key: cord-0947035-n3zwd9mu authors: Emara, M. M.; Elsedeiq, M.; Elmorshedi, M.; Neamatallah, H.; Abdelkhalek, M.; Yassen, A.; Nabhan, A. title: COVID-19 in 823 Transplant patients: A Systematic Scoping Review date: 2021-01-20 journal: nan DOI: 10.1101/2021.01.18.21250025 sha: 9177f1c177af6aac0ea7b7bd2e9c61351518175a doc_id: 947035 cord_uid: n3zwd9mu Abstract Background: Management of COVID-19 in transplant patients is a big challenge. Data on immunosuppression management, clinical picture, and outcomes are lacking. Objectives: To summarize the current literature on COVID-19 in transplant patients especially the data regarding the immunosuppression protocols, clinical presentation, and outcomes. Search strategy: A systematic search of MEDLINE, EBSCO, CENTRAL, CINAHL, LitCovid, Web of Science, and Scopus electronic databases. The references of the relevant studies were also searched. The search was last updated on June 3, 2020. Selection Criteria: Primary reports of solid organ transplant patients who developed COVID-19. An overlap of cases in different reports was checked. Data collection and analysis: A descriptive summary of immunosuppression therapy (before and after COVID-19), clinical presentation (symptoms, imaging, laboratory, and disease severity), management (oxygen therapy, antiviral, and antibacterial), major outcomes (Intensive care admission, invasive mechanical ventilation, acute kidney injury), and mortality. Main results: We identified 74 studies reporting 823 cases of solid organ transplantation with COVID-19. Among 372 patients, 114 (30.6%) were mild COVID-19, 101 (27.2%) moderate, and 157 (42.2%) severe or critical. Major outcomes included intensive care unit admission, invasive ventilation, and acute kidney injury, which occurred in 121 (14.7%), 97 (11.8%), and 63 (7.7%) of patients, respectively. Mortality was reported in 160 (19.4%) patients. Missing individual data hindered making clinical correlations. Conclusion: COVID-19 in solid organ transplant patients probably has a more disease severity, worse major outcomes (Intensive care admission, invasive ventilation, acute kidney injury), and higher mortality than in non-transplant patients. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint 5 (7.7%) of patients, respectively. Mortality was reported in 160 (19.4%) patients. Missing individual data hindered making clinical correlations. Conclusion: COVID-19 in solid organ transplant patients probably has a more disease severity, worse major outcomes (Intensive care admission, invasive ventilation, acute kidney injury), and higher mortality than in nontransplant patients. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the clinical syndrome called COVID-19. Infections in organ transplant patients are of special concern due to lifelong immunosuppression, common comorbidities, and the effects of some immune suppressants (diabetogenesis, neutrocytopenia, or lymphopenia). 1 Reports are controversial regarding the clinical presentation and outcomes in those patients in comparison to the general population. The ideal management of immunosuppressive therapy during COVID-19 in transplant patients is unclear. The balance between the increased risk of infections and graft rejection is vital. Theoretically, immunosuppression may reduce the cytokine storm syndrome -a major pathology in COVID-19 -and calcineurin inhibitors (CNI) reduce in vitro viral replication. 2 The lack of data in the time of the COVID-19 pandemic pushed us to systemically review and summarize the available knowledge of COVID-19 in transplant patients, especially as regards the immunosuppressive management, clinical presentation, and major outcomes (admission to Intensive Care Unit (ICU), invasive mechanical ventilation (MV), acute kidney injury (AKI)), and mortality. This review followed the Arksey and O'Malley framework for scoping reviews and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA)extension for scoping review. 3, 4 . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint We searched the list of references for the selected study and contacted authors of published reports for additional information. The detailed search strategy is supplemented in the file (S1). Two authors (MME and MEs) independently screened the titles and abstracts of the primary search results, then reviewed the full relevant articles. We included any article reporting original research on organ transplant patients with COVID-19. The diagnosis of COVID-19 was considered either by clinical, radiological, or reverse-transcription polymerase chain reaction (rt-PCR). We reported case severity as reported in the primary studies. If MME and MEs could not agree on the inclusion of any study, a third reviewer's opinion (AY or AN) was asked. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint A data-charting electronic sheet was developed by MME and revised by all authors. Two authors (MEs and HN) independently extracted data and (MEm and MA) continuously updated the datasheet. Then, the data was collated by MME. We extracted the following data: (1) General data (title, year of publication, authors, and country); (2) Methodological data (study design, sample, and patient characteristics -e.g. age, the transplanted organ, from living or deceased donor, duration since transplantation); (3) Immunosuppressive therapy (before and after COVID-19); (4) Clinical data (clinical presentation, imaging, laboratory investigations, and disease severity); (5) Management including (oxygen therapy, antiviral, antibacterial, mechanical ventilation); (6) Outcomes (ICU admission, Invasive MV, AKI, mortality). This scoping review did not include a critical appraisal of the primary studies. We organized our results in categories: immunosuppression, the clinical presentation including severity, and major outcomes. We presented the results as number (%) based on the available data. We identified 74 primary studies reporting 823 organ transplant cases who developed COVID-19 after organ transplantation. (Figure 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint 9 These reports included 617 kidney, 98 liver, 59 heart, 31 lung, 17 combinedorgan transplants, and 1 pancreas. We tabled the studies according to the study design, country, and the number of cases (Table 1) . Demographic data Adult patients' age ranged from 19-81 years. Seven pediatric patientsaged 6 months, 3 years, 4.5 years, 13 years, and 3 with unavailable age datawere also reported. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. Clinical presentation, diagnosis, and case severity The most common symptoms were fever (n= 577, 70%), cough (n= 520, 63%), dyspnea (n= 277, 33.7%), diarrhea (n= 153, 18.6%), myalgia (n= 105, 12.7%), and fatigue (n= 104, 12.6%). While, anorexia, loss of smell or taste, sore throat, nausea, and nasal congestion were infrequent (6.8%, collectively). SARS-CoV-2 was confirmed with rt-PCR in 300 cases (36.5%). Chest x-ray and computed tomography (CT) scans showed abnormalities at the time of presentation in 255 (31%) and 97 (11.8%), respectively. Radiological findings were variable (bilateral or unilateral) in the form of ground-glass opacity, interstitial thickening, or infiltration. Lung ultrasound was available only in one . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint case that showed progressive thick and confluent B lines, which improved with patient improvement. 9 Sixty patients and twelve cases showed no abnormalities in chest x-ray and CT scans, respectively, at the time of is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint Oxygen therapy was reported in 212 patients (53 nasal cannulas, 20 noninvasive ventilation (NIV), 13 high-flow nasal cannula, and 126 non-specified) and 46 cases reported no oxygen therapy. One-hundred and twenty-one (14.7%) cases required ICU admission and 97 (11.8%) were mechanically ventilated. Acute kidney injury (AKI) developed in 63 (7.7%) of cases. Twenty-two (35%) were kidney, 14 (22.2%) liver, 14 (22.2%) heart, 1 lung, and 12 non-specified organ transplant. De novo dialysis started in 29 (3.5%) cases (14 kidney, 5 heart, 1 lung, and 9 non-specified organ transplant patients) and extracorporeal membrane oxygenation (ECMO) in 3 patients. Mortality was reported in 160 (19.4%) of cases. None of the 7 pediatric patients in our cohort died. Of those 160 patients, 104 were kidney-transplant patients, 20 liver, 9 heart, 1 lung, and 26 non-specified organ-transplant patients. The is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. Table 4 presents the common presentations of those patients versus nontransplant COVID-19 patients. 81 Diarrhea was more frequent in transplant patients with COVID-19 (18.6% versus 3.8%); however, some reports showed a higher incidence of diarrhea in COVID-19 non-transplant cases. 82 In a report of 90 organ transplant recipients, the incidence of diarrhea was even higher . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint 14 (31%). 48 This may be attributed to MMF, which causes diarrhea. 83 Diarrhea may be also associated with COVID-19 severity and the need for MV. 81 Fatigue was less common in the transplant population (12.6% vs 38%). Dyspnea is the third common in both groups with a greater presence in transplant, 33.7 % vs 18.7% in non-transplant patients. In Covid-19 patients, dyspnea upon presentation is associated with a severe clinical course. 48 This may be a marker of pulmonary disease severity in transplant recipients. Among 442 available laboratory results, 90% of transplant patients showed lymphopenia vs 83.2% in the non-transplant population. 81 Lymphopenia is associated with more ARDS, ICU admission, higher troponin, and more myocardial injury, and death. 84 According to our findings, elevated CRP, D-dimer, ferritin, troponin, and LDH were higher in transplant patients when compared with the general population. 81 Elevation of some or all of these parameters is associated with a severe COVID-19 course and a more unfavorable outcome. 48, 81 Unfortunately, among our 823 cases, we could identify the disease severity of only 372 patients. Classification of severity was different between reports; some classified cases as mild, moderate, and critical, while others classified cases as mild, moderate, and severe. 5,48 Therefore, we collected severe and critical cases in the same category as severe or critical illness. In our review, 42.2 % of reported patients were severe or critical, which is significantly higher when compared with the general population (15.7%). 81 In a large nontransplant Chinese cohort, severe cases represented 14% and critical cases represented 5%. 85 This copes with that immunosuppressed transplant recipients are at a higher risk for severe COVID-19 course. 79 . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint the outpatient settings. This decision should be taken case-by-case keeping in mind the comorbidities and ability of rapid transfer to a transplant center in case of deterioration. 87 Chloroquine, hydroxychloroquine, and various antiviral therapies were commonly used despite the lack of evidence and the known interactions with CNI. 87 We had some limitations in our scoping review. This report only included case-reports, case series, and one case-control study; however, this was the best available data. Missed individual data and the aggregate data from the case series hindered us from extracting proper associations between case severity, immunosuppression protocol, and major outcomes. Our reporting was only up to the date of June 3, 2020. We did not include a critical appraisal of the primary reports. Patient duplication should be minimal as we traced cases carefully and contacted authors for primary source overlap. In conclusion, our results suggest that COVID-19 in transplant patients has a more severe course, worse major outcomes (ICU admission, Invasive MV, AKI), and higher mortality than non-transplant patients. Additional supporting information may be found online in the Supporting Information Section at the end of the article. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm? 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Hematological findings and complications of COVID-19 Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Outpatient Management of the kidney transplant recipient during the SARS-Cov-2 virus pandemic It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted January 20, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted January 20, 2021. ; https://doi.org/10.1101/2021.01.18.21250025 doi: medRxiv preprint