Emotion Dysregulation (ED), childhood trauma and personality are linked to the occurrence of maladaptive behaviours in adolescence which, in turn, may be related to increased risk for psychopathology in the life course. We sought to explore the relationship among the occurrence of different clusters of maladaptive behaviours and ED, clinical features  and personality traits that have been found to be associated to Borderline Personality Disorder (BPD), in a sample of 179 adolescent students.Multiple Correspondence Analysis (MCA) was applied to detect clustered types of maladaptive behaviours and groups of students were defined as individuals engaging in these clustered behaviours . Logistic models were used to evaluate the association among clinical scales, and student groups. Mediation analysis was used to evaluate whether clinical features affected the association between personality traits and student groups.MCA analysis allowed to identify three student groups: NSSI/binge eating (NSSI-BE) behaviours, other maladaptive behaviours and “none”. Higher scores in ED, impulsivity, childhood maltreatment, anxiety and depressive symptoms increased the risk of belonging to the cluster of NSSI-BE behaviours compared to the other two groups. ED, depression and anxiety symptoms were found to be mediators of the relationship between specific personality traits, mainly pertaining to the negative affectivity construct, and NSSI/BE.Individuals engaging in NSSI-BE behaviours represent a vulnerable adolescent population. ED, depression and anxiety were mediators of the relationship between a variety of personality traits related to BPD and NSSI and binge eating behaviours. Findings have important clinical implications in terms of prevention and interventions among adolescents engaging in self-damaging behaviours.The online version contains supplementary material available at 10.1186/s40479-021-00154-w. Adolescence represents a sensitive and vulnerable period for the development of internalising and externalising symptoms  and of aAccording to the biosocial model, temperamental vulnerability to ED becomes a core feature of externalizing problems and internalizing problems and places adolescents and young individuals at risk for more serious forms of psychopathology . PersonaThe present study aimed to clarify the association among maladaptive behaviours, clinical dimensions and personality traits. Firstly, we sought to describe the presence of maladaptive behaviours  in a sample of Italian community-dwelling students and to define different groups of adolescents, based on their engaging in types of maladaptive behaviours. Considering that it is well-established that NSSI and eating disordered behaviours frequently co-occur  we expec. The study was approved by the Local Ethical Committee (n 113/2017).This is a cross-sectional observational study on ED and maladaptive behaviours among adolescent students that was conducted in 2018 at the IRCCS Centro San Giovanni di Dio Fatebenefratelli in Brescia Four high schools were invited to participate based on a well-established relationship developed during previous collaborations between the Center and the schools. The principal of each school selected the classes on the basis of organization set-up and was not influenced by the study investigators in any way. Inclusion criteria were: 1. attending one of the last two grades  of upper secondary school, 2. being able to understand Italian language, 3. ability to give an informed consent. Exclusion criteria: mild or severe cognitive impairment. The students of the 4th and 5th year of upper secondary school who agreed to participate in the study signed an informed consent . The convenience sample included 9 classes (5 classes of the 4th year and 3 classes of the 5th year) from 4 schools located in Brescia. The participating schools were 4 State upper secondary schools (2 human sciences lyceums (6 classes); 1 sciences lyceum (1 class) and a publicly subsidized upper secondary school . Questionnaires were administered anonymously during class time by two researchers and students had approximately 60 min to complete them. After the assessment completion all classes received a two-session psycho-educational intervention focused on ED and impulsive behaviours in adolescence. The psycho-educational sessions (2 h each) were conducted by two clinical psychologists in usual classroom settings and during school hours.Difficulties in Emotion Regulation Scale (DERS) . The DERPersonality Inventory for DSM-5 (PID-5) . The PIDBarratt Impulsiveness Scale-11 (BIS-11) . The BISPatient Health Questionnaire (PHQ-9) . The PHQScreen for Child Anxiety Related Emotional Disorders (SCARE) . The SCAChildhood Trauma Questionnaire Short Form (CTQ SF) . The CTQEmotion Regulation Questionnaire (ERQ) . The ERQFurthermore, we also collected socio-demographics variables and a checklist including yes/no questions exploring lifetime history of a variety of maladaptive behaviours  or being victims of bullying.Participants underwent a comprehensive assessment including the following measures:Absolute frequencies and the description of the presence of multiple behaviours across students were represented by using a Venn diagram. Subsequently, Multiple Correspondence Analysis (MCA)  was perfComparison of categorical variables was performed by using the Chi-Square test. Clinical scales and personality traits were compared across groups by using ANOVA or Kruskal-Wallis tests. Post-hoc comparisons were adjusted by using Bonferroni correction.ρ.The association between the groups of students (defined by MCA technique described above) and the clinical scales and personality traits was evaluated through the use of univariate logistic models with group as dependent variable and clinical scales and personality traits as independent ones. Odds Ratios (ORs) were used to evaluate the strength of the association. Correlations between the clinical scales and the traits were evaluated by using the Spearman coefficient Finally, any potential mediator effect of clinical scale on the group-trait relations was evaluated following the Baron and Kenny’s procedure  performed by the Structural Equation Model -SEM- approach in order to model the variance-covariance structure of the variables involved in the mediation models. To summarize all the SEM finding and for improving the readability of any mediation effect, the outputs of the mediation models were reported in terms of associations between personality traits and the student groups evaluated also in a multiple logistic model setting, by adjusting for the clinical scales.p < .05. The descriptive analyses were performed using IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp. The multivariate MCA technique, the correlations and logistic models were carried out by software R .All tests were two-tailed, and the probability of a type I error was set at The overall sample was composed of a total of 179 students . Out of the 179 participants, 46 (25.7%) reported lifetime NSSI engagement, 68 (38.0%) binge eating episodes, 107 (59.8%) binge drinking behaviours, 56 (31.3%) practiced unsafe sex and 39 (21.8%) reported intake of cannabis. The frequency as well as the presence of multiple maladaptive behaviours in the student sample is represented in Fig. n = 29, 16.0%), hereafter NONE group; ii) a second group of students who engaged in at least one behaviour between NSSI or binge-eating, independently of the other maladaptive behaviours , hereafter NSSI-BE group; and iii) a third group including the remaining students , hereafter OTHER group.MCA data-driven technique was performed to detect which behaviours were associated each other and clustered, as the majority of the students presented more than one maladaptive behaviour. The MCA results are shown through the Biplot representation Fig. . A firstp = .146) and age (p = .433) thus no further adjustment for these variables was performed in the subsequent analyses. The NSSI-BE group exhibited higher mean scores in all the clinical scales and in all the BPD-related traits  and in the model with hostility . The AIC values markedly decreased when these variables were individually added , showing that the goodness of fit improved when each of DERS or PHQ-9 scale were added to the multiple model together with trait. In other words, DERS and PHQ-9 scales affected the relation group-trait making it no longer significant. Then, considering the significant association of these scales with the group variable (Table All the traits were significantly associated with the group variable (first column of Table This study sought to explore the associations between ED, impulsivity, trauma experiences, depression, anxiety symptoms, personality traits and the occurrence of maladaptive behaviours.Consistent with other findings among European adolescents , 39, 40,Our findings confirmed that personality traits described as key BPD features are able to differentiate adolescents with NSSI-BE behaviours from their adolescent counterpart in the NO-NSSI-BE group, except for risk taking and suspiciousness. Separation anxiety, emotional lability, hostility and anxiousness are facets that are all included in the affective negative domain in the DSM-5 AMPD model; while impulsivity and distractibility are akin to the disinhibition domain . In the Lastly, we have explored the relationship between self-reported personality traits and the NSSI-BE cluster after controlling for the effect of the clinical variables. In our study, ED, depression severity and, to a lesser extent, anxiety symptoms mediated the relationship with a variety of traits, mainly pertaining to the negative affectivity construct. Notably, some researchers proposed that deficits in ED increase the use of NSSI as an escape strategy in the presence of internalizing symptoms and internal emotional states perceived as aversive . AnotherSome limitations of the current study should be acknowledged. First, the cross-sectional design of our study does not allow to test any causal relationships. Secondly, as our sample was predominantly female, same conclusions for male adolescents cannot be drawn. Recruitment was not heterogeneous for type of schools and our undergraduate student sample may exhibit better overall functioning than other community or clinical samples, hence findings may not generalize to other populations of adolescents. Thirdly, although our findings were largely consistent with previous studies, our study was exclusively focused on BPD-related traits. Further studies should explore other putative personality predictors of maladaptive behaviours in adolescence. Fourth, we assessed NSSI presence, but we did not use a scale to assess types and severity of NSSI. Finally, retrospective or longitudinal studies need to assess whether the traits observed in this study are factors of vulnerability for later BPD or if indeed they may be a generic risk factor for a variety of mental disorders associated to NSSI-BE behaviours.Our findings highlight the potential importance of focusing on depressive and anxiety symptoms and ED in school-based interventions aimed at preventing NSSI and BE behaviours. Recently, interventions focused on ED, such as acceptance-based emotion regulation group therapy and dialectical behaviour therapy , 56 adapAdditional file 1: Figure S1 Correlation matrix of the clinical scales and personality traits in the overall sampleAdditional file 2:.


Accurate seroprevalence estimates of SARS-CoV-2 in different populations could clarify the extent to which current testing strategies are identifying all active infection, and hence the true magnitude and spread of the infection. Our primary objective was to identify valid seroprevalence studies of SARS-CoV-2 infection and compare their estimates with the reported, and imputed, COVID-19 case rates within the same population at the same time point.We searched PubMed, Embase, the Cochrane COVID-19 trials, and Europe-PMC for published studies and pre-prints that reported anti-SARS-CoV-2 IgG, IgM and/or IgA antibodies for serosurveys of the general community from 1 Jan to 12 Aug 2020.Of the 2199 studies identified, 170 were assessed for full text and 17 studies representing 15 regions and 118,297 subjects were includable. The seroprevalence proportions in 8 studies ranged between 1%-10%, with 5 studies under 1%, and 4 over 10%—from the notably hard-hit regions of Gangelt, Germany; Northwest Iran; Buenos Aires, Argentina; and Stockholm, Sweden. For seropositive cases who were not previously identified as COVID-19 cases, the majority had prior COVID-like symptoms. The estimated seroprevalences ranged from 0.56–717 times greater than the number of reported cumulative cases–half of the studies reported greater than 10 times more SARS-CoV-2 infections than the cumulative number of cases.The findings show SARS-CoV-2 seroprevalence is well below “herd immunity” in all countries studied. The estimated number of infections, however, were much greater than the number of reported cases and deaths in almost all locations. The majority of seropositive people reported prior COVID-like symptoms, suggesting that undertesting of symptomatic people may be causing a substantial under-ascertainment of SARS-CoV-2 infections. Globally, over one hundred and twenty million coronavirus disease COVID-19) cases have been reported to World Health Organization as of 15 March 2021 [9 cases hValid seroprevalence estimates for a population rely on two major factors: (i) a representative population sample and (ii) accurate antibody testing. For example, testing should not be biased by including predominantly symptomatic people or those exposed to a person with COVID-19 . InapproSystematic Reviews of the diagnostic accuracy SARS-CoV-2 antibodies have found concerns about bias and applicability in the available studies. The sensitivity of most antibody-tests, which measure immunoglobulin (Ig) M, IgG, and occasionally IgA antibodies against SARS-CoV-2, appears to be low in the first week after onset of symptoms and increases up to maximum value in the third week; data beyond three weeks are scarce –7. SpeciWe aimed to identify all studies that reported seroprevalence estimates for SARS-CoV-2 infection using a representative sample of the target population, and to compare to these seroprevalence estimate with the cumulative incidence of confirmed COVID-19 cases, and imputed case rates from the death rates, to establish the likely true extent of the infection among a population.We conducted a systematic review using enhanced processes with initial report completed within two weeks, using daily short team meetings to review the progress, plan next actions, and solve discrepancies and other obstacles . We alsoWe included seroprevalence studies which attempted complete or random sample of the population with more than 25% response rate to assess overall seroprevalence in general community. We included seroprevalence testing that tested for anti-SARS-CoV-2 IgG, IgM, and IgA antibodies in combination or separately.We excluded studies with high risk of bias in sampling, i.e. the study sample was likely not representative of the target population such as health care workers, blood donors, or dialysis patients; government reports without sufficient details to evaluate risk of bias; modelling or simulation studies even if they used real data ; lack of information about the antibody test(s) used to determine seroprevalence; and editorial or historical accounts without sufficient data to calculate the primary outcome . A list of excluded studies can be found in Our primary outcomes were (1) the comparison of the seroprevalence based on antibody testing in the study sample with the cumulative reported case incidence of people tested positive for SARS-CoV-2 by RT-PCR in the same sample or in the target population cross-checked by a cumulative incidence estimated from the cumulative COVID-19-specific mortality two weeks after the seroprevalence and assuming a case-fatality rate of 1% ; and (2)Two authors (OB and CCD) independently screened titles, abstracts, and full texts according to inclusion criteria. All discrepancies were resolved via group discussion with the other authors. Reasons for exclusion were documented for all full text articles deemed ineligible —see PRISFive authors  extracted the following information from each study and from related external sources:Participants: sampling frame, sample size, age, sex, setting, previous exposure or testing for COVID-19Methods: study authors, country or region of the study, publication type, types of tests used, date of seroprevalence sampling .Outcomes: study seroprevalence , adjusted seroprevalence (point estimate for the population adjusted for study design and test accuracy), and cumulative COVID-19 cases in the study sample.Other information: when not provided in the study, we looked for publicly available data on the cumulative incidence of COVID-19 and COVID-19 specific mortality in the study population as close to the time of the study as possible.We used a combination of risk of bias tools for prevalence studies  and diagWe used absolute numbers and proportions for the primary outcome. As only studies deemed to be of sufficient quality after critical appraisal were included in the analysis, no sensitivity analysis of high versus low quality studies was undertaken. We did not pool the estimates due to heterogeneity of populations and study methods.We screened titles and abstracts of 2,199 articles and the full text of 170 articles for potential inclusion . The majFour studies provide national level data , 20, 24,The seroprevalences ranged considerably : eight sThe cumulative case incidence in the study population (based on RT-PCR testing) was reported in five studies , 22–24. The cumulative incidence rates at the regional levels (red squares and diamonds) ranged from 0.006% in Utsunomiya, Tokyo  to 9.22%The relationship between all the outcome estimates for each study/region on the log scale are shown in Typical COVID-like symptoms prior to serologic testing  could heThe seroprevalence rates in eight studies ranged between 1%-10%, with 5 studies under 1%, and 4 studies over 10%—notably hard-hit regions of Gangelt, Germany, Northwest Iran, the Barrio Mugica slum of Buenos Aires, Argentina, and Stockholm, Sweden. For all but two studies, the seroprevalence estimate was higher than the cumulative reported case incidence, by a factor between 1.5 to 717 times higher. However, the seroprevalence estimates were generally much closer to the cumulative incidence imputed from deaths. Finally, we noted that many of the seropositive cases had either typical or atypical symptoms.The difference between seroprevalence and cumulative reported incidence might be explained by three components: (i) asymptomatic cases (ii) atypical or pauci-symptomatic cases, or (iii) the lack of access to, and uptake, of testing in different regions and countries. The asymptomatic proportion found in studies of quarantine is around 17% , and so Strengths of this review lie in the thorough search for published and unpublished literature, strict inclusion criteria, and critical appraisal potential studies. However, there are several limitations. First, while we excluded several studies because of their volunteer and/or responder bias, several of the included studies still had significant degrees of non-response. Second, the accuracy of the serological tests used was often unclear. A particular concern was the specificity and possibility of false positive results in lower prevalence settings leading to potential overestimation of seroprevalence . For exaThere has been a couple of previous reviews of seroprevalence studies, but these focused on using the studies to infer the infection fatality rate , 34. We The results of this review have several implications for policy and practice. First, in all studies the estimated seroprevalences falls well short of that required for herd immunity suggesting that herd immunity is unlikely to be achieved without mass vaccinations. Herd immunity notion is often not based on robust data and policy makers need as much reliable data to make better decisions as possible. Additionally, infection fatality rates are shown to increase severalfold as the age of the people advance, further proving that herd immunity should not be pursued through the natural course of a pandemic . ReachinRoutine testing for an immune response to COVID-19 in recovered patients allows not only evaluation of the transmissibility of infection in general and specific populations, but would provide improved estimations of attack rates and infection fatality rates, estimates of possible immunity and evidence of reinfection –41. The Findings of this review should help inform policy globally, but also trigger improved research methods and better reporting of any future studies on seroprevalence. When there is a large gap between seroprevalence estimates and incidence rates, strategies to extend case finding and testing needs to be implemented. Evidence-based and targeted public health measures informed by accurate real-world data will help us successfully navigate the uncertain dynamics of this new pandemic.S1 Checklist(DOC)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


COVID-19 pandemic has resulted in significant strain on healthcare resources and this requires diligent resource re-allocation. We aim to describe the incidence and outcomes of in-hospital cardiac arrest (IHCA) during this period as compared to non-pandemic period.We conducted a retrospective study in a tertiary care hospital in Singapore. The study compared the incidence and outcomes of code blue activations over a 3-month period from March to May 2020 (COVID-19 period) with the same months in 2019 (pre-COVID-19 period). The primary outcome of the study was the rate of survival to hospital discharge for IHCA. The secondary outcomes included incidence of all code blue activation per 1000 hospital admissions, incidence of IHCA per 1000 hospital admissions.The rate of survival to hospital discharge for IHCA was 5.88% in the COVID-19 period as compared to 10.0% in the pre-COVID-19 period . Compared to pre-COVID-19 period, there were more IHCA incidences per 1000 hospital admissions in the COVID-19 period .The study observed a trend towards higher incidence of IHCA and lower rate of survival to hospital discharge during COVID-19 pandemic compared to pre-COVID-19 period. Whilst the recent study about IHCA done by Miles et al. also observed decreased survival rate of IHCA during the COVID-19 pandemic as compared to pre-COVID-19 pandemic, 79% of the IHCA patients in their study were COVID-19 positive, which was a major difference as compared to our study [COVID-19 has imposed a strong demand on the public healthcare system with the result of resource redistribution and reprioritisation to minimise COVID-19 transmission risk. Since late February 2020, as part of COVID-19 preparedness, the inpatient facilities in our institution were reorganised and adapted to ever changing circumstances. A number of rehabilitation wards in Jurong Community Hospital (JCH), a subacute hospital linked to NTFGH via a link bridge, were converted to acute care wards to admit acute non-COVID patients, a common resource reallocation strategy nationwide in pandemic , 13. WhiIt is expected the survival of in-hospital cardiac arrest (IHCA) during COVID-19 pandemic will be lower due to precautions taken before initiating resuscitations . Our stuWhilst it is imperative for code blue responders to take appropriate precautions during the COVID-19 pandemic, we should also make every effort to reduce the incidence and improve the outcome of IHCA. Our institutional experience has demonstrated that the code blue activation system with peri-arrest criteria might have a role in reducing IHCA incidence . In our The study has a few limitations. Firstly, due to the single-centre, retrospective and observational nature of the study, other confounders may have contributed to the trend of increased IHCA incidence and reduction in survival rate. Secondly, none of the results were statistically significant though there was a consistent trend of more IHCA and decreased survival rate of IHCA. This could be due to overall low incidence of IHCA in our institution and relative short study period.Our study observed a trend towards higher incidence and lower rate of survival to hospital discharge for IHCA during COVID-19 pandemic. This is likely indirectly related to healthcare resource constrain and precautions taken to reduce nosocomial transmission during pandemic, rather than directly related to COVID-19 disease given the relative low COVID-19 incidence and mortality in Singapore. This reminds us that in a pandemic situation, whilst mobilising and maximising available resources to reduce nosocomial transmission risk is undoubtfully important; it is equally important to implement strategies to ensure the quality of care for acutely ill non-COVID-19 patients.


O-glycans deficient in galactose  and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some  O-glycans than does circulating IgA1 in healthy persons  . Below,While effective in many cases, the current treatments for IgAN fail to address the key causation of the disease, formation of pathogenic immune complexes. In principle, methods to prevent or interfere with the process can be developed. From the perspective of the IgG autoantibodies, smaller versions of IgG that retain the capacity to bind Gd-IgA1, but are reduced to monovalent interactions, could be generated . ExampleOne pathway to a better understanding how these disease-causing immune complexes are formed may be the use of structural biology, an area of science that aims to define the molecular structure of proteins, protein complexes, and other biological elements to better understand the correlation between structure and function. Techniques for this pursuit include x-ray crystallography (XRC), electron microscopy (EM), small-angle x-ray scattering (SAXS), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS). These tools have been critical for defining the structures of antibodies  and theStreptococcus pneumoniae IgA1 protease [O-glycans on the hinge-region.Despite this wealth of information, there is no structure of the glycosylated HR of IgA1 or structures of IgG or Fabs derived from patients associated with IgAN. In recent years, the field of cryo-EM has undergone what has been termed the “resolution revolution”, meaning that this technique has come of age, maturing to a high-resolution structural technique on par with XRC ,203. Theprotease . These sAs noted, a paramount goal in determining these structures is to provide a better understanding of function and, in part, to generate hypotheses on possible approaches to inhibit protein-protein associations. Still, the missing key elements in this pathway toward disease-specific therapy for IgAN include knowledge of structures of the complexes of IgG autoantibodies with Gd-IgA1autoantigen. Cryo-EM appears to be the likely avenue to acquire this information. To go a step further and better define the epitopes on Gd-IgA1, a panel of autoantibodies representing a comprehensive repertoire from patients with IgAN is needed. Each structure will presumably reveal a snapshot of a unique binding-interface. These data will provide a comprehensive topographical representation of the VH/VL surfaces involved in Gd-IgA1 recognition and differences in binding associated with IgG variability. Defining the same, overlapping, and/or distinct epitopes on the Gd-IgA1 will provide an opportunity to design strategies for disrupting the interaction of IgG and Gd-IgA1. It remains to be determined if small molecules can be designed that disrupt formation of pathogenic immune complexes, but discovery of the structures of each IgG autoantibody and Gd-IgA1 affords the opportunity to perform in silico screening of ligand libraries ,209 in hO-glycans. These immunodeposits are thought to originate from Gd-IgA1-IgG complexes formed in the circulation. It was recently shown experimentally that human IgG autoantibodies bind to human Gd-IgA1 to form immune complexes that in a murine model induce pathogenic changes consistent with IgAN. It is hoped that a better understanding of the key players in IgAN, autoantibodies, and autoantigens, will enable development of disease-specific treatments.IgAN is characterized by glomerular immunodeposits enriched for Gd-IgA1 glycoforms and for IgG autoantibodies with specificity for the IgA1 with galactose-deficient


Local treatment for oligometastatic hormone-naive prostate cancer has been shown to be effective in phase II trials. As for the efficacy of targeted therapy for oligometastatic castration-resistant prostate cancer, the results of the phase trial are not yet available, but the number of reports showing efficacy by retrospective analysis is increasing. Progressive site-directed therapy has been shown to delay the next intervention and prolong progression-free survival, but its impact on subsequent treatment efficacy and contribution to overall survival has not been reported. The purpose of this retrospective study is to evaluate the impact of progressive site-directed therapy for oligometastatic castration-resistant prostate cancer on the subsequent treatment outcomes. We found that progressive site-directed therapy was associated with better response to subsequent androgen receptor axis-targeted drugs and better overall survival. Progressive site-directed therapy for oligometastatic castration-resistant prostate cancer may improve subsequent oncological outcomes.p = 0.010). The median OS was not reached in the PSDT group and was significantly longer than 44.5 months in the non-PSDT group . In OM-CRPC, PSDT may improve the efficacy of subsequent ARAT and OS.The purpose of this study was to evaluate the impact of progressive site-directed therapy (PSDT) for oligometastatic castration-resistant prostate cancer (OM-CRPC) on the efficacy of subsequent androgen receptor axis-targeted (ARAT) drugs, and to demonstrate the possibility of prolonging overall survival (OS). We performed a retrospective analysis of 15 OM-CRPC patients who underwent PSDT and subsequently received first-line ARAT drugs (PSDT group) and 13 OM-CRPC patients who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing sites detected by whole-body diffusion-weighted MRI with radiotherapy. Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. The median PSA progression-free survival (PFS) for PSDT was 7.4 months. The median PSA-PFS for ARAT was 27.2 months in patients in the PSDT group and 11.7 months in the non-PSDT group, with a significant difference between the two groups (hazard ratio [HR], 0.28;  In oligometastatic cancer, a disease with limited number of metastases, local treatment of metastases was proposed to be effective based on the idea that the oligometastatic cancer has a similar biological behavior as localized disease ,2,3,4,5.As the benefits of local treatment for metastatic hormone-naive prostate cancer become more established, there is growing interest in the implications of a multidisciplinary treatment option that combines systemic therapy with progressive site-directed therapy (PSDT) for castration-resistant prostate cancer (CRPC) in which only a few lesions have progressed  ,11,12,13Considering that progressing lesion in OM-CRPC includes cancer cell clones that are resistant to systemic therapy being administered, PSDT may be effective in reducing these treatment-resistant clones and thus contributing to improved efficacy of subsequent systemic therapy. Although our results are from a small number of cohorts with short follow up after PSDT, we have reported a trend towards better efficacy of ARAT drugs administered to patients with OM-CRPC after undergoing PSDT compared with those who did not undergo PSDT . The purThis study included 71 patients diagnosed with OM-CRPC by whole-body diffusion-weighted MRI (WB-DWI) who underwent diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) before starting a new line of anticancer therapy at a single institution between 2014 and 2020. Seventeen patients with prior ARAT treatment were excluded from the study. Twenty-six were also excluded from the analysis because ARAT was not introduced as the first systemic treatment after the diagnosis of OM-CRPC.CRPC patients were defined as having serum testosterone < 50 ng/dL, and biochemical or radiological progression according to the European association of urology guideline . The detOf the OM-CRPC patients, we evaluated the treatment outcomes in patients who underwent PSDT and were subsequently treated with first-line ARAT drugs (PSDT group) and those who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing lesions detected by WB-DWI with radiotherapy. Prostate/lymph node metastases were treated with 60–78 Gy (2 Gy per fraction), and bone metastases were treated with 30–39 Gy (2–3 Gy per fraction) external beam radiotherapy. Systemic treatment was unchanged when PSDT was performed according to the institutional treatment protocol; after 2019, PSDT was combined with radium-223 and bone-modifying agent in cases where progressing metastatic lesions was confined to bone. Patients were typically visited every 1–3 months and based on an evaluation that included a physical examination, PSA, and imaging studies, changes in systemic therapy and repeated PSDTs were performed by their respective physicians.® 14 , and p < 0.05 was considered significant.Differences in the characteristics of patients in the PSDT and non-PSDT groups were compared using the Wilcoxon test for continuous variables, and Fisher’s exact test for nominal variables. The PSA-PFS for PSDT was calculated as the time from the start of radiotherapy to PSA progression (2 ng/mL increase from the PSA nadir), and patients who did not show a decrease in PSA were considered to have PSA progression at time point 0. PSA-PFS for ARAT was defined as the date when an increase of 25% or more from the nadir and an absolute increase in PSA of at least 2 ng/mL are confirmed by a second measurement obtained at least 3 weeks later. PFS and OS were estimated by the Kaplan–Meier method and compared among subgroups using the log-rank test. To identify variables associated with PSA-PFS and OS, Cox regression analysis was performed using clinical factors at the time of WB-DWI examination—notwithstanding if PSDT was performed—and ARAT drugs administered as analysis factors. Early adverse effects of PSDT treatment were assessed using the Radiation Therapy Oncology Group (RTOG) scale . All stap = 0.030). Of the PSDT group, all 11 patients with a history of definitive prostate treatment had no progressing disease within the prostate and did not include the prostate in their PSDT, while two of the remaining four patients with no prior definitive prostate treatment had progressing disease in the prostate along with metastatic disease and included the prostate in their PSDT.Of the 28 patients included in the analysis, 15 patients were in the PSDT group and 13 patients were in the non-PSDT group. The median follow-up time for the PSDT and non-PSDT groups was 38.5  months and 33.3  months, respectively. The characteristics of the PSDT and the non-PSDT groups at WB-DWI examination are shown in n = 9), followed by lymph nodes alone (n = 3). Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. PSDT was combined with radium-223 and bone-modifying agent in one patient. The median time to PSA progression was 7.4 months , and the median time from WB-DWI to PSDT was 1.6  months. The most frequent target organ of PSDT was bone alone (p = 0.0085).As the first ARAT, eight patients (53.3%) received enzalutamide and seven (46.7%) received abiraterone in the PSDT group, and nine patients (69.2%) received enzalutamide and four (30.8%) received abiraterone in the non-PSDT group. The median number of lines of systemic treatment administered after the diagnosis of OM-CRPC was one (1–4) in the PSDT group and three (1–7) in the non-PSDT group, significantly more in the non-PSDT group  due to the therapeutic effect of PSDT. PSDT for OM-CRPC is recommended because of the potential to improve the subsequent clinical course and mild adverse effects.In progressing metastatic CRPC, there is a mixture of responsive and non-responsive lesions when the disease becomes drug resistant, confirming the heterogeneity of lesion response to treatment in metastatic CRPC ,28. Clonp = 0.05), DMFS , and TTNI  in OM-CRPC who underwent SABR in addition to change in systemic therapy compared with OM-CRPC who underwent change in systemic therapy alone and no SABR, indicating that the combination of SABR and change in systemic therapy for OM-CRPC has the potential to improve oncologic outcome [Several retrospective cohort studies have investigated the therapeutic effect of PSDT to OM-CRPC and have reported promising results ,17,18,19 outcome .p = 0.006) for patients with a controlled primary tumor and five or fewer metastatic lesions [The effect of metastasis-directed therapy on OS prolongation has been shown in a randomized, open-label, phase II trial, SABR-COMET (NCT01446744), in oligometastatic cancers of various types, of which prostate cancer accounts for 16%. SABR-COMET showed that adding SABR to consolidate all metastatic sites in addition to standard treatment improved OS  to evaluate the effect of adding SBRT to abiraterone acetate, the DECREASE trial (NCT04319783) to evaluate the effect of adding SBRT to dalolutamide, and the FORCE trial (NCT03556904) to evaluate the effect of adding SBRT to standard therapy.There are several limitations to this study. First, this study has a small number of cases and is retrospective in nature. In this study, the diagnosis of OM-CRPC was made by WB-DWI using a uniform protocol in both PSDT and non-PSDT groups, and although there were no significant differences in patient characteristics between the PSDT and non-PSDT groups, other than the history of definitive therapy for prostate cancer, there is an inherent potential for bias in the selection of patients for PSDT. Second, in order to evaluate the contribution of PSDT to the subsequent course of treatment for OM-CRPC, this study compared a cohort of patients in whom PSDT was not performed at the time of diagnosis of oligoprogression and only ARAT initiation was performed, with a cohort of patients in whom PSDT was followed by ARAT initiation. Therefore, of the patients who underwent PSDT, only those with disease progression after PSDT were included in the analysis, while those with continued therapeutic response to PSDT were excluded. This led to underestimation of the therapeutic effect of PSDT. Third, SBRT, which has been shown to be effective in treating metastatic disease in recent years, was not used in the PSDTs in this study, which may also underestimate the therapeutic effect of PSDTs. Fourth, the non-PSDT group included one case each of liver and lug metastasis, which generally have a poor prognosis. This patient selection bias may have affected the results of this study.In OM-CRPC, PSDT may result in a better response to subsequent ARAT and better OS. Future prospective studies are necessary to confirm these results.


Background: Modes of transmission of SARS-CoV-2 are of key public health importance. SARS-CoV-2 has been detected in the feces of some COVID-19 patients, suggesting the possibility that the virus could, in addition to droplet and fomite transmission, be transmitted via the orofecal route. Methods: This review is part of an Open Evidence Review on Transmission Dynamics of COVID-19. We conduct ongoing searches using WHO COVID-19 Database, LitCovid, medRxiv, and Google Scholar; assess study quality based on five criteria and report important findings. Where necessary, authors are contacted for further details on the content of their articles. Results: We include searches up until 20 December 2020. We included 110 relevant studies: 76 primary observational studies or reports, and 35 reviews  examining the potential role of orofecal transmission of SARS-CoV-2. Of the observational studies, 37 were done in China. A total of 48 studies  reported single cases, case series or cohort data on individuals with COVID-19 diagnosis or their contacts and 46 (96%) detected binary RT-PCR with 535 out of 1358 samples positive for SARS-CoV-2 (average 39.4%). The results suggest a long duration of fecal shedding, often recorded after respiratory samples tested negative, and symptoms of gastrointestinal disease were reported in several studies. Twenty-nine studies reported finding SARS-CoV-2 RNA in wastewater, river water or toilet areas. Six studies attempted viral culture from COVID-19 patients’ fecal samples: culture was successful in 3 of 6 studies, and one study demonstrated invasion of the virus into intestinal epithelial cells. Conclusions: Varied observational and mechanistic evidence suggests SARS-CoV-2 can infect and be shed from the gastrointestinal tract, including some data demonstrating viral culture in fecal samples. To fully assess these risks, quantitative data on infectious virus in these settings and infectious dose are needed. Current evidence suggests SARS-CoV-2 is primarily transmitted via respiratory droplets and fomites between infected individuals and others in close contactSARS-CoV-2 has been shown to contaminate and survive on certain surfaces, and has also been detected in the feces of some patients, suggesting the possibility that SARS-CoV-2 could transmit via the orofecal route, including potentially via contamination of food. It is well recognized that coronaviruses are major pathogens in many mammalian species and predominantly target epithelial lining cells in the respiratory and gastrointestinal (GI) tracts. Many animal coronaviruses are transmitted by the fecal-oral route and there are several reports of intestinal disease associated with SARS-CoV-1 and other human coronaviruses. Main causes include lack of adequate sanitation and poor hygienic practices. Identifying infectious virus and quantifying viral load within human GI tissues, feces, and contaminated materials including fomites and sewage would help understand the potential for transmission. We aimed to systematically review the evidence on orofecal SARS-CoV-2 transmission. Terminology for this article can be found inOrofecal: describes a route of transmission where the virus in fecal particles can pass from one person to the mouth of another.Viral load:A measure of the number of viral particles present in an individual typically quantified by the number of virions, gene copies or equivalents, or amount of viral proteins present.Cycle threshold: The number of cycles required for the fluorescent signal to cross the threshold. Ct levels are inversely proportional to the amount of target nucleic acid in the sample.Extended data: Appendix 1). For the original protocol, seehttps://www.cebm.net/evidence-synthesis/transmission-dynamics-of-covid-19/. In brief, this review aims to identify and evaluate relevant articles (peer-reviewed or awaiting peer review) that examine the mode of viral transmission and ecological variables influencing the mode of transmission. We conduct an ongoing search using WHO COVID-19 Database, LitCovid, medRxiv and Google Scholar for keywords and associated synonyms. Results are reviewed for relevance and for articles that looked particularly relevant forward citation matching was undertaken and relevant results were identified. Studies with modelling are only included if they report transmission outcome data and not predicted outcomes (see further details of the search strategy in theExtended data: Appendix 2). Searches are updated every two weeks.We are undertaking an open evidence review investigating factors and circumstances that impact on the transmission of SARS-CoV-2, based on our protocol .We extracted data on the type of study, setting, sample source and methods, fecal PCR positive samples for SARS-CoV-2 RNA including cycle threshold (including methods), symptom chronology in relation to PCR testing and/or taking samples and viral culture. We tabulated the data and summarised data narratively by mode of sample. We assessed quality using a modified QUADAS-2 risk of bias toolExtended data: Appendix 3 for references of included studies): 76 primary studies or reports, and 35 reviews, one of which also reported primary study results from a cohort study [Cheung K 2020].This update includes searches up until 20 December 2020 see. We idenThe included reviews summarised a range of observational studies including studies of detection of SARS-CoV-2 RNA in fecal samples of individuals testing positive for SARS-CoV-2 in respiratory samples, frequency of GI symptoms among those with COVID-19, and observations of SARS-CoV-2 RNA in toilets and wastewaters. The reviews included overlapping studies and must therefore not be considered as entirely additional information. Five followed systematic review methodology and reporting . The quality of the other reviews was low to moderate, with none assessing included study quality, and with reporting of methods often missing or very limited.None of these reviews focussed on the infectiousness  of SARS-CoV-2 identified in fecal or wastewater samples. A review on the potential for foodborne transmission of SARS-CoV-2 found no published studies of SARS-CoV-2 survival in or on food products. The totality of the reviews’ evidence shows that the SARS-CoV-2 RNA is commonly present in stool samples of COVID-19 patients but it is unknown if this represents primary invasion of enterocytes or simply saliva and sputum that has been swallowed and is transiting it way through the GI tract. The presence of viral RNA in the feces does not allow any conclusions to be drawn about infectiousness. The contribution of orofecal transmission to viral spread in the pandemic has not been established or quantified.Quality of included studies. Overall the quality of the evidence was low to moderate mainly due to a lack of standardisation of techniques, omissions in reporting and a failure to account for biases in the research process  studies reported single cases, case series or cohort data on individuals with COVID-19 diagnosis or their contacts and 46 studies (96%) detected binary RT-PCR with 535 out of 1358 samples RT-PCR positive for SARS-CoV-2 (average 39.4%). All but five studies were in hospitalized patients; 31 were done in China; the others were in East Asia, South East Asia, South Asia, USA and Europe  detected binary RT-PCR, with 522 positive tests out of 1293 fecal samples (average 40.4%) from COVID-19 patients . However, several observational studies report the presence of GI symptoms among COVID-19, including Chan 2020, Cheung 2020 and Han C 2020. GI symptoms do not necessarily correlate in severity or time with other COVID-19 disease symptoms. et al. reported an apparently asymptomatic (no fever or cough) 10-year-old child, from whom, 17 days after the last close contact with individuals testing positive for SARS-CoV-2, a fecal sample was positive for SARS-CoV-2 RNA. A retrospective study of 133 hospitalised COVID-19 patients identified 22 whose sputum or fecal samples tested positive after pharyngeal swabs became negative [Chen C 2020]. A study of 59 hospitalised COVID-19 patients reported that fecal discharge of SARS-CoV-2 RNA continued long after respiratory shedding had ceased [Cheung 2020]. Among fecal samples from 69 hospitalized COVID-19 patients, 20 tested PCR positive; SARS-CoV-2 RNA persisted for significantly longer in fecal samples than in oropharyngeal swabs .Fecal shedding of SARS-CoV-2 has been reported throughout the disease course and also continuing after respiratory samples tested negative. A five-person family with a confirmed COVID-19 case was hospitalized and observed: the parents and two children aged two and five years became infected but the youngest child was not infected. These children shed infectious virus via the respiratory system, and this shedding observed in the nasopharynx cleared after five to 6 days; however, viral RNA was continuously detected in the children’s stool for more than four weeks [Wolf 2020]. Tang 2020The role of aerosol-generating procedures in relation to orofecal transmission. One study reported the results of PCR tests among participants attending for upper GI endoscopy at a UK hospital [Hayee 2020]. Only individuals testing PCR negative in a nasopharyngeal swab underwent their booked procedure. Post-procedure follow-up of 6,208 patients at one and two weeks identified no incident case of COVID-19.Viral culture using fecal samples was attempted in 6 studies , three reported culture of SARS-CoV-2 from stool samples , and three did not .et al. reported two of four viral culture samples were positive, however, no culture methods were reported; electron microscopy was performed suggesting the presence of the virus, but this observation does not show that the virus was viable. In Xiao F Sun J 2020, viral culture was attempted from an unreported number of specimens and cases and a cytopathic effect in Vero E cells was observed 2 days after a second-round passage. Zhang Y 2020et al. reported isolating the virus from the stools of one severe hospitalised COVID-19 pneumonia case. The number of samples taken was unclear and while Vero cells were used for viral isolation from stool samples, culture methods were not described.Wang W 2020Additional evidence of SARS-CoV-2 replication activity was observed within the intestine: an inpatient for treatment of a rectal adenocarcinoma had samples taken from enteric sections, and the mucosa of rectum and ileum analysed [Qian 2020]. The rectal swab sample tested negative for SARS-CoV-2 RNA by PCR. However, typical coronavirus virions in rectal tissue were observed under electron microscopy with abundant lymphocytes and macrophages (some SARS-CoV-2 positive) infiltrating the lamina propria.Methodological issues across these studies including variability in sample selection and methods of viral culture, reported inStudies of wastewater and sewage. Twenty-two global studies investigated SARS-CoV-2 in wastewater or sewage, four looked at the role of toilets or sewage, and one reported observation in river water .All reported the detection of SARS-CoV-2 RNA and/or SARS-CoV-2 viral proteins; a number of studies suggested the potential of detection in sewage to be used as a public health monitoring system.Wastewater surveillance may anticipate outbreaks: a Brazilian study identified SARS-CoV-2 RNA from sewage samples collected in November 2019 [Fongaro 2020]; a Spanish study detected sewage samples from 41 days prior to the declaration of the first COVID-19 case in Spain, and additionally in frozen samples dating back to 12 March 2019 [Chavarria-Miró 2020]. Virus concentrations found in wastewaters may correlate with prevalence in the local community. At very low community levels of circulation, sewage surveillance could detect SARS-CoV-2 RNA presence . A study of hospital surfaces and sewage areas in China reported no virus was detected by culture of surface swabs or sewage samples [Wang J 2020]. Another study in China tested hospital sewage and found SARS-CoV-2 RNA but no viral culture of SARS-CoV was present in the sewage in their assays .Toilets. An additional four studies investigated SARS-CoV-2 in toilets  in hospital settings were PCR-positive; anteroom and corridor samples were negative [Ong 2020].River water. One study tested river water for SARS-CoV-2: taking samples from three urban river locations in a low sanitation urban context (i.e. highly impacted by raw sewage) in Quito, Ecuador, during a peak of COVID-19 cases. SARS-CoV-2 RNA was detected in all samples, at levels similar to those in wastewater from cities during outbreaks [Guerreo-Latorre 2020]. Evidence from reviews can be found inThe evidence from 110 relevant studies supports a potential role of orofecal transmission of SARS-CoV-2. Fecal shedding of SARS-CoV-2 RNA has been reported in 96% of the included observational studies, often for relatively long durations. Three studies reported the culture of SARS-CoV-2 using fecal samples, but requisite methods to confirm viral growth were lacking. One study demonstrated viral isolation from rectal tissue of a COVID-19 patient. Studies in hospitals show the presence of SARS-CoV-2 RNA at and around toilets and toilet rooms; there is evidence that disinfectant cleaning leaves no SARS-CoV-2 RNA detectable. Many studies report identifying SARS-CoV-2 RNA in sewage and wastewaters, but viral culture from such sources has not been demonstrated, so there is no evidence of infection risk from those sources; however, detection of SARS-CoV-2 RNA in sewage and wastewaters can be useful as a surveillance tool.). Zang 2020 demonstrated that human enterocytes express high ACE2 receptor levels, supporting viral invasion at these sites. Zang 2020 and Lamers 2020et al. showed that SARS-CoV-2 productively infected human small intestinal organoids. Zhou J 2020et al. and co-workers showed active replication of SARS-CoV-2 in human intestinal organoids, and isolated infectious virus from the stool specimen of a patient with diarrheal COVID-19. Yaoet al. investigated the mutation spectrum, replication dynamics, and infectivity of 11 patient-derived SARS-CoV-2 isolates in diverse cell lines; the authors report that "three of our viral isolates were extracted from stool samples (two of which were very potent) indicating that viable SARS-CoV-2 particles could be found in stool samples".Experimental models of the human intestinal epithelium show that SARS-CoV-2 can infect this tissue and replicate, supporting the rationale for the human GI tract as a possible transmission routeThese studies do not provide an estimate of infectious virus concentration; nor has the infectious dose for humans been established, so at this point it is unwarranted to deduce a human transmission risk based on this small number of virus-positive fecal samples.. MERS-CoV has been detected in 42% of milk samples collected from lactating camels where it can survive for a prolonged period. A study of human primary intestinal epithelial cells and small intestine explants of MERS-CoV patterns identified the viral replication intermediates in stool specimens. MERS-CoV was found to be resistant to fed-state gastrointestinal fluids but less tolerant to the high acidic fasted-state gastric fluid.MERS-CoV has been shown to infect human primary intestinal epithelial cells, small intestine explants and intestinal organoids. In the SARS-CoV-1 outbreak in 2002-03, a significant portion of patients had enteric involvement. In the Toronto outbreak in 2003, 6% of 144 patients had diarrhoea on presentation. Among 138 patients with SARS in Hong Kong, 20% presented with watery diarrhoea and 38% had symptoms of diarrhoea during the illness. Intestinal biopsy specimens showed the presence of active viral replication, and SARS-CoV RNA was detected in the stool of some patients for more than ten weeks after symptom onset. A retrospective study on specimens from 154 patients in Hong Kong with laboratory-confirmed SARS found the viral load to be the highest in stool specimens. Up to 70% of 75 patients in a community outbreak in Hong Kong developed watery diarrhoea. This outbreak was linked to a faulty sewage system in the Amoy Gardens apartment complex, further suggesting orofecal transmission might be a route for transmission.Prolonged excretion of coronaviruses in feces was first observed in 1977et al. used a monoclonal antibody specific for the SARS‐CoV nucleoprotein, and probes for the RNA polymerase gene fragment in four patients who died from SARS‐CoV-1. Virus was detected in the stomach, small intestine, distal convoluted renal tubule, sweat gland, parathyroid, pituitary, pancreas, adrenal, liver and cerebrum. The authors discussed that viruses in contaminated food and water may enter the human body through epithelial cells covering the surface of the gastrointestinal tract, although there was no direct evidence to show that food‐borne transmission had occurred. A study from the sewage of two hospitals receiving SARS patients in Beijing found no infectious SARS-CoV contamination in any of the samples collected but did detect the nucleic acid in the sewage from the two hospitals before disinfection - providing further evidence that SARS-CoV-1 can be excreted by feces into the sewage system.The human gastrointestinal tract can act as a primary infection site for SARS-CoV. Ding. Pigs are also infected by the transmissible gastroenteritis coronavirus via the orofecal. Bat coronavirus infects the gastrointestinal and respiratory tracts of bats, seemingly without causing disease. Transmission following exposure to camel feces has also been considered biologically plausible.Transmission of coronaviruses via the feces is established among animals: feline coronavirus, for instance, is typically shed in feces of healthy cats and transmitted by the orofecal route to other cats.There is evidence that SARS-CoV-2 can survive adverse conditions in the gastrointestinal system. It has been identified in endoscopic specimens of the oesophagus, stomach, duodenum, and rectum of COVID-19 patients; substantial amounts of SARS-CoV-2 RNA have been consistently detected in stool specimens, and evidence suggests that SARS-CoV-2 can survive the adverse conditions in the gastrointestinal system. Heavy glycosylation of the large spike S protein has been shown to lead to resistance to the proteases, the low pH and bile salts found in the gastrointestinal system. Some gastric processes may actually facilitate viral entry into the enterocytes: in bovine coronavirus, one specific site on the S glycoprotein has to be cleaved by an intracellular protease or trypsin to activate viral infectivity and cell fusionEvidence of ingestion, penetration of enterocytes and excretion of live SARS-CoV-2 is possible; however, this working hypothesis requires testing by conducting case-control studies during the investigation of outbreaks, following a set protocol. For such investigations, cases of COVID-19 (categorised by symptom presence and severity) either fecally excreting virions or not (cases and contacts) and controls would be healthy matches. Exposure to potentially fecally contaminated materials and protective measures taken would be elicited at interview. To minimise the play of recall and ascertainment bias, interviewers should be blind to fecal excretion status and the interview should take place as soon as possible after the event. Viability of fecal isolates and their possible pathogenicity should be tested in outbreaks.Strengths and limitations. This review is limited by the quality of included studies: many were small and did not provide a protocol that established a priori methods. Studies were often poorly reported and often did not take biases into account. Reporting is often heterogeneous and essential information such as symptom onset and cycle threshold values were often missing. We do not have information on publication bias, but the current urgency to understand SARS-CoV-2 may have an impact on research, with unknown implications and a tendency to publish those studies with positive results. We note the possibility that some cases may be reported in more than one publication, but there is no adequate method by which to identify this. It is likely we missed some studies, but we plan to keep updating this review. Furthermore, our judgments of quality are to some extended subjective and open to disagreement. This does not, however, undermine our overall assessment of the quality of the included studies. We perceive that standardization of methods in this area would improve the quality of the research. Some of these limitations increase uncertainties and prevent firm conclusions being drawn; however, this body of research provides largely consistent evidence on the main conclusions that SARS-CoV-2 is excreted fecally, is found in sewage and can be cultured from fecal samples.Observational and mechanistic evidence as well as established animal orofecal transmission of coronaviruses suggests SARS-CoV-2 can infect and be shed from the human gastrointestinal tract. However, quantitative data on infectiousness and the consequent likelihood of transmission from orofecal contamination is not available. Whilst SARS-CoV-2 RNA is observed in sewage and wastewaters, there is no evidence of infectiousness in these sources and a transmission risk from these sources is considered unlikely based on the reviewed studies. To properly assess these risks, quantitative data on infectious virus are needed, along with information on likely infectious dose in humans.All data underlying the results are available as part of the article and no additional source data are required.https://doi.org/10.6084/m9.figshare.14247470.v1.Figshare: Extended data for SARS-CoV-2 and the role of orofecal transmission: a systematic review,This project contains the following extended data:- Appendix 1: Updated protocol- Appendix 2: Search strategy- Appendix 3: References to included studies.https://doi.org/10.6084/m9.figshare.14247470.v1.Figshare: PRISMA checklist for ‘SARS-CoV-2 and the role of orofecal transmission: a systematic review’,Creative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of the I have read the revised article and the response of the manuscript authors. I agree with the authors' response and the changes in the manuscript. The authors now make clear that so far, there is no evidence for the presence of infectious SARS-CoV-2 in sewage, other wastewater and environmental waters. I support this position. In my judgement, I now consider the article acceptable without reservations. ). Furthermore, the authors and other readers of the manuscript may be interested to know that I recently published an invited review article in the Journal of Water and Health, a journal of the international Water Association, that is entitled: "Absence of virological and epidemiological evidence that SARS-CoV-2 poses COVID-19 risks from environmental fecal waste, wastewater and water exposures'  from searches up until 20th December 2020. Potential orofecal transmission of SARS-CoV-2 is an important public health issue. They found the observational evidence suggested SARS-CoV-2 infects and is shed from the gastrointestinal tract (GIT) and with further testing could allow the development of appropriate public health measures. This systematic review has followed the PRISMA guidelines including developing a review protocol and completing the PRISMA checklist. All underlying data is available and extended data has been uploaded onto Figshare. This review is very well-written and the references relevant. The authors have undertaken this review thoroughly, with the largely low-moderate data available. There are, however, some points that should be addressed to strengthen the review and conclusions.The aim was to systematically review evidence on orofecal SARS-CoV-2 transmission while the conclusion focuses on SARS-CoV-2 fecal excretion and presence in sewage, which is not evidence of transmission. Detection of SARS-CoV-2 in stool samples and in ecological settings is important but it should be noted that was not the aim of this review. Viral culture data from six studies is included but this is a small minority of studies, and as the authors note due to methodological issues should be interpreted with caution.Examining the ecological studies and review is very worthwhile but none address the issues of orofecal SARS-CoV-2 transmission. Perhaps ecological factors are a secondary outcome?While the authors do note in the results that some reviews included overlapping studies, there is no figure/percentage given for this. How much overlap in total is there, is the overlap greater for cohort/case series or ecological studies? What is the quality of the overlapping studies – are they over-representing the low-quality data?What is the breakdown for included reviews between cohort/case series and ecological studies? This is provided for primary studies in Figure 1 but I can’t find it for the reviews.Have you considered a sub analysis of the studies in children?Is gender reported routinely across the studies?How many/percentage of the studies are only on MedRxiv? Consider including breakdown by primary/review, cohort-case series/ecological. This could be a source of bias.HeneghanMinor:Table 1 pages 10, 11 & 12 – total patient number from the cohort/case series (9081) appears in the “sewage” header rows.Are the rationale for, and objectives of, the Systematic Review clearly stated?YesIs the statistical analysis and its interpretation appropriate?PartlyAre sufficient details of the methods and analysis provided to allow replication by others?YesAre the conclusions drawn adequately supported by the results presented in the review?PartlyReviewer Expertise:I am a Clinical Research Fellow with a major research interest in HIV-Hepatitis co-infection, and since 2020 also COVID-19 infectionI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Thank you for these helpful suggestions to improve the review. Please see our changes made, noted below.  1. Added: typically quantified by the number of virions, gene copies or equivalents, or by antigen indicators of viral load. 2. Added to the Discussion: these studies do not provide an estimate of infectious virus concentration; nor has the infectious dose for humans been established, so at this point it is unwarranted to deduce a human transmission risk based on this small number of virus-positive fecal samples. 3. Changed Discussion sentence: Many studies report identifying SARS-CoV-2 RNA in sewage and wastewaters, but viral culture from such sources has not been demonstrated, so there is no evidence of infection risk from those sources; however, detection of SARS-CoV-2 RNA in sewage and wastewaters can be useful as a surveillance tool. 4. Added: However, quantitative data on infectiousness and the consequent likelihood of transmission from orofecal contamination is not available. Whilst SARS-CoV-2 RNA is observed in sewage and wastewaters, there is no evidence of infectiousness in these sources and a transmission risk from these sources is therefore unlikely. To properly assess these risks, quantitative data on infectious virus are needed, along with information on likely infectious dose in humans. 5. Added to Discussion: We note the possibility that some cases may be reported in more than one publication, but there is no adequate means by which to identify this. 6. Unclear reporting in the reviews did not allow full analysis of their included studies. To do this we could revisit the full text of their included studies, but this is beyond the scope of this review. Inclusion of these reviews represents a level of interest in the field but necessarily they will overlap in scope and therefore we do not analyse their findings in detail. 7. Thank you for the suggestion to further sub analyse the data; at this stage there are insufficient data for such sub analyses including among children. 8. Unfortunately there are several studies in which sex of participants is not reported and so we were limited by this.  9. This was a very interesting suggestion to sub-analyse according to preprint publication and examine possible publication biases; this is unfortunately beyond the scope of this review, not least because this changes over time. The next time we update this review we hope to have a better breakdown of those fully published, and hopefully a better bank of evidence to analyse. 10. Thank you for noting the anomaly in the table, we have checked and rectified and hopefully this will all be in the right place now.  Thank you for these comments. In Box 1. Terminology, Viral load is defined in a rather vague and insufficiently quantitative way. Viral load can be quantified on the basis of virions , gene copies or equivalents based on RNA units or CT values, antigen units such viral proteins quantified in different ways, including immunofluorescence intensity observed in infected tissues and as infectious units for replication competent virus based on titers in susceptible cell cultures or experimental animals. There is value in focusing on quantified "viral load" in human gastrointestinal tissues, intestinal contents and fecally contaminated materials such as fomites, wastewater  and water . These nuances in "viral load" are important in interpreting and communicating the transmission-relevant results reported in the research studies reviewed..The data found in the study and provided in Table 1 indicate that only a few studies (5 according to table 1) attempted to detect infectious or replication-competent SARS-CoV-2 in either feces, sewage or a related sample, of which only 3 reported the presence of infectious virus. Further, infectious virus results are reported as "yes" or "no" (presence or absence) per sample. The data for infectious virus are not quantified in typical units such as plaque-forming units or TCID-50 units. Therefore, the concentrations of the detected viruses are unknown. Such lack of quantitative data on infectious virus concentration makes it impossible to determine if sufficient infectious virus is present to pose a transmission risk from human exposure. This point should be mentioned in the overall presentation of the infectious virus results. Furthermore, we do not know the infectivity dose-response relationship of SARS-CoV-2 for human hosts, such an estimate of 50% infectious dose. Unless we know what virus concentration is in samples such as feces or sewage/wastewater and unless we know what the likelihood of human infection is from exposure to known concentrations of infectious virus, it is probably unjustified to suggest that the presence of an unknown concentration of infectious virus in a very small number of reported virus-positive fecal samples poses a human health risk from exposure. While infectious virus presence in a few samples is noteworthy, the lack of quantitative infectivity data makes it impossible to judge that there is plausible human health exposure risk from this infectious virus-positive fecal matter of unknown concentration. The best one can say is that the risk of infection or other health effects from exposure is not zero, but is also not quantifiable due to lack of data on virus concentration in feces and lack of knowledge of human infectivity dose-response for infection or other health endpoints. For sewage and water, the lack of data on virus infectivity in such samples makes it impossible to determine if these samples pose risks of human infection from exposure. Although some data on concentrations of viral RNA are reported based on estimated gene copies or CT values, the quantitative relationship of virus infectious units to RNA concentration units is highly variable and therefore uncertain This is especially so for samples that have been in the environment for unknown and variable periods of time since the feces were shed from a human host. This is due to the variable and difficult-to-quantify effects of exposure time, temperature, microbial activity, predation and other environmental stressors on virus survival. These factors are not mentioned in the paper, even though we know they are important for determining the quality and validity of the results for infectious virus presence and concentrations. The last sentence of the first paragraph of the Discussion section does not adequately address the issue of lack of evidence of virus culture in wastewater and sewage and its implications for human health risks from sewage. Instead it sidesteps to the potential value using SARS-CoV-2 RNA in sewage and wastewater as a surveillance tool. This seems to miss the main point of assessing the evidence for human health risk from exposure to sewage or wastewater.In the "strengths and limitations section of the Discussion section, the authors state "however, this body of research provides largely consistent evidence on the main conclusions that SARS-CoV-2 is excreted fecally, is found in sewage and can be cultured from fecal samples." While there there is some evidence that unknown but probably low concentrations of infectious SARS-CoV-2 have been occasionally found in excreted feces, they have not been found in sewage or wastewater. The wording of the above sentence conflates feces with wastewater and sewage, even though there is only limited and poor evidence for infectious virus in the latter and no evidence for it in sewage or wastewater. I recommend that the sentence be revised to avoid conflating these rather separate exposure sources of feces versus sewage and wastewater.The Conclusion sentence is short and limited in scope. It does not adequately address the issue of whether sufficient infectious SARS-CoV-2 is or is not likely to be present in feces or wastewater and sewage to pose human health risks from exposure. The available evidence seems to indicate that such risks are not possible to assess or quantify without better and more rigorous and as well as more quantitative data that is still not available.This article is of generally high quality, but improvements are suggested in some areas, including in the conclusions. Starting from the beginning of the article here are some points that should be clarified or improved:Are the rationale for, and objectives of, the Systematic Review clearly stated?YesIs the statistical analysis and its interpretation appropriate?PartlyAre sufficient details of the methods and analysis provided to allow replication by others?PartlyAre the conclusions drawn adequately supported by the results presented in the review?PartlyReviewer Expertise:I am an environmental and public health virologist and microbiologist with expertise in infection protection and control and water-sanitation and hygiene, as well as in infectious disease epidemiology in the context of environmental exposure risks and disease transmission of human pathogens .I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Thank you for these helpful suggestions to improve the review. Please see our changes made, noted below.  1. Added: typically quantified by the number of virions, gene copies or equivalents, or by antigen indicators of viral load. 2. Added to the Discussion: these studies do not provide an estimate of infectious virus concentration; nor has the infectious dose for humans been established, so at this point it is unwarranted to deduce a human transmission risk based on this small number of virus-positive fecal samples. 3. Changed Discussion sentence: Many studies report identifying SARS-CoV-2 RNA in sewage and wastewaters, but viral culture from such sources has not been demonstrated, so there is no evidence of infection risk from those sources; however, detection of SARS-CoV-2 RNA in sewage and wastewaters can be useful as a surveillance tool. 4. Added: However, quantitative data on infectiousness and the consequent likelihood of transmission from orofecal contamination is not available. Whilst SARS-CoV-2 RNA is observed in sewage and wastewaters, there is no evidence of infectiousness in these sources and a transmission risk from these sources is therefore unlikely. To properly assess these risks, quantitative data on infectious virus are needed, along with information on likely infectious dose in humans.


The recent pandemic of coronavirus disease 2019 (COVID-19) has resulted in many challenges to the healthcare organizations around the world. Unfortunately, until now, there are no proven effective therapeutic agents against this virus.Several evolving studies suggest repurposing a potential list of drugs which have appropriate pharmacological and therapeutic effects to be used in treating COVID-19 cases. In the present review, we will summarize the potential drugs suggested to be repurposed to be utilized in the treatment of COVID-19 patients like lopinavir-ritonavir, ribavirin, baloxavir marboxil, favipiravir, remdesvir, umifenovir, chloroquine, hydroxychloroquine, azithromycin, corticosteroids, losartan, statins, interferons, nitric oxide, epoprostenol, tocilizumab, siltuximab, sarilumab anakinra, and ruxolitinib. In addition, we discussed the possible future therapeutic regimens based on the recent molecular and genomic discoveries.This review could provide beneficial information about the potential current and future treatment strategies to treat the pandemic COVID-19 disease. In December 2019, an epidemic of cases having unexplained low respiratory tract infections detected in Wuhan, China, was first reported. The etiology of this disease was then attributed to a new virus that belongs to the coronavirus (CoV) family called coronavirus disease 2019 (COVID-19). It is also termed SARS-CoV-2 as it is very similar to SARS-CoV. This novel virus is very contagious and it has a very quick spread worldwide [In the past 20 years, many viral epidemics like the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, HCoronaviridae family, which is the largest family in the order Nidovirales. Family Coronaviridae comprises two subfamilies: subfamily Orthocoronavirinae and subfamily Torovirinae. The subfamily Orthocoronavirinae includes four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. The viruses SARS-CoV, MERS-CoV, and COVID-19 are betacoronaviruses [The CoVs are positive-stranded RNA viruses isolated from different animal species. They can be transmitted to humans where they can cause illness that range from common cold to more serious diseases like MERS and SARS. They belong to the aviruses .Coronaviruses are spherical and they are characterized by the presence of spike proteins that project from the viral surface. Due to the appearance of the viral particle under the electron microscope as a royal crown, it was named coronavirus from the Latin word corona meaning crown. CoVs are enveloped viruses and they have some structural proteins like spike (S), membrane (M), envelope (E), hemagglutinin-esterase (HE), and nucleocapsid (N) proteins. The S, M, and E, HE proteins are embedded in the envelope of the virus . NeverthThere are a number of challenges in the treatment and prevention of COVID-19 that contributes to the high threat of the disease. They are summarized below. A prior good understanding of these difficulties is essential in strategizing new therapeutic alternatives.Similar to all RNA genomes, the COVID-19 genome lacks the proofreading mechanism and so it mutates frequently. Mutations can offer the virus certain selective advantages, for instance resistance to the currently developed vaccines and antiviral drugs. In addition, mutation enables the virus to escape from the adaptive immunity of the host and increases its infectivity and virulence. Also, it can lead to greater spread of the virus either horizontally  and/or vertically  .A clinically relevant aspect of the pandemic COVID-19 is its ability to induce the so-called cytokine storm (CS) that consists of interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α). These pro-inflammatory mediators can provoke systemic inflammatory response syndrome, resulting in acute respiratory distress syndrome (ARDS). The pathological changes that usually occur include diffuse alveolar damage due to immunological injury and viral infection, as well as multi-organ failure including airways destruction, vascular endothelial damage, plasma leakage, and extensive microthrombus formation . PneumonCOVID-19 can be deadly to particular groups in the population, like the elderly and individuals having immune deficiency. Thus, this group is in the highest need of prophylaxis or more intensive treatments against COVID-19 .The brief background discussed above clearly showed that the reliable prevention and treatment of COVID-19 represent a very critical public health need. In this review, we started with summarizing the current treatment for COVID-19. We then presented and critically reviewed the prospective future treatments for COVID-19 which are at various stages of development.At the present time, the treatment strategies dealing with COVID-19 infection is mainly supportive, like mechanical ventilation and oxygen supplementation, and the reduction of the viral transmission in the community is the greatest weapon. Although antiviral treatments for COVID-19 have not been approved yet, several approaches have been proposed including repurpose (reposition) some therapeutics approved for other conditions for COVID-19 patients  type 1. It is used in combination with ritonavir in order to increase its plasma half-life by inhibition of the cytochrome P450. It has an in vitro activity against SARS-CoV, MERS-CoV, and COVID-19 . On the It is a guanosine analog which interferes with the replication of RNA and DNA viruses. Nevertheless, the antiviral activity of ribavirin is not only limited to its interference with polymerases but also it interferes with RNA capping that is essential to prevent RNA degradation. It presented an in vitro activity against SARS-CoV, MERS-CoV, and COVID-19 . HoweverThey are new inhibitors of RNA replication in influenza virus that act by targeting different protein subunits of the influenza polymerase complex. Baloxavir marboxil inhibits cap-dependent endonuclease enzyme which is involved in the initiation of mRNA synthesis . Thus, tIt is a guanine analogue and prodrug which first enters the infected host cells through endocytosis and then it is transformed into active form through phosphorylation. Its antiviral activity is demonstrated through selectively targeting the viral conservative catalytic domain of RNA-dependent RNA polymerase, leading to interruption the process of the nucleotide incorporation during the viral RNA replication. Recent in vitro and human studies have used favipiravir as an experimental agent against COVID-19 . CurrentRemdesivir is a prodrug of an adenosine analogue having a broad antiviral spectrum. In vitro, remdesivir inhibits all human and animal coronaviruses, including COVID-19, and has shown antiviral and clinical effects in animal models of SARS-CoV and MERS-CoV. Furthermore, remdesivir has already had effective results in the USA in the fight against COVID-19 . In a coIt is an antiviral drug used in treatment of influenza infection. It can interact with the viral hemagglutinin (HA) and thus inhibiting the fusion of the viral particle to the host cell membrane. It is found that this drug inhibited crucial stages of the COVID-19 replication cycle in vitro . In addiChloroquine and hydroxychloroquine (a less toxic derivative of chloroquine) are antimalarial drugs which are widely used in the treatment of rheumatic diseases and have also presented a promising activity against COVID-19. Interestingly, they inhibited the virus when the tested cells were treated with it before and/or after exposure to COVID-19, which suggests both prophylactic and therapeutic effects of these drugs. They can also affect the entry and replication of COVID-19  reportedIt is bacteriostatic antibiotic that is widely used in treatment of many Gram-positive infections. Secondary bacterial infection pneumonia has been reported in several patients with COVID-19. Thus, azithromycin is important in treatment of pneumonia caused by bacteria . In addiThey are potent anti-inflammatory drugs which may prevent the occurrence of CRS in patients with COVID-19. Current animal experiments provided evidence for the effect of corticosteroids like dexamethasone, hydrocortisone, and methylprednisolone in decreasing the mortality, reduction of inflammation, attenuating the acute lung injury, reduction the period of hospitalization, decreasing the need for ventilation, and improving the survival in the severely ill patients having ARDS with doses of 15 mg/day, 400 mg/day, and 1 mg/kg/day, respectively . When coLosartan is an angiotensin receptor blocker that blocks angiotensin II. There has been considerable controversy over the use of angiotensin receptor blocker (ARBs) like losartan and angiotensin-converting enzyme (ACE) inhibitors (which are mainly used in treatment of elevated blood pressure) in patients with COVID-19 . COVID-1They are lipid-lowering drugs which have exhibited anti-inflammatory and immune-modulatory effects. Previous studies suggested the effectiveness of statin therapy in treating hospitalized influenza patients. In addition, statins have proven to have an anti-thrombotic and anticoagulant effects  via inteType I interferons (IFNs)-α/β are broad spectrum antivirals which can exhibit both direct inhibitory effects on the viral replication and supporting the host immune response in order to clear the viral infection . Recent Both inhaled nitric oxide and inhaled epoprostenol  have been widely studied pulmonary vasodilator agents which are used as rescue therapy in mechanically ventilated patients with COVID-19, having severe ARDS and hypoxemia . A studyThey are recombinant humanized monoclonal antibodies which are IL-6 receptor antagonists that block the biological activity of IL-6. They may potentially combat the release of cytokine and pro-inflammatory mediators leading to reduction in the pulmonary symptoms in severely ill patients having COVID-19 . Khan anIt is a recombinant monoclonal antibody which is IL-1 receptor antagonist and is proposed to be used in severely ill patients with COVID-19 to overcome the CRS . A studyIt is a selective inhibitor of Janus kinases (JAK) 1 and 2 which are tyrosine kinases in the host cell cytoplasm. They link cytokine signaling from the membrane receptors. As several patients with COVID-19 having severe respiratory disease due to CRS, it is hypothesized that JAK-inhibitors might have a beneficial role in treating such patients . D'AlessIndividuals who are hospitalized with COVID-19 are frequently having serious respiratory failure and have elevated serum levels of D-dimer which is an initial screening indicator for venous thromboembolism (VTE). So thromboprophylaxis  is an important part in the management of the critically ill patients having COVID-19 . AnticoaConvalescent plasma (CP) therapy involves a recovery of blood plasma  from persons who have recuperated from an infection, and its administration to infected patients to improve the clinical outcomes. Patients with resolved viral infection will have high titer of polyclonal antibodies to different viral antigens of SARS-CoV-2 which will neutralize the virus . Some stAs there is no approved treatment for COVID-19 till the present time, the researchers all over the world are working hard in order to find an effective treatment for this pandemic disease. In an attempt to participate in this battle, we proposed some new therapeutic approaches which could be used in the future in the fight against COVID-19, some of which are being studied as future treatment options for other viruses like influenza virus, SARS-CoV, MERS-CoV, and Ebola virus.An interesting therapeutic strategy of blocking the viral entry to the human host cells was proposed by many researchers , 56. BriSmall interfering RNA (siRNA) is a class of double-stranded RNA molecules having length ranged from 20 to 25 base pairs. siRNAs have the ability to regulate the expression of certain genes, by a phenomenon known as RNA interference (RNAi). The siRNA-based therapeutic strategies have been developed and applied for antiviral, anticancer, and genetic diseases . Some prSphingosine 1-phosphate (S1P) is a lipid mediator which has diverse cellular activities. The sphingosine mimics are a group of immunosuppressants that can be used in certain infectious diseases. They can act as agonists of the sphingosine receptors leading to lymphopenia via sequestration of the lymphocytes in the lymph nodes causing immunosuppression. Recent studies have shown the therapeutic efficacy of using S1P in influenza-infected mice . They noRecently, it is found that the severity of SARS-Cov-2 lies partially in its ability to activate the nuclear factor-kappa B. Nuclear factor-kappa B (NF-kB) stimulates the expression of several genes which encodes the production of cytokines leading to the CRS that frequently occurs in patients with COVID-19 . FurtherRecently, there are reports from Cambridge University which suggest that cytokine receptors Fc-fusion proteins can potentially serve as an antibody-like decoy to decrease the excessive levels of cytokines as a strategy of the treatment of COVID-19-infected patients , 60. TheAlthough the main symptoms of patients having COVID-19 are respiratory symptoms like fever, cough, and dyspnea, there are less common symptoms like the headache and some gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Interestingly, it is observed that notable percentage of patients initially presented with those atypical gastrointestinal symptoms. As mentioned before, SARS-CoV-2 binds with ACE2 receptors which are highly abundant in the epithelia of both lungs and intestine of healthy individuals. Further analysis revealed that exposure of the epithelial cells of the small intestine to foreign pathogens significantly increased the expression of ACE2. Mutations in the ACE2 receptor may decrease expression of the antibacterial peptides in the cells of the intestine leading to changes in the intestinal microecology. Thus, researchers supposed that COVID-19 may have an effect on the intestinal flora by the ACE2 receptor . Recent Targeting the host genes which are necessary for the viral growth and replication is called host interactome  which isOver the years, much research on coronaviruses has been conducted and produced various treatment strategies. Such results are likely to be applied to SARS-CoV-2 or any other evolving coronavirus in the future. With the continued hard efforts to prevent spread of SARS-CoV-2 globally, we hope that this pandemic disease will subside in a few months like SARS and MERS. Yet, this outbreak highlights the urgent need to design and produce new treatment strategies to fight against coronaviruses. Currently, our immediate action must be to achieve the infection control measures in order to prevent further worldwide transmission of COVID-19 and parallel conduction of clinical trials on the proposed therapeutic options.The increased number of people infected with SARS-CoV-2 all over the world and the associated increase in the mortality rate is an important public health issue. As the number of COVID-19 cases increase, the disease control become more difficult particularly that we have no effective drugs against COVID-19. In the current review, we presented some therapeutic strategies that could be used for the current and future treatment of SARS-CoV-2 infection. Nevertheless, further research and clinical studies would elucidate the significance of the findings of the current review.