Journal Logo

Original Clinical Science—General

Initial Report From a Swedish High-volume Transplant Center After the First Wave of the COVID-19 Pandemic

Felldin, Marie MD, PhD1; Søfteland, John Mackay MD, PhD1,2; Magnusson, Jesper MD, PhD1; Ekberg, Jana MD1; Karason, Kristjan MD, PhD1,3; Schult, Andreas MD1,3; Larsson, Hillevi MD, PhD4,5; Oltean, Mihai MD, PhD1,2; Friman, Vanda MD, PhD6

Author Information
doi: 10.1097/TP.0000000000003436
  • Free

Abstract

INTRODUCTION

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China in late 2019 and rapidly evolved into a global pandemic.1 Most of the infected individuals develop only mild to moderate illness characterized by fever and respiratory symptoms. Still, almost 20% of patients with COVID-19 may develop severe forms of the disease.2 Despite optimal supportive care ranging from oxygen therapy to mechanical ventilation and extracorporeal membrane oxygenation,3 many of the patients developing severe forms of the disease ultimately die.4,5

The majority of solid organ transplant (SOT) recipients developing COVID-19 reported to date have received hydroxychloroquine (HCQ), while a considerable proportion has also received antiviral drugs.6 Several recent reports have indeed indicated significant drug interactions between the immunosuppressant drug tacrolimus and the antivirals lopinavir/ritonavir (LPV/r). These interactions have been proven difficult to manage and may be responsible for adverse effects leading to severe liver and kidney dysfunction as well as neurologic abnormalities.7,8

Due to the lack of clinical benefit for targeted antiviral therapies and their potential serious adverse effects, the Swedish Public Health Agency did not recommend the use of either HCQ or LPV/r in the management of COVID-19 at any point during the pandemic. Until recently, the only therapeutic interventions recommended by the Public Health Agency were optimal supportive measures as summarized by Surviving Sepsis Campaign COVID-19 panel3 and the expert opinion of the European Renal Association—European Dialysis and Transplant Association9 and included prophylactic anticoagulation with low-molecular-weight heparins (LMWHs).

During the first wave of the COVID-19 pandemic, Sweden did not enforce a strict lockdown policy and instead issued recommendations on voluntary self-isolation and social distancing. This strategy has been debated and by some perceived as controversial,10,11 as it resulted in a broad COVID-19 community spread and one of the highest mortality rates in COVID-19 in Europe (552 deaths per 1 million of population as of July 29, 2020). Therefore, it would be reasonable to expect a high infection rate and subsequent mortality in the Swedish transplant population.

We report herein our preliminary experience with the first 53 SOT recipients diagnosed with COVID-19 by June 22, 2020, at the largest Swedish transplant center.

MATERIALS AND METHODS

This study included all the patients transplanted at Sahlgrenska University Hospital, or otherwise belonging to our catchment area, diagnosed with COVID-19 between February 21 (the first COVID-19 case diagnosed in Sweden) and June 22, 2020. In each patient, COVID-19 was diagnosed whenever a patient had typical symptoms (either a temperature >38°C, cough, rhinitis, dyspnea, gastrointestinal symptoms, or a combination of these) and was positive for SARS-CoV-2 RNA with real-time polymerase chain reaction using a throat swab, nasal swab, or in most cases, both. The electronic medical records of the patients were reviewed. Data on demographics, medical history, renal function (estimated glomerular filtration rate), disease course, laboratory test results within 24 hours of diagnosis, comorbidities, treatment measures (changes in immunosuppression, corticosteroid therapies, and respiratory support), and outcomes were collected and analyzed.

Disease severity upon contact with the healthcare provider was classified from mild to critical according to the COVID-19 Treatment Guidelines Panel of the National Institutes of Health.12 Patients with a definitive outcome, that is, death or hospital discharge, were defined as closed cases. Renal function before COVID-19 was estimated using the Modification of Diet in Renal Disease formula. The comorbidity assessment was performed using the age-adjusted Charlson Comorbidity Index (CCI).13 CCI includes 19 different medical conditions, and each comorbid condition ranged from 1 to 6 points to sum an index score. Additional points were added for age, and each decade above the age of 40 years was assigned a comorbidity score of 1. Outcomes were reported after at least 14 days of follow-up, with the end of follow-up on July 14, 2020. The study was reviewed and approved by the Swedish Ethical Review Authority (#2020-02153).

Information on the number of individuals in Sweden developing COVID-19 was retrieved from the website of the Public Health Agency of Sweden (https://experience.arcgis.com/experience/09f821667ce64bf7be6f9f87457ed9aa).

Data are shown as mean ± SD or as median/range or as absolute and relative frequencies as appropriate. Continuous variables were compared using the Mann-Whitney U test. Baseline characteristics were compared between groups with mild, moderate, severe, and critical COVID-19 infection, as defined above. Proportions were compared using the chi-square test. Analyses were performed using GraphPad Prism v. 6 (GraphPad software), and a P < 0.05 was considered significant.

RESULTS

Patients

At the start of the study period, our transplant center had a total of 4578 SOT recipients (2563 kidney transplants, 1131 liver transplants, 449 heart transplants, 339 lung transplants, 80 pancreas transplants, and 16 visceral transplants) who were alive and participated in follow-up. Fifty-three SOT recipients tested positive for SARS-CoV-2: 31 kidney-, 8 liver-, 5 lung-, and 5 heart-transplant recipients. Four patients had multiple transplants, 3 combined kidney-liver transplants, and 1 kidney-after-heart transplant.

Characteristics of all 53 infected SOT recipients are detailed in Table 1. The median age of the patients was 56 years (range 22–70), and the majority of patients were male. Patients were at a median of 83 months (range 1–318) after transplantation; 7 patients were within the first year after receiving their grafts. Two of these patients were diagnosed with COVID-19 within 3 months from transplantation. None of the patients with critical COVID-19 were within 1 year after the transplant. Comorbidities were present in 45 (85%) of patients, with hypertension being the most common (53%), followed by diabetes (28%), cardiovascular disease (21%), and chronic kidney disease (26%). The median body mass index was 29 (range 18.8–42).

TABLE 1. - Patient demographics, management, and outcome in 53 SOT recipients with COVID-19
Transplant type Age (y) Gender Months from transplant Comorbidities eGFR BMI Maintenance immunosuppression Disease severity Oxygen therapy Immunosuppression management Other interventions Outcome
Heart 65 M 120 DM, stroke, CKD 7 26 CyA, MMF, Pred Critical NRB No changes Death
Heart 50 M 132 HTN 85 24 CyA, MMF, Pred Mild None MMF ↓ Outpatient
Heart 64 M 228 HTN, hyperparathyroidism 114 21.3 Tac, MMF, Pred Mild NC Pred ↑ LMWH Discharge
Heart 62 F 128 IHD 40 29 Tac, Eve, MMF, Pred Mild None No changes Discharge
Heart 67 M 148 CKD, CHF, HCV-cirrhosis 12 20 CyA, Eve Mild None No changes Outpatient
Heart-kidney 22 M 276 KTx 2016 78 21 Tac, MMF, Pred Moderate None MMF ↓ Apixaban Outpatient
Kidney 65 M 143 HTN, AF, CHF 43 28 Tac, MMF Critical NC Tac and MMF out Dead
Kidney 58 M 61 HTN 8 30 Tac, MMF, Pred Critical MV MMF out LMWH, CRRT Discharge
Kidney 67 M 52 HTN, aortic aneurysm 20 32 Tac, Pred Critical MV Stress-dose steroids LMWH, tocilizumab, HCQ + azithromax Dead
Kidney 65 M 16 HTN, IHD, sleep apnea 18 37 Tac, MMF, Pred Critical MV Tac ↓, MMF out, steroids iv LMWH, CRRT In hospital
Kidney 61 F 181 HTN, DM 36 38 Tac, AZA, Pred Critical MV Tac ↓, AZA out, steroids iv LMWH, CRRT In hospital
Kidney 56 M 168 HTN 3 35 Cya, MMF Critical MV Cya out, MMF out LMWH, CRRT Dead
Kidney 55 F 240 HTN, DM, IHD, asthma <5 23.7 Tac, MMF, Pred Severe NIV Tac and MMF out Discharge
Kidney 56 F 221 None 42 20 Tac, Pred Severe NIV No changes LMWH Discharge
Kidney 49 M 318 HTN 30 28 CyA, MMF, Pred Severe NC MMF out LMWH Discharge
Kidney 58 M 36 None 42 33 Tac, Pred Severe NC No changes LMWH Discharge
Kidney 56 M 113 HTN, HLP 77 22 Tac, MMF Moderate NC No changes LMWH Discharge
Kidney 69 F 262 HTN 16 33 Tac, Pred Severe MV Tac ↓ LMWH, CRRT In hospital
Kidney 45 M 7 DM, HTN, PAD 43 35 Tac, MMF, Pred Severe NIV MMF ↓, Pred ↑ LMWH Discharge
Kidney 62 M 61 HTN 37 25 Tac, MMF, Pred Severe NC Tac ↓, MMF out, Pred ↑ LMWH Discharge
Kidney 61 M 34 DM 53 25 CyA, MMF, Pred Severe NIV CyA ↓, MMF out LMWH Discharge
Kidney 54 M 9 HTN 25 24 Tac, MMF, Pred Moderate None MMF out LMWH Discharge
Kidney 54 M 296 HTN <5 33 CyA, Pred Moderate None No changes Discharge
Kidney 50 M 65 HTN 50 32 Tac, MMF, Pred Mild None No changes LMWH Discharge
Kidney 60 F 3 HTN 13 29 Tac, MMF, Pred Mild None Tac ↓, MMF out Outpatient
Kidney 45 F 9 HTN, DM 44 30 Tac, MMF, Pred Mild None Tac ↓, MMF out Outpatient
Kidney 50 F 66 None 85 28.5 Tac, MMF, Pred Mild None MMF ↓, Pred ↑ Outpatient
Kidney 35 M 6 HTN, DM 64 29 Tac, MMF, Pred Mild None MMF out LMWH Discharge
Kidney 63 M 10 HTN, DM 33 25 Tac, MMF, Pred Mild None No changes Outpatient
Kidney 41 M 173 AF, ulcerative colitis 23 27 Tac, AZA, Pred Mild None No changes LMWH Discharge
Kidney 48 F 58 HTN 36 38.5 Tac, MMF, Pred Mild None No changes LMWH Outpatient
Kidney 25 F 50 None 70 37 Tac, AZA, Pred Mild None No changes Outpatient
Kidney 31 F 26 HTN 79 34 Tac, AZA, Pred Mild None No changes Outpatient
Kidney 49 F 13 HTN, bipolar disorder 67 22 Tac, MMF, Pred Mild None No changes Outpatient
Kidney 34 M 85 HTN, gout 66 37 Tac, MMF, Pred Mild None No changes Outpatient
Kidney 52 M 281 HTN 45 24 CyA, MMF, Pred Mild None Pred ↑ Outpatient
Kidney 62 F 101 HTN 49 38 Tac Mild None No changes Outpatient
Liver 67 F 149 DM, CKD 43 22.6 Tac, MMF Severe NIV MMF out LMWH, dialysis Dead
Liver 42 F 153 PSC recurrence 73 18.8 Tac, AZA Moderate None No changes LMWH Discharge
Liver 52 F 1 DM, COPD, asthma 36 42 Tac, MMF Mild None MMF ↓ LMWH Discharge
Liver 70 F 28 IHD, DM, hypothyroidism 50 38 Tac, MMF, Pred Mild None MMF out LMWH Discharge
Liver 27 F 299 None 90 20.9 Tac Mild None No changes Outpatient
Liver 68 M 132 Sarcoidosis 58 24.6 Tac, Pred, MTX Mild None MTX out Discharge
Liver 62 F 41 Polymyalgia rheumatica 67 19.2 Tac, MMF, Pred Mild None No changes Outpatient
Liver 72 F 83 Psychosis, CLL 88 19 Tac Mild None No changes LMWH Discharge
Liver-kidney 59 M 153 DM, CKD 29 33 Tac, Pred Moderate NC Tac ↓ LMWH Discharge
Liver-kidney 72 M 186 HTN, DM 71 20 Tac Mild None No changes Discharge
Liver-kidney 69 M 162 DM 13 27 Tac, MMF, Pred Mild None MMF out Discharge
Lung 52 F 6 None 59 NA CyA, MMF, Pred Severe None MMF out Discharge
Lung 60 M 57 HTN, DM 41 29 CyA, MMF, Pred Moderate NC Pred ↑ LMHW Discharge
Lung 50 F 78 None 61 22 Tac, AZA, Pred Mild None No changes Discharge
Lung 65 F 38 None 66 25 Tac, MMF, Pred Mild NC MMF out, Pred ↑ LMWH Discharge
Lung 56 M 63 DM 77 30 CyA, MMF, Pred Mild None MMF out, Pred ↑ Discharge
AF, atrial fibrillation; AZA, azathioprine; BMI, body mass index; CHF, chronic heart failure; CKD, chronic kidney disease; CLL, chronic lymphatic leukemia; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease of 2019; CRRT, continuous renal replacement therapy; CyA, cyclosporine A; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; Eve, everolimus; HCQ, hydroxychloroquine; HLP, hyperlipidemia; HTN, arterial hypertension; IHD, ischemic heart disease; iv, intravenous; KTx, kidney transplant; LMWH, low-molecular-weight heparin; MMF, mycophenolate mofetil; MTX, methotrexate; MV, mechanical ventilation; NA, not available; NC, nasal cannula; NIV, noninvasive ventilation; Pred, prednisolone; PSC, primary sclerosing cholangitis; SOT, solid organ transplant; Tac, tacrolimus.

The severity of disease was mild in 29 patients (55%), moderate in 7 (13%), severe in 10 (19%), and critical in 7 (13%) patients. Critical patients tended to have a higher age (median 65; range 56–67) and have a higher CCI (median 5; range 3–6) than those experiencing less severe disease.

The most common presenting symptoms were fever (34/53) and cough (21/53), followed by gastrointestinal manifestations (diarrhea and nausea) (16/53), and dyspnea (13/53). Median white blood cell upon admission was 6.45 × 109 cells/L (range 1.9–16). Six patients had leukopenia, whereas 3 patients had leukocytosis. Patients with severe and critical COVID-19 had significantly higher median white blood cell compared with patients presenting with mild and moderate disease (8.2 ± 3.1 × 109 cells/L versus 6 ± 2.8 × 109 cells/L, P < 0.01). Elevated laboratory markers of inflammation (C-reactive protein and ferritin) were common. In the whole cohort, median serum creatinine was 143 µmol/L (range 61–1440). Patients with severe and critical COVID-19 had significantly higher median serum creatinine at presentation compared with patients developing mild and moderate disease (P < 0.01).

Patient Management

Thirty-seven patients were admitted to hospital, while 16 patients (30%) were managed entirely as outpatients. Twelve patients with mild disease and a positive polymerase chain reaction for SARS-CoV-2 were initially managed on an outpatient basis but were hospitalized within 1 week from the first contact with the healthcare providers. Of these 12 patients, 2 developed mild, 3 moderate, 5 severe, and 2 critical disease.

Supportive care and oxygen therapy (ranging from a nasal cannula to mechanical ventilation) and adjustments in immunosuppression were the main interventions (Table 1). Only 1 kidney transplant recipient (presenting with critical disease) received HCQ and tocilizumab: the patient died 5 days after the admission. Another critical patient died within hours from admission, before any immunosuppression adjustment could be considered.

Of the 37 patients requiring hospital admission, 27 (73%) were treated with anticoagulation in the form of subcutaneous injections of LMWH. One patient received Apixaban. Twenty-one patients (57%) required supplemental oxygen, 8 patients (22%) were admitted to intensive care unit, and 7 (19%) required mechanical ventilation.

In the whole cohort, immunosuppression was left unchanged in 22 patients (42%), of which 16 had mild disease. Mycophenolate mofetil was reduced in 5 patients and discontinued altogether in 18 of the 35 patients initially receiving it. Calcineurin inhibitors (mainly tacrolimus) were reduced in 11 patients. In general, the more severe COVID-19 disease, the more pronounced reduction of the total immunosuppression with the exception of steroids which were usually increased with increasing disease severity.

Outcomes

At the time of article submission, 50 (94%) patients had a definitive outcome. Overall survival was 90.5%. Of the hospitalized patients, 5 patients (14%) died, 29 patients (78%) were discharged alive, and 3 patients (8%) were still hospitalized. Sixteen patients were managed as outpatients, with at least 2 weeks of follow-up. Survival among patients with mild and moderate disease was 100%, whereas those patients with severe and critical forms had a survival of 90% and 43%, respectively. The median length of hospital stay among those discharged (regardless of disease severity) was 7 days (range 3–33). There were no suspected episodes of rejection. A summary of the outcome data according to disease severity is shown in Table 2.

TABLE 2. - Patient characteristics and outcomes stratified according to COVID-19 severity
Disease severity Type of SOT Age (y) CCI BMI IS adjustment Outpatient Survival
Mild (n = 29) 14 KTx, 6 LTx, 4 HTx, 3 LuTx, 2 combineda 56 (27–69) 2 (0–7) 27 (19–42) 13/29 (45%) 15 29/29
Moderate (n = 7) 3 KTx, 1 LTx, 1 LuTx, 2 combinedb 55 (22–60) 3 (2–3) 25.0 (18.8–33) 4/7 (57%) 1 7/7
Severe (n = 10) 8 KTx, 1 LTx, 1 LuTx 56 (45–69) 3.5 (1–5) 25 (20–35) 8/10 (80%) 9/10
Critical (n = 7) 6 KTx, 1 HTx 65 (56–67) 5 (3–6) 32 (19–38) 6/7 (86%) 3/7c
Numbers for age, CCI, and BMI are given as median and range in parenthesis.
aKidney/liver transplant.
bKidney/liver and heart/kidney transplants.
cThree patients still hospitalized.
BMI, body mass index; CCI, Charlson Comorbidity Index; COVID-19, coronavirus disease of 2019; HTx, heart transplant; IS, immunosuppression; KTx, kidney transplant; LTx, liver transplant; LuTx, lung transplant; SOT, solid organ transplant.

Epidemiological Considerations

As of July 14, 2020 (the last day of the follow-up in the study), Sweden has recorded 76 332 confirmed cases of COVID-19 according to the Swedish Public Health Agency, resulting in a prevalence of 738 of 100 000 inhabitants (0.74%). At the same time, 53 transplanted patients with COVID-19 were reported at our center. Considering our total transplant population currently alive at our center, this translates into a prevalence of 1.15%.

DISCUSSION

The Swedish approach in handling the COVID-19 pandemic has resulted in an extensive community spread of the disease. This is also reflected in the number of approximately 1% of our transplanted patients developing the disease, which is a higher figure than the 0.64% reported at a Dutch center of similar size.14 This difference may be explained by stricter governmental regulations on social distancing and face masks enforced in the Netherlands and underscores the potential benefits of social distancing measures for patients and their family members. Although all transplant recipients are advised to keep strict social distancing measures, to which they in our experience adhere to a high degree, the prevalence of COVID-19 in our transplanted cohort does not seem to be lower than in the general Swedish population (1.15% versus 0.74%). This could be caused by an increased susceptibility to SARS-CoV-2 but most probably also reflects a higher frequency of testing in the transplant population.

Most of the case series published to date report on hospitalized transplant patients, which tended to have more severe disease. Our analysis, which is one of the largest single-center reports so far, describes the outcomes of an unselected group of patients covering a wide spectrum of SOT recipients that displayed varying degrees of COVID-19 disease severity.

Although our patient cohort had a high burden of comorbidities, the observed mortality rate appeared to be lower than that in similar patient groups reported in the literature6 or in databases.15 The outcome of the patients with severe and critical disease presented herein is similar to the literature data from the general population.2,16,17

A novel finding is that transplant patients with mild and moderate forms display a very good prognosis. Half of the patients with mild disease were managed entirely on an outpatient basis. On the contrary, 12 patients with initially mild disease were ultimately admitted to the hospital due to clinical deterioration. This is in line with a recent report showing that more than half of the patients initially managed as outpatients were later hospitalized.18 We believe the threshold for admission should be low as these patients often have multiple comorbidities19 as risk factors for severe disease. Therefore, the responsible healthcare facility should establish a close contact with the SARS-CoV-2 positive patients to allow early detection of clinical deterioration.

Although the lower mortality in our study may be due to a higher proportion of patients with milder forms of the disease, there could be an effect of different patient management.

Repurposing medications4,20-22 has been one of the few early therapeutic alternatives in COVID-19. Until now, neither HCQ, inhibitor LPV/r, nor remdesivir could demonstrate a survival benefit when used in COVID-19 patients. In SOT recipients, there probably is a higher risk for adverse effects due to drug-drug interactions and impaired kidney function in transplant patients, potentially resulting in over- or underimmunosuppression, cardiac arrhythmia due to QT prolongation and other iatrogenic adverse events.7,23 Besides 1 patient receiving HCQ and tocilizumab (in March 2020) who died after 4 days of hospitalization, our patients did not receive any specific drug intervention targeted against SARS-CoV-2.

The mainstay of therapy in our patient group was adjustment of immunosuppression and use of anticoagulants, mainly LMWHs. Immunosuppression was lowered in a majority of our patient cohort, in particular, if the patient was hospitalized. In general, the more severe disease, the more radical the reduction, which is a common clinical approach during other bacterial or viral infections in SOT recipients. In spite of early speculations about a positive effect of immunosuppression on COVID-19, we chose to continue our standard practice and lowered the total immunosuppression stepwise according to the individual immunological risk. The first step was the lowering or even discontinuing the antimetabolite, followed by the dose reduction of calcineurin inhibitors, particularly if the renal function was poor, targeting tacrolimus trough levels around 5 ng/dL. A similar approach has also been reported by other centers as well.14,24,25 After the infection has resolved and upon hospital discharge, the regular the medication was usually restored. Although no early rejection episode has been noted in our cohort of patients both the COVID 19 infection and immunosuppression adjustments could trigger or worsen an already ongoing chronic rejection process.

Steroids are an important part of the management of acute respiratory distress syndrome and sepsis3 as well as following organ transplantation. Recent evidence from Randomised Evaluation of COVid-19 thERapY trial suggested that dexamethasone may reduce mortality of severe COVID-19 patients by one-third,26 indicating a potential benefit of increased corticosteroids in the management of COVID-19. Increased prednisolone dose has been one of the main therapeutic interventions in our patient group. However, this increase did not reach the bioequivalent doses of dexamethasone used in the Randomised Evaluation of COVid-19 thERapY trial. While it would be tempting to adopt this strategy routinely, one should weigh the potential benefits of high-dose steroids against its effects on the T and B cells that may result in impaired virus clearance or lower production of protective antibodies.27

A key element in the management of these patients was the prophylactic use of subcutaneous LMWH to prevent thromboembolism. In patients with COVID-19, systemic inflammation is frequently associated with disseminated intravascular coagulation.28-30 As heparins have both anticoagulant and immunomodulatory properties,31,32 it is likely that prophylactic anticoagulation with LMWHs may have improved the microvascular perfusion via an anti-inflammatory action, limiting the impairment of pulmonary microcirculation and the coagulopathy. The dose of LMWH was chosen on an individual basis, considering body size, renal function, concomitant medications, and preexisting pathology. Renal impairment is frequently encountered in transplant recipients, necessitating an optimal LMWH strategy for this patient population.

Of notice is the high proportion of kidney transplant recipients developing severe forms of the disease. Moreover, most of the patients developing critical disease and 3 of 5 patients who died had preexisting severe renal dysfunction. This supports the hypothesis that the kidneys may play an important role with respect to adverse outcomes in transplant recipients with COVID-19 either due to a virus-induced direct cytotropic effect or cytokine-induced systemic inflammatory response.33,34 The presence of renal dysfunction could be a part of a severe infection or a disease marker indicating a more advanced course.

In contrast with previous reports spanning several weeks in the early stages of the pandemic, this report summarizes an evolutionary experience covering a more extended period. This enabled us to include a larger patient cohort, to perform a longer follow-up, and reach a very high percentage of closed cases. Although the current data confirm the poor prognosis of transplanted patients developing severe and critical disease forms, it also suggests that milder forms can be successfully managed with careful observation, brief hospitalizations, transient anticoagulation with LMWHs, and adjustment of immunosuppression. Our data could indicate that the outcome of transplant recipients developing COVID-19 does not necessarily has to be worse than for nontransplanted individuals.

The study is limited by its retrospective nature, the single-center setting, and the low patient numbers preventing in-depth statistical analyses. We may also have missed further patients with mild symptoms which may not have sought medical attention.

Future meta-analyses and consensus conferences will need to assess the various treatment strategies in this patient population, overcome the limitations of single-center observational studies, and make rational use of the rapid accumulation of knowledge.35 Future studies will need to assess the immunologic risks and consequences of different therapeutic strategies as well as the long-term impact on graft function.

REFERENCES

1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733.
2. Wu Z, McGoogan JM. 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. JAMA. 2020;323:1239–1242.
3. Alhazzani W, Møller MH, Arabi YM, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48:e440–e469.
4. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062.
5. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:e206775
6. Oltean M, Søfteland JM, Bagge J, et al. COVID-19 in kidney transplant recipients: a systematic review of the case series available three months into the pandemic. Infect Dis (Lond). 2020;52:830–837doi: 10.1080/23744235.2020.1792977.
7. Xia T, Wang Y. Coronavirus disease 2019 and transplantation: the combination of lopinavir/ritonavir and hydroxychloroquine is responsible for excessive tacrolimus trough level and unfavorable outcome. Am J Transplant. 2020;20:2630–2631doi: 10.1111/ajt.15992.
8. Bartiromo M, Borchi B, Botta A, et al. Threatening drug-drug interaction in a kidney transplant patient with coronavirus disease 2019 (COVID-19). Transpl Infect Dis. 2020;22:e13286doi: 10.1111/tid.13286
9. Maggiore U, Abramowicz D, Crespo M, et al. How should I manage immunosuppression in a kidney transplant patient with COVID-19? An ERA-EDTA DESCARTES expert opinion. Nephrol Dial Transplant. 2020;35:899–904.
10. Paterlini M. Closing borders is ridiculous: the epidemiologist behind Sweden’s controversial coronavirus strategy. Nature. 2020;580:574
11. Kamerlin SCL, Kasson PM. Managing COVID-19 spread with voluntary public-health measures: Sweden as a case study for pandemic control. Clin Infect Dis. [Epub ahead of print. 2020]. doi: 10.1093/cid/ciaa864.
12. COVID-19 treatment guidelines panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2020National Institutes of Health; Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed July 1, 2020.
13. Koppie TM, Serio AM, Vickers AJ, et al. Age-adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. Cancer. 2008;112:2384–2392.
14. Hoek RAS, Manintveld OC, Betjes MGH, et al. COVID-19 in solid organ transplant recipients: a single-center experience. Transpl Int. 2020. doi: 10.1111/tri.13662
15. https://www.era-edta.org/en/wp-content/uploads/2020/05/ERACODA-Study-Report-2020-05-06.pdf
16. Argenziano MG, Bruce SL, Slater CL, et al. Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series. BMJ. 2020;369:m1996
17. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395:1763–1770.
18. Husain SA, Dube G, Morris H, et al. Early outcomes of outpatient management of kidney transplant recipients with coronavirus disease 2019. Clin J Am Soc Nephrol. 2020;15:1174–1178.
19. Cen Y, Chen X, Shen Y, et al. Risk factors for disease progression in patients with mild to moderate coronavirus disease 2019—a multi-centre observational study. Clin Microbiol Infect. 2020;26:1242–1247.
20. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382:2411–2418.
21. Rosenberg E.S., Dufort E.M., Udo T. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323:2493–2502doi: 10.1001/jama.2020.8630.
22. Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19:102568
23. Jain AB, Venkataramanan R, Eghtesad B, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl. 2003;9:954–960.
24. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: initial report from the US epicenter. Am J Transplant. 2020;20:1800–1808.
25. Yi SG, Rogers AW, Saharia A, et al. Early experience with COVID-19 and solid organ transplantation at a US high-volume transplant center. Transplantation. 2020. doi: 10.1097/TP.0000000000003339
26. Horby P, Lim WS, et al. Randomised Evaluation of COVid-19 thERapY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020. doi: 10.1056/NEJMoa2021436
27. Solinas C, Perra L, Aiello M, et al. A critical evaluation of glucocorticoids in the management of severe COVID-19. Cytokine Growth Factor Rev. 2020;54:8–23.
28. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18:167–169.
29. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–847.
30. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Engl J Med. 2020;383:120–128doi: 10.1056/NEJMoa2015432
31. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122:743–752.
32. Magro G. COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking. Virus Res. 2020;286:198070
33. Sardu C, Gambardella J, Morelli MB, et al. Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J Clin Med. 2020;9:1417
34. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97:829–838.
35. Fragkou PC, Belhadi D, Peiffer-Smadja N, et al. Review of trials currently testing treatment and prevention of COVID-19. Clin Microbiol Infect. 2020;26:P988–998.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.