key: cord-1011533-z4rcczki authors: Moris, Dimitrios; Kesseli, Samuel J.; Barbas, Andrew S. title: Kidney Transplant Recipients Infected By COVID‐19: Review of the Initial Published Experience date: 2020-07-23 journal: Transpl Infect Dis DOI: 10.1111/tid.13426 sha: cde3513aec0ddf7c3e5d311a7215a81009228dcb doc_id: 1011533 cord_uid: z4rcczki There is an accumulating body of literature surrounding the impact of COVID‐19 infection in solid organ transplant recipients. The aim of this review is to summarize the existing literature specifically in kidney transplant (KTx) recipients, with an emphasis on the epidemiology, clinical presentation, laboratory findings, post‐operative outcomes and therapeutic strategies currently employed. We identified thirty‐seven studies published between January 1(st) 2020 to June 10(th) 2020 that were included in our analysis. As is reported in the general population, there is a wide variation in COVID‐19 presentation among KTx patients, ranging from asymptomatic to life‐threatening end‐organ failure. The most common symptoms are predominantly respiratory and associated with fever. On lab evaluation, many patients present with lymphopenia and increased CRP, which are both associated with inferior outcomes. The majority of patients with severe symptoms have been managed with reduction of immunosuppression, including decreased doses of CNIs and withdrawal of MMF. Lastly, although there is no high‐level data supporting the use of immunomodulatory drugs, such as IL‐6 inhibitors, early experiences have suggested these drugs may improve outcomes in KTx patients with severe COVID‐19. of data granularity on the KTx recipients 8, 9, [11] [12] [13] [14] and reports of pediatric 15 , dual or multiorgan transplantation 16, 17 . In total, 37 studies were included in the final analysis . All studies were evaluated to prevent overlap of published patients and related data. Twelve of 37 (32.4%) articles were case series while the remaining 25 (67.6%) were individual case reports. Not surprisingly, most publications came from China, USA and Italy, countries with high incidence of COVID-19 ( Fig.1) 55 . We identified 221 KTx recipients infected by COVID-19 . Among these, 156 (70.6%) were men and 65 (29.4%) women. The average age at the time of diagnosis was 50.8 years (SD=10.8, range=28-78), however, the average age of patients with severe symptoms was significantly higher (58.3 ± 8.4, p=0 .005), which is comparable to the non-transplant COVID-19 literature 56 . Most patients in our cohort had multiple comorbidities with the most prevalent being hypertension, diabetes, cardiovascular disease, chronic kidney disease, and obesity, all of which are disproportionately represented in the KTx patient population. Less than 10% of the patients had a history of malignancy (solid organ or hematologic), perhaps reflecting those precluded from transplant eligibility due to active malignancy. Reporting of donor specific information was available in all studies, but most kidney allografts came from deceased donors (>80%). These trends are comparable to the demographics of the general KTx populations 57 . Many studies (31/37) reported the time from KTx to COVID-19 diagnosis 18, 21-28, 30-40, 42-53 ; 77.4% of KTx recipients received their allograft more than 1 year before COVID-19 diagnosis (range 8 days-31 years). It is unclear whether this trend is simply a reflection of the patients with KTx or it disproportionally represents chronic transplant patients. Most COVID-19 positive KTx recipients included in the analyzed literature were treated as inpatients (193/221, 87.3%). All included studies reported symptoms at the time of initial physical exam . Fever was the most common symptom (84.5%), followed by cough (64%), and hypoxia mandating oxygen supplementation (54%). Other reported, but less common symptoms included gastrointestinal (diarrhea, abdominal pain) and musculoskeletal pain (arthralgias and myalgias). This article is protected by copyright. All rights reserved Laboratory evaluation was included in 33 of 37 studies 18, 19, 21-34, 36-44, 46, 48-54 There are two proposed mechanisms that might lead to lymphopenia duringCOVID-19 infection; 1) the virus may directly infect lymphocytes or lymphatic organs resulting in lymphocyte dysfunction or death, or 2) upregulation of of inflammatory cytokines such as tumor necrosis factor-α, IL-6, and others might directly induce lymphocyte apoptosis 58 . A recent meta-analysis showed that lymphopenia at admission was correlated with worse outcomes in patients with COVID-19, including increased mortality and intensive care unit (ICU) admission 59 . In our analysis, very few patients were found to have leukopenia or leukocytosis, mostly attributable to septic complications during their admission. Another commonly utilized lab marker is C-reactive protein, which was elevated in 78.8% of the patients. Other inflammatory markers such as Interleukin-6 (IL-6), ferritin and procalcitonin are less consistently reported but have been found elevated in many patients. Finally, 58.5% of the patients presented or developed acute kidney injury (AKI) during their admission. Most of these patients recovered without intervention although 4 patients required renal replacement therapy and only 1 developed chronic kidney disease during follow-up. Of interest, 12 patients developed moderate hyponatremia (121-131 mEq/L), that was resolved during the index admission. One proposed mechanism of hyponatremia in COVID-19 patients hypothesizes that increased inflammation leads to hypersecretion of antidiuretic hormone. Still, this phenomenon appears to be self-limited and its clinical implications are not well described in the literature 60 . Regarding radiographic findings in KTx COVID-19 patients, 78.5% presented with bilateral ground glass opacities in both chest plain radiograph and CT-scan of the chest 18, 19, 21-28, 30-34, 36-42, 44, 46-54 . Of note however, about 10% had normal imaging at the time of presentation. Less common findings included unilateral opacities and septal interstitial changes. Lower lung fields were usually affected (70%). Some discrepancies between Xray and CT scan findings were noted in few patients (negative Xraypositive CT scan). Table 1 summarizes the demographic, clinical and laboratory data of our cohort. This article is protected by copyright. All rights reserved Regarding ICU admission rates, 33.7% (55/163) of KTx recipients needed ICU care 18, 21-25, 27-29, 31, 32, 34-54 . More than 80% of them were older than 60 years of age. This is nearly double that reported in the liver transplant population reported in the ELITA/ELTR COVID-19 registry (15%) 61 . Pooled data in cancer patients reported an even lower ICU admission rate of 12.6% 62 . These findings might indicate a need for increased resource in the kidney transplant setting and may influence the decision to perform this semi-elective operation considering ICU availability during pandemic. Cumulative COVID-related mortality was 19.9% (44/221) ; 65.9% (29/44) of these deaths were noted in KTx recipients older than 60 years of age. Also, 68.1% (30/44) of the deaths occurred in KTx recipients with longer time since transplantation (>1 year). These findings are of paramount clinical importance since due to intensive immunosuppression, recent transplant recipients (<3 months post-transplant) were expected to develop severe disease due to COVID-19 more frequently than old transplants. It is unclear whether this trend is simply a reflection of the patients with KTx or it disproportionally represents chronic transplant patients. Data from the ELITA/ELTR COVID-19 registry showed similar findings in liver transplant patients. More specifically, the mortality in liver transplant recipients was 16% and was higher in older recipients (>60 years old) and in patients with longer time since transplantation (>2 years) 61 . Data from cancer literature also report variable mortality rates related to COVID-19, though a recent metaanalysis estimates a 16.6% mortality among cancer patients with concomitant COVID-19 62 . There is no consensus on the management of immunosuppression among KTx recipients with COVID-19, and the present literature review found a significant heterogeneity in management strategies among studies and patients . More than 80% of the patients included in our analysis This article is protected by copyright. All rights reserved were on standard triple therapy with MMF, calcineurin inhibitors and steroids. Most patients were on tacrolimus, though cases of patients on mTOR inhibitors, azathioprine and belatacept are also reported. In general, the mainstay of treatment was the decrease or withdrawal of immunosuppression. Only 5 studies reported no change in immunosuppression 22, 24, 49, 50, 52 . In the studies where management of antimetabolite therapy was reported, most patients had MMF withheld and very few continued MMF with decreased dose. A smaller proportion of KTx had the calcineurin inhibitor held or decreased. Some studies reported switching of tacrolimus to cyclosporine. In patients on costimulation blockade, data are limited however patients had belatacept withheld, noting that the half-life of infusional therapies makes complete abrupt withdrawal impossible 27, 42 . Interestingly, the two reports of patients on belatacept had relatively mild COVID-19 courses, that was partially attributed to the belatacept-related blockade of cytokine production 42 Hydroxychloroquine sulfate and chloroquine phosphate, historically, anti-malaria drugs, have also been investigated for treatment of COVID-19 in clinical trials 64, 65 . In the current study, hydroxychloroquine was used in 54.8% (121/221) of KTx patients, most frequently in those with severe symptomatology 18-21, 24, 27, 28, 30-32, 34, 36-41, 43-48, 51 and in combination with antibiotics and immunomodulatory drugs. Several case reports noted improvement or even resolution of symptoms, although it is important to acknowledge potential toxicities associated with hydroxychloroquine, as well drug interaction effects with cyclosporine, tacrolimus and mammalian target of rapamycin inhibitors (mTORs). Hydroxychloroquine and lopinavir/ritonavir may interact causing a prolongation of the cardiac QTc interval; however, currently this complication is unreported specifically in KTx patients. Like tacrolimus, hydroxychloroquine is also a substrate of CYP3A, necessitating careful monitoring of drug levels if concurrently used. A recent report by Xia et al has recommended against using immunosuppressants in combination This article is protected by copyright. All rights reserved with protease inhibitors or hydroxychloroquine due to over-immunosuppression and potential cardiac toxicity 66 . Other experimental treatments have included antiviral drugs such as protease inhibitors (lopinavir, ritonavir, darunavir (protease inhibitors), oseltamivir (neuraminidase inhibitor), ribavirin (nucleoside inhibitor) and umifenovir, alone or in combination [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] . Early data on hospitalized patients with severe COVID-19 showed potential clinical benefit 67 This review highlights the clinical spectrum currently reported in COVID-19 infected KTx patients, which may vary from asymptomatic and treated on an outpatient basis, to severely This article is protected by copyright. All rights reserved symptomatic mandating ICU admission. The symptoms are predominantly respiratory and associated with fever. On lab evaluation, most patients present with lymphopenia and increased CRP, both of which are associated with inferior outcomes. CT scan of the chest is the most sensitive imaging modality for diagnosis, with the most common finding being bilateral groundglass opacities. Most patients with severe symptoms are treated with reduction of immunosuppression, including decreasing doses of CNIs and withdrawal of MMF along with supportive therapy. Currently there is no high-level evidence supporting the use of immunomodulatory drugs, such as IL-6 inhibitors, but early experience suggests these drugs might be beneficial in improving outcomes in KTx patients with severe COVID-19. This article is protected by copyright. All rights reserved This article is protected by copyright. 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