{"paper_id":"96520e56-bbb6-4ab8-8e43-d49706416b21","body_text":"Moazzami et al. BMC Women’s Health          (2021) 21:119  \nhttps://doi.org/10.1186/s12905-021-01270-z\nRESEARCH ARTICLE\nDoes endometriosis increase susceptibility \nto COVID-19 infections? A case–control study \nin women of reproductive age\nBahram Moazzami1, Shahla Chaichian1* , Saeed Samie1, Masoumeh Majidi Zolbin2, Fatemeh Jesmi1, \nMeisam Akhlaghdoust1, Mahin Ahmadi Pishkuhi3, Zahra Sadat Mirshafiei1, Fereshteh Khalilzadeh1 and \nDorsa Safari1 \nAbstract \nBackground: In today’s world, coronavirus disease 2019 (COVID-19) is the most critical health problem and research \nis continued on studying the associated factors. But it is not clear whether endometriosis increases the risk of \nCOVID-19.\nMethods: Women who referred to the gynecology clinic were evaluated and 507 women with endometriosis (case \ngroup) were compared with 520 women without endometriosis (control group). COVID-19 infection, symptoms, \nexposure, hospitalization, isolation, H1N1 infection and vaccination, and past medical history of the participants were \nrecorded and compared between the groups using IBM SPSS Statistics for Windows version 21.\nResults: Comparison between the groups represent COVID-19 infection in 3.2% of the case group and 3% of the \ncontrol group (P = 0.942). The control group had a higher frequency of asymptomatic infection (95.7% vs. 94.5%; \nP < 0.001) and fever (1.6% vs. 0%; P = 0.004), while the frequency of rare symptoms was more common in the case \ngroup (P < 0.001). The average disease period was 14 days in both groups (P = 0.694). COVID-19 infection was cor-\nrelated with close contact (r = 0.331; P < 0.001 in the case group and r = 0.244; P < 0.001 in the control group), but not \nwith the history of thyroid disorders, H1N1 vaccination, traveling to high-risk areas, and social isolation (P > 0.05).\nConclusion: Endometriosis does not increase the susceptibility to COVID-19 infections, but alters the manifestation \nof the disease. The prevalence of the disease may depend on the interaction between the virus and the individual’s \nimmune system but further studies are required in this regard.\nKeywords: Endometriosis, Coronavirus, COVID-19, SARS-CoV-2, Risk factors, Immunologic factors\n© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, \nadaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and \nthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material \nin this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material \nis not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds \nthe permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea-\ntivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo-\nmain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\nCoronavirus disease 2019 (COVID-19) is one of the most \ncritical pandemics ever, resulting in about 15% mortal -\nity rate in hospitalized patients [1]. As a newly emerging \ndisease, ongoing research is running on different aspects \nof the disease [2]. The virus mainly affects the respiratory \nsystem, presenting with cough, difficult breathing, pneu -\nmonia, and in severe cases, results in acute respiratory \ndistress syndrome (ARDS), need for intensive care unit \n(ICU) admission, and mechanical ventilation [3]. Some \ncases may even be complicated by multiple organ failure \n(MOF) which results in death [4].\nSusceptibility of specific organs to COVID-19 has \nprovoked research towards the disease mechanisms [5], \nwhich resulted in identification of spike glycoprotein \nOpen Access\n*Correspondence:  shchaichian@gmail.com\n1 Pars Advanced and Minimally Invasive Medical Manners Research \nCenter, Pars Hospital, Tehran, Iran\nFull list of author information is available at the end of the article\n\nPage 2 of 7Moazzami et al. BMC Women’s Health          (2021) 21:119 \n(S protein), one of the main structural components of \nSARS-CoV-2, which facilitates binding of the envelope \nviruses to host cells by forming homotrimers protrud -\ning on the viral surface, which attracts angiotensin-con -\nverting enzyme 2  (ACE2) [6]. Therefore, SARS-CoV-2 \ncan directly damage organs that express  ACE2, including \nlungs, heart, kidneys, and intestines [7]; accordingly, the \nvirus entry through this receptor depends on the cleavage \nof the S protein, which varies in different virus strains and \ncell types [8].  ACE2 protein is also effective in the physiol-\nogy and pathology of the female reproductive system and \nfertility processes through production of sex hormones \n[9, 10], which is also affected during COVID-19 infec -\ntion [11]. As suggested, the renin-angiotensin system \n(RAS) in ovaries and angiotensin (Ang)-II and Ang [1–7] \nfacilitate follicle development, steroid secretion, oocyte \nmaturation, and follicle atresia, as well as steroidogenesis \nand ovulation [12, 13], which justifies the association of \novarian  ACE2 malfunction with reproductive disorders, \nlike polycystic ovary syndrome and ovarian hyperstimu -\nlation syndrome [14], uterine leiomyoma [15], as well as \nendometriotic lesions [16, 17]. The expression of  ACE2, \nthe SARS-CoV cellular receptor, has been also detected \nin the endometrial tissue [15, 18]. Although the endo -\nmetrium has an overall low risk of COVID-19 infection, \ndue to the low expression of  ACE2 and transmembrane \nprotease serine protease-2 (TMPRSS2), but the expres -\nsion of these host receptors increase at specific stages \nof the menstrual cycle and varies based on the woman’s \nage and endometrial susceptibility to the infection [19]. \nPrevious studies on the endometrial disease have also \ndetermined the presence of  ACE2 in the glandular epithe-\nlium, stroma, perivascular space, and endothelium [20, \n21]. However, as the only study on the gene expression of \nSARS-CoV states, because of several limitations such as \nthe small sample size, variability in the genetic profile of \nindividuals and their ethnicity, and medical comorbidi -\nties, the endometrial susceptibility to the virus could dif -\nfer based on viral cell entry mechanisms [19]. Although \nseveral animal studies have suggested the possibility of \ninhibition and regression of endometriotic lesions by \nblocking ACE II type 1 receptor (AT1R) and suggest that \nactivation of peroxisome proliferator-activated receptor \n(PPAR)-g prevents vascularization and growth in murine \nmodel [22, 23]; human studies are required to determine \nthe risk of COVID-19 infection in the endometrial tissue \n[24].\nFrom the clinical perspective, it is not yet clear whether \npatients with thoracic endometriosis have a higher risk \nof pulmonary disease or COVID-19 infection [25]. An \nexpert opinion has suggested specific treatment guide -\nlines, in order to reduce the susceptibility of endo -\nmetriosis patients to COVID-19 infection [26]. As an \ninflammatory disease, endometriosis stimulates immune \nresponse and inflammation in the body [27], which is also \na common feature of COVID-19, during which the overly \nvigorous immune response can result in cytokine storm \n[28]. So, we hypothesized that while a patient suffer -\ning from this inflammatory disease (endometriosis), the \npatient can be more susceptible to COVID-19, compared \nto the normal population. As, to date, there is no evi -\ndence about the risk of COVID-19 infections in patients \nwith endometriosis, the present study aimed to compare \nthe risk of COVID-19 between women with and without \nendometriosis.\nMethods\nStudy design\nThis study was designed as a case–control study and con-\nducted at Pars general hospital from May 21st to July 3rd, \n2020. The study population consisted of women with his-\ntologic confirmation of endometriosis (extracted sample \nduring laparoscopy), diagnosed at least a year before and \nmaximum of 10 years before the study, compared with an \nage-matched control group, selected from women with -\nout endometriosis who referred to the gynecologic clinic \nfor screening Pap smear test and had no complaints of \nany symptom related to endometriosis. All participants \nwere asked to complete a researcher-designated check -\nlist via email or social networks or cell phone for evalu -\nation of Real-Time Polymerase Chain Reaction (rt-PCR) \nscreening test and symptoms of COVID-19, a recent \nhistory of traveling to the high-risk areas, commitment \nto social distancing, relationship with a patient infected \nwith COVID-19, positive COVID-19 rt-PCR test, his -\ntory of isolation due to COVID-19 infection, hospitaliza -\ntion due to COVID-19, H1N1 infection, and vaccination \nduring last year, and other medical diseases. The symp -\ntoms asked from patients included fever, sore throat, \nnasal congestion, cough, shortness of breath, headache, \nweakness and muscle pain, reduced sense of smell and/\nor taste, ocular problems, and other (including gastroin -\ntestinal, skin, hematologic, and neuronal) complications. \nThe rt-PCR test is performed by Dacron or Rayon swabs \ntaken from naso- or oro-pharyngeal, from any patients \nwith suggestive symptomsDacron or Rayon swabs taken \nfrom naso- or oro-pharyngeal, from any patients with \nsuggestive symptoms, perform the rt-PCR test. The \nsamples were sent to the laboratory immediately, where \nCOVID-19 nucleic acid was extracted and used for \nmolecular detection by fluorescence probing. Patients, \nyounger than 18 or older than 45 were excluded from the \nstudy.\nThe sample size of the study was considered at a mini -\nmum of 507 in each group. For sample size calculation, \nwe considered the prevalence of COVID-19 reported \n\nPage 3 of 7\nMoazzami et al. BMC Women’s Health          (2021) 21:119 \n \nby Quartuccioa et al. at 3.8; in every 1000 patients with \nchronic inflammatory disease due to the lack of evidence \non COVID-19 in women with endometriosis) (and 2 in \nevery 1000 in general population) [29], using the follow -\ning equation and considering the power of the study at \n80% and alpha error at 0.05.\nThe researcher selected the participants according to \nthe inclusion criteria, explained the study design and \nobjectives to the eligible participants, and asked them \nto read and sign the written informed consent; then, the \nresearcher included the eligible participants (who gave \nconsent) into the study by census method. The protocol \nof the present study was approved by the Ethics Com -\nmittee of Pars Advanced and Minimally Invasive Medi -\ncal Manners research center, Pars Hospital, Tehran, Iran. \n(Code: 99G5018).\nStatistical analysis\nFor describing the categorical variables, frequency (per -\ncentage) was reported. For numeric variables, first, \nKolmogorov–Smirnov test was used to assess the nor -\nmal distribution of data and according to the results \nof this test, the numeric variables were described by \nmean ± standard deviation (SD) or median and com -\npared between the groups using independent t-test or \nMann–Whitney U test, whenever the data did not appear \nto have normal distribution or when the assumption of \nequal variances was violated across the study groups. \nCategorical variables were, on the other hand, compared \nusing chi-square or Fisher’s exact test. The association \nof variables was tested by Spearman’s correlation coeffi -\ncient. For the statistical analysis, the statistical software \nIBM SPSS Statistics for Windows version 21.0 (IBM \nCorp. 2012. Armonk, NY: IBM Corp.) was used. P values \nof 0.05 or less were considered statistically significant.\nResults\nA total of 507 women were evaluated in the case group \nand 520 women in the control group. The mean ± SD \nof the women’s age was 29.08 ± 14.29 in the case group \nand 33.00 ± 7.06 in the control group (P = 0.379). The \nmajority of the case group had stage IV endometrio -\nsis (N = 110, 63.2%), 17.2% had stage III (N = 30), 8% \nhad stage II (N = 14), 11.4% had stage I endometriosis \n(N = 20). In the case group, 18.3% (N = 93) had a positive \nhistory of infertility.\nThe results of comparing the COVID-19 character -\nistics between the case and control groups, as shown \nin Table  1, showed no difference between the groups in \nm =\n{\nz1−a/2\n√\n[2pq] + z1−β\n√\n[p1q1 + p2q2]\n}\nδ2\nplan\nterms of COVID-19 infection (P = 0.942), frequency of \nH1N1 vaccination, recent traveling to high-risk prov -\ninces, social distancing, close contact with an infected \npatient, as well as the frequency of performing screening \ntest, admission and isolation due to COVID-19 (P > 0.05); \nbut, the frequency of symptoms (P < 0.05) and H1N1 \ninfection were significantly different between the groups \n(P < 0.001). As shown in Table 1, the frequency of asymp -\ntomatic cases and the frequency of fever was higher in \nthe control group (P < 0.001 and 0.004, respectively), and \nthe frequency of other symptoms was higher in the case \ngroup (P < 0.001). The average disease period was 14 days \nin both groups (P = 0.694).\nThe frequency of underlying diseases is shown in \nTable  2. As demonstrated in this table, 80.5% in the \ncase group and 72.3% in the control had no underlying \ndisease (P = 0.002) and the frequency of diabetes mel -\nlitus (P = 0.038), cardiovascular disease, hypertension, \nand lupus erythematosus were higher in the control (all \nP < 0.001; Table 2).\nStudying the association of the study variables with \nCOVID-19 infection identified “close contact with a \npatient infected with COVID-19” as a significant risk fac-\ntor, both in the case (r = 0.331, P < 0.001) and the control \ngroup (r = 0.244, P < 0.001), while other variables such as \nsocial distancing, traveling, underlying diseases, thyroid \ndisease, and endometriosis stage were not associated \nwith COVID-19 infection (P > 0.05; Table 3).\nDiscussion\nComparing two groups of women with and without \nendometriosis showed no difference in the frequency \nof COVID-19 infection, which is contrary to the initial \nhypothesis of our study, as we assumed that patients with \nendometriosis, an inflammatory disease, have a greater \nsusceptibility to COVID-19 infection, because of their \nbaseline disorder in the immune system, as well as the \nevidence on the expression of  ACE2 in the endometrial \ntissue [15, 18]. Studies have reported different diseases \nthat can predispose the individual to COVID-19 and \nreported that malnutrition [30], serum parameters, such \nas blood group [31], and elevated plasmin(ogen) [32], as \nwell as underlying autoimmune diseases, such as tuber -\nculosis [33] and lupus erythematosus [34] can increase \npatients’ susceptibility to COVID-19. However, as far as \nthe authors are concerned, the risk of COVID-19 infec -\ntion in women with endometriosis has not been clinically \nevaluated, to date.\nThe endometrial susceptibility to COVID-19 is still \nunder investigation. Molecular investigations have shown \nthat  ACE2 is expressed in endometrial epithelial cells \nand stromal cells in the proliferative phase of the men -\nstrual cycle, which increases in the secretory phase and \n\nPage 4 of 7Moazzami et al. BMC Women’s Health          (2021) 21:119 \naffects the in  vivo decidualization, embryo implanta -\ntion, and placentation [18]. The expression of  ACE2 has \nbeen also confirmed in the myometrium and uterine \nleiomyoma [15]. In another molecular genetic study, it \nwas demonstrated that the lower expression of host pro -\nteases, related to SARS-CoV-2 infection, such as  ACE2 \nand TMPRSS2 may result in a lower risk of endometrial \nsusceptibility to COVID-19 infection, but the expres -\nsion of these proteins varies in different phases of the \nmenstrual cycle and increases during implantation and \nin older women [19]. It is also assumed that COVID-19 \ncan induce changes in endometrial tissue and affect the \nfemale reproductive system [12]. However, the studies \navailable in this regard are expert opinion or molecu -\nlar based and the susceptibility of endometrial tissue to \nCOVID-19 has not been confirmed in the clinical setting \n[24].\nIt has been previously demonstrated that despite \nthe indefinite pathophysiology of endometriosis, the \nimmune system is considered as a cause of develop -\nment of endometriosis and several immunologic and \ninflammatory changes are observed in endometriosis \n[35]. The main immunologic changes in endometriotic \npatients include reduction of T cell reactivity, natural \nkiller (NK) cell’s cytotoxicity, increased antibody pro -\nduction, macrophages polarization and augmented \nrelease of inflammatory disease [36]. The increased \ninfiltration level of immune cells, including B cell, \n CD4+T cell, neutrophil, and dendritic cells as well as \nincreased expression of  ACE2 has been correlated with \nSARS-CoV-2 susceptibility in endometrial cancer [31]. \nHowever, such association has not been found in endo -\nmetriosis and the results of our study showed no differ -\nence in susceptibility to COVID-19 disease in women \nTable 1 The results of comparing the coronavirus disease characteristics between the case and control groups\nResults of: aChi square test, bFisher’s exact test\nVariable Categories Case group (N = 507) Control group (N = 520) p-value\nNumber Percent Number Percent\nH1N1 infection No 462 91.1 490 2.0  < 0.001a\nYes 44 8.7 10 2.0\nH1N1 vaccine No 488 96.3 495 97.4 0.212a\nYes 18 3.6 13 2.6\nTravel No 470 92.7 370 69.7 0.059a\nYes 36 7.1 24 4.5\nSocial distancing No 397 78.3 267 67.8 0.256a\nYes 109 21.5 127 32.2\nClose contact No 475 93.7 358 91.8 0.979a\nYes 31 6.1 32 8.2\nCOVID-19 infection No 490 96.6 515 97 0.942a\nYes 16 3.2 16 3\nsymptoms None 479 94.5 508 95.7  < 0.001a\nFever 0 0 8 1.6 0.004b\nSore throat 7 1.4 6 1.2 0.745a\nNasal congestion 8 1.6 2 0.4 0.050a\nCough 7 1.4 6 1.2 0.747a\nShortness of breath 8 1.6 6 1.2 0.558a\nHeadache 4 0.8 3 0.6 0.486a\nWeakness and muscle pain 5 1.0 13 2.6 0.094a\nReduced sense of smell and/or taste 9 1.8 7 1.4 0.622a\nOcular problems 4 0.8 1 0.2 0.179b\nOther 11 2.2 0 0  < 0.001b\nScreening No 477 94.1 476 89.6 0.137a\nYes 29 5.7 42 7.9\nAdmission No 505 99.6 520 100 0.494b\nYes 1 0.2 0 0\nIsolation No 493 97.2 420 97.2 0.790a\nYes 13 2.6 12 2.8\n\nPage 5 of 7\nMoazzami et al. BMC Women’s Health          (2021) 21:119 \n \nwith endometriosis, the underlying reason requires fur -\nther investigations.\nIn the current study, it was found that the frequency \nof COVID-19 symptoms differed between women with \nand without endometriosis; endometriotic women had \na lower frequency of asymptomatic and febrile infec -\ntion, but higher frequency of other symptoms, including \ngastrointestinal, dermatologic, hematologic, and neu -\nronal disorders. Keeping in mind that the difference in \nthe symptoms may, also, be related to the difference in \nthe underlying diseases of the patients and the medica -\ntions they use [37], our results suggest that more atten -\ntion should be paid to women with endometriosis for \ndiagnosis of COVID-19 infection, as they mainly do not \npresent common symptoms, which can make diagno -\nsis difficult [38]. COVID-19 infection interferes with the \nantigen-presenting cells in the immune system and cre -\nates bilayer vesicles, which can block the expression of \nPattern Recognition Receptor (PRR) and, as a result, the \npatient’s innate immune system does not recognize them \nand continue to proliferate within the vesicle, they also, \ndisable the production of Type I interferon as one of the \nmost important antiviral factors so it will develop as an \nasymptomatic disease in some cases [39]. Asymptomatic \nCOVID-19 is considered the Achilles’ heel for disease \ncontrol, due to the strong infectivity and transmission \nduring this period, and the major role of asymptomatic \ncarriers in the person-to-person disease transmission \n[40]. We suppose that the different clinical presentation \nof COVID-19 in women with endometriosis in the pre -\nsent study can be attributed to the altered immune inter -\nactions in endometriosis [41, 42], similar to the different \ndisease characteristics of COVID-19 in other immune-\nmediated inflammatory diseases/conditions, such as \nrheumatoid arthritis, psoriatic arthritis, ankylosing spon -\ndylitis, psoriasis, inflammatory bowel disease [43], and \npregnancy [44]. Further molecular studies are required to \nunderstand the exact mechanism of this finding.\nWe also analyzed factors associated with COVID-19 \ninfection and the results revealed that close contact with \na patient infected with COVID-19 was the only risk fac -\ntor in both groups that resulted in a slightly increased \nchance (0.3- and 0.2-folds higher odds in the case and \nTable 2 The results of comparing the frequency of underlying \ndiseases between the study groups\nResults of: aChi-square test, bFisher’s exact test\nCase group \n(N = 507)\nControl group \n(N = 520)\np-value\nFrequency Percent Frequency Percent\nNone 408 80.5 376 72.3 0.002a\nThyroid disease 5 0.98 3 0.57 0.501b\nDiabetes mellitus 11 2.2 23 4.6 0.038a\nCardiovascular \ndisease\n2 0.4 36 7.2  < 0.001a\nHypertension 13 2.6 42 8.4  < 0.001a\nAsthma 1 0.2 6 1.2 0.124b\nAllergy 13 2.6 23 4.6 0.057a\nCancer 5 1.0 11 2.2 0.097a\nSinusitis 6 1.2 2 0.4 0.173b\nLupus erythema-\ntosus\n2 0.4 6 1.2 0.156b\nRheumatoid \narthritis\n4 0.8 26 5.2  < 0.001b\nOther 18 3.6 24 4.8 0.314a\nTable 3 The association of COVID-19 infections with the study variables in each study group\nCOVID-19-positive cases in the case group (N = 16) COVID-19-positive cases in the control group \n(N = 16)\nN (%) Pearson’s coefficient p value N (%) Pearson’s coefficient p value\nUnderlying diseases\nDiabetes mellitus – 0.108 0.611 1 (6.2%) 0.202 0.533\nCardiovascular disease – 1 (6.2%)\nHypertension – 2 (12.5%)\nAsthma – 1 (6.2%)\nAllergy – 1 (6.2%)\nRheumatoid arthritis 2 (12.5%) 1 (6.2%)\nThyroid disease 5 (31%) 0.032 0.471 3 (18.6%) 0.026 0.588\nAdmission due to COVID-19 1 (6.2%) 0.246  < 0.001 0 – –\nH1N1 vaccination 1 (6.2%) 0.026 0.445 13 (81.2%) 0.026 0.554\nTravel 1 (6.2%) 0.006 1.000 4 (25%) 0.803 0.465\nSocial distancing 5 (31%) 0.043 0.355 4 (25%) 0.089 0.510\nClose contact 8 (50%) 0.331  < 0.001 6 (37.5%) 0.244  < 0.001\n\nPage 6 of 7Moazzami et al. BMC Women’s Health          (2021) 21:119 \ncontrol groups, respectively), while other variables such \nas social distancing, traveling, underlying diseases, thy -\nroid disorders, and endometriosis stage were not associ -\nated with COVID-19 infection. As suggested, preventive \nmeasures should be considered by everyone to reduce \ncontact with an infected person (possibly in the incuba -\ntion or asymptomatic period) to reduce the transmission \nrate and the prevalence of this epidemic [45, 46], which \nrequires increasing the knowledge and awareness of the \ngeneral population about the necessary precautions to be \ntaken during the current outbreak [47].\nThe limitations of the present study include the cross-\nsectional nature of the study and lack of follow-up. \nTherefore, we could only suggest associations, rather \nthan the causal relationship between the study variables. \nFurthermore, we matched the control group in terms of \nage with the case group and selected women were from \nthe same medical center; however, differences in other \ncharacteristics between the groups may affect the results. \nAlso, we recruited participants by census method and the \nnonrandomized patient selection increases the chance of \nconfounders on the results. For sample size calculation, \nwe could not use the statistics of our own region, as pub -\nlished data was not available at the time of sample size \ncalculation and we had to estimate the real prevalence \nbased on the available evidence.\nConclusions\nThe results of the present study suggested that endome -\ntriosis does not increase the susceptibility to COVID-\n19 infection, but it changes the presenting symptoms; \nalthough more homogenous groups are required for defi-\nnite conclusions. It is thus suggested to pay more atten -\ntion for accurate diagnosis of COVID-19 in women with \nendometriosis. Since the exact mechanism of infection \nwith this virus in these patients is not fully understood, \nthe most important task at present is to eliminate the \ntransmission cycle, for which identifying the predispos -\ning factors can help diagnose high-risk patients.\nAbbreviations\nCOVID-19 infection: Coronavirus disease 2019; ARDS: Acute respiratory \ndistress syndrome; ICU: Intensive care unit; MOF: Multiple organ failure; ACE2: \nAngiotensin-converting enzyme 2; TMPRSS2: Transmembrane protease \nserine protease-2; rt-PCR: Real-time polymerase chain reaction; SD: Standard \ndeviation; NK: Natural killer; PRR: Pattern recognition receptor; CT: Computed \ntomography.\nAcknowledgements\nThe authors of the present study sincerely thank patients who answered the \nquestions very carefully and with patience in the critical ere of COVID-19.\nAuthors’ contributions\nStudy concept and design: SC and BM, Data collection: SS and MMZ, drafting \nthe manuscript FJ, MA, and DS, critical revision of the manuscript: FJ, SC, ZSM, \nSS, and MMZ, Statistical Analysis: MAP and FK. All of the authors have given \nfinal approval of the submitted and revised versions and have agreed to be \npersonally accountable for the author’s own contributions and to ensure that \nquestions related to the accuracy or integrity of any part of the work, even \nones in which the author was not personally involved, are appropriately inves-\ntigated, resolved, and the resolution documented in the literature. All authors \nread and approved the final manuscript.\nFunding\nThis study is supported by, Pars General hospital, Tehran, Iran. The funder had \na role in data collection, but had no role in decision to publish, or preparation \nof the manuscript.\nAvailability of data and materials\nThe corresponding author, Shahla Chaichian, can be contacted if someone \nwants to request the data.\nDeclarations\nEthics approval and consent to participate\nThe protocol of the present study was approved by the Ethics Committee \nof Pars Advanced and Minimally Invasive Medical Manners research center, \nPars Hospital, Tehran, Iran. (Code: 99G5018). Written informed consent was \nobtained from the participants.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors of the present study declare that they have no competing \ninterests.\nAuthor details\n1 Pars Advanced and Minimally Invasive Medical Manners Research Center, \nPars Hospital, Tehran, Iran. 2 Pediatric Urology and Regenerative Medicine \nResearch Center, Section of Tissue Engineering and Stem Cells Therapy, Chil-\ndren’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, \nIran. 3 PhD Student in Epidemiology, Department of Epidemiology and Biosta-\ntistics, School of Public Health, Tehran University of Medical Sciences, Tehran, \nIran. \nReceived: 3 August 2020   Accepted: 16 March 2021\nReferences\n 1. Harapan H, Itoh N, Yufika A, Winardi W, Keam S, Te H, et al. Coronavirus \ndisease 2019 (COVID-19): A literature review. Journal of Infection and \nPublic Health. 2020.\n 2. Cunningham AC, Goh HP , Koh D. 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Int J Surg. 2020.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}