LDH, n = 82	68 (82.9)	43 (89.6)	25 (73.5)	3.1	0.057
Hemoglobin (g/dL)	13.3 ± 2.0	14.0 ± 1.7	12.5 ± 2.1		<0.001
ULN hemoglobin, n = 180	57 (31.7)	39 (43.3)	18 (20.0)	3.2	<0.001
Symptom status
Chest pain	62 (29.1)	28 (27.2)	34 (30.9)	0.8	0.550
Shortness of breath	54 (25.4)	21 (20.4)	33 (30.0)	0.6	0.107
Fatigue	84 (39.4)	26 (25.2)	58 (52.7)	0.3	<0.001

Table 2.. PROMIS Scales in COVID-19 Survivors When Stratified by Gender

	All (n = 213)	Male (n = 103)	Female (n = 110)	p
Physical function	48.0 ± 9.5	49.9 ± 8.2	46.2 ± 10.3	0.004
Social participation	52.6 ± 10.6	55.1 ± 9.1	50.4 ± 11.4	0.001
Anxiety	52.2 ± 10.8	50.0 ± 10.0	54.2 ± 11.2	0.005
Depression	48.0 ± 9.1	46.5 ± 8.2	49.4 ± 9.7	0.011
Fatigue	49.7 ± 11.5	46.5 ± 10.3	52.8 ± 11.8	<0.001
Sleep disturbance	51.4 ± 5.2	50.6 ± 5.0	52.2 ± 5.3	0.037

Table 3.. PROMIS Scales in COVID-19 Survivors When Stratified by Age in Women

	All (n = 110)	Under 50 (n = 50)	Over 50 (n = 60)	p
Physical function	46.2 ± 10.3	47.3 ± 10.0	45.3 ± 10.6	0.307
Social participation	50.4 ± 11.4	51.1 ± 11.7	49.8 ± 11.7	0.555
Anxiety	54.2 ± 11.2	55.3 ± 10.3	53.2 ± 11.9	0.327
Depression	49.4 ± 9.7	49.3 ± 9.6	49.5 ± 9.9	0.888
Fatigue	52.8 ± 11.8	54.9 ± 12.2	51.0 ± 11.3	0.082
Sleep disturbance	52.2 ± 5.3	51.4 ± 5.5	52.7 ± 5.2	0.223

Table 4.. Six-Minute Walk Test and Dyspnea in COVID-19 Survivors When Stratified by Gender

	All (n = 213)	Male (n = 103)	Female (n = 110)	p
Heart rate pre (bpm)	73.7 ± 11.4	72.2 ± 12.2	75.0 ± 10.5	0.088
Heart rate post (bpm)	79.6 ± 13.7	78.2 ± 14.0	81.0 ± 13.4	0.174
Heart rate difference (bpm)	0.1 ± 2.4	0.0 ± 2.3	0.2 ± 2.5	0.532
Systolic BP pre (mmHg)	135.0 ± 18.9	137.1 ± 16.6	133.0 ± 20.6	0.140
Systolic BP post (mmHg)	135.7 ± 19.3	138.3 ± 16.7	133.4 ± 21.2	0.082
Systolic BP difference(mmHg)	0.8 ± 12.1	1.2 ± 11.8	0.4 ± 12.3	0.649
Diastolic BP pre (mmHg)	83.5 ± 11.4	84.8 ± 10.6	82.2 ± 12.0	0.125
Diastolic BP post (mmHg)	84.2 ± 11.5	85.5 ± 10.7	82.9 ± 12.2	0.121
Diastolic BP difference (mmHg)	0.1 ± 2.3	0.1 ± 2.6	0.2 ± 2.0	0.608
Time walked (mins)	5.9 ± 0.5	5.9 ± 0.5	5.9 ± 0.4	0.483
Predicted distance walked (m)a	569.6 ± 98.7	583.2 ± 103.3	556.8 ± 92.7	0.050
Distance walked (m)	410.0 ± 90.8	428.6 ± 78.6	393.0 ± 98.0	0.006
Proportion of predicted distance walked (m)	0.7 ± 0.2	0.7 ± 0.2	0.7 ± 0.2	0.424
Borg dyspnea pre	0.5 ± 1.1	0.3 ± 0.9	0.6 ± 1.3	0.094
Borg dyspnea post	1.5 ± 2.0	1.0 ± 1.5	2.0 ± 2.3	<0.001
Borg dyspnea difference	1.0 ± 1.6	0.6 ± 1.2	1.4 ± 1.7	<0.001
Borg fatigue pre	1.1 ± 1.7	0.6 ± 1.3	1.5 ± 2.0	<0.001
Borg fatigue post	1.5 ± 2.1	1.0 ± 1.6	2.0 ± 2.3	0.001
Borg fatigue difference	0.4 ± 1.6	0.4 ± 1.0	0.5 ± 2.0	0.717

Table 5.. Imaging Characteristics in COVID-19 Survivors When Stratified by Gender

	All (n = 213)	Male (n = 103)	Female (n = 110)	p
Echo values
LVEF	63.9 ± 6.9	62.2 ± 7.4	65.4 ± 6.3	0.002
LVIDd	4.8 ± 0.5	5.0 ± 0.5	4.6 ± 0.4	<0.001
LVIDs	3.1 ± 0.5	3.3 ± 0.5	2.9 ± 0.4	<0.001
LVEDV (indexed)	57.7 ± 11.9	58.9 ± 11.4	56.7 ± 12.3	0.235
LVESV (indexed)	21.2 ± 7.7	22.6 ± 7.7	20.0 ± 7.4	0.018
LV mass (indexed)	73.3 ± 19.0	81.3 ± 21.8	66.3 ± 12.5	<0.001
LA volume index	25.6 ± 10.1	26.5 ± 12.4	24.7 ± 7.2	0.223
RVDd	3.7 ± 0.9	4.1 ± 0.4	3.4 ± 1.2	0.012
PASP	26.3 ± 10.1	26.6 ± 5.8	26.0 ± 5.8	0.543
Cardiac MRI values
LVEDV (indexed)	70.2 ± 15.1	72.6 ± 16.1	67.9 ± 13.7	0.031
LVESV (indexed)	26.3 ± 13.8	28.8 ± 16.8	23.9 ± 10.0	0.014
LVEF	64.3 ± 8.2	62.5 ± 8.3	66.0 ± 7.4	0.001
RVEDV (indexed)	75.5 ± 18.0	78.3 ± 17.9	73.0 ± 17.8	0.047
RVESV (indexed)	32.7 ± 11.5	35.0 ± 10.3	30.6 ± 12.2	0.009
RVEF	57.8 ± 6.3	56.1 ± 5.7	59.3 ± 6.5	<0.001
LV mass (indexed)	53.8 ± 12.6	59.3 ± 13.5	48.9 ± 9.5	<0.001
Prevalence of LGE	0.1 ± 0.3	0.2 ± 0.4	0.1 ± 0.3	0.090
Global LV infarct sizea	0.6 ± 3.2	1.1 ± 4.5	0.2 ± 0.7	0.042

Full text

Introduction

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has affected more than 103 million people in the United States.^1^ Despite the substantial mortality risk, a growing population of COVID-19 patients survive acute illness but remain at risk for long-term deleterious consequences, including impaired exercise tolerance.^2^ Of patients surviving from COVID, a significant proportion has persistent symptoms or new symptoms attributed to their initial infection.^3^ In 2021, the diagnosis of “long COVID” was defined as the persistence of physical and/or psychological symptoms for more than four to 12 weeks after recovery from acute COVID-19 disease.^4^ Many patients experiencing long COVID specifically report cardiopulmonary symptoms, such as dyspnea, chest pain, and palpitations.^5^ While many studies have looked at the cardiovascular implications of COVID-19 in the acute and long-term phases, there is still more understanding needed of the cardiovascular outcomes related to COVID-19 infection.

Prior studies have shown that there are significant differences in both short- and long-term complications of COVID when stratifying by gender, which can potentially impact cardiovascular risk. The results show that women tend to experience less severe acute infections but suffer from long COVID more frequently.^6–9^ The underlying mechanism for this gender disparity is currently unknown. In this study, we aim to investigate these gender differences in COVID-19 outcomes using a prospective cardiovascular imaging study, which evaluates both baseline and follow-up characteristics of COVID-19 survivors to better understand whether there are cardiovascular structural differences that may be attributable to observed gender differences.

Methods

Data source and study population

A total of 213 COVID-19 survivors were recruited through ongoing registries of COVID-19 patients in the NewYork-Presbyterian Hospital networks and were cross-referenced with electronic medical records to screen for inclusion and exclusion criteria. Patients were then contacted for follow-up, and multiple attempts were made to ensure a representative cohort, regardless of the severity of long-term symptoms. Men and women aged ≥18 years with documented COVID-19 infection, inclusive of patients with residual cardiopulmonary symptoms and asymptomatic patients, were included. Patients who had a contraindication to cardiac magnetic resonance imaging (MRI), an inability to provide informed consent, and/or an unrelated condition with life expectancy <12 months were excluded. All patients provided informed written consent at the time of enrollment. This study was conducted with the approval of the institutional review board at Weill Cornell Medicine.

Study variables and end points

Baseline data were collected to assess demographics, initial disease severity, including biomarkers of inflammation/thrombosis and cardiac structure/function, treatments received, and inpatient complications. Gender was defined as male vs. female based upon sex assigned at birth in the electronic medical record. Biomarker data encompassed prespecified indices generally associated with adverse prognosis, including troponin, B-type natriuretic peptide, C-reactive protein, erythrocyte sedimentation rate, ferritin, D-dimer, white blood cell count, hemoglobin, hematocrit, and platelet count. For patients with biomarkers obtained at multiple time points, peak values were used for study-related data analyses. Elevated thresholds for elevated biomarkers were defined based on site-specific laboratory thresholds at participatory hospitals. Intensive care unit (ICU) admission included any ICU stay during hospitalization. Hypoxia was defined as any need for supplemental oxygenation. Acute kidney injury was defined as an increase in serum creatinine by 0.3 mg/dL (26.5 mol/L) within 48 hours or an increase in serum creatinine to 1.5 baseline within the prior 7 days. Vasopressor use was defined as need for any vasopressor support during hospitalization.

After infection, patients were evaluated by study team members to assess myocardial tissue properties, functional recovery, effort tolerance, and short-term symptoms after COVID-19 infection. Post-acute sequelae of COVID-19 (PASC) were assessed using a symptom-limited 6-minute walk test (100-foot corridor). Clinical symptoms were assessed using surveys including the Patient-Reported Outcomes Measurement Information System (PROMIS-29 Questionnaire), which consist of a group of patient-reported outcome measures that span a wide array of physical, social, and emotional health outcomes. Patient dyspnea was evaluated utilizing the Borg dyspnea score. Myocardial tissue properties were assessed via cardiac MRI and echocardiography. Cardiac MRI was performed to assess structural/functional remodeling, myocardial tissue properties (fibrosis and edema), and cardiopulmonary blood oxygenation. Magnetic resonance angiography was acquired adjunctively during IV gadolinium administration. Echocardiogram was performed using commercial transthoracic ultrasound equipment.

Statistical analysis

All analyses were performed using IBM SPSS Statistics version 27.0 (SPSS, Chicago, IL). Continuous variables are summarized as means ± standard deviations. Categorical variables are summarized as frequencies and percentages. Normally distributed continuous indices were compared via t-tests (for two group comparisons) or analysis of variances with linear test of trends (for multiple group comparisons). Categorical variables were compared using chi-square tests. A two-sided p < 0.05 was considered statistically significant.

Results

In this prospective cohort of COVID-19 survivors, there were significant differences observed in acute hospitalization variables when stratified by gender (Table 1). Male patients had 3.5-fold longer ICU stays when compared with female patients (p = 0.009). Male patients had higher rates of hypoxia (p = 0.026) and were more likely to require nasal cannula use (p = 0.023). There were higher rates of acute kidney injury in males at 14.6% compared with 3.6% of females (p = 0.005). There were no differences in cardiac arrest, vasopressor use, or COVID-19 therapy use. For the lab analyses done during the hospitalization, males had higher rates of troponin elevations (p = 0.018), higher hemoglobin (p < 0.001), higher hematocrit (p < 0.001), higher ferritin (p = 0.013), and higher D-dimer (p = 0.033).

In the post-hospitalization follow-up with the PROMIS scale (Table 2), females reported lower physical function (p = 0.004) and social participation (p = 0.001). Females were more likely to have post-COVID fatigue (p < 0.001), depression (p = 0.011), and anxiety (p = 0.005). No significant differences were observed in subgroup analysis of women stratified by age (Table 3). Table 4 demonstrates that males walked farther in the 6-minute walk test (428.6 ± 78.6 vs. 393.0 ± 98.0, p = 0.006). Females reported more dyspnea after the test in the Borg dyspnea score (2.0 ± 2.3 vs. 1.0 ± 1.5, p < 0.001) and a significantly higher difference in the pre and postdyspnea score (p < 0.001). Females reported higher Borg fatigue scores pre and post (p < 0.001), but there was no significant change in fatigue between the two groups. In Table 5, post-infection cardiac imaging shows differences in myocardial structure and tissue substrate. For example, female patients had higher left ventricular ejection fractions by both echo (p = 0.002) and cardiac MRI (p = 0.001). Similarly, female patients also had higher right ventricular ejection fraction by cardiac MRI (p < 0.001). Regarding tissue characterization, females had smaller infarct size (p = 0.042) despite a similar prevalence of late gadolinium enhancement (LGE) by gender.

Discussion

Our study shows that men have worse acute COVID-19 infections, including longer ICU stays, higher needs for supplemental oxygen, and higher rates of elevated inflammatory markers.

This hypothesis is in line with previous studies, which implicate a systemic inflammatory response to COVID causing structural remodeling of cardiac or pulmonary system through the fibrosis activation pathway.^10^ Our data showed inflammatory markers appeared to be lower in females as compared to men during acute infection, which appears to benefit females in the acute phase of infection. Beyond end-organ damage from acute phase infection, the cause of long COVID symptoms is still unclear. Other studies have highlighted this trend of worse acute infection in males and higher incidence of long COVID symptoms and mood disorders in women.^11^ However, immune dysregulation appears to play a role.^10^

Long COVID has also been characterized by impaired systemic oxygen extraction seen on invasive cardiopulmonary exercise testing. The spectrum of phenotypes of long COVID correlates to different degrees of impaired oxygen extraction associated with aberrant protein expression and cardiopulmonary physiological response. Patients with severely impaired oxygen extraction appear to show a maladaptive physiological and proteomic signature, which is consistent with persistent inflammatory state and endothelial dysfunction. The exertional intolerance appears to be related more to impaired oxygen extraction and is independent of cardiac etiologies, given that there are no long-term cardiopulmonary disease sequalae.^12^ Impaired peripheral oxygen extraction, rather than cardiac dysfunction, may therefore be another major factor contributing to this gender difference, which is further supported by our data showing favorable cardiac imaging parameters in female patients.

Another factor that may explain the gender difference in COVID-19 outcomes is the role of increased estrogen levels. A 2021 study found that women under 60 were more likely to develop long COVID, with the risk leveling off after age 60.^13^ This led to the hypothesis that long COVID could be an estrogen-mediated condition, given its higher prevalence in younger females compared to males. This hypothesis suggests that symptoms such as dyspnea and fatigue, as observed in our follow-up, could be related to estrogen’s influence on long COVID. Although our current study was not designed to test this hypothesis specifically, further research with larger populations is needed to validate these findings.

Finally, autonomic dysfunction has also been seen as a mediator of long COVID.^14^ The symptoms of long COVID have been recognized as similar to those of postural orthostatic tachycardia syndrome (POTS). POTS has been considered a major phenotype in the new postacute COVID-19 syndrome, with an approximate prevalence of 30% in highly symptomatic patients with long COVID.^14^ This finding appears to be unrelated to the severity of the initial infection. The mechanism of COVID-19 postinfection autonomic dysfunction is thought to be multifactorial. Given that acute COVID-19 infection and COVID-19 vaccination can trigger POTS and other types of cardiovascular autonomic dysfunction, it has been hypothesized that these factors might be potent immune triggers that evoke an autoimmune response in susceptible individuals. Microvascular dysfunction has also been hypothesized to be a factor contributing to autonomic dysfunction in COVID, thereby preferentially affecting young- and middle-aged women, possibly suggesting a mechanistic role for sex hormones.^14^ Other proposed mechanisms include persistent viremia leading to a persistently high inflammatory state with cellular injury, cytokine- and hypoxia-induced injury leading to neuronal apoptosis causing impaired neurological function, and the inflammatory pathway leading to autonomic and small fiber neuropathies, as previously seen in viral infections from herpes simplex and infectious mononucleosis.^15^ As more data arises, research can focus on phenotyping of autonomic dysfunction in cohorts of patients with long COVID syndrome to identify biomarkers of the condition and ultimately focus on effective therapies.

This study has several limitations, including the lack of stratification by menopausal status and the absence of long-term cardiovascular outcomes. While many results were statistically significant, the clinical relevance of these findings requires further investigation, particularly given the emerging role of various factors, as previously mentioned. Additionally, autonomic dysfunction has been proposed as a possible mediator of long COVID symptoms, but a limitation of our study is the absence of autonomic dysfunction measures. Although we observed higher ejection fractions and smaller infarct sizes in female patients, long-term cardiovascular outcomes were not the primary focus of this research. Future studies with larger cohorts and extended follow-up periods are needed to better understand the mechanisms driving these differences and to assess whether gender-related differences translate into meaningful long-term health outcomes. Moreover, research with longer follow-up durations will be crucial in addressing these important questions and further clarifying the interplay between sex hormones, immune responses, autonomic dysfunction, and impaired systemic oxygen extraction in shaping the long-term consequences of COVID-19 infection.

Conclusion

This study demonstrates that males have greater morbidity during acute COVID hospitalization than female patients with higher rates of ICU admissions, hypoxia, acute kidney injury, and elevations in troponin and inflammatory markers. Female patients were disproportionately impacted by post-COVID symptoms of fatigue, anxiety, and depression. Female patients performed worse in the 6-minute walk test and reported more dyspnea and fatigue than males. Contrary to these symptoms, cardiac imaging parameters demonstrated significantly better biventricular ejection fractions in females with trend toward smaller infarct size. Findings of this study contribute to improved understanding of gender-specific impacts of COVID-19 and have the potential to inform targeted interventions toward the goal of mitigating gender-based cardiovascular risks associated with COVID-19 infection.