key: cord-0728495-5lr7yirs authors: Monaco, Andrea; Manzia, Tommaso Maria; Angelico, Roberta; Iaria, Giuseppe; Gazia, Carlo; Al Alawi, Yousef; Fourtounas, Konstantinos; Tisone, Giuseppe; Cacciola, Roberto title: Awareness and Impact of Non Pharmaceutical Interventions during COVID-19 Pandemic in Renal Transplant Recipients. date: 2020-07-21 journal: Transplant Proc DOI: 10.1016/j.transproceed.2020.07.010 sha: fd3289bb299a8dc3bf95b64eac6f09994e7c9dc3 doc_id: 728495 cord_uid: 5lr7yirs Abstract The concerns generated by Coronavirus Disease 2019 (COVID-19) pandemic are having profound impact on Solid Organ Transplantation (SOT). The Non Pharmaceutical Interventions (NPI) are currently the only measures available to contain COVID-19 in the general population and in more vulnerable recipients of any organ transplant. In this cross-sectional case control study from a patient survey, undertaken in two Transplant Centers (TxC) in the Kingdom of Saudi Arabia and Italy, we aimed to appraise the awareness of the NPI implemented by respective Governments. We have also evaluated the impact of COVID-19 on our Kidney Transplant (KT) Recipients and a control group of Kidney Living Donors (KLD). in the survey demonstrated excellent awareness of the NPI. In our series there were zero cases of COVID-19 among 111 KT recipients and 70 KLD of the control group. Demography, transplant type, immunosuppression regimes and, as importantly, the different COVID-19 prevalence in the two regions of the TxC, did not appear to influence incidence of COVID-19 in our KT recipients. The absence of COVID-19 cases in our series was unexpected. Our findings suggest that awareness of NPI is associated with a successful containment of COVID-19 in vulnerable, immunosuppressed KT recipients. The pandemic is not sparing any country; however, the observation that some countries are affected less than others, is a matter of constant comparison and analysis. Interestingly, also large Regions part of the national territory of Countries afflicted by relevant incidence of COVID-19 are relatively spared by the pandemic. Italy and the Kingdom of Saudi Arabia (KSA) are witnessing different incidence of COVID-19 with substantially different rates of mortality and hospitalization. Furthermore, the two TxC involved in this study, linked by an ongoing collaboration, are located in regions with remarkably different incidence of COVID-19, compared to their respective national averages. The growing concerns of Severe Acute Respiratory Syndrome due to Coronavirus 2 (SARS-CoV-2) transmission, led to the suspension or restriction of SOT to immediately life-saving procedures 1 The legitimate concerns are accrued by the absence of specific antiviral treatment and vaccination against COVID-19. In this context, the Non Pharmaceutical Interventions (NPI) represent the main measures that can be applied to protect the wider population 4,5 and in particular to shield the more vulnerable, immunosuppressed recipients of any organ transplant. In our observational study we appraised the level of awareness of NPI, implemented by respective Governments in the KSA and Italy, of the KT recipients in both institutions. Subsequently, we have evaluated the impact of COVID-19 on our KT recipients. The analysis included also a control group of patients who were not immunosuppressed; for this purpose we extended the same evaluation on the Kidney Living Donors (KLD) of both institutions. Finally, our study aimed to assess whether the KT recipients hosted different outcomes in substantially different geographic areas with different incidence of COVID-19. Since the COVID-19 was declared a pandemic, the governments of the KSA and Italy promulgated emergency legislation aiming to guarantee the containment of the COVID-19 spread by the implementation of the NPI. Both countries adopted similar policies on the use of NPI, which are summarized in table 1. We evaluated all the KT Recipients attending the post-transplant follow-up clinics at the TxC of King Salman Armed Forces Hospital (KSAFH) in Tabuk, KSA and Tor Vergata University Hospital (TVUH) in Rome, Italy. We did not apply any clinical selection criteria. In order to create a control group of non-immunosuppressed patients, we evaluated also the KLD of our patients who received a LDKT. We designed a survey based on the available evidence on COVID-19 and its impact on SOT, focusing more specifically on KT recipients. We reviewed the NPI aimed to contain COVID-19 implemented in the recent legislation of the KSA and Italy (Table 1) . The questionnaire aimed to appraise the awareness of NPI, as well as to cover clinically relevant events related to COVID-19, over a period of thirteen weeks, extending from 1st February 2020 to 3rd May 2020. These dates embrace the time period, extending from the day after the WHO declared COVID-19 a global Health Emergency to the relaxation of strict restrictions enabled by the Government of the KSA and Italy. The survey was structured following discussion with the lead clinicians of both institutions in the KSA and Italy. The final version of the survey was approved by the lead clinicians and wider transplant team members involved in the study, including nurse specialist, nephrologist and transplant surgeons. The survey started on 4th May 2020 and it was completed on 18th May 2020; it was carried out by telephone or in person during attendances at follow-up clinics. Our specialist nurses and junior staff with consultant supervision have carried out the survey in both institutions. The information regarding the type and date of transplant, induction and maintenance immunosuppression were obtained from our out-patient clinic database and cross referenced with our patients during the survey. The survey was articulated in two main areas of questions aimed to achieve a cross sectional analysis of NPI awareness and clinical status of KT recipients, members of their household, and KLD in relation to the COVID-19 pandemic. In the first area of the survey we focused on the appraisal of KT recipients and KLD on their awareness of the NPI aimed to prevent COVID-19. All patients underwent two screening questions to evaluate their knowledge of the current pandemic and vulnerability as recipient of SOT. Subsequently, we enquired on their awareness of the NPI. The second area of the survey aimed to identify any clinically relevant events related to COVID-19, occurred to KT Recipients, members of their household and KLD. Those events included the observation of any symptoms suggesting COVID-19, including any combination of fever, dyspnoea, headache and anosmia 6 . We enquired of any admission to hospital with pneumonia and whether the patient was tested for COVID-19. All the answers to the questions were also cross-referenced with our electronic hospital record systems. The official data of the Ministry of Health in the KSA 7 and Italy 8 were extracted from the open access database in order to calculate Regional incidence of COVID-19 cases. The same official Ministerial data in conjunction with official census data were used in order to calculate the regional prevalence of COVID-19. In the first qualitative area of the survey, the awareness of NPI was considered as independent single outcome and analyzed as unique event. After the completion of the survey, we scored the awareness of KT recipients and KLD for each group of NPI with a mark of 1 or zero according to their answers. The scoring system is summarized in table 2. The total score obtained from the answers to each group of NPI was categorized as poor if zero to two, acceptable if scored three, good if it was four, excellent if it scored five. In the second quantitative area of the survey, the KT Recipients characteristics were first analyzed separately by type of transplant, either LDKT or DDKT. Subsequently, we merged LDKT and DDKT in one single group of KT recipients and compared their clinical outcomes with the control group of KLD. Where appropriate Fischer's exact and chi square was performed, using SPSS program. We reported a significance level using p<0.05. The Regional differences of reported COVID-19 cases and related mortality were also analyzed with G Test. One hundred-eleven KT Recipients participated to the survey (LDKT=58/111 [52.2%] and DDKT= 53/111 [47.8%]). Characteristics of the study population are reported in Table 3 . The median follow-up from transplantation was 14 (IQR 9-33) months for the patients in the LDKT group, and 8 months (IQR 5-11) for the DDKT group. The median age of LDKT and DDKT recipients were 35.5 years (IQR 28-51) and 56 years (IQR 47-63) respectively (p<0.001). The induction immunosuppression with Thymoglobulin (ATG) was significantly different in the LDKT group (p<0.001); as well as the avoidance of induction immunosuppression in DDKT group (p<0.001). There were no differences in the maintenance immunosuppression regimes ( Table 3 ). All patients in both LDKT and DDKT groups are fully adherent to their medications and follow-up clinic attendance. The control group consisted of seventy KLD; the majority are male 51/70 (72.8%) with a median age of 33 (IQR = 27-41.65) years. The median follow-up after the donor nephrectomy was 23 (IQR = 9-32) months. All KT recipients and KLD had a highly successful appraisal of the NPI implemented by the respective Governments. The level of awareness was evaluated as Excellent (5/5) in both KT Recipients and KLD Groups (Table 4 ). Our survey has shown that in the study period, 111/111 (100%) of our KT recipients (LDKT and DDKT) were COVID-19 free, with zero case of SARS-CoV-2 infection reported and zero hospital admissions. Symptoms that could have raised concerns of possible COVID-19 infection were observed in 11/111 (10%) KT recipients; of whom only one patient reporting all symptoms of fever, cough, headache and anosmia. The patient had a negative test for COVID-19 and developed a spontaneous regression of symptoms after 24 hours, without requiring hospital admission. In the study period 5 (4.5%) KT Recipients were admitted to hospital with pneumonia that resulted negative to COVID-19. Similarly, also the control group of KLD has shown that 70/70 (100%) were COVID-19 free, with zero cases reported and zero hospital admissions. Among the members of the households of the survey participants there were no reported cases of COVID-19. Out of these, there was one case of hospital admission with pneumonia who tested negative for COVID-19 and one case who reported symptoms of cough and fever but not requiring hospitalization, who was not tested. The COVID-19 pandemic had very different impact in the two regions of the two TxCs (Table 5 ). In the North-West Region the COVID-19 cases represented 1.15% of the total cases reported in the KSA 6 . Whereas, in the Lazio Region the COVID-19 cases represented 3.23% of the total cases reported in Italy 7 . The calculated COVID-19 prevalence was respectively 0.013% in North-West Region of the KSA, and 0.11% in the Lazio region. Notably, the number of cases and mortality in the two Regions was statistically significant (p=0.001). Our survey was prompted by the concerns generated by a growing number of case reports and database analysis 15 , indicating an increasing morbidity and mortality of KT recipients from COVID-19. Notably, preliminary report from countries heavily affected by the pandemic have indicated a mortality rate ranging between 21-23% among KT recipients with COVID-19 8 . We are conscious that the voluntary information conveyed by our patients through the survey may represent a limiting factor. However, we validated the clinically relevant data of the survey reviewing our hospital database, both hospitals are referral centres in the region for all their respective KT Recipients. The absence of COVID-19, associated with excellent awareness of NPI, among our KT recipients and KLD was a major relief; as much as it was unexpected. The successful implementation of NPI is strongly linked to the behavior of the population 9 ; certainly, during the pandemic we have observed a major national effort in developing the necessary awareness aimed to safeguarding everyone, as well as shielding the most vulnerable individuals. The correct divulgation of the risks related to COVID-19 together with the implementation of clear NPI, aiming to contain COVID-19, have undoubtedly contributed to the development of a collective responsibility in both countries. Such event reinforces the concept that patient awareness and associated adherence to medical advice represents a useful metric of future clinical outcomes, including the attention to public health matters 10 . Similarly, it has been demonstrated that high levels of awareness are linked with a diligent adherence to medication and protocols 11 . The recipients of any organ transplant currently represent one of the most vulnerable categories of our society. Therefore, ensuring that our KT recipients with the members of their households have a sufficient awareness, may represent an effective measure to enhance their safety during the COVID-19 pandemic. In the period of our study, the NPI were also enforced by new legislation, urgently brought forward by the respective Governments. It certainly explains the excellent awareness we have observed in the appraisal of our patients. In our opinion, it is also possible that the excellent awareness and reported adherence to NPI of our patients, might have also been favored by the geographical and temporal distance from the National and Global epicenters of COVID-19. In our study there is the possibility of a non-intentional bias, represented by the fact that our cohort of patients may be a self-selected group of highly compliant individuals. In point of fact, our KT recipients are conscious of the risks linked to the immunosuppression regimes they follow. Italy. However, the hypothesis of a progressive weakening of COVID-19 is currently strongly debated and it remains to be fully demonstrated 13 . In our series, the absence of COVID-19 cases was not influenced by the demography of our patients or by the type of transplant received; either a LDKT or DDKT. Also, the induction and maintenance immunosuppressive regimes did not appear to affect, at present, the incidence of COVID-19 in our cohort of patients. Although our survey did not reveal any differences between recipients of a LDKT with those who received a DDKT, we cannot state with confidence that all KT recipients may have both the same risk of Considering the uncertainty dictated by the risks of a second wave of pandemic, it may be taken under careful consideration, as well as a realistic option, the possibility of channeling SOT in those regions and TxC with lower incidence of COVID-19. In particular, conveying LDKT to safer "Hubs" may be amenable, also it may host the added benefit of preserving the viability of the Kidney Paired Donation schemes already in place. Necessarily, future collaborations between TxC will require the creation of new Transplant Consortia and Alliances able to operate at Regional, Trans-Regional, National and even International level. The challenges posed by COVID-19 are bound to influence SOT activity worldwide for the foreseeable future and till when effective remedies may be available. The international transplant community is facing a remarkable and unexpected dilemma; weighing risk avoidance and cautious risk management. Undoubtedly, we will need the prompt implementation of innovative, comprehensive and adequate strategies, aimed to mitigate the secondary mortality caused by the reduction of SOT inflicted by the current healthcare crisis. 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I also acknowledge that if accepted, I am responsible for all manuscript page charges, which will be billed to me by Elsevier, the publisher of Transplantation Proceedings, at the rate of US$99.95 per submitted manuscript page, understanding that each Table and Figure Additionally, I agree that this manuscript has not been submitted or published in any other journal, including Transplantation Proceedings, and no parts of the manuscript are duplicated. I understand that if the manuscript is accepted for publication, copyright of the manuscript is transferred to Elsevier. Printed Name (family name in bold) Printed Name (family name in bold) of person to be invoiced Signature of Person to be invoiced: Early Impact of COVID-19 on Transplant Center Practices and Policies in the United States World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 -11 outbreak in Italy: initial implications for organ transplantation programs Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand Effects of non-pharmaceutical interventions on COVID-19 cases, deaths, and demand for hospital services in the UK: a modelling study Registry -COVID-19: Information on Registry Initiatives Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study An Appraisal of the Level of Awareness and Utilization of the Pap Smear as a Cervical Cancer Screening Test Among Female Health Workers in a Tertiary Health Institution Johan W de Fijter Medication Non-Adherence After Kidney Transplantation: A Critical Appraisal and Systematic Review Transplant Rev (Orlando) Effect of non-pharmaceutical interventions to contain COVID-19 in China Profile of a Killer: The Complex Biology Powering the Coronavirus Pandemic Two Distinct Cases With COVID-19 in Kidney Transplant Recipients We thank our colleagues Mr. Majed Lafieid, Ms. Maha Suliman Almshouri, Ms Bedoor Salem Alatawi, Ms Amani Basher Albalawi who provided insight and expertise that greatly assisted the research, and for the assistance with database work and patient contact. 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