key: cord-0879570-z905nqzc
authors: Hardesty, Anna; Pandita, Aakriti; Vieira, Kendra; Rogers, Ralph; Merhi, Basma; Osband, Adena J.; Aridi, Jad; Shi, Yiyun; Bayliss, George; Cosgrove, Christopher; Gohh, Reginald; Morrissey, Paul; Beckwith, Curt G.; Farmakiotis, Dimitrios
title: COVID-19 in kidney transplant recipients: Single-center experience and case-control study
date: 2021-01-13
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.01.002
sha: 9b8b0242437505ccb5070acab9f6bcd1b1969186
doc_id: 879570
cord_uid: z905nqzc

Background Kidney transplant recipients (KTR) are considered high-risk for morbidity and mortality from COVID-19. However, some studies did not show worse outcomes compared to non-transplant patients and there is little data about immunosuppressant drug levels and secondary infections in KTR with COVID-19. Herein, we describe our single-center experience with COVID-19 in KTR. Methods We captured KTR diagnosed with COVID-19 between 3/1 and 5/18/2020. After exclusion of KTR on hemodialysis and off immunosuppression (IS), we compared the clinical course of COVID-19 between hospitalized KTR and non-transplant patients, matched by age and sex (controls). Results Eleven KTR were hospitalized and matched with 44 controls. One KTR and four controls died (case fatality rate: 9.1%). There were no significant differences in length of stay or clinical outcomes between KTR and controls. Tacrolimus or sirolimus levels were >10 ng/mL in 6/9 KTR (67%). Bacterial infections were more frequent in KTR (36.3%), compared to controls (6.8%, P=0.02). Conclusions In our small case series, unlike earlier reports from the pandemic epicenters, the clinical outcomes of KTR with COVID-19 were comparable to those of non-transplant patients. Calcineurin or mTOR inhibitor levels were high. Bacterial infections were more common in KTR, compared to controls.

COVID-19, the disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created the worst pandemic since the 1918 Spanish flu. Since its first appearance in December 2019 in China, there have now been over 15 million cases of COVID-19 world-wide and over 600,000 deaths 1 . Despite the ongoing surge of COVID-19 cases, leading to widespread epidemiological and clinical investigations throughout the world 2 , our understanding of outcomes in high-risk populations is still incomplete.

Organ transplant recipients (OTR) are considered high-risk for morbidity and mortality from COVID-19, due to the unique combination of immunosuppression (IS) and other chronic illnesses [3] [4] [5] .

Case-fatality rates (CFR) vary significantly in different case series, anywhere from significantly higher than the general population (30%-64%) 4, 6-11 to much lower, comparable to the CFR of nonimmunosuppressed individuals [12] [13] [14] . Notably, in many studies, few patients were still hospitalized at the time of data analysis, therefore the CFR may be underestimated 4, 5, 7, 10, 12, 13 .

To our knowledge, only one case-control study of COVID-19 in OTR has been published todate, which showed similar CFR between OTR and consecutive non-transplant patients (controls), despite more comorbidities in OTR 15 . In this study, we describe our institutional COVID-19 preparedness, and analyze baseline characteristics, clinical course, outcomes and therapeutic interventions in kidney transplant recipients (KTR) with COVID-19, compared to age-and sexmatched non-transplant patients (controls), all of whom were either discharged home or died.

The first case of COVID-19 was diagnosed in RI on 3/1/2020. The Division of Infectious Diseases (ID) created two dedicated COVID-19 inpatient services, one for each teaching Hospital affiliated with Brown University in Providence, RI (The Miriam Hospital, (TMH), and Rhode Island Hospital, (RIH)). Admitted patients with COVID-19 were evaluated by ID, either in-person or remotely. Starting on 3/19, our first-line treatment for COVID-19 was remdesivir, through enrollment in a clinical trial, or under emergency use authorization after 5/15. Starting on 4/15, convalescent plasma was also offered as adjunct or alternative (for patients who did not meet criteria for remdesivir) treatment. Most patients admitted to the intensive care unit (ICU) were empirically treated with broad-spectrum antibiotics. Overall, providers at both institutions had a low threshold for empiric anticoagulation, based on D-dimer level and clinical suspicion for any thrombotic event.

Unlike other centers 3, 4, 6, 9, 10, 14-20 , use of hydroxychloroquine in OTR and cancer patients was discouraged from early on at our centers, given its potential of added IS and side-effects. This approach was the result of our early participation in studies showing no benefit from hydroxychloroquine 21, 22 , and timely review of emerging data, including concerns about validity of the seminal report that suggested the drug may be an effective treatment for COVID-19 23 . Most of our transplant patients receive low-dose prednisone; high-dose corticosteroids were not widely used for COVID-19 alone, although short courses were given in a small number of patients 24 .

Starting on 3/15, living-donor kidney transplants were suspended; deceased-donor kidney offers were assessed on a case-by-case basis, prioritizing recipients who would benefit the most.

Listed transplant candidates with significant comorbidities, and those who would likely need induction IS with anti-thymocyte globulin were made temporary unavailable. KTR with negative SARS-CoV-2 PCR were hospitalized in a different building than patients with positive SARS-CoV-2 PCR. Throughout the study period, outpatient clinic visits and inpatient consultations were done remotely through tele-health, with very few exceptions.

Our approach to outpatient KTR with positive SARS-CoV-2 PCR or person under investigation evolved with medical knowledge and availability of testing kits, personal protective J o u r n a l P r e -p r o o f equipment (PPE), and promising treatments for COVID-19. Asymptomatic KTR with positive SARS-CoV-2 PCR, or those only with mild, upper respiratory symptoms were initially advised to isolate and rest at home, with daily follow-up phone calls from the transplant team. Patients with diarrhea were advised to have routine blood work including tacrolimus or sirolimus trough levels. Those with shortness of breath at rest or exertion, persistent high fever (>101 o F), or self-reported deterioration in any way, were advised to present to the nearest emergency room or electively admitted to the hospital.

Once testing and PPE became widely available, KTR with mild or moderate symptoms were also provided additional recommendations, as needed. Adjustments in IS were evaluated on a case-by-case basis; as a rule, the antimetabolite was discontinued or its dose was reduced in KTR with COVID-19 at the time of diagnosis, and resumed once their symptoms had improved or resolved, depending on severity of illness, the net state of IS, and risk for rejection.

We captured KTR who were diagnosed with COVID-19 during the study period (3/1-5/18/2020). KTR on hemodialysis and off IS were excluded from the analysis, as they no longer classic hosts on immunosuppressive medications. KTR on IS who were admitted to the hospital were matched by age and sex with non-transplant patients, admitted during the same period to TMH or RIH (controls). Given a relatively uneven distribution of cases due to the significant surge in April, each KTR was matched with 3-5 controls of the same sex and age (± 2 years), prioritizing, when feasible, those admitted to the hospital within 2 weeks, in order to adjust for potential evolution of medical J o u r n a l P r e -p r o o f knowledge and institutional standards of care. We only included KTR and controls who either died or were discharged home from the hospital at the time of data analysis.

We extracted the following features from electronic medical records, which were then compared between hospitalized KTR on IS and controls: 

Data are presented as n (%) for categorical variables, or median (range) for continuous variables. Categorical variables were compared with x 2 or Fisher's exact tests. For those with >2 categories (e.g. race), P-values refer to 2x2 comparisons (corresponding row vs. all others combined).

The results were not different for 2x3 comparisons by x 2 test. Continuous variables were compared with the Mann-Whitney U-criterion. Given the small number of cases and especially deaths, we did not perform multivariate analyses. Two-tailed P-values of <0.05 were considered significant, whereas those between 0.05 and 0.1 were also noted as trends.

During the study period, we identified 16 Both patients were cured of their UTIs. One additional KTR had Pseudomonas and Stenotrophomonas growth from tracheal aspirate with concern for ventilator-associated pneumonia and died; one KTR presented with COVID-19, diarrhea and acute uncomplicated diverticulitis, which resolved completely with antibiotics (Table 1) .

IS was reduced in 11/13 (84.6%) KT, in all 11 who were hospitalized, most often by discontinuation of the antimetabolite (azathioprine or mycophenolate). Goal tacrolimus or sirolimus trough levels were 4-6 ng/mL, except for one patient who had KT <1 month prior to COVID-19. In one patient with diarrhea, the first dose of tacrolimus was empirically held, before obtaining a trough level. It should be noted that, despite lowering the trough goal, tacrolimus or sirolimus levels were >10 ng/mL in 4/9 (44.4%) KTR with available levels on admission and 6/9 KTR (67%) at any point during the hospital stay (Table 1) .

Four hospitalized KTR (30.7%) received remdesivir, 4 convalescent plasma, 3 (23%) tocilizumab. Notably, interleukin-6 (IL-6) levels were extremely high, >1,000 (normal: <5) pg/mL in 3/6 KTR (50%) with IL-6 levels measured during their hospital stay. Only one KTR, who did not qualify for enrolment in the remdesivir clinical trial (the only treatment trial available at the time) and subsequently died, was started on azithromycin and hydroxychloroquine; the latter was discontinued after four of five planned days of treatment because of leukopenia and concern for arrhythmia, both of which were likely multifactorial, as this patient was hypothermic, intubated, on vasopressors, and receiving CVVH.

The differences in the proportions of patients treated with remdesivir or hydroxychloroquine between KTR and controls were not statistically significant. KTR received more broad-spectrum antibiotics (90.9% vs. 61.3%, P=0.08), convalescent plasma (30.7 vs. 0%, P=0.001) or tocilizumab (27.2% vs. 0%, P=0.006), compared to controls (Table 2 ).

Discussion This is the second, to our knowledge, case-control study evaluating OTR with COVID-19, and the only one to exclusively study KTR. Furthermore, we investigated immunosuppressive drug levels, and rates of bacterial co-infections in KTR with COVID-19.

Our CFR was lower than most previous reports, and we found comparable outcomes between KTR and matched controls in mortality, O 2 requirements, and length of stay, in agreement with another case-control study 15 . There may be several reasons for these observations: First, although our hospitals experienced some strain in terms of resources, Rhode Island was less stretched than the pandemic epicenters in the United States 4, 9, 15, 27 , Europe 9-11 or Iran 3 . Our center had enough time to adopt a structured, intensive and evidence-based approach to the management of KTR with COVID-19, including low thresholds for hospital admission and close follow-up of all outpatients. Second, no KTR with COVID-19 in our study had underlying chronic pulmonary disease, unlike other series 15, 20 .

Third, OTR, one of the highest-risk groups for infectious complications, are often followed closer by ID specialists, and may be started on anti-effective treatment earlier than non-transplant patients. Such approaches may account for better outcomes reported by some investigators in OTR with serious infections other than COVID-19, including sepsis, compared to matched non-transplant patients 28, 29 . Some also argue that IS may have a protective role against the detrimental inflammatory cascade 28, 29 . Nevertheless, our finding of a higher risk of infectious complications in KTR with COVID-19, compared to non-transplant controls, does not support a net beneficial effect from IS on the course of SARS-CoV-2 infection.

It should be noted that very few of our patients received hydroxychloroquine, compared to the vast majority of previous case series 3, 4, 6, 9, 10, [14] [15] [16] [17] [18] [19] [20] . Instead, most of our KTR received remdesivir or convalescent plasma (Tables 1 & 2) . This high enrollment in clinical trials may have also contributed to improved outcomes, given emerging literature on the efficacy of these treatments 25, 26, 30-32 , as opposed to hydroxychloroquine, which likely has no role in the treatment of COVID-19 16-18, 21, 22, 33-35 .

We found higher rates of bacterial co-infections and antibiotic use in KTR, compared to controls (Table 2) . Antibiotic administration in critically ill patients is often empirical, even more so in the setting of a pandemic 36 . Nonetheless, in our study, there was significant evidence of more J o u r n a l P r e -p r o o f severe, proven bacterial infections in KTR, compared to controls. This increased rate could be due to baseline IS with higher than usual tacrolimus or sirolimus levels (Table 1) , possibly in addition to immune dysregulation from SARS-CoV-2; the latter could make immunocompromised patients even more susceptible to bacterial infections. Further studies are needed to confirm our findings, which could dictate important management decisions such as earlier empiric use of antibiotics. Also, these observations possibly justify the decision to decrease IS as tolerated in hospitalized OTR with COVID-19, as well as symptomatic outpatients. This has been the practice at our hospitals, and most, if not all, transplant centers 3-5, 7, 12-15, 19, 20, 37, 38 , so far.

Tacrolimus or sirolimus levels were elevated in most KTR with COVID-19 at some point during their hospital stay, despite lower trough goals. This could be secondary to diarrhea, but also hepatic dysfunction in COVID-19 39 , resulting in decreased glycoprotein-P and CYP-mediated clearance 40, 41 , respectively. With this knowledge, some clinicians may choose to preemptively aim for lower than usual doses of calcineurin or mTOR inhibitors in KTR with SARS-CoV-2 infection, in order to achieve the desired trough levels, given the risk for bacterial coinfections and the potential severity of COVID-19 itself.

High levels of IL-6 were noted in most KTRs in our study (Table 1 ), in agreement with previous case series [42] [43] [44] [45] . High (>0.5 pg/mL) IL-6 levels seem to be common in patients with COVID-19. Moreover, some KTR in our study and one previous report 4 had "extreme" IL-6 levels (>1,000 pg/mL), which have been mainly described during the cytokine storm of CART-cell immunotherapies, the only indication for which tocilizumab is FDA-approved 46 .

At our center, tocilizumab has so far only been used in KTR. All three KTR who received it survived; one subsequently developed graft pyelonephritis and ESBL bacteremia (Table 1 ). In recent observational studies, tocilizumab was shown to improve outcomes in patients with severe COVID-19 38, [47] [48] [49] [50] , including OTR 51 . However, in one retrospective study of ventilated patients, the rate of coinfections in patients who received tocilizumab was significantly higher compared to the standard of care, but use of tocilizumab was still associated with improved survival 48 . Pending more definitive results from randomized-controlled trials, we usually reserve use of tocilizumab for KTR with convincing symptoms or signs of (impending) cytokine storm, such as high fever and rapid Our study has limitations: It is a single-center study with small, although comparable to that of other case-series 11, 19, 37, 51, 54 , sample size. Therefore, our findings need to be validated by larger cohort studies, prospective registries and randomized-controlled clinical trials. Second, we did not compare presenting symptoms, signs, routine laboratory results or imaging between KTR and nontransplant recipients with COVID-19. Last, we matched cases to controls, rather than perform multivariate analyses in a large cohort of consecutive patients, which could potentially mask important associations 55 .

In summary, unlike early reports from the pandemic epicenters, the clinical course and outcomes of KTR with COVID-19 in our small case series were comparable to those of age and sexmatched non-transplant patients, with low CFR. Calcineurin or mTOR inhibitor levels were high, likely due to COVID-19-related intestinal and hepatic dysfunction. Bacterial infections were more frequent in KTR. Extremely high IL-6 levels were common in KTR with COVID-19. The role of adjustments in IS and potential benefits from empiric antibiotics or investigational treatments remain to be elucidated.

J o u r n a l P r e -p r o o f 

Johns Hopkins COVID-19 Map

Conquest of COVID-19. Publish it to death?

COVID-19 and Kidney Transplant Recipients

Covid-19 and Kidney Transplantation

COVID-19 in Immunocompromised Hosts: What We Know So Far

A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter

COVID-19 in kidney transplant recipients

First experience of SARS-CoV-2 infections in solid organ transplant recipients in the Swiss Transplant Cohort Study

Preliminary data on outcomes of SARS

CoV-2 infection in a Spanish single center cohort of kidney recipients

Early Experience With COVID-19 and Solid Organ Transplantation at a US High-volume Transplant Center

Clinical Characteristics and Outcomes of COVID-19 in Solid Organ Transplant Recipients: A Case-Control Study

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

A Randomized Trial of Convalescent Plasma for COVID-19-Potentially Hopeful Signals

Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Bacterial and Fungal Coinfection in Individuals With Coronavirus: A Rapid Review To Support COVID-19 Antimicrobial Prescribing

Clinical outcomes and serologic response in solid organ transplant recipients with COVID-19: A case series from the United States

Tocilizumab for the treatment of adult patients with severe COVID-19 pneumonia: a single-center cohort study

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19

Coronavirus disease 2019 and transplantation: The combination of

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Detectable Serum Severe Acute Respiratory Syndrome

Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6

Level in Critically Ill Patients With Coronavirus Disease

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

Cytokine release syndrome in severe

interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia

Tocilizumab for the treatment of severe coronavirus disease 2019

Tocilizumab for treatment of mechanically ventilated patients with COVID-19

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Tocilizumab for the treatment of severe COVID-19

pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in

Tocilizumab therapy in 5 solid and composite tissue transplant recipients with early ARDS due to SARS-CoV-2

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Early Short Course Corticosteroids in Hospitalized Patients with COVID-19

COVID-19 in recent kidney transplant recipients

Observational Studies: Matching or Regression? Biology of Blood and Marrow Transplantation

Table 1 Footnotes: y: years; Ordinal (modified NIH/WHO) scale: 1, dead (DE); 2, mechanical ventilation (MV)

Infx, (bacterial) infection

VAP, ventilator-associated pneumonia

Abx, broad-spectrum antibacterials; LOS, length of stay (d, days)

*First dose held until the trough level was back