How are transplant recipients suspected to be infected with SARS-CoV-2 (COVID-19 virus) handled?

While the severity of COVID-19 infection seems to be milder in dialysis patients (www.medrxiv.org/content/10.1101/2020.02.24.20027201v2), there is no published data on COVID-19 infection in transplant recipients, though one might expect a higher risk of more severe COVID-19 infection based on the natural history of viral infections in immunosuppressed patients.

The rules to prevent viral infection in the general population apply to transplant patients. In particular, patients with potential COVID-19 infection should not access the transplant center due to the risk of viral spread.

Patients with mild flu-like symptoms may be followed-up by the GP and/or by phone consultation with the transplant outpatient clinic. Otherwise, patients should be directed to a COVID-19 specific ER. In hospitals lacking a dedicated ER response area (especially in areas with low prevalence), plan for access to dedicated ambulances, corridors, elevators, and direct access to COVID-19 sections/hospitals should be established immediately. It is crucial to prevent access of COVID-19 positive patients to regular ERs.

What is the management and course of COVID-19 in kidney transplant patients?

In case of COVID-19-associated pneumonia, immunosuppressive therapy should be significantly reduced (one approach would be to do IV steroids as a single antirejection drug until signs of recovery). Antiviral agents should be started immediately, based on CT scan findings only, whenever swab test results are not readily available. In COVID-19 patients with pneumonia, the respiratory condition may remain stable for a few days before abrupt deterioration requiring intubation and ventilator support (likely due to acute inflammation). Because at that point ICU beds may be not available, the use of anti-inflammatory agents may be beneficial. A randomized controlled trial is testing the safety/efficacy of steroids (NCT04273321). Until results are available, broad use of steroids is discouraged (Russell, et al.; Lancet, 2020). Pending results from clinical studies (see below), various non published reports have shown the benefit of the use anti-IL6 receptor agents to block the inflammatory response in the lung.

 

Living Donation

In general, living donation should not put the donors at risk. In countries with widespread community transmission (e.g., Italy), living-donor kidney and liver transplant programs have been temporarily suspended.

In countries where community transmission is lower, living donation should not be performed on either a donor or recipient who has returned from places with high incidence of infections or been exposed to a patient with confirmed or suspected COVID-19 within 14 days.

Transplantation can be considered in highly selected cases when required as a life-saving procedure.

 

Donation from deceased donors

There is no clear reason to suspend deceased donor transplants in countries only experiencing sporadic COVID-19 infection cases. However, since the risk of donor-derived transmission is possible (RNAemia was reported in at least 15% in one case series; Huang C, et al. Lancet 2020), donors at risk of infection should not be accepted.

Suspension of all transplants that require T cell depletion should be considered even in countries where the incidence of COVID-19 positive individuals is low.

In countries with widespread community transmission, temporary suspension of the deceased donor program for non life-saving organs should be considered in order to prevent infection of the recipient during the post-transplant period. Even then, kidney transplants can be considered on a case-by-case basis.

 

Experimental treatments

Many treatments are being tested.

 

To limit viral replication:

Convalescent Plasma

Preliminary clinical studies in China have shown that early application of convalescent plasma in patients with COVID-19 could accelerate clinical recovery (Huang, The Lancet 2020).

Remdesivir

Roche’s antiviral drug, an adenosine analogue targeting RNA viruses, was developed to treat Ebola is being used on compassionate basis in efforts to treat COVID-19. While Gilead is boosting production, supplies are insufficient in the short-term.

Hydroxychloroquine

Hydroxychloroquine is effective and inhibiting entry and replication of the virus in in vitro assays (Vero-E6 cells) at similar concentrations to those achieved with current use in rheumatological diseases (Cell Res. 2020 Mar;30(3):269-271). Early hydroxychloroquine use presents a low risk intervention despite unclear clinical benefits.

To limit inflammatory response:

IL6 Targeting Therapy

A monoclonal antibody against the IL-6 receptor (Tocilizumab), has achieved encouraging preliminary clinical results in treating acute systemic inflammation in patients with serious lung damage (and elevated levels of IL-6 in the blood). The safety and efficacy of Tocilizumab in COVID-19 infection is undergoing evaluation by a multicenter randomized controlled trial in China (ChiCTR2000029765). Encouraging results with the same antibody have been reported also in a few Italian Centers.

RAS inhibitors

The use of non-ACEI RAS inhibitors is controversial. On the one hand they could effectively relieve symptoms of acute severe pneumonia and respiratory failure reducing lung inflammation and hypertension. On the other hand, the use of ACEI could upregulate ACE2 (Li XC, et al. Pharmacol Res 2017; 125: 21–38), which is used for the virus to enter the cells, and could facilitate COVID-19 spreading.