Abstract
Background
The coronavirus disease 2019 (COVID-19) pandemic has become a major challenge to healthcare systems and public health policies globally. Older adults and those with underlying diseases such as hypertension and diabetes are more susceptible to coronavirus. The impact of opium use as a risk factor for COVID-19 is yet uncertain. This study investigates the effect of opium consumption on the severity of COVID-19, and its adverse consequences in opium users compared to the general population.
Methods
This cross-sectional study included 2945 COVID-19 patients that had been referred to health care centers affiliated to Rafsanjan University of Medical Sciences between February and December 2020. Opium use was defined as self-reported consumption at least once per week. COVID-19 severity was assessed based on routinely collected clinical and radiological indicators, including respiratory symptoms, oxygen saturation, and imaging findings, rather than a standardized severity scale. The personal, and clinical data including clinical presentation, the severity of symptoms, and outcome were collected. Then, the COVID-19 severity, and outcome between opium users and opium non-users were compared using Logistic regression models.
Results
The rate of opium users was 5.13%. Among opium users, 87.42% recovered from COVID-19, compared with 86.07% of non-users (p = 0.641). Opium use was associated with lower odds of moderate-to-severe COVID-19 in the crude model (OR = 0.48; 95% CI: 0.34–0.66), and this association remained significant after adjustment for confounders. Opium consumption was not significantly associated with COVID-19 mortality in either crude or adjusted models.
Conclusion
Opium use was associated with lower COVID-19 severity but not with mortality. These findings represent associations and should be interpreted with caution given the observational design and it is suggested more laboratory and clinical trial studies using pharmaceutical morphine products, the main component of opium.
Clinical trial
Not applicable.
Keywords: COVID-19, Opium, Severity, Outcome
Background
The COVID-19 pandemic has become a major challenge to healthcare systems and public health policies globally since it requires new treatment and prevention strategies to decrease its mortality [1]. Respiratory droplets and physical contact are transmission factors of COVID-19 and the latency period of the virus is 4–7 days [2]. Viral properties and immune system condition participate in the duration and severity of the disease, patient state, and reinfection [3]. People with underlying diseases, such as diabetes, asthma and heart disease, and the elderly are more susceptible to coronavirus with more severe symptoms [4]. Some studies have shown that increased IL6 concentration in blood and hyper inflammation might be the reason for fatality in COVID-19 patients. Therefore, immunotherapy with several immunomodulating agents, such as convalescent plasma, immunoglobulins, glucocorticoids, recombinant human IL-6 receptor monoclonal antibody (Tocilizumab), JAK inhibitors (Jakotinib, Ruxolitinib), and chloroquine/ hydroxychloroquine is being experimented. Also, opioid agents (morphine or fentanyl) are used for relieving discomfort, and treating pain [5].
The impact of opium use as a risk factor for COVID-19 is yet uncertain [6], but, one of the most important problems of modern human societies is opioid addiction [7]. Opium contains various alkaloids, such as morphine and codeine, that causing pain palliation and cough elimination to euphoria, sleepiness, and addiction [8]. Morphine as a traditional pain controller, analgesic drug, and a natural opioid can mediate their effects via three receptors termed of δ, µ, and κ [9, 10]. These receptors are found in the perception of pain, dyspnea, as well as in the digestive system, inhibiting bowel movement and having immunomodulatory effects on the surface of immune cells. Opioid receptors present in the CNS and the cardio-respiratory systems are responsible for developing the mechanisms of their anti-dyspneic effects [11]. Although angiotensin-converting enzyme 2 (ACE2(, as the main receptor for COVID-19, is overexpressed in opium users [12, 13] morphine and codeine extensively compete with the virus for binding to the receptor [14, 15]. According to the National Health Service (NHS) in England, breathlessness in severe COVID-19 patients can be decreased in their last days and hours of life with morphine sulfate administration [16]. Indeed, in COVID-19 patients, morphine could be a prime therapy to reduce pain, breath shortness, and coughing [17]. Based on experimental investigations, morphine treatment mitigates hyper-inflammatory status and suppresses some inflammatory cytokines such as IL-6, interferon (IFNs(, and tumor necrosis factor-alpha (TNF-a), significantly [14]. On the other hand, researchers claim that a history of opium abuse does not significantly raise the mortality risk of COVID-19. however, the opium abusers confront many complications [2].
Despite therapeutic effects, evidences indicate that opioid consumption is also associated with adverse outcomes in respiratory and infectious diseases. Opioid use has been linked to immune suppression, and increased susceptibility to respiratory infections [18–20]. Several studies have shown that individuals with a history of opium use are more susceptible to COVID-19 and may experience higher rates of mortality compared with the general population [21–23].
Elevated levels of Interleukin-6 (IL-6) followed by a cytokine storm in such patients is expressed as the etiology of mortality [24]. It is anticipated that opioid consumption suppresses the immune system and increases the probability of end-organ damage phase of COVID-19, leading to endothelium injury of lung alveolar and bacterial pneumonia [3]. Furthermore, studies demonstrated that individuals with opioid use disorder or active opioid consumption experience higher rates of hospitalization, intensive care unit admission, need for ventilatory support, and adverse clinical outcomes following SARS-CoV-2 infection. Overall, the existing literatures on opioid use and COVID-19 outcomes remains inconsistent and sometimes contradictory. Thus, more investigation about the correlation between opium and COVID-19 is necessary to determine an exact risk of incidence, severity, and outcome of COVID-19 among abusers. This accurate observational study is conducted to investigate the COVID-19 severity and adverse consequences in the abusers compared to the general population.
Methods
This cross-sectional study included 2945 COVID-19 patients (tested positive (through real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR)) and negative coronavirus with corona symptoms) referred to health care centers affiliated to Rafsanjan University of Medical Sciences, in the southeast of Iran, from February 11 to December 15, 2020. Patients comprised both real-time reverse-transcriptase polymerase chain reaction (RT-PCR) verified positive cases and individuals who tested negative yet had characteristic COVID-19 symptoms. Symptomatic PCR-negative patients were clinically identified by physicians based on symptoms such as fever, cough, dyspnea, oxygen saturation, and distinctive imaging abnormalities on chest X-ray or CT scan. This methodology sought to identify potential COVID-19 cases while reducing misclassification and ensuring that cases with false-negative test results were not missed.
The personal data including sex, age, history of cigarette smoking or opium use, and underlying diseases (e.g., respiratory diseases, cancer, hypertension, cardiovascular disease, liver and renal diseases, hyperlipidemia, and diabetes) and clinical data of patients including clinical presentation, the severity of symptoms, and outcome were collected from medical records. In this study, an opium user is defined as a participant who reports using opium at least once per week [25]. Participants were divided into two groups of opium users (OUs = 151 subjects) and opium non-users (ONUs = 2794 subjects).). Then, the COVID-19 severity, and outcome between the groups were compared. The severity of the disease was measured using the severity of symptoms such as body temperature, and cough, dyspnea, respiratory rate, O2 saturation, chest X-ray and CT scan [26].
Some potentially important confounding variables, including COVID-19 vaccination status, socioeconomic status, alcohol consumption, and BMI, were not collected. The absence of these data may limit the interpretation.
This study is observational and has been approved by the ethics committee of Rafsanjan University of Medical Sciences (Ethical codes: IR.RUMS.REC.1399.195). The study’s objectives and procedures were fully explained to all participants, either verbally or in writing, depending on their literacy level. Informed consent was then obtained from each participant before their data was included in the study.
Statistical analysis
Frequency (%) for categorical variables and mean (SD: standard deviation) for the quantitative variables were used. To analyze categorical variables including gender, cigarette smoking, underlying disease and symptoms across opium use categories the chi-square test or fisher test was used. To conduct the Chi-Square test effectively, it is essential to satisfy key criteria: all cells must have expected values of zero or more, and less than 20% of cells should have expected counts under five. t-test was used to compare continuous variables (age) among the groups. The normality of the data distribution was evaluated through skewness and kurtosis indices, alongside histogram analysis. A distribution was deemed approximately normal if the skewness values ranged between − 1 and + 1, and the kurtosis indices fell within − 1.96 to + 1.96. Furthermore, Levene’s test was conducted to examine the assumption of variance homogeneity. In addition, patients were stratified into two groups based on disease severity: mild and moderate-severe and we used dichotomous logistics regression models’ analysis to estimate odds ratios (ORs) with 95% confidence intervals (CIs) to investigate the relationships between opium use and the severity, and outcome of COVID-19. All models were assessed for multicollinearity. All logistic regression models were checked for key assumptions. Multicollinearity was assessed using the Variance Inflation Factor (VIF), calculated from linear regression models of each independent variable against the others. Maximum VIF values were 2.8 (well below the conservative threshold of 5–10), indicating no problematic multicollinearity. Linearity of the continuous predictor (age) with the logit of the outcome was visually inspected using scatter plots of the predictor against the logit-transformed outcome, and no substantial non-linearity was observed. Influential observations were examined using standardized residuals and Cook’s distance; no observations exceeded common thresholds for influence (Cook’s distance < 1). Model goodness-of-fit was evaluated using the Hosmer-Lemeshow test, with p-values > 0.05 indicating adequate fit.
Adjusted model 1 included socio-demographic characteristics (age and gender) considered to be the most strongly related to both opium use and COVID-19. Adjusted model 2 adjusted for underlying disease and smoking to additionally confound opium use – COVID-19 associations. All Statistical analyses were performed using Stata version 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.), All p-values are two-sided, and p-values < 0.05 and 95% confidence intervals were considered as statistically significant.
Results
Data from 2,945 patients were included in the analysis. from 2945 participants, 1,436 (48.76%) were male and 1,509 (51.24%) were female.
The demographic and clinical characteristics of participants are shown in Table 1. The mean age of the patients was 58.85 ± 20.60 years old. 1,357 patients were aged ≤ 57 years, and 1,588 were aged ≥ 58 that 66 (16.18%) and 342 (83.82%) of them died, respectively (p < 0.001). In addition, 8.69% (n = 256), 58.23% (n = 1715) and 33.07% (n = 974) of patients had severe, moderate and slight form of the disease, respectively. The rate of opium users was 5.13% corresponding to 151 patients that 87.42% of them recovered while this percentage for non-users was 86.07% (p ꞊ 0.641). The amount of underlying disease in all of the participants was 1326 (45.03%) that 19.32% of them died (p < 0.001). The more frequent of this disease were diabetes, hypertension, and cardiovascular disease. Prevalence of COVID-19 with mild symptoms was more common among men and with moderate symptoms was more in women (p < 0.001) but the patients with severe symptoms did not differ according to gender. Also, the severity of the disease was higher in participants with underlying disease (p < 0.001).
Table 1.
The demographic and clinical characteristics of participants (n = 2,945)
| Characteristics | All (n = 2,945) | Slight (n = 974) |
Moderate (n = 1,715) | Severe (n = 256) | P-Value |
|---|---|---|---|---|---|
| Age ‑ yr. Mean ± SD | 57 ± 20 | 974 | 1715 | 256 | |
| Age‑ no. (%) | |||||
| ≤ 57 | 1357 (47.57) | 422 (43.33) | 878 (51.20) | 57 (22.27) | < 0.001 |
| ≥ 58 | 1588 (52.43) | 552 (56.67) | 837 (48.80) | 199 (77.73) | |
| Gender‑ no. (%) | |||||
| Female | 1436 (48.76) | 452 (46.41) | 929 (54.17) | 128 (50.00) | 0.001 |
| Male | 1509(51.24) | 522 (53.59) | 786 (45.83) | 128 (50.00) | |
| Cigarette smoking‑no. (%) | |||||
| Yes | 40 (1.36) | 22 (2.26) | 13 (0.76) | 5 (1.95) | 0.004 |
| No | 2905 (98.64) | 952 (97.74) | 1702 (99.24) | 251 (98.05) | |
| Opium use-no. (%) | |||||
| Yes | 151 (5.13) | 52 (49.67) | 52 (3.03) | 24 (9.38) | < 0.001 |
| No | 899 (92.3) | 1663 (33.65) | 1678 (96.97) | 232 (90.63) | |
| Underlying disease-no. (%) | |||||
| Yes | 1326 (45.03) | 449 (46.10) | 694 (40.47) | 183 (71.48) | < 0.001 |
| No | 1619 (54.97) | 525 (53.90) | 1021 (59.53) | 73 (28.52) | |
| Symptoms-no. (%) | |||||
| Fever | |||||
| Yes | 1061 (36.03) | 330 (33.88) | 645 (37.61) | 86 (33.59) | |
| No | 1884 (63.97) | 644 (66.12) | 1,070 (62.39) | 170 (66.41) | = 0.1 |
| Cough | |||||
| Yes | 776 (26.35) | 182 (18.69) | 520 (30.32) | 74 (28.91) | |
| No | 2169 (73.65) | 792 (81.31) | 1195 (69.68) | 182 (71.09) | < 0.001 |
| Muscular pain | |||||
| Yes | 1133 (38.47) | 328 (33.68) | 734 (42.80) | 71 (27.73) | |
| No | 1812 (61.53) | 646 (66.32) | 981 (57.20) | 185 (72.27) | < 0.001 |
| Respiratory distress | |||||
| Yes | 1603 (54.43) | 440 (45.17) | 978 (57.03) | 185 (72.27) | |
| No | 1342 (45.57) | 534 (54.83) | 737 (42.97) | 71 (27.73) | < 0.001 |
| Decreased sense smell | |||||
| Yes | 11 (0.37) | 1 (0.1) | 7 (0.41) | 3 (1.27) | |
| No | 2934 (99.63) | 973 (99.90) | 1708 (99.59) | 253 (98.83) | 0.04 |
| Decreased sense taste | |||||
| Yes | 3 (0.1) | 0 (0.00) | 3 (0.17) | 0 (0.00) | |
| No | 2942 (99.90) | 974 (100) | 1712 (99.83) | 256 (100) | 0.34 |
| Nausea | |||||
| Yes | 133 (4.52) | 41 (4.21) | 70 (4.08) | 22 (8.59) | |
| No | 2812 (95.48) | 933 (95.79) | 1645 (95.92) | 234 (91.41) | 0.004 |
| Vomiting | |||||
| Yes | 125 (4.24) | 43 (4.41) | 61 (3.56) | 21 (8.20) | |
| No | 2820 (95.76) | 931 (95.59) | 1654 (96.44) | 235 (91.80) | 0.003 |
| Diarrhea | |||||
| Yes | 83 (2,82) | 27 (2.77) | 42 (2.45) | 14 (5.47) | |
| No | 2862 (97.18) | 947 (97.23) | 1673 (97.55) | 242 (94.53) | 0.02 |
| Headache | |||||
| Yes | 184 (6.25) | 46 (4.72) | 116 (6.76) | 22 (8.59) | |
| No | 2761 (93.75) | 928 (95.28) | 1599 (93.24) | 234 (91.41) | 0.02 |
Table 2 presents the association of opium use with severity, and outcome of COVID-19, using the crude and two adjusted models. In the crude regression model, the odds of the death due to COVID-19 is 0.88 (odds ratio (OR): 0.88, 95%CI 0.54 to 1.45). The odds of the severity of COVID-19 is almost half among opium users compared with non-users (odds ratio (OR): 0.48, 95%CI 0.34 to 0.66). Hence, opium consumption decreased effect on the severity of COVID-19. This association persisted after adjustment for confounders (adjusted models 1 and 2). The corresponding adjusted ORs calculated for opium users in comparison to non-users are 0.52 (95% CI 0.37 to 0.72) and 0.54 (95% CI 0.39 to 0.76) respectively for adjusted model 1 and 2. However, this finding should be interpreted with caution, as severity was assessed based on clinical parameters rather than a standardized scale, and opium use was self-reported.
Table 2.
Association of opium consumption with severity and outcome of COVID-19 diseases (n = 2945*)
| Severity of COVID-19 (mild versus moderate-severe) | Crude model OR (95%Ci) a |
Adjusted model 1 OR (95%Ci) b |
Adjusted model 2 OR (95%Ci) c |
|---|---|---|---|
| Opium use: Yes | 0. 48 (0. 34-0.66) | 0.52 (0.37–0.72) | 0.54 (0.39–0.76) |
| Opium use: No | 1 | 1 | 1 |
| Outcome of COVID-19 (Recover or death) | |||
| Opium use: Yes | 0.88 (0.54–1.45) | 0.74 (0.44–1.23) | 0.66 (0.39–1.10) |
| Opium use: No | 1 | 1 | 1 |
aThe baseline model is stratified on the status of opium consumption
bThe adjusted model 1 is adjusted for confounding variables age (continuous variable), gender (male/ female)
CThe adjusted model 2 has additional adjustment for confounding the variables underlying disease and smoking (yes/no)
Also, we observed that opium consumption has no significant effect on mortality (p ꞊ 0.641). The corresponding adjusted ORs calculated for opium users in comparison to non-users is available in Table 2. It should be noted that the 95% confidence intervals for these estimates are wide and include 1, indicating statistical insignificance and suggesting that these results should be interpreted with caution.
Discussion
This study aims to investigate the effect of opium consumption on the severity, and outcome of COVID-19. The results show that the rate of opium users is lower in symptomatic COVID- 19 patients than in the general population. According to a recent cohort study, 23.81% of the Rafsanjanian adults population (46.19% of men and 4.27% of women) use opium at least once per week for 6 months further, opium consumption has a low social stigma in this population [25]. In the present research, the rate of opium user’ patients is 5.13%. According to these two studies, although opium users compose approximately a quarter the population, they included just about one twentieth of symptomatic COVID-19 patients, thus it could be concluded that opium users may have a lower probability of developing symptomatic COVID- 19 infection than the general population. However, this observation should be interpreted with caution, as it is based on the proportion of opium users in the study sample rather than population-based denominator data. Additionally, it is possible that some participants have not completely reported their status of opium consumption. The sensibility of reporting in participants of both groups may have been different and has not been declared something. Therefore, we cannot conclude that opium consumption reduces the probability of developing symptomatic COVID-19.
The main finding of the current study is that the severity of COVID-19 is lower in opium users than in the general population however, there is no significant difference in mortality. Some studies have shown that opium consumption causes increased severity and mortality in COVID-19 patients. Various reasons have been reported for this claim, including changes in the immune system, changes in the amount of TNF-α, IL-1, and IL-6, and an increase in ACE2 expression in the opium users [2, 3, 27, 28]. The presents research results are contrary to those of these studies, possibly due to the difference in opioid type, dosage, method of opium intake and purity, population characteristics, unaccounted confounders, study design and methodology and culture and behavioral factors Consequently, these findings necessitate cautious interpretation, and further research is essential to address these discrepancies.
On the other hand, researchers have shown more than 70 different types of alkaloids and compounds in opium some of which may have anti-inflammatory and antioxidant properties. One of the main compounds is morphine, which could exhibit anti-inflammatory effect even in low doses. Morphine as a traditional pain controller, analgesic drug, and a natural opioid can mediate their effects via three receptors of δ, µ, and κ [9, 10]. These receptors are found in the perception of pain, dyspnea, and have immunomodulatory effects on the surface of immune cells [11]. The lower severity of COVID-19 observed in opium users can be due to these morphine features, especially its anti-inflammatory effects.
These effects might contribute to modulation of the inflammatory response and could hypothetically influence symptom severity. Some studies are in line results with the present research. Khoshab et al. have stated that opium consumption could have prophylactic effects on COVID-19 [29]. Cismaru et al. have also declared that opioids can potentially be used in the treatment of COVID-19 through their effects on both the viral infectious cycle and the host response to the infection [11]. Opioids are the best pharmacological agents in the palliation of dyspnea recommended by European and US therapeutic guidelines [11]. Furthermore, according to the National Health Service (NHS) in England, breathlessness in severe COVID-19 patients can be decreased in their last days and hours of life with morphine sulfate administration [16]. In COVID-19 patients, morphine can be used as a prime therapy for diminution of pain, breath shortness, and coughing [17]. The effect of opioids on the outcome of the viral infection depends on the type of virus. Activation of opioid receptors is useful for the controlling immunopathology in viral infection with an immunopathogenic response (such as COVID-19) [30]. “Previous studies have suggested that opioids may have potential utility in the management of COVID-19, with three possible effects: inhibiting the cytokine storm, improving dyspnea, and disrupting lysosomal acidification. However, these mechanisms require further investigation [11, 31]. Increasing the levels of inflammatory cytokines and chemokines increase bronchoalveolar infection. Chronic morphine treatment can reduce IL-1 and IL-6 production [3] and lead to immunosuppression, potentially increasing susceptibility to opportunistic infections and altering the course of viral illnesses [32–34]. Thus, immunosuppression by using opium might have a potential role in the treatment of COVID-19 patients [14]. This immunosuppressive effect could counteract any potential acute anti-inflammatory benefits. In the present study the observed association between opium use and decreased COVID-19 severity should be interpreted cautiously and does not support the use of opium as a preventative or treatment strategy. This study does not directly investigate physiological mechanisms, and these explanations should be considered as hypotheses rather than confirmed conclusions. The complex interplay of these factors warrants further investigation in future studies.
ACE2 has been shown to be a receptor for COVID-19 to enter host cells [35, 36], and the use of inhibitors of the ACE2 receptor has been proposed prevent the disease. Although is ACE2 overexpressed in opium users morphine and codeine extensively compete with the virus for binding to the receptor [6, 14]. The anti-inflammatory, anti-fibrotic, antitumor, cardioprotective, and reno -protective effects of morphine have been demonstrated in in-vitro and in-vivo animal experiments. These effects could nullify the inordinate inflammation, fibrosis, as well as cardiac and renal charges associated with COVID-19 [11]. The present research results could confirm these findings since the severity of COVID-19 has been lower in opium users. In patients with systemic infection, an increased amount of endogenous opioids could have a protective function and reduces inflammatory processes [37]. Analgesia based on opioids is one of the most effective and cheap treatments for the palliation of severe pain [8]. Opioids may be used for the treatment of pain and palliation of suffocation sense in COVID-19 patients [38].
However, due to the high potential for addiction to opioids, adequate attention should be paid with them. In critical situations such as ARDS due to COVID-19, the advantages of using opioids could dominate their undesirable side-effects [11]. Hudzik et al. have concluded that morphine in the primary stages of COVID-19 could have a useful effect by inhibiting the cytokine storm however, in late stages it could be damaging (such as making septic shock) [5]. Our findings need careful consideration in light of the possible increased risk of the long-term harmful consequences of morphine consumption. Our findings suggest a diminished severity of COVID-19 in opium users; however, inconsistencies with previous studies, potential biases, and unconsidered confounders require cautious interpretation and further research.
One of the most important limitations of this study is the absence of key data, including socioeconomic status, route and duration of opium use, alcohol consumption, body mass index (BMI), physical activity, mental health, healthcare access, and COVID-19 vaccination status, along with potential selection bias and the lack of dose-response analysis—which may relate to disease severity—precluding definitive conclusions about opium’s effects on COVID-19. Additionally, the cross-sectional design prevented causal inferences regarding the potential role of opium and its derivatives in reducing COVID-19 severity, and we lacked information on specific opium types, duration, amount, and route of use (oral/inhaled). Although the study adjusted for several confounders and proposed a hypothesis that opium may mitigate COVID-19 severity, these limitations necessitate cautious interpretation; thus, future prospective studies, laboratory investigations, and clinical trials using pharmaceutical morphine products (opium’s main component) are essential to clarify this relationship.
Conclusion
The present research results suggest that opium consumption may reduce the severity of COVID-19. The physio-pathological reason underlying this effect may involve morphine and its features such as anti-inflammatory, and immunomodulatory pain, reduction breath shortness palliation, and cough elimination. While morphine’s pharmacological properties may offer a theoretical basis for further investigation, the current study did not evaluate morphine as a clinical intervention. Therefore, no therapeutic conclusions should be drawn. Any potential benefits must be interpreted with caution and require validation through rigorous clinical research. Future studies should explore the effects of opium and morphine in population-based and clinical trials to clarify their safety and efficacy in COVID-19 management.
Acknowledgements
We thank the people who participated in the study and health care center personnel in Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Author contributions
FA, HO and HE analyzed and interpreted the data and contributor in writing the manuscript. FA, NP, HM and SK performed the data collection, methodology and contributor in writing the manuscript. All authors read and approved the final manuscript.
Funding
This study has also been supported by the Vice Chancellery for Research & Technology of Rafsanjan University of Medical Sciences. The context of this article is the views of the authors and the funder had no role in the design of the study and collection, analysis, and interpretation of data, the decision to publish, and writing the manuscript.
Data availability
All data that support the conclusions of this manuscript are included within the article.
Declarations
Ethics approval and consent to participate
This study has been approved by the ethics committee of Rafsanjan University of Medical Sciences with Ethical codes of IR.RUMS.REC.1399.195 in accordance with the Declaration of Helsinki. Also, the informed consent to participate was obtained from all of the participants in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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