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LETTER TO EDITOR
COVID-19 Infection in Kidney Transplant Recipients in Italy: Management Issues in a Kidney Transplant Center

Dear Editor:

Coronavirus disease 2019 (COVID-19), first detected at the end of 2019 in China,1 is a worldwide pandemic burden. Globally, as of December 16, 2020, there have been more than 71 million confirmed cases of COVID-19, including over 1.6 million deaths, as reported by the World Health Organization.2 Italy was the first European country to be substantially affected by the spread of COVID-19 outside of China; as December 16, 2020, the total number of assessed cases in Italy was about 1.9 million with about 66 537 deaths (although not yet confirmed upon certification of cause of death by the “Istituto Superiore di Sanità”), thus highlighting a presumed death rate of 3.4%.3 With the spread of the virus through the population, kidney transplant (KT) recipients are also at risk of infection and development of COVID-19 disease. In Italy, at present, there are about 26 500 KT patients who are regularly being followed,4 and transplant profes­sionals must give extra efforts for the best standard of care for this more fragile cohort of patients.

In its more aggressive form, COVID-19 disease can cause severe atypical pneumonia and death, with pulmonary damage similar to that shown in those with acute respiratory distress syndrome.5 Presently, a validated therapeutic approach is not yet confirmed and a vaccine has not yet reached the general population. In addition, current evidence, as derived from single reports and epidemiological data, although not yet definitive, have shown that COVID-19-related deaths occur more often in elderly patients who have multiple comorbidities.6,7

Less is known about COVID-19 infections in KT recipients, a population with more challenging and more complex management needs than for the general population. Because of scarce published evidence in the transplant population, no definitive conclusions have been made on COVID-19 care. Because of several risk factors, in addition to the required immunosuppressant regimen, the disease may have a dramatic evolution in this population, which can increase the risk of mortality. Although there have been reports of recovery in several cases,8,9 mortality in KT recipients varies from 50%10 to 100%.11 This evidence drives the need for attention and the need for a multidisciplinary team composed not only of transplant surgeons and nephrologists but also pneumologists, anesthesiologists, immuno­logists, and all the other physicians who may be involved to find the best treatment options.

The influence of immunosuppressants on the course of COVID-19 disease in KT patients is still unclear. The routinely employed calcineurin inhibitors (eg, cyclosporine and tacrolimus) are effective in reducing naïve T cells but not memory T/B cells. Thus, especially in those whose immune system is less reactive to new pathogens, such as in the elderly, an effective adaptive response against the virus is difficult to achieve, partly explaining the worse outcomes due to cytokine overload and proinflam­matory agents.12 Recently, Romanelli and colleagues13 postulated a somewhat protective effect on the disease progression sustained by chronic immunosuppressive therapy with a mechanism based on a reduction in the T-cell immune response, whereas Huang and colleagues11 identified lower T-cell count as a factor predisposing a poorer outcome. Favorable results in respiratory disease outcomes have been achieved after reduction of immunosuppression.8-10 Through experimental tries, this led to hydroxychloroquine, which was able to modulate the inflammatory response,8,10 whereas tocilizumab has shown promising results in the general population14 and has been proposed for KT recipients10 but not yet administered.

Comorbid conditions in KT patients may also play roles in increasing the susceptibility to the infection and increasing the aggressiveness of pneumonia. Underlying chronic kidney disease can contribute, through altered lipid and calcium-phosphate metabolism, to hyperparathyroidism, hyperhomocysteinemia, microalbuminuria, chronic inflammation, anemia, and volume overload, which may increase cardiovascular risk. These conditions can be further augmented by the effects of immunosuppressants.15 Pretransplant and post­transplant diabetes can also increase cardiovascular risk and the risk of infections and has been found to be strongly associated with an unfavorable course in COVID-19 patients.6,7 This occurs probably through a mechanism already described for the Middle East Respiratory Syndrome (MERS), which involves a similar virus. In a murine model, MERS-coronavirus was found to bind to the receptor for dipeptidyl peptidase IV (expressed by pulmonary alveolar cells), thus increasing pulmonary inflammation and macrophage infiltration and leading to the same inflammatory condition seen in the clinical setting.16,17 In view of the spread of COVID-19 in KT recipients with diabetes, strict surveillance and prompt hospital referral, even for mild respiratory symptoms, are warranted to allow diagnosis at an early stage of the disease and for the best therapeutic approach to be defined, reducing the risk of severe pneumonia.

Patients with underlying cardiovascular risk factors have been reported to be more susceptible to higher risks of adverse outcomes and death during the severe and aggressive inflammatory responses to COVID-19 versus individuals who are younger and healthier. This occurs because the high increase in myocardial demand triggered by infections could precipitate myocardial injury or infarction. Alternatively, circulating cytokines released during severe systemic inflammatory stress could lead to atherosclerotic plaque instability and rupture.18

Kidney transplant recipients are known to have some degree of vitamin D deficiency19; this is also commonly found in intensive care unit patients and associated with adverse outcomes, including higher rate of mortality, higher sepsis incidence, and longer mechanical ventilation and length of hospitalization.20 Vitamin D has been found to regulate several metabolic pathways since its receptors are widely distributed in the human body.19 Evidence has also reported the role of vitamin D in reducing the risk of viral infections, enhancing innate immunity, and modulating the immune response by a reduction in the proinflammatory cytokine storm.21 These effects can play a role in prevention of COVID-19 infection and thus play a role in treatment by reducing the severity of pneumonia. Therefore, despite the lack of studies in this specific cohort of patients, obtaining satisfactory levels of circulating vitamin D should be warranted in KT patients. Unfortunately, there is a lack of consensus on the adequate blood levels, dose levels, and which formulation of vitamin D to prescribe as a supplementation in KT patients, and further studies are needing to clarify this issue.

In conclusion, KT recipients may show a higher fragility to COVID-19 infection and may develop severe disease with an adverse outcome. These patients have an increased risk of an impaired immune system due to the necessary immunosuppressive therapy and may have cardiovascular and metabolic disorders. The lack of both a validated treatment and a not yet available vaccine for COVID-19 disease requires strict surveillance of KT recipients; immuno­suppressive therapies should be tailored to minimize the risk of infection, and cardiovascular and metabolic status of each patient should be evaluated. These strict strategies of prevention could reduce the risk of infection; in addition, prompt referral to transplant centers and care from a dedicated multidisciplinary medical team can be used to achieve better outcomes.


References:

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DOI : 10.6002/ect.2020.0151


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From the 1General Surgery and Transplantation Unit, “San Giovanni di Dio e Ruggi D’Aragona,” University Hospital, Scuola Medica Salernitana; and the 2Division of Nephrology, Dialysis and Renal Transplantation, “San Giovanni di Dio e Ruggi D’Aragona,” University Hospital, Scuola Medica Salernitana, Salerno, Italy
Acknowledgements: The author declares that there is no conflict of interest or any grants or financial support regarding the publication of this article.
Corresponding author: Gerardo Sarno, General Surgery and Transplantation Unit, “San Giovanni di Dio e Ruggi D’Aragona” University Hospital, Scuola Medica Salernitana, 84131 Salerno, Italy
Phone: +39 089 67 3079
E-mail: gsarno79@yahoo.it