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PLOS ONE logoLink to PLOS ONE
. 2022 Oct 20;17(10):e0276429. doi: 10.1371/journal.pone.0276429

Erectile dysfunction after COVID-19 recovery: A follow-up study

Kawintharat Harirugsakul 1, Sorawit Wainipitapong 2, Jeerath Phannajit 3, Leilani Paitoonpong 4, Kavirach Tantiwongse 1,*
Editor: Taeyun Kim5
PMCID: PMC9584530  PMID: 36264947

Abstract

Objectives

Several studies confirm multiple complications after COVID-19 infection, including men’s sexual health, which is caused by both physical and psychological factors. However, studies focusing on long-term effects among recovered patients are still lacking. Therefore, we aimed to investigate the erectile function at three months after COVID-19 recovery along with its predicting factors.

Methods

We enrolled all COVID-19 male patients, who were hospitalized from May to July 2021, and declared to be sexually active within the previous two weeks. Demographic data, mental health status, and erectile function were collected at baseline and prospectively recollected three months after hospital discharge. To determine changes between baseline and the follow-up, a generalized linear mixed effect model (GLMM) was used. Also, logistic regression analysis was used to identify the associating factors of erectile dysfunction (ED) at three months.

Results

One hundred fifty-three men with COVID-19 participated. Using GLMM, ED prevalence at three months after recovery was 50.3%, which was significantly lower compared with ED prevalence at baseline (64.7%, P = 0.002). Declination of prevalence of major depression and anxiety disorder was found, but only major depression reached statistical significance (major depression 13.7% vs. 1.4%, P < 0.001, anxiety disorder 5.2% vs. 2.8% P = 0.22). Logistic regression, adjusted for BMI, medical comorbidities, and self-reported normal morning erection, showed a significant association between ED at three months and age above 40 years and diagnosis of major depression with adjusted OR of 2.65, 95% CI 1.17–6.01, P = 0.02 and 8.93, 95% CI 2.28–34.9, P = 0.002, respectively.

Conclusion

Our study showed a high ED prevalence during the third month of recovery from COVID-19. The predicting factors of persistent ED were age over 40 years and diagnosis of major depression during acute infection.

Introduction

Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been spreading worldwide. Because of the virus’ highly contagious rate and mutation ability, nowadays, more than 440 million people are infected in 150 countries [1]. Essentially, sequelae of COVID-19 were reported in the multiorgan system throughout the body [2], and several studies found that the virus negatively affected male reproductive health and sexual function [3, 4]. For erectile dysfunction (ED), the etiology of its impacts is believed to be contributed by multi-dimensional causes, and the outcome after recovery remains mysterious regarding limited data about long-term effects, biologically in particular, of COVID-19 infection [5].

Pathophysiology of ED includes biological and psychological etiology [6]. SARS-CoV-2 can affect erectile function via various methods, and it may also target the genitourinary system by entering host cells through angiotensin-converting enzyme 2 receptor of vascular endothelial cells. Accordingly, the hyperinflammation stage from the secretion of inflammatory cytokines (TNF-∝, IL-6, and IL-1), a thrombo-embolic phenomenon and effect on other organ systems, especially endocrine, may lead to ED [7]. A study reported the presence of SARS-CoV-2 in penile vascular endothelial cell, crucial to penile erection, of post-infected COVID-19 patients with severe ED. The study also reported a decreased nitric oxide synthase expression in corpus cavernosum, which can be a consequence of endothelial dysfunction [8].

Besides physical causes mentioned above, psychosocial sequelae of COVID-19, including socioeconomic and mental problems, also alter men’s sexual health [5, 9]. COVID-19 pandemic leads to economic hardship, including job loss and financial burden, which are critical psychosocial stressors. They can co-exist with multiple psychiatric morbidities such as depression, anxiety, stress, suicidal ideation, and sleep problems [1012]. Moreover, the reduction of sexual intercourse frequency, which might represent the sexual impacts of COVID-19, is reported during this pandemic [12]. Some online surveillances indicated a deteriorated erectile function and sexual dissatisfaction globally [14], and a higher prevalence of ED was observed compared with the matched population [15].

Even though we currently understand more about COVID-19, the complication after recovery should receive much more academic attention. Long COVID or post-COVID syndrome [16] is still poorly understood but believed to affect the quality of life regarding individual’s risk factors. Clinicians worldwide recognized this persistent discomfort and disability and, consequently, some guidelines, such as National Institute for Health and Care Excellence (NICE) and CDC (Center for Disease Control), toward Long COVID are now established [17, 18].

Long COVID might be termed ‘symptomatic syndrome beyond three weeks after COVID-19 infection’ [19]. The largest descriptive study reported that 37.7% among 508,707 recovered patients have at least one symptom at the twelfth week. Risk factors of long COVID include biologically female gender, high body mass index (BMI), smoking, and having lower incomes; meanwhile, Asian ethnicity is a protective factor [20]. A systematic review of 57 studies showed that the rate of post-acute sequelae of COVID-19 at six months is approximately 54%. Long COVID patients show systemic sequelae, and abnormal chest imaging remained the most frequent pulmonary sequelae (median [IQR], 62.2% [45.8%-76.5%]). Neuropsychiatric consequences are also common but have a lower prevalence: difficulty concentrating (median [IQR], 23.8% [20.4%-25.9%]) and generalized anxiety disorder (median [IQR], 29.6% [14.0%-44.0%]) [21].

Sexual long COVID syndrome, referred to as persisting sexual dysfunction after COVID-19 infection [5], is a concerning problem that may affect the quality of life. Nonetheless, it is being endured in silence due to clinicians’ disregard, especially in the Asian context where sexual problems are underrecognized and avoided [22].

Studies about this syndrome are still limited. One research indicated the prevalence of ED at 6–9 months after recovery [23]. However, further post-COVID ED studies are also necessary regarding differences in sociocultural contexts or periods after recovery. Also, this might be beneficial in predicting other long-term complications since ED could reflect other organ functions, a cardiovascular system in particular, as the “tip of the iceberg” [24]. An earlier ED presentation, such as three months after COVID-19 recovery could be advantageous for both clinicians and patients for raising awareness of further complications afterward. Thus, our study aimed to examine the three-month changes in erectile function and its associated factors among patients who recover from COVID-19 infection.

Materials and methods

Study design and participants

This is the observational cohort study of COVID-19 male patients hospitalized at King Chulalongkorn Memorial Hospital, the Thai Red cross society, one of the largest university hospitals in Bangkok, Thailand. Between May and July 2021, we enrolled all male patients aged between 18–70 years old, tested COVID-19 positive for a reverse transcriptase-polymerase chain reaction assay using nasopharyngeal swab specimen, and declared being sexually active within the previous two weeks. Patients with severe medical and mental conditions were excluded.

The study was registered with the Thai Clinical Trials Registry, with case number TCTR20210617008, and was approved by Chulalongkorn University’s Institutional Review Board (COA No. 659/2021). The sample size of seventy-eight participants at a minimum was calculated using the previous study’s ED prevalence [15].

Data collection

Study design

From May 2021, patients according to the inclusion and exclusion criteria were invited to participate. Inform consent was obtained prior to the assessment. The assessment was conducted online or through a phone interview with illiterate patients to prevent viral transmission. All participants were reassessed three months after recovery by the same questionnaires. Then, the study excluded individuals reporting being sexually inactive.

Demographic data

At baseline, recorded demographic included age, BMI, underlying diseases, education and marital status, and history of alcohol and nicotine use. Details about COVID-19 vaccination and treatment during hospitalization were extracted.

During and three months after the COVID-19 infection, all participants’ erectile function was assessed by the Thai version of the International Index of Erectile Function 5 (IIEF-5) [25]. Mental health status was screened by the Thai Patient Health Questionnaire 9 (PHQ-9) for major depression [26] and the Generalized Anxiety Disorder Scale (GAD-7) for anxiety [27].

In addition, individuals’ report of penile morning erection was accumulated in our study.

Assessment of erectile function

Thai IIEF-5 is a self-rated measurement containing five questions focusing on erectile function and sexual intercourse satisfaction, validated in the Thai population. It is a standard assessment tool for ED assessment and diagnosis. Its scores negatively correlated with ED severity and could be classified into five levels: severe [57], moderate [811], mild to moderate [1216], mild [1721], and no ED [2225].

Assessment of mental health status

Thai PHQ-9 was used to evaluate depressive symptoms, including depressed mood, loss of interest and energy, sleep and appetite problems, feelings of worthlessness, trouble concentrating, psychomotor abnormalities, and thoughts of death or self-injury. A PHQ-9 score of ≥ 9 is considered positive for major depression, with sensitivity and specificity of 0.84 and 0.77, respectively. The test was validated in the Thai population and showed good psychometric properties [26].

The GAD-7 scale is an assessment for generalized anxiety disorder and anxiety severity. The measured symptoms included nervousness, uncontrolled and excessive worrying, trouble relaxing, restlessness, irritability, and fear that something awful might happen. A GAD-7 score of ≥ 10 represents a cut point for identifying generalized anxiety disorder with sensitivity and specificity of 0.89 and 0.82, respectively [27].

Statistical analysis

Categorical variables were presented as counts with percentages; meanwhile, continuous variables were reported as mean with standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normally distributed data. Shapiro-Wilk test was used to test for normality. All non-normally distributed data were log-transformed before comparison. To determine the difference in clinical characteristics between the baseline and the follow-up cohort, in which some participants were lost, the independent t-test and chi-square test were used to compare continuous and categorical variables, respectively. Temporal changes of erectile dysfunction status and psychological parameters after the 3-month recovery from COVID-19 infection were tested using a linear mixed effect model (LMM) for continuous data including IIEF-5, GAD-7, and PHQ-9 scores using visit (baseline vs. 3-month) as a covariate and participant ID as fixed intercept. Binary variables, including ED status, presence of normal morning erection, diagnosis of anxiety, and major depression were tested using a generalized linear mixed effect model (GLMM) with the same covariate and fixed intercept as the LMM. To determine the association between the 3-month post-recovery ED and relevant factors, bivariate and multivariable logistic regression were used. Factors with a P value below 0.2 from the bivariate analysis and those with theoretically ED associated were recruited to the multivariable logistic regression. Adjusted odds ratios (OR) were reported with 95% confidence intervals (95%CI). After the 3-month follow-up, participants were classified into four groups based on ED statuses: no ED, transient ED (ED at baseline and without ED at the follow-up), Persistent ED (ED at baseline and the follow-up), and later onset ED (ED at the follow-up without ED at baseline). One-way analysis of variance (ANOVA) and chi-square test were used to compare continuous and categorical clinical characteristics between these four groups, respectively. A P value of < 0.05 was considered statistically significant. All P values were unadjusted for multiplicity since only exploratory analyses were planned. All analyses were performed using STATA-IC Version 16.1.

Results

From May to July 2021, 153 from 654 hospitalized COVID-19 male patients had reported being sexually active and eligible for the study. During the admission, the first assessment was done, and their COVID-19 treatment history until their discharge was collected. Three months after the COVID-19 infection, a completed second evaluation was obtained from 141 participants (Fig 1).

Fig 1. Study protocol.

Fig 1

Table 1 displays demographic data at each point of the assessment. Mean age (40.8 and 41.0 years), BMI (25.6 and 25.7 kg/m2), and other characteristics showed no significant differences between the first and second evaluations. Most were married or in a relationship as a couple, employed, and had educational attainment lower than a bachelor’s degree.

Table 1. Demographic data at baseline and three months after COVID-19 recovery.

Variables Baseline (N = 153) 3 months (N = 141) P value
Age (mean ± SD) 40.8 ± 10.9 41.0 ± 10.5 0.81
Body mass index (mean ± SD) 25.6 ± 4.4 25.7 ± 4.4 0.88
Marital status 0.98
    • Single 25 (16.3%) 22 (15.6%)
    • Married or couple 125 (81.7%) 116 (82.3%)
    • Separated or divorced 3 (2.0%) 3 (2.1%)
Education 0.88
    • Lower than bachelor’s degree 129 (84.3%) 118 (83.7%)
    • Bachelor’s degree or upper 24 (15.7%) 23 (16.3%)
Medical comorbidities 29 (19%) 28 (19.9%) 0.84
    • Diabetes Mellitus 13 (8.5%) 13 (9.2%) 0.83
    • Hypertension 16 (10.5%) 15 (10.6%) 0.96
    • Hypercholesterolemia 11 (7.2%) 11 (7.8%) 0.84
Substance use
Active alcohol drinking 26 (17.0%) 24 (17.0%) 0.99
Active smoking 57 (37.3%) 51 (36.2%) 0.85
COVID-19 vaccination 50 (32.7%) 48 (34%) 0.80
Severity of COVID-19 0.94
Pneumonia 63 (41.2%) 60 (42.6%)
Pharyngitis 79 (51.6%) 70 (49.6%)
Asymptomatic 11 (7.2%) 11 (7.8%)
COVID-19 treatment
Favipiravir 70 (45.8%) 65 (46.1%) 0.95
Corticosteroids 36 (23.5%) 36 (25.5%) 0.69
Remdesivir 10 (6.5%) 10 (7.1%) 0.85
Tocilizumab 5 (3.3%) 5 (3.5%) 0.90
Oxygen supplement 20 (13.1%) 20 (14.2%) 0.78

Data were shown in counts (%) for categorical variables and mean ± standard deviation (SD) for continuous variables.

P value for unpaired difference between two groups using chi-square test for categorical variables and independent t-test for continuous variables in order to determine the differences between baseline and the follow-up cohorts.

Erectile function, self-reported normal morning erection and mental health status, including anxiety and depression, were evaluated at baseline. After reassessment at three months following COVID-19 recovery, we found statistically significant differences in all dimensions except prevalence of anxiety disorder and self-reported normal morning erection (Table 2).

Table 2. Temporal changes in erectile function and mental health status at baseline and three months after COVID-19 recovery (N = 141).

Variables Baseline (N = 153) 3 months (N = 141) P value
Erectile dysfunction 99 (64.7%) 71 (50.3%) 0.002(b)
IIEF-5 score 21 [1823] 20 [1822] 0.02(a)
Anxiety disorder (GAD-7 ≥ 10) 8 (5.2%) 4 (2.8%) 0.22(b)
GAD-7 score 2 [1–5] 1 [0–4] 0.03(a)
Major depression (PHQ-9 ≥ 9) 21 (13.7%) 2 (1.4%) < 0.001(b)
PHQ-9 score 3 [1–7] 0 [0] 0.002(a)
Normal morning erection 129 (84.3%) 125 (88.7%) 0.10(b)

Abbreviations: IIEF-5 = International Index of Erectile Function 5; GAD-7 = General Anxiety Disorder Scale PHQ-9 = Patient Health Questionnaire 9.

Data were shown in counts (%) for categorical variables and median [interquartile range] for continuous variables.

P value for difference between two visits using (a) linear mixed effect model for log-transformed continuous variables and (b) generalized linear mixed effect model for binary variables.

To determine factors associated with ED at three months, all participants whose IIEF-5 results were positive for ED underwent a logistic regression (Table 3). Variables with significant association (P < 0.2) from the bivariate model were additionally analyzed in the multivariable logistic regression. We also considered the age and medical comorbidities, which were notable ED risk factors. Age over 40 years old (adjusted OR 2.65, 95% CI 1.17–6.01, P = 0.02) and major depression during infection (adjusted OR 8.93, 95% CI 2.28–34.9, P = 0.002) were significantly associated with ED at three months; meanwhile, overweight (P = 0.05) and presence of hypertension, diabetes mellitus, or hypercholesterolemia (P = 0.06) were nearly significant.

Table 3. Associated factors of erectile dysfunction after three months after recovery from COVID-19 infection using bivariate and multivariable logistic regression model.

Variables Bivariate model Multivariable model
Crude OR (95%CI) P value Adjusted OR (95% CI) P value
Age (years) 1.01 (0.98–1.04) 0.625
Age over 40 years 1.54 (0.79–2.99) 0.208 2.65 (1.17–6.01) 0.02 *
Body mass index (kg/m2) 0.96 (0.89–1.04) 0.318
Overweight (Body mass index ≥ 23) 0.61 (0.28–1.30) 0.199 0.43 (0.18–1.00) 0.05
Married or couple 0.92 (0.39–2.19) 0.856
Active smoking 1.18 (0.59–2.34) 0.644
Active alcohol drinking 0.98 (0.41–2.37) 0.970
Medical comorbidities (HT, DM, HCL) 0.82 (0.36–1.88) 0.643 0.37 (0.13–1.06) 0.06
COVID-19 vaccination 1.43 (0.71–2.89) 0.315
COVID-19 pneumonia 1.23 (0.63–2.40) 0.543
Anxiety disorder (baseline) 3.14 (0.61–16.12) 0.171 2.62 (0.34–20.39) 0.36
Major depression (baseline) 7.58 (2.12–27.12) 0.002 8.93 (2.28–34.9) 0.002 *
Normal morning erection (baseline) 0.55 (0.22–1.36) 0.195 0.49 (0.19–1.31) 0.15

Abbreviations: HT–Hypertension, DM–Diabetes mellitus, HCL–Hypercholesterolemia.

* P value < 0.05

As ED is a dynamic disorder, changing over time [28] and there are still no gold standard categorizing ED related with COVID-19. Thus, we categorized all participants into four groups regarding their ED course and onset; no ED, transient ED, persistent ED, and later onset ED. Persistent ED was the most prevalent (42.6%) and related to major depression during infection. A statistically significant difference in self-reported normal morning erection after recovery was also found (P = 0.01). Table 4 shows the demographic data and associated factors among each group.

Table 4. Demographic data and associated factors among four groups of erectile dysfunction.

Variables No ED (N = 37) Transient ED (N = 33) Persistent ED (N = 60) Later onset ED (N = 11) P value
Age (years) 41.1 ± 11.2 40.1 ± 9.8 42.7 ± 10.4 34.6 ± 9.7 0.11
Body mass index (kg/m2) 25.6 ± 4.0 26.5 ± 4.4 25.7 ± 4.6 23.4 ± 4.5 0.24
Medical comorbidities 8 (21.6%) 7 (21.2%) 12 (20.0%) 1 (9.1%) 0.82
    • Diabetes mellitus 3 (8.1%) 3 (9.1%) 6 (10.0%) 1 (9.1%) 0.99
    • Hypertension 6 (16.2%) 3 (9.1%) 5 (8.3%) 1 (9.1%) 0.65
    • Hypercholesterolemia 2 (5.4%) 2 (6.1%) 6 (10.0%) 1 (9.1%) 0.83
Substance use
Active alcohol drinking 8 (21.6%) 4 (12.1%) 10 (16.7%) 2 (18.2%) 0.77
Active smoking 11 (29.7%) 13 (39.4%) 22 (36.7%) 5 (45.5%) 0.75
COVID-19 vaccination 12 (32.4%) 9 (27.3) 23 (38.3) 4 (36.4) 0.74
Anxiety disorder (baseline) 0 (0%) 2 (6.1%) 6 (10.0%) 0 (0%) 0.17
Anxiety disorder (3 months) 0 (0%) 0 (0%) 4 (6.7%) 0 (0%) 0.14
Major depression (baseline) 0 (0%) 3 (9.1%) 17 (28.3%) 1 (9.1%) 0.001 *
Major depression (3 months) 0 (0%) 0 (0%) 2 (3.3%) 0 (0%) 0.43
Normal morning erection (baseline) 30 (81.1%) 31 (93.9%) 47 (78.3%) 9 (81.8%) 0.28
Normal morning erection (3 months) 36 (97.3%) 31 (93.9%) 51 (85.0%) 7 (63.6%) 0.010 *

Data were shown in counts (%) for categorical variables and mean ± standard deviation for continuous variables.

P value for difference between groups using chi-square test for categorical variables and one-way analysis of variance for continuous variables.

* P value < 0.05

Discussion

As COVID-19 continues to spread globally, it is predicted that it will infect more than half of the world population [17]. Clinicians should prepare to overcome complications after COVID-19 infection or long COVID, which is considered common (37.7–54.0%) in recovered patients [20, 21].

Despite several etiologies or pathogenesis of long COVID, multiple studies hypothesized that long COVID might be due to several factors. The factors include incomplete viral eradication, prolonged inflammatory response resulting from poor immune system and residual viral remnant, or direct viral infiltration into organ system and cytokine network dysregulation [2931] Additionally, ED, as a consequence of long COVID, is also complicated by both aforementioned biological and notorious psychological factors including socioeconomic problems, social isolation, or traumatic events.

Notably, impaired erectile function was reported to be a part of sexual long COVID (SLC) [5]. We found that the prevalence of ED at the third month compared with during COVID-19 infection, was significantly lower (50.3% vs. 64.7%, P = 0.002), which implied the erectile function improvement. However, the number was still higher than ED in the general Thai population (37.5–42.2%) [32, 33]. Association between lower prevalence and a longer period after recovery was also reported in one study from China with ED prevalence of 44.8% and 30%, at six and nine months after recovery of COVID-19, respectively [23].

We speculate that improvement of ED could be explained by gradual recuperation of physical competency. Apart from ED, other symptoms during COVID-19 infection, including mental health, anosmia and ageusia, were also significantly improved after three months of infection [3436].

Moreover, mentality during infection might be accountable for the higher prevalence of ED. Physical stress that became intact after recovery and psychosocial difficulties that tended to be relieved at three months also led to better mental status and resulted in better erectile function. Bidirectionally, improvement in sexual function could enrich sexual health and, consequently, promote psychological well-being [9]. This confirms the complexity between ED and mental health which requires further bio-psycho-social investigations. In addition, studies on SLC are still limited and its risk factors are questionable. Thus, future SLC research would be immensely beneficial [37].

Adjusted for BMI, medical comorbidities, anxiety severity, and normal morning erection, multivariable logistic regression identified age over 40 years old (adjusted OR 2.65, 95% CI 1.17–6.01, P = 0.02) and having major depression during infection (adjusted OR 8.93, 95% CI 2.28–34.9, P = 0.002) as predicting factors of ED at three months. Both older age and depression are established risk factors for ED [38, 39] and our result emphasized the role of a bio-psychological issue in the pathogenesis of ED. Interestingly, only mental conditions without aging were found to be associated with ED during infection [40], but patients over 40 years of age were also at risk for ED at three months. Elderly COVID-19 patients should be screened for SLC, and long-term follow-up is still necessary.

ED course found in our participants was both persistent and self-remitted. This was similar to the prognosis of other long COVID complications, which were wax and wane or uncertain [41]. Improvement of COVID-19 symptoms, especially anosmia and ageusia, which contributed to ED etiologies could explain a recovery in patients whose ED was transitory [42].

To our knowledge, our study was the first ED cohort study on COVID-19 patients for three months after recovery. Our sample size was considerable, and all participants were confirmed COVID-19 diagnosis by a gold standard method. Both biological and psychosocial aspects were measured, and our dropout rate was low. However, this study is not without limitations. Firstly, because of a lack of comparison group and pre-existed erectile function status, the assumption of whether COVID-19 was the cause of ED could not be concluded and the confounding bias from social situations such as health policy during pandemic and change in sexual habit might affect the erectile function. Nevertheless, the improvement of ED three months after COVID-19 recovery could be assumed from our study except in older and major depression patients who needed further monitoring. Secondly, limited generalizability should be declared, considering all participants were hospitalized and those with severe symptoms were excluded. The questionnaire used in our study was self-rated and affected by a recall bias. Treatment of persistent ED should be further studied to help clinicians and patients globally, as the number of COVID-19 patients, both recovered and infected, is still increasing.

Conclusion

Although long COVID has been widely studied, only a few studies have focused on erectile function as its complication. Our study showed that, even though the erectile function was significantly improved after three months of COVID-19 infection, the prevalence of ED was still high. In addition, male patients older than 40 years or having major depression during COVID-19 were at risk to be screened positive for ED at three months. Future studies focusing on ED treatment, especially in persistent ED, would be helpful for both clinicians and patients in the time after pandemic cessation.

Acknowledgments

We would like to acknowledge and sincerely thank our staff who help carried out this research to contribute to the medical research society, including our friends and family, whose encouragement comforted and propelled our work to be done successfully and fantastically. We immensely appreciate both direct and indirect help from all of you.

Data Availability

All relevant data are available in the Harvard dataverse: Erectile Dysfunction after COVID-19 Recovery, site https://doi.org/10.7910/DVN/C9UT0Q.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Taeyun Kim

20 Jul 2022

PONE-D-22-17958Erectile dysfunction after COVID-19 infection: A follow-up studyPLOS ONE

Dear Dr. Tantiwongse,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Additional Editor Comments:

* This paper provides very useful information and implicates the possible relationship between ED and COVID-19, although I would like to suggest several points especially regarding the methodology.

* Materials and methods; This section is very important, although lots of researchers would not pay much attention to the methodology the authors utilized. In this regard, I suggest to be more specific with the subheadings as 1) Study design and participants, 2) Data collection (in this part, authors can use sub-subheadings such as 2-1) study design, 2-2) demographic data, 2-3) assessment of erectile function), and 3) Statistical analysis.

* Statistical analysis; Please be specific on the statistical method they used to calculate the significant level. It seems vague to just state: "~~ tests were used regarding variables' nature and distribution.

* Statistical analysis; It seems they used one-way anova test. However, to compare the values within the repeated measurements, RM-ANOVA would be more accurate. Furthermore, the linear mixed-effect model would be more accurate than RM-ANOVA, because this method requires several fastidious assumptions. Therefore to confirm the effect of covid-19 on the ED, which was dichotomized by the score like in Table 2, I suggest authors using the LMEM model. It would be more informative to be visualized.

* Please explain the meaning of round brakets used in Table 1. Also, please indicate the method by which P value was calculated in the footnote of Table 1.

* Please explain the meaning of round and square brakets which were used in Table 2. Also, please indicate the method by which P value was obtained in the footnote of Table 2.

* Please explain the meaning of round and square brakets which were used in Table 4. Also, please indicate the method by which P value was obtained in the footnote of Table 4. In addition, I couldn't find the method by which P value was calculated in the section of Statistical Analysis. Also, please explain the definition of four groups of ED with relevant citations.

* Please discuss that this study did not demonstrate the effect of COVID-19 on the ED in compliance with the Reviewer's comment. And, please discuss other confounding factors that could also impact the ED.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

Congratulations on your research. I have read the manuscript with keen interest, being this topic one of my main foci of research in the last couple of years, and I am positively impressed by this manuscript.

I have a few minor suggestions.

Line 70: I believe that our study https://pubmed.ncbi.nlm.nih.gov/33234430/ would be a better fit than the reference used here. It's also worth mentioning that sexual health and depression/anxiety, while bidirectionally associated, follow a particular relationship: indeed, being more sexually active can improve psychological health more than the opposite, suggesting that in fact COVID patients with more depressed/anxious mood could also have had experienced negative effects of restriction measures (e.g. lockdowns) for sexual health.

Lines 86-87: missing a '

Reviewer #2: The study appears to be sound, and it is clearly designed and written. The statistics are well done. The article treats an actual problem related to COVID-19, as sexuality and functional sexuality, in this case: ED.

The Title is providing a distorted understanding, giving the impression that ED would be due to COVID-19. The authors should clarify the title section to avoid this confusion.

As this study determines, the age and mental status, the major depression due to health problems clearly influence the erectile functioning. There is no evidence that in this population there would be a direct relationship between the virus and the ED. Neither is there a reference group, formed from subjects that would have been severely ill, and long-time hospitalized, for other reasons than COVID-19, but with same demographic characteristics.

In this study, the only illness discussed is COVID-19. Evidently, the results would come as for patients recovering from COVID-19, not necessary having any relationship between the SARS-CoV-2 viral infection and ED.

Additionally, as it results from this study, the morning erection was normal both at baseline and after 3 months follow-up (p=0,13).

To admit for publication the title should be changed, as the authors did not study different groups of severe illnesses and prolonged hospitalization, which should have been studied in order to be able to say that ED is indeed after COVID-19 infection and not just related to age and major depression as an effect of a difficult illness.

The first sentence of the second paragraph from Discussion is not clear. The authors should indicate precisely what they are referring to with “it”. Please replace it with the exact meaning.

The topic of the study is of great importance. In the Discussion part, the authors clarified well the ambiguous relation between ED and COVID-19. This is not yet seen in the title. This study brings a great potential for further studies on the topic.

**********

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Reviewer #1: No

Reviewer #2: Yes: Dr Corina Rosemarie Iire

**********

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PLoS One. 2022 Oct 20;17(10):e0276429. doi: 10.1371/journal.pone.0276429.r002

Author response to Decision Letter 0


18 Aug 2022

Dear Editor and Reviewers,

Thank you for your letter and the opportunity to revise our manuscript. All suggestions offered by the editor and reviewers have been immensely helpful, and we appreciate the insightful comments on every aspect of the paper. We are happy to inform you that all the suggestions are complied with and detailed below. We hope that the revised manuscript will better suit for publication.

Regards,

On behalf of all authors,

Kavirach Tantiwongse

August 19, 2022

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: Our revised manuscript was edited to comply with PLOS ONE’s style requirements.

2. Please specify at which institutions (e.g. hospital or University) the study was conducted.

Response: Thank you for your comment. We have added the name of our study location in the method section. (Page 5 Line 115-116)

3. PLOS ONE follows the WHO criteria for clinical trials, and during the internal evaluation of your mansucript we did not feel that the study met this criteria. Therefore we would recommend excluding all clinical trial references within the mansucript text to avoid confusion.

Response: Thank you for your suggestion. Clinical trial references have been removed.

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available.

Response: Thank you for this point. Since our dataset consists of sensitive information, identifiable data of all participants have been removed. We have deposited our data set in the repository site and mentioned about this in the manuscript. (Page 23 Line 476-478)

5. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 3 in your text; if accepted, production will need this reference to link the reader to the Table.

Response: Thank you. The text referring to Table 3 has been added. (Page 11 Line 234)

Additional Editor Comments:

* Materials and methods; This section is very important, although lots of researchers would not pay much attention to the methodology the authors utilized. In this regard, I suggest to be more specific with the subheadings as 1) Study design and participants, 2) Data collection (in this part, authors can use sub-subheadings such as 2-1) study design, 2-2) demographic data, 2-3) assessment of erectile function), and 3) Statistical analysis.

Response: Thank you very much for these positive comments and suggestion. We agree with the editor that the methods section is very important and we try our best to add more important information. We have now modified the subheadings and sub-subheadings within the materials and methods regarding your suggestions in our revised manuscript. (Page 6 Line 127 -

Page 9 Line 191)

* Statistical analysis; Please be specific on the statistical method they used to calculate the significant level. It seems vague to just state: "~~ tests were used regarding variables' nature and distribution.

Response: Thank you. We have specified the statistical methods used in our study and they have been rearranged appropriately in the statistical analysis sub-subheading. (Page 8 Line 167 –

Page 9 Line 191)

* Statistical analysis; It seems they used one-way anova test. However, to compare the values within the repeated measurements, RM-ANOVA would be more accurate. Furthermore, the linear mixed-effect model would be more accurate than RM-ANOVA, because this method requires several fastidious assumptions. Therefore to confirm the effect of covid-19 on the ED, which was dichotomized by the score like in Table 2, I suggest authors using the LMEM model. It would be more informative to be visualized.

Response: Thank you for your suggestion. In this revised version, we use the linear mixed effect model for continuous repeated measurements (including IIEF-5 score, GAD and PHQ) and generalized linear mixed effect model for binary data (ED status, morning erection, depression, and anxiety). The model is comprised of visit (baseline vs. three-month) as a co-variate and patient ID as fixed intercept in order to demonstrate the temporal effects on each variable after recovery from COVID-19. The detailed of models are described in ‘Statistical analysis’ section (Page 8 Line 167 - Page 9 Line 191) and results are presented in table 2.

* Please explain the meaning of round brakets used in Table 1. Also, please indicate the method by which P value was calculated in the footnote of Table 1.

* Please explain the meaning of round and square brakets which were used in Table 2. Also, please indicate the

method by which P value was obtained in the footnote of Table 2.

* Please explain the meaning of round and square brakets which were used in Table 4. Also, please indicate the method by which P value was obtained in the footnote of Table 4. In addition, I couldn't find the method by which P-value was calculated in the section of Statistical Analysis.

Response: Apologize for the initially confusing tables, we have edited all suggested and added footnotes on each table explaining all abbreviations, data presentation, and statistical analysis methods. (please see table 1, 2 and 4)

* Also, please explain the definition of four groups of ED with relevant citations.

Response: Our study categorized patients into four groups based on the onset of ED relating with COVID-19. However, up to our knowledge, there is still no standard definition to categorize the ED related to COVID-19. We have discussed more about this in our revised manuscript. (Page 12 Line 252-253)

* Please discuss that this study did not demonstrate the effect of COVID-19 on the ED in compliance with the Reviewer's comment. And, please discuss other confounding factors that could also impact the ED.

Response: Thank you for the crucial point. According to our methodology, we are not able to conclude the direct effect of COVID-19 and ED as the reviewer’s comment. However, our study could imply that ED improvement could be found after COVID-19 recovery and some associated factors are worth to be mentioned. Because of the complexity of ED etiologies, several confounding factors might impact the ED and we have discussed about this more in the discussion section as your recommendation. (Page 16 Line 325-327)

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

3. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Response: Now, we have uploaded our dataset in the repository and provided the available link in the data availability section of our revised manuscript. (Page 23 Line 476-478)

Reviewer #2: Yes

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #1: Dear Authors,

Congratulations on your research. I have read the manuscript with keen interest, being this topic one of my main foci of research in the last couple of years, and I am positively impressed by this manuscript.

I have a few minor suggestions.

Line 70: I believe that our study https://pubmed.ncbi.nlm.nih.gov/33234430/ would be a better fit than the reference used here. It's also worth mentioning that sexual health and depression/anxiety, while bidirectionally associated, follow a particular relationship: indeed, being more sexually active can improve psychological health more than the opposite, suggesting that in fact COVID patients with more depressed/anxious mood could also have had experienced negative effects of restriction measures (e.g. lockdowns) for sexual health.

Response: Thank you. We appreciate your helpful suggestion. We found your study suit our finding and have now added this in the introduction part and references. (Page 3 Line 70). Moreover, we also added information about bidirectional effects in sexual health and psychological health in the discussion part. (Page 14 Line 299 - Page 15 Line 301)

Lines 86-87: missing a '

Response: Thank you. This mistake has been corrected. (Page 4 Line 87)

Reviewer #2: The study appears to be sound, and it is clearly designed and written. The statistics are well done. The article treats an actual problem related to COVID-19, as sexuality and functional sexuality, in this case: ED.

The Title is providing a distorted understanding, giving the impression that ED would be due to COVID-19. The authors should clarify the title section to avoid this confusion.

Response: Thank you for this comment. We have renamed our title to ‘Erectile Dysfunction after COVID-19 Recovery: A follow-up study’ according to your suggestion. (Page 1 Line 1)

As this study determines, the age and mental status, the major depression due to health problems clearly influence the erectile functioning. There is no evidence that in this population there would be a direct relationship between the virus and the ED. Neither is there a reference group, formed from subjects that would have been severely ill, and long-time hospitalized, for other reasons than COVID-19, but with same demographic characteristics. In this study, the only illness discussed is COVID-19. Evidently, the results would come as for patients recovering from COVID-19, not necessary having any relationship between the SARS-CoV-2 viral infection and ED. Additionally, as it results from this study, the morning erection was normal both at baseline and after 3 months follow-up (p=0,13).

Response: Thank you for this point. We have mentioned the limitation of our study design that cannot conclude the direct effect of COVID-19 and ED. (Page 16 Line 325-327)

To admit for publication the title should be changed, as the authors did not study different groups of severe illnesses and prolonged hospitalization, which should have been studied in order to be able to say that ED is indeed after COVID-19 infection and not just related to age and major depression as an effect of a difficult illness.

Response: Thank you. We greatly appreciate your comment helping us to improve our manuscript. Our title has been changed to comply with our study design and reduce confusion regarding your suggestion.

The first sentence of the second paragraph from Discussion is not clear. The authors should indicate precisely what they are referring to with “it”. Please replace it with the exact meaning.

Response: Thank you for this point. We have replaced ‘it’ with the referred word ‘long COVID’. (Page 13 Line 276)

The topic of the study is of great importance. In the Discussion part, the authors clarified well the ambiguous relation between ED and COVID-19. This is not yet seen in the title. This study brings a great potential for further studies on the topic.

Response: Thank you for your helpful comments and hope that our revised manuscript and renamed title will suit for the publication.

Attachment

Submitted filename: Response to Reviewers.docx

Decision Letter 1

Taeyun Kim

3 Oct 2022

PONE-D-22-17958R1Erectile Dysfunction after COVID-19 Recovery: A Follow-Up StudyPLOS ONE

Dear Dr. Tantiwongse,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Kind regards,

Taeyun Kim

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

* I have a few minor comments regarding the Abstract.

* Abstract Method; please briefly introduce the main methods that was used in the current study: mixed-effect model and logistic regression model.

* Abstract Results; This section should be in line with the methods section. That is, when method A is introduced in Method section, the results from this method also should be described in Results section.

* Abstract; If the word count exceeds, introduction section could be simplified, just stating "The present study aimed to ~".

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

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Reviewer #1: I wish to thank the Authors for addressing all comments I raised during the first iteration of peer review. I have no further remarks.

Reviewer #2: Dear Authors,

I appreciate the corrections and additions were done to the manuscript, as improving the description of your statistical analysis, tables and all together the “Materials and Methods” section. Also the title is a better one in cleaning the previous confusion. I thank you for the rigorous work on your study, with a very important topic. That is a good study.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2022 Oct 20;17(10):e0276429. doi: 10.1371/journal.pone.0276429.r004

Author response to Decision Letter 1


4 Oct 2022

Response to Editor and Reviewers

Dear Editor and Reviewers,

We appreciate all your kind comments and suggestions. Hereby, please find our point-by-point responses listed below.

Regards,

On behalf of all authors,

Kavirach Tantiwongse

October 4, 2022

Journal requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: All references have been reviewed, and none of them has been retracted.

Additional Editor Comments:

* Abstract Method; please briefly introduce the main methods that was used in the current study: mixed-effect model and logistic regression model.

Response: Thank you for this important point. We have now mentioned both generalized linear mixed-effect model (GLMM) and logistic regression, the main methods of our study, in the abstract, according to your suggestion. (Page 2 Line 35-38)

* Abstract Results; This section should be in line with the methods section. That is, when method A is introduced in the Method section, the results from this method also should be described in Results section.

Response: Thank you for your helpful advice. Additional results from GLMM have been added. (Page 2 Line 39-44)

* Abstract; If the word count exceeds, introduction section could be simplified, just stating "The present study aimed to ~".

Response: Regarding all changes that have been made, the total word count is 287 for the abstract.

Attachment

Submitted filename: Response to Reviewers.docx

Decision Letter 2

Taeyun Kim

7 Oct 2022

Erectile Dysfunction after COVID-19 Recovery: A Follow-Up Study

PONE-D-22-17958R2

Dear Dr. Tantiwongse,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Taeyun Kim

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Taeyun Kim

12 Oct 2022

PONE-D-22-17958R2

Erectile Dysfunction after COVID-19 Recovery: A Follow-Up Study

Dear Dr. Tantiwongse:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Taeyun Kim

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Response to Reviewers.docx

    Attachment

    Submitted filename: Response to Reviewers.docx

    Data Availability Statement

    All relevant data are available in the Harvard dataverse: Erectile Dysfunction after COVID-19 Recovery, site https://doi.org/10.7910/DVN/C9UT0Q.


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