key: cord-0814551-4fx8prm3 authors: Søfteland, John M.; Friman, Gustav; von Zur‐Mühlen, Bengt; Ericzon, Bo‐Göran; Wallquist, Carin; Karason, Kristjan; Friman, Vanda; Ekelund, Jan; Felldin, Marie; Magnusson, Jesper; Haugen Löfman, Ida; Schult, Andreas; de Coursey, Emily; Leach, Susannah; Jacobsson, Hanna; Liljeqvist, Jan‐Åke; Biglarnia, Ali R.; Lindnér, Per; Oltean, Mihai title: COVID‐19 in solid organ transplant recipients: A national cohort study from Sweden date: 2021-05-06 journal: Am J Transplant DOI: 10.1111/ajt.16596 sha: 5d9f0130837df1ace59bc57e93559e06acb35f0c doc_id: 814551 cord_uid: 4fx8prm3 Solid organ transplant (SOT) recipients run a high risk for adverse outcomes from COVID‐19, with reported mortality around 19%. We retrospectively reviewed all known Swedish SOT recipients with RT‐PCR confirmed COVID‐19 between March 1 and November 20, 2020 and analyzed patient characteristics, management, and outcome. We identified 230 patients with a median age of 54.0 years (13.2), who were predominantly male (64%). Most patients were hospitalized (64%), but 36% remained outpatients. Age >50 and male sex were among predictors of transition from outpatient to inpatient status. National early warning Score 2 (NEWS2) at presentation was higher in non‐survivors. Thirty‐day all‐cause mortality was 9.6% (15.0% for inpatients), increased with age and BMI, and was higher in men. Renal function decreased during COVID‐19 but recovered in most patients. SARS‐CoV‐2 antibodies were identified in 78% of patients at 1–2 months post‐infection. Nucleocapsid‐specific antibodies decreased to 38% after 6–7 months, while spike‐specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score. This may be due to, in part, immunosuppressive treatment and frequent comorbidities. A recent meta-analysis reports an overall mortality of 18.6% among SOT recipients. 1 However, three relatively large studies from different countries [2] [3] [4] have reported a mortality rate of around 10%, which is lower than observed in other extensive studies on SOT recipients with COVID-19. [5] [6] [7] [8] [9] [10] This heterogenicity may be due to inherent shortcomings of singlecenter reports 11 or limitations of registry studies. 12 The majority of previously reported cohorts included a high proportion of hospitalized patients who are more likely to have severe disease. Outpatients who have less severe symptoms and better prognosis may have been missed, which could partly explain the difference between studies. This inconsistency of available data confounds interpretation of the impact of COVID-19 on the transplanted patient population. Large and detailed studies of the relationship between patient management and outcomes, preferably in a multicenter setting, are crucial to creating efficient guidelines for managing affected transplant recipients. Furthermore, it is essential to explain how age, sex, body mass index (BMI), immunosuppression, and comorbidities affect the clinical course and outcomes. COVID-19 is known to have adverse effects on renal function, 13 and it is important to understand how this affects transplanted patients, particularly those with a renal graft. Lastly, given the rapid development of vaccines, it is crucial to examine whether patients on immunosuppressants can mount an adequate and lasting serological response. Sweden has a highly developed, universally free, public healthcare system. While it was strained in the spring and autumn of 2020, it was not overwhelmed. From a policy viewpoint, the country has tackled the pandemic differently from many other countries, with no mandatory lockdowns and fewer obligatory restrictions. Authorities emphasized general recommendations concerning hygienic measures and social distancing to reduce the spread of the infection in the population. Transplant recipients were initially encouraged to follow the agestratified general recommendations from the public health agency without any additional self-isolation practices. This report describes the Swedish national experience with COVID-19 in SOT recipients, accumulated at Sweden's transplant centers. We present a national perspective on the patient variables, clinical management, outcomes, renal function, and serological response. The present study included all known SOT patients with real-time polymerase chain reaction (RT-PCR) confirmed COVID-19 diagnosed between March 11 and November 20, 2020 (n = 230). Patients were identified through a dedicated COVID- 19 were collected and analyzed. The assessment of comorbidities was performed using the non-age-adjusted Charlson comorbidity index decreased to 38% after 6-7 months, while spike-specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score. clinical research / practice, health services and outcomes research, immunosuppressant, infection and infectious agents -viral, infectious disease, kidney (allograft) function / dysfunction, organ transplantation in general, patient characteristics, patient survival (CCI). 14 CCI includes 19 different medical conditions, and each comorbid condition is ranked from 1 to 6 points to sum an index score. Patients were allocated to one of the three categories (0, 1-2, and ≥3). Disease severity was classified as mild, moderate, severe, and critical, as defined by the COVID-19 Treatment Guidelines Panel of the National Institutes of Health. 15 Comparisons of laboratory results were made between patients with mild/moderate versus severe/critical. The National Early Warning Score 2 (NEWS2) was registered upon contact with the healthcare provider. 16 NEWS2 is used to score physiological parameters and includes the respiratory rate, oxygen saturation, need for supplemental oxygen, body temperature, blood pressure, heart rate, and consciousness. Patients were allocated to one of the three categories (0-2, 3-5, and ≥6). Kidney function was expressed as estimated glomerular filtration rate (eGFR) using the creatinine-based Modification of Diet in Renal Disease (MDRD) formula. We defined baseline eGFR as the most recent measurement before the debut of COVID-19 symptoms and compared it to the lowest eGFR during COVID-19 and eGFR at the most recent outpatient visit (0.5-8 months). A reduction >35% during COVID-19 and a failure to attain at least 90% of baseline at follow-up were noted. Antibody results were received from accredited virology labora- Statistical analyses were performed using JMP 10 RT-PCR test. Thus, the cumulative incidence of COVID-19 among Swedish SOT recipients was 2.3%. Divided by organ type, the infection affected 162 kidney-, 35 liver-, 17 heart-, and 16 lungtransplant recipients. Of these, 19 patients had multiple transplants (Table S1 ). Among the 230 included patients, 17 (7.4%) had been re-transplanted. The mean patient age was 54.0 (13.2) years, 64% were male, and the median BMI was 26.9 (15.2-42) kg/m 2 . Baseline and clinical characteristics of the study cohort are detailed in Tables 1 and 2, respectively. All patients included in this study were evaluated for at least Of the 147 inpatients, a total of 125 patients were discharged alive (85%) (Figure 1 ). Survival among patients presenting with mild, moderate, severe, and critical disease was >99%, 93%, 95%, and 56%, respectively. Total 30-day all-cause mortality among liver transplant recipients was 17.1%, kidney transplant recipients, 9.3%, heart transplant recipients, 5.9%, and lung transplant recipients, 0% (Table S1) . The associations between different factors and 30-day all-cause mortality are presented in Table 4 . Mortality increased along with older age groups, male sex, and increasing BMI categories but not higher CCI scores. There was a tendency toward worse outcomes during the pandemic's first wave, but this did not reach significance (p = .08). No patients infected within 1 year after organ transplantation died. In addition, we analyzed the impact of different NEWS2 scores on death using NEWS2 score 0-2 as a reference. The risk for death increased along with a higher NEWS2 score ( Among hospitalized patients, 49 were initially managed as outpatients but deteriorated and required inpatient care within 2 weeks from their initial contact with healthcare providers (Figure 1 ). Of these 49 patients, 13 presented to the emergency department with mild, 10 moderate, 16 severe, and 10 with critical disease. In all, 31 patients required oxygen therapy (13 NC, 11 HFNC, and 7 MV), 14 were admitted to the ICU, and five patients died. Predictors of transition from outpatient to inpatient status due to clinical deterioration included higher age, higher CCI score, and male sex, but not BMI (Table 7) . greater relative decrease in eGFR than women (p = .019). There was no difference between the ability to return to baseline eGFR based on sex or organ type (Table S3) The serologic response to SARS-CoV-2 nucleocapsid (N) and spike (S) antigens was assessed in 117 patients during follow-up using several different antibody assays ( The present report is the first in-depth, long-term, nationwide analysis of COVID-19 in solid organ recipients from a country with a high incidence of infections. The total 30-day all-cause mortality in this study (9.6%) was lower than that observed in most previous reports on SOT recipients 1 but higher than the general Swedish population during the same period (3.1%). 17 However, the cumulative incidence of PCR confirmed SARS-CoV-2 infections among Swedish SOT recipients during the study period were comparable to that of the general Swedish population, 2.3% vs. 2.0%, respectively. Therefore, any differences in the case-fatality rate between these two populations Although reducing immunosuppressants has become an essential part of transplanted patients' management, this was applied to a lesser degree in Sweden than in other countries. 3, 5 Over half of the patients continued with their regular immunosuppressive regimen, and reductions were uncommon in outpatients. In part, this may be explained by the high frequency of mild disease. It could also reflect an attitude of watchful waiting facilitated by frequent patient contact and iterative reassessments of outpatients. Antimetabolites were the first drugs to be reduced or withdrawn, followed by CNI. The degree of reduction occurred in parallel with the gravity of the COVID-19 infection, except steroids, which were usually increased along with increasing disease severity. This approach seems to have yielded good overall outcomes without increasing the risk for rejections during the hospital stay and resulting in mostly mild and infrequent rejection episodes during follow-up. Although a recent analysis has suggested a protective effect of tacrolimus among transplanted patients, 27 this finding could not be confirmed in the present cohort. Our analysis confirms that a high proportion of transplanted patients mount an antibody response to COVID-19. 28, 29 While Nspecific antibodies decrease rapidly, S-specific antibodies are more durable, showing similar longevity as the general population. 30, 31 Hence, this finding is promising when utilizing S-antigen-based vaccines in the SOT population. In the present study, we did not identify any cases of RT-PCR confirmed reinfection during follow-up. However, we did find one patient whose antibody levels suddenly increased following typical but mild symptoms 6 months after the primary infection, despite negative RT-PCR (data not shown). The study's extended follow-up time also allowed us to study renal function, which declined during the illness but had returned to baseline values in the majority of patients during follow-up. However, 14% of patients did not return to baseline levels suggesting a minority of patients may suffer from long-lasting renal impairment as a complication after COVID-19. Somewhat surprisingly, kidney graft recipients were not overrepresented in this group (Table S3) . We identified five episodes of rejection in kidney recipients during the follow-up period, but many patients with renal grafts and eGFR below baseline values were not assessed for rejection. Furthermore, no negative biopsies were identified during follow-up. This study has several strengths, including a broad, national coverage, completeness of variable data, and extended follow-up. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score. The study was financed by grants from The Kidney Foundation The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. The data that support the findings of this study are available from the corresponding author upon reasonable request. John M. 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