This study showed a significant association of prior COVID-19 infection with a new diagnosis of erectile dysfunction when evaluated on a population level and when controlled for common risk factors for erectile dysfunction (age, diabetes, prostate cancer, hypogonadism, BMI, and smoking status. COVID-19 infection was associated with a 27% increased risk of ED, roughly comparable to a new diagnosis of diabetes.
i. The Link Between ED and COVID-19
Although the overall body of literature linking COVID-19 infection to ED is limited, there has been increasing evidence of this association over the past 18 months. The role of endothelial cell dysfunction during COVID-19 infection and its subsequent impact on organ systems has been well documented in the literature.19–21 This led many to hypothesize that COVID-19 infection may influence subsequent risk of ED. However, the initial studies evaluating this association were limited by small sample size and short follow up.
In March 2021, Sansone et al. reported increased self-reported ED men with recent COVID-19 infection compared to age matched controls.7 Between April and May 2020, 25 men with a recent COVID-19 infection were assessed for ED using an online survey and were compared to 75 age-matched controls. The authors reported increased risk of ED in the COVID-19 cohort (28%) compared to controls (9.33%). In this study, COVID-19 infection was independently associated with ED (OR 5.66).7
In July 2021, further basis for a potential pathophysiologic basis was described by Kresch et al. who confirmed the presence of COVID-19 peplomers in corporal tissue of two patients undergoing inflatable penile prosthesis surgery for newly reported erectile dysfunction after COVID-19 infection.8 The authors concluded that COVID-19 infection related endothelial dysfunction may increase risk of ED.8
In August 2021, Nassau et al reviewed potential mechanisms for COVID-19 related ED highlighting the increased susceptibility of men for developing COVID-19 infection related morbidity and mortality.22 The authors further described the role of ACE2 and TMPRSS2 which are required for SARS-CoV-2 uptake and are ubiquitous within endothelial cells. These findings further reinforced the potential association of COVID-19 infection with vasculogenic ED.22
In November 2021, Hu et al. assessed the risk of new erectile dysfunction in 67 men following COVID-19 infection 6 months prior.5 At 3 and 6 months following infection, patients were evaluated with symptom checklist 90 and IIEF5. Compared to controls, men with prior COVID-19 infection had increased risk of a first time ED diagnosis (44.8% versus 17.1%).5
To date, only two studies have assessed the association of COVID-19 and ED on a population level. In February 2022, Chu et al. compared 230,517 men with prior COVID-19 infection to 232 645 men without documented COVID-19 infection using the TriNETx database between January 2020 and November 2021.23 The authors found an increased association of ED following COVID-19 infection, OR 1.20 (1.004–1.248; P = 0.04).23 A similar association was shown by Katz et al. using a database of participating University of Florida Healthcare System centers.24 The authors identified 3098 COVID-19 recovered men between January 2020 and June 2021 with this cohort being 3.68 times more likely to report ED compared to controls.24 Although, electronic health record (EHR) databases such as TriNetX have the distinct advantage of including both insured and uninsured patients, there are many limitations of longitudinal data in these databases, since patients may often get care outside of the health care system that is used for the study.
i. Why our data is unique
EHR based databases such as TriNetX, and Informatics for Integrating Biology and the Bedside Database collate medical records from participating healthcare institutions medical records. The Informatics for Integrating Biology and the Bedside Databse, utilized by Katz et al. included participating University of Florida Healthcare Centers.24 While, the TriNetX Database is made up of 63 participating institutions in 8 countries with 93% of patients being from the United States.25 However, a significant limitation of these databases is that it requires patients to seek longitudinal medical care at the institutions represented in the database. For example, a patient is admitted to a tertiary center for a COVID-19 infection early in the pandemic, recovers, and then subsequently presents to their local primary care provider to report new onset ED. Both the primary care provider and the tertiary center must be members of the same EHR database to adequately capture this longitudinal data which likely underestimates the effect of COVID-19 infection. This limitation is a unique strength of the IBM MarketScan database.
The IBM MarketScan commercial claims database includes over 3 billion medical encounters made by 215 million policy holders, spouses, and dependents. Most importantly medical visits and associated diagnoses are captured longitudinally as long as insurance is billed, thus, patients do not have to receive all of their care in a participating EHR database institution to be captured. In the previously discussed example, a patient presenting to a tertiary hospital for a COVID-19 infection early in the pandemic who subsequently received follow up care at a primary care physician’s office would be accurately captured as long as insurance was billed for each encounter. This unique characteristic allows increased accuracy for longitudinally collected data and may explain why our cohort had an increased rate of newly diagnosed ED following COVID-19 infection (1.42%) compared to Chu et al. (0.48%).23 It should be emphasized, that this higher capture rate using MarketScan occurred with shorter follow up of 6.5 months compared to Chu et al. (exact follow up not reported; estimated Jan 2020 to time of manuscript acceptance Aug 2021).23
Despite a maximum follow up time of 6.5 months, our findings showed a 27% increased risk of first-time ED compared to controls over the same timeframe. (Table 2) The results of our study indeed likely is biased towards less of an association of COVID-19 and ED, since there were likely some patients in the control arm with COVID-19 that were never captured in claims data. If everyone that had COVID-19 was captured the association may be higher between COVID-19 and erectile dysfunction. However, it should be acknowledged that this selection bias occurs at baseline in the population given that patients may have cleared a COVID-19 infection without symptoms and thus without a positive test. In fact, the COVID-19 positive test rate in our study mirrored the positive test rate seen in the US through 2020. (Fig. 1 & Supplemental Fig. 2)
As the most recent available data in MarketScan is January 2021, our data only represents the first 9 months of the pandemic and limits our ability for long term follow up. However, our dataset removes vaccine administration, over the counter home testing, and variant strains as potential confounders. The first COVID-19 vaccine administered in the US was on December 14th, 2020, with only 2.8 million Americans receiving the first dose of the two-shot series by the conclusion of 2020 (< 1% of US population).26 Likewise, FDA approval of the first over-the-counter COVID-19 antigen test did not occur until December 15th, 2020.27 Lastly, variant strains of SARS-COV-2 are associated with varying degrees of transmissibility and pathogenicity. Initial SARS-COV-2 variants Alpha (B.1.1.7) and Beta (B.1.351) were first documented in the United Kingdom and South Africa, respectively.28 However both strains were not labeled variants of concern by the World Health Organization until December 18th, 2020.28 Thus, our findings may be more representative of the association of COVID-19 infection prior to widespread vaccine uptake, home testing, and variant strain transmission.
ii. Next steps
This initial data, showing increased association of new onset erectile dysfunction following COVID-19 recovery warrants further evaluation. First, our findings should be confirmed in claims databases with longer follow up as it becomes available. This data along with population data in the setting of increasing vaccination should be evaluated to determine if vaccination on a population level reduces the risk of new onset erectile dysfunction. Until data is available on the impact of asymptomatic infection and infection in the setting of prior vaccination, our data should reinforce the findings from Katz and Chu et al. 23,24 and be used to inform patients of the short-term risks associated with COVID-19 infection.
iii. Limitations
Our study is not without limitations that are inherent to retrospective analysis of an insurance claim database. The available data is based on medical diagnoses associated with an insurance claim. Thus, COVID-19 home tests or outpatient tests in which an insurance claim is not submitted are not captured. As a result, it is likely that our capture rate of COVID-19 infection is underestimated. Likewise, MarketScan data is only available through the end of 2020 which represents the early stage of the COVID-19 pandemic and limited the follow up window to observe our outcome.
Additionally, individual medical records (paper charts or electronic medical records) are not available in this database which has several implications. First, we are unable to specifically assess the morbidity associated with each COVID-19 infection. As a result, we intentionally did not stratify COVID-19 cohort by diagnosis location (inpatient versus outpatient) as MarketScan lacks the granular details that would allow us to delineate an admission which was primarily related to a COVID-19 infection versus an admission for a different diagnosis with an associated finding of COVID-19 positivity. It should be acknowledged that there is likely a step wise increase in risk of erectile dysfunction following COVID-19 infection depending on location of diagnosis (outpatient versus inpatient) and intensive care utilization. However, it is important to note that these limitations would bias our findings to a lower association between erectile dysfunction and COVID-19 and there is likely a stronger association than our study results show.