Comparing Risk of Post Infection Erectile Dysfunction Following SARS Coronavirus 2 Stratified by Acute and Long COVID, Hospitalization Status, and Vasopressor Administration

doi:10.21203/rs.3.rs-3958803/v1

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Comparing Risk of Post Infection Erectile Dysfunction Following SARS Coronavirus 2 Stratified by Acute and Long COVID, Hospitalization Status, and Vasopressor Administration

https://doi.org/10.21203/rs.3.rs-3958803/v1

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Journal Publication

published 31 May, 2024

Read the published version in International Journal of Impotence Research →

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No study has yet assessed the risk of developing erectile dysfunction (ED) after a diagnosis of long COVID-19, especially when compared to those diagnosed with only acute COVID or cases in which more severe treatment is required. To assess these risks, we queried the TriNetX COVID-19 Research Network from December 1st 2020 through June 2023. Men aged ≥ 18 diagnosed with long COVID-19 were compared to those diagnosed with acute COVID-19 and analyses were performed to compare men who were/were not hospitalized within 1 month of acute COVID diagnosis and men who did/did not need vasopressors. Cohorts were propensity score matched and compared for differences in new ED diagnosis and/or prescription of phosphodiesterase-5 inhibitors (PDE5i). After propensity score matching, the long and acute COVID cohorts included 2839 men with an average age of 54.5±16.7 years and 55.1±17.1 respectively. Men with long COVID-19 were more likely to develop ED or be prescribed PDE5i (3.63%) when compared to men with only acute COVID-19 infections (2.61%) [RR 1.39; 95% CI 1.04, 1.87]. There was no statistically significant risk of developing ED or being prescribed PDE5i for individuals who received vasopressors [RR 0.922; 95% CI 0.774,1.098] or were hospitalized [RR 0.933; 95% CI 0.824,1.056].

Health sciences/Risk factors

Health sciences/Diseases/Urogenital diseases/Erectile dysfunction

Since the outbreak of Coronavirus disease 2019 (COVID-19), over 750 million cases have been confirmed and nearly 7 million people have died due to the infection.¹ The range of post-COVID-19 sequelae impacts many organ systems, including the cardiovascular, pulmonary, immunologic, endocrine, vascular, reproductive, and neurologic systems. These severe systemic effects raise concerns among professionals in a variety of fields who must now confront both the acute and chronic nature of this infection. From a urologic perspective, patients are at a much higher risk of erectile dysfunction (ED) following COVID-19 infections, with some studies reporting up to 50.3% of men developing ED within 3 months of the index infection.²

COVID-19 infections present with a broad range of manifestations, varying from acute symptoms to long-lasting effects. The latter has been referred to as “long COVID,” also known as “post-COVID conditions.” This is defined by the Centers for Disease Control and Prevention as the persistence or presence of new symptoms at least 4 weeks after initial SARS-CoV-2 infection.³ Acute COVID, on the other hand, is defined as illness that resolves within 4 weeks, although symptoms may continue or develop after this acute phase.³ Data from the National Center for Health Statistics (NCHS) revealed that 1 in 13 US adults and almost 1 in 3 US adults who ever had COVID exhibit “long COVID” symptoms. Moreover, the NCHS reports that adults in the 50–59 year range, an age cohort with an increased risk of erectile dysfunction, are three times more likely to have long COVID compared to men in the 18–29 age cohort.^4,5

Mechanistic differences in acute and long COVID-19 infections are the subject of ongoing research.⁶ Even though it has been demonstrated that men have an increased rate of de novo ED following COVID-19, no study has yet assessed whether long COVID-19 infections pose a higher risk of ED than acute infections. Additionally, there is limited literature which analyzes the risk of post-infection ED following more severe cases. Therefore, we aimed to assess the risk of de novo ED development in individuals with long COVID-19 infections compared to individuals with acute infections, as well as the risk following more severe cases requiring hospitalization or vasopressors.

We conducted a retrospective cohort analysis utilizing electronic health records (EHRs) supplemented with insurance claims from the TriNetX COVID-19 Research Network (Cambridge, MA, USA), which provided access to electronic medical records (diagnoses, procedures, medications, laboratory values, and genomic information) as well as pharmaceutical claims for over 109 million patients from 81 healthcare organizations and is specifically designed to assess trends in COVID-19 outcomes. Data used in this study was collected and analyzed as of June 2023. Information regarding demographics, diagnoses from International Classification of Disease (ICD-10) codes, and procedures from Current Procedural Terminology (CPT) codes were used for analysis. The use of ICD-10 and CPT codes have been validated across multiple specialties and various procedures.^7–9

TriNetX adheres to the Health Insurance Portability and Accountability Act (HIPAA). The process by which the data was de-identified is attested to through a formal determination by a qualified expert as defined in Section § 164.514(b)(1) of the HIPAA Privacy Rule. Because this study used only de-identified patient records and did not involve the collection, use, or transmittal of individually identifiable data, this study was exempted from the Institutional Review Board. As a result, only aggregate patient counts and statistical summaries are provided to protect all patient health information and retain de-identification.

Cohorts and Outcome Measures

All cohorts included men over the age of 18 who received a positive result for SARS COVID-2 RNA (TNX Curated 9088) during the time frame of December 1, 2020 to June 1, 2023. All men that were included in this study were required to have at least one follow up outpatient visitation (CPT 1013627, 1013638) after at least two weeks of the initial positive test result.

Men were excluded if they have previously received an ED diagnosis (ICD10 N52), prescription for phosphodiesterase-5 inhibitors (PDE5i) (RxNorm 1231301, 598, 358263, 306674, 136411), prescription for intracavernosal injections (CPT 54235, J0270, J2760, J2440), or a history of a penile prosthesis (CPT 54405-11, 54415-7; ICD-10 N48.6). Additionally, men with a prior prostatectomy (SNOMED 9047006), pelvis radiation (ICD-10 DWY6, DW06, D7Y7, D707), or pulmonary hypertension diagnosis of any cause (ICD-10 I27.0, I 27.2, I 27.20) were excluded.

Three analyses were performed to identify risks for the following variables: 1) patients that had received a diagnosis of Long COVID (ICD-10 U09) at least four weeks after the initial infection; 2) need of vasopressors (RxNorm 7512, 3992, 11149, 3628, 8163, 3616; ICD-10 3E033XZ, 3E043XZ, 3E053XZ, 3E063XZ, 3E060XZ, 3E040XZ, 3E050XZ, 3E030XZ) within one month of the index diagnosis; 3) need of inpatient hospital services (CPT 1013659) within one month of index diagnosis. The outcomes of interest were comparing subsequent rates of new diagnosis of ED (ICD-10 N52), new prescription of PDE5i (sildenafil, tadalafil 10 or 20mg doses, vardenafil, or avanafil), and either a new diagnosis of ED or prescription of PDE5i 1 month to 18 months following the index diagnosis of COVID-19 infection. Men were presumed to have the diagnosis if the corresponding ICD-10 or RxNorm was linked to their EHR.

Statistical Analysis

Propensity score matching was performed using a 1:1 matching using greedy nearest neighbor algorithms with a width of 0.1 pooled standard deviations. The TriNetX database randomizes the order of rows to alleviate bias from nearest neighbor algorithms. Propensity score matching was performed using age at index infection, race, ethnicity, type 2 diabetes mellitus (ICD-10 E11), overweight and obesity (E66), hypertension (I10), ischemic heart disease (I20-I25), pure hypercholesterolemia (E78.0), alcohol dependence (F10), nicotine dependence (F17), mood disorders (F34), atherosclerosis (I70), obstructive sleep apnea (G47.33), testicular hypofunction (E29.1), inpatient hospital services (CPT 1013659), and outpatient services (CPT 1013626) as covariates (Supplemental Table 1). These variables were chosen because they are established risk factors for erectile dysfunction or were significantly different between the 2 cohorts. For each patient in the smaller cohort, the system chooses a 1:1 match from the larger cohort based on the propensity scores generated by using greedy nearest neighbor algorithms utilizing a caliper width of 0.1 times pooled standard deviations. Balance on covariates was assessed using standardized mean difference and absolute values > 0.1 were considered positive for residual imbalance. The order of records is randomized to eliminate bias using a fixed seed during matching, allowing for reproducibility. A two-sided alpha of less than 0.05 was defined a priori for statistical significance. The TriNetX Platform calculates risk ratios and associated 95% CIs, using R’s Survival package, version 3.2-3 (R Group for Statistical Computing).

A total of 184,253 men met both the inclusion and exclusion criteria. Prior to the propensity score match, 2,839 (1.5%) men received a diagnosis of long COVID at least four weeks after the index diagnosis, 181,414 (98.5%) patients were found to have only acute COVID, 173,411 (94.1%) men did not receive vasopressors within one month of the initial diagnosis, 10,842 (5.9%) received vasopressors within one month, 161,383 (87.6%) men were not treated using any inpatient hospital services, and 24,726 (13.4%) patients were treated using inpatient hospital services. Following propensity-matched scoring, cohorts of an equal number of patients were the following: 1) 2,839 men with and without long COVID, 2) 10,842 men with and without vasopressor administration, 3) 19,695 men with and without inpatient hospital services. The demographics of each variable’s cohorts before and after propensity score matching are found in Tables 1–3.

There was a statistically significant increased risk of ED in men diagnosed with long COVID, with 3.63% of patients with long COVID being diagnosed with ED or prescribed PDE5i compared to 2.61% with acute COVID (RR 1.392, 95% CI 1.037,1.868). There was no statistically significant increased or decreased risk for those that received vasopressors, as 2.06% of patients that received vasopressors were found to have been diagnosed with ED or prescribed PDE5i compared to 2.23% of patients that did not (RR 0.922, 95% 0.774,1.098). Similarly, there was no statistically significantly increased or decreased risk for patients received inpatient hospital services, with 2.40% of patients that received hospital inpatient services being found to have been diagnosed with ED or prescribed PDE5i compared to 2.57% of patients that did not (RR 0.933, 95% CI 0.824,1.056). A summary of the results can be found in Fig. 1.

Using a large claims database, we compared rates of ED and new PDE5i prescriptions following long COVID and acute infections, as well as following hospitalization or the use of vasopressors. We found a statistically significant increased risk of ED following long COVID infections; however, there was no significant change in ED risk for individuals who received vasopressors or required hospitalization due to more severe COVID-19 infection. This demonstrates the unique impact of long COVID on sexual health. Moreover, our rates of diagnoses of ED following long COVID is lower than has been previously reported in much smaller cohorts, with rates approaching close to 50% in some of these studies.²

The pathophysiology of long COVID and acute COVID infection offers a plausible explanation for the increased risk of ED. A meta-analysis comparing long COVID patients to those who experienced only acute COVID infections revealed significantly elevated serum levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), D-dimer, IL-6, and lymphocytes in long COVID patients.¹⁰ A study found that C-reactive protein levels increased from 5 months post-hospital discharge to 1 year post-discharge in patients with long COVID, suggesting that the hyperinflammatory state persists in long COVID patients compared to those with acute COVID infections.^11,12 Erectile function has been shown to worsen with systemic inflammation, thereby providing a possible explanation for our findings.¹³ These heightened inflammatory biomarkers, and their relationship to ED, display that long COVID may cause endothelial damage.

The effects of long COVID are seen in various organ systems. The respiratory system is particularly vulnerable to long-term damage from COVID, as pulmonary function is greatly compromised due to microangiopathy and endothelial dysfunction in small pulmonary vessels.¹⁴ Pulmonary dysfunction may progress to pulmonary fibrosis in a significant number of long COVID patients, further decreasing oxygen saturation.¹⁵ The consequences of COVID-19 on the cardiovascular system are complex but are believed to originate from diffuse endotheliitis once the virus gains entry and begins causing microcirculatory dysfunction.¹⁶ The impact of long COVID on respiratory and cardiovascular systems leads to a decrease in systemic nitric oxide levels, providing a systemic explanation for the increased risk of developing ED.⁶

While the results of our study showed that there was no significant increase in ED risk, there is a small body of literature which supports that vasopressors may promote development of ED. A study by Shin et al. demonstrated that administration of vasopressin contracted strips of rabbit cavernosal smooth muscle, indicating vasopressors may worsen erectile outcomes.¹⁷ Similarly, a single-center case-control study supported the association between vasopressors and ED by displaying a negative correlation between systemic epinephrine levels and International Index of Erectile Dysfunction for ED scores.¹⁸ When considering our results, it is possible that vasopressors, albeit potent vasoconstrictors, only temporarily alter patients’ vasculature and do not provide significant enough changes to impact erectile function.

Interestingly, we demonstrated that ED is associated with long COVID versus acute COVID rather than degree of severity of disease requiring hospitalization or vasopressor support. It has been previously shown that persistent symptoms, exercise intolerance, and significant deterioration in health one year after COVID infection among patients admitted to the hospital for inpatient care versus patients directly discharged from the emergency department did not differ.¹⁹ The lasting effects of COVID seem to be at least partially independent of severity of index infection. These findings point toward long COVID causing these changes we have demonstrated rather than sequela of critical illness.

There are limitations associated with this study. Due to the large-scale nature of the database, as well as the deidentification of patients, we were unable to gain more specific insight into individual cases, such as the severity of symptoms as measured by the international index of erectile function or hormone levels. TriNetX analytics do not support multivariate regression analysis, which would allow for including multiple independent variables as well as exposures of interest. Rather, we were confined to results stemming from cohorts created through propensity score matching. Furthermore, the use of propensity score matching as opposed to multivariate regression analysis increases the number of men that are unable to be matched, widening the range of confidence intervals. In addition, analysis using TriNetX can only be done when the patient receives an ICD-10 coded diagnosis rather than based on symptomatology. Consequently, those patients who did not receive the aforementioned format of diagnosis would not have been included in our study, regardless of if they had the condition or not. Another limitation is that COVID-19 infections are generally viewed as acute in nature. As a result, research into long COVID sequelae has not been emphasized due to the abundance of initiatives targeted towards management of respiratory and cardiovascular symptoms, which has decreased the emphasis on sexual health. Nevertheless, the notable strength of this study is the large, diverse, multi-institutional cohort we were able to create using this database as opposed to single or few-institutions as previous studies have been.

The presented findings demonstrate the importance of focusing on sexual health to improve outcomes of patients impacted by chronic COVID-19 infections. Further studies are needed to investigate the causal relationship between long COVID and the development of de novo ED.

We found that patients with long COVID are at a higher risk of being diagnosed with ED than patients with only acute COVID, while there was no significantly increased risk for patients with more severe infection requiring hospitalization or vasopressors. Future research should emphasize sexual health outcomes following long COVID-19 infection, as well as hospitalization and vasopressor medication use. Finally, further research is necessary to elucidate the mechanisms behind what may cause increased ED risk in those with long COVID in comparison to those with acute COVID.

Data Availability

The information utilized in this study originates from the TriNetX deidentified database, accessible through TriNetX, LLC (https://trinetx.com/). Due to third-party restrictions, these data cannot be publicly shared or redistributed. Researchers can obtain access to the TriNetX database directly through TriNetX, LLC.

Competing Approval

The authors have no competing interests.

Ethical Approval

This study was deemed exempt by the IRB because only anonymized data was used.

Funding

None

Disclosures

None

Author Contributions

AJ.G., K.G., A.P.M, M.N.A, and U.C. helped with interpretation of the data and drafting/revising the manuscript. C.A. was instrumental in data analysis, interpretation of the data, and reviewing of the manuscript. T.P.K. conceived of, implemented the project, including statistical analysis, and critically reviewed the manuscript. All authors approved of the final version to be published and agreed to the accuracy of the work.

Attestation Statement

Data regarding any of the subjects in the study has not been previously published.

Available data will be made available to the editors of the journal for review or query upon request.

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Tables 1 to 3 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

SupplementalTable1IJIRcopy.docx
Supplemental Table 1. Matched Variables
Table1IJIRcopy.docx
Table 1. Baseline and Matched Demographics of Included Men Assessing Acute vs. Long COVID Infections
Table2IJIRcopy.docx
Table 2. Baseline and Matched Demographics of Included Men Assessing Erectile Dysfunction Following Vasopressor Use for COVID Infection
Table3IJIRcopy.docx
Table 3. Baseline and Matched Demographics of Included Men Assessing Erectile Dysfunction Following Hospitalization for COVID Infection

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You are reading this latest preprint version

Comparing Risk of Post Infection Erectile Dysfunction Following SARS Coronavirus 2 Stratified by Acute and Long COVID, Hospitalization Status, and Vasopressor Administration

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Abstract

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INTRODUCTION

METHODS

Cohorts and Outcome Measures

Statistical Analysis

RESULTS

DISCUSSION

CONCLUSION

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REFERENCES

Tables

Additional Declarations

Supplementary Files

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