Transplant Capacity in the COVID-19 Era and Early Vaccine Recommendations

December 3, 2020

The protracted nature of the COVID-19 pandemic has taken its toll on many aspects of our professional and personal lives. Though this pandemic has been ongoing in the US since the Spring of 2020, in most regions there are clear signs that another major resurgence of infections and illness has begun. The situation is worsening as the winter season unfolds. Key issues to be addressed include waitlist management in the context of Covid-19, the health of our recipients, and the well-being of our community as providers. We feel at this time that these aforementioned issues need to be addressed, and in some cases modified.

What has been of recent interest is the issue of vaccination. From the onset of the pandemic, the holy grail has been to acquire protective immunity to SARS-CoV-2. It now appears that viable vaccines will be available within a short time.

Vaccine: Early release of information about vaccines to prevent Covid-19 are promising.

Two vaccine manufacturers, Moderna and Pfizer BioNtech, have filed for emergency use authorization (EUA) with the FDA. These two vaccines appear to be similar in method to elicit a viral specific immune response.

The Moderna vaccine uses mRNA that enters the patient cell and uses host protein transcription pathways to produce viral proteins that subsequently stimulate a viral-specific immune response. This vaccine requires two parenteral injections over a four week interval. It can be stored in a normal freezer at -4 degrees Celsius. There is a significant incidence of arm pain, fever, and chills. The Pfizer vaccine is also an mRNA vaccine and is thought to act in a similar fashion to Moderna’s. The inoculum interval is three weeks. It needs to be stored at -80 C or lower requiring specialized storage, opposed to a normal freezer. This vaccine is known to produce an antibody and T cell response.

Neither of these vaccines have been tested in transplant candidates or recipients. There is some proprietorial information about the vaccine; the mRNA is lipid encapsulated and mechanism of cell entry is undisclosed. Non-specific fusion with cell membranes and endocytosis of the mRNA is possible, but if specific receptor-ligand interaction are operative, signaling pathways may cause cell stimulation. Further study is necessary to determine the degree of protective immunity provided the waitlist and transplant patient. It is necessary to be mindful that the effect of the mRNA vaccines may alter other immune responses, with the potential to heighten the alloimmune response. Vigilance will be necessary to determine that the desire to induce protective viral immunity is not associated with an increased risk for rejection episodes. It is the Strike Force’s belief that these two vaccines are the safest alternatives for the transplant population at this time, but come with unknown consequences for our patients. Patient immunoresponsiveness and duration of antibody, will need to be studied in our patient population.

Two other vaccines are also preparing to file for EUA. AstraZeneca and Johnson & Johnson. They are both adenovirus vector vaccines where the coronavirus genetic material is carried into the cell on a live virus. The AstraZeneca vaccine is based on a chimpanzee virus. It’s trial was paused and restarted due to neurologic side effects. It requires two shots. It can be stored at -4 degrees Celsius. The Johnson & Johnson vaccine trial, previously paused, is the only single dose vaccine. It is also stored at -4 degrees Celsius. These vaccines have similar side effect profiles. Historically we have not recommended live viral vector vaccines for transplant patients that take immunosuppressive agents. The safety for the severely ill waitlist population could also have difficulty clearing the viral vector

Waitlisted patients testing positive for SARS-CoV-2 & consideration for transplant:

The Strike Force continues to recommend that transplant candidates do NOT receive an organ transplant when there is evidence of active (even if asymptomatic) infection (PCR positivity excludes transplantation). In order to assure that a candidate has cleared the virus, we recommend that two consecutive negative PCR tests separated by at least a week interval be performed prior to reactivation. It should be recognized that some symptoms and organ damage may persist long after the virus has been cleared. Anosmia and mental confusion can persist for months after viral clearance. Pulmonary, cardiac and renal injury may necessitate reconsideration of transplant candidacy by assessment of Covid-induced organ injury. Most patients should have undetectable viral RNA after 2-4 weeks or 30 days. These recommendations are opinions of members of the Strike Force and not supported by Level 1 evidence.

Transplant recipients with SARS-CoV-2:

While there is no definitive data supporting immunosuppression modulation for transplant recipients contracting SARS-CoV-2 infection, there are increasing numbers of observations about varying severity of infection. Those with more severe disease develop a significant inflammatory response and rising levels of inflammatory markers e.g., crp, procalcitonin, IL-6, d-dimer. They should be carefully monitored.

Asymptomatic patients: Routine covid testing prior to procedures or hospitalizations has identified many people with asymptomatic Covid-19 infection. Those with minimal to no symptoms must be watched carefully for disease progression, but with low proinflammatory markers, do not seem to benefit from reduction in immunosuppression. The virus appears to clear without modification of drug regimen. We have concern that allograft rejection may be induced through aggressive “pre-emptive” reduction and create added complications. Asymptomatic transplant recipients should be monitored with PCR until negative and home bound and isolated from uninfected individuals. Immunosuppressed transplant recipients clear virus at a slower rate than the non-transplant patient, typically for 30 days and may remain PCR positive for several months.

Patients with Mild-Moderate Disease: In recipients with mild, short-lived fever, cough and “feel bads”, reduction in immunosuppression does not appear necessary. In those with shortness of breath, reduction of oxygen saturation and needing supportive care, many centers have been reducing or dropping MMF/antimetabolites as a first step. This approach seems consistent with standard practice, and thus far not shown to be detrimental. We are inclined to agree with this approach.

Patients with Severe Disease: Disease requiring hospital/ICU care is very serious. To promote viral clearance, people requiring ICU/ventilator support have had all immunosuppression stopped except for steroid supplementation. Conventional immunosuppression is resumed as the patients recover. The rate of complications due to rejection in this setting has not been fully assessed.

Isolation is a hardship for individuals with disease Testing of coronavirus infected transplant patients has shown a longer time to become PCR negative and often with a delayed antibody conversion to the virus. Immunosuppressed recipients remain PCR+, an average of twice as long as non-immunosuppressed individuals. The recommended self isolation for 10 days after testing positive may not apply to transplant recipients. The PCR positive state can persist for a month or longer. It is important that programs have a standard approach of isolation and testing for the protection of others. We know of no Level 1 study that has assessed the infection spread potential of the transplant recipient.

Treatment: Currently there are ongoing changes to treatment regimens for moderate to severe Covid-19 disease. To our knowledge there are no transplant specific reasons that recipients should be excluded from any of the treatment regimens currently approved/accepted for Covid-19 disease.

Self and staff care:

Covid-19 is taking a toll on the uninfected. We must recognize the price that the medical staff have paid during the pandemic. It is key to protect them from the disease with sufficient PPE, but it is equally important to support their mental health. It is necessary to work with your administration to address morale and retention.

Ensure front line staff are confident that the design and implementation of patient flow plans minimize exposures, contain barrier protections and allow for easy access for hand hygiene.This is a tough time for all. Take one day at a time.