The outbreak of novel coronavirus (SARS-CoV-2) that causes COVID-19 has affected all spheres of human life across the globe. First reported in city of Wuhan, China in late 2019, the virus spread rapidly to the rest of the world getting a WHO pandemic designation by March 2020. In the United States alone, as of March 2022, nearly 957,000 deaths have been reported from COVID-19, the highest recorded of any country. The virus belongs to the Coronavirus family of viruses known to be associated with common colds. The virus has a simple single-stranded RNA genome which gains rapid access into cells through the ACE-2 receptors which are especially abundant in the human lung tissues. The RNA genome is inherently unstable, leading to replicational mutations that can make the virus more transmissible, more virulent, and less susceptible to vaccines and novel therapies. The mutations allow new variants to evade host immunity and existing therapies causing fresh waves of infections.
The world of transplantation has been hit especially hard by the rampaging COVID-19 pandemic. With a need to conserve healthcare resources and a desire to avoid COVID-19 related sickness and death in ever so vulnerable immunosuppressed patients, the pandemic has forced transplant programs across Unites States and Europe to suspend transplant surgeries from time to time. This has put end organ disease patients awaiting a lifesaving transplant at high risk of death. In 2020, 11% of all deaths in kidney waitlisted patients were attributed to COVID-19. Each successive variant of SARS-CoV-2, with its unique mutations, brings in fresh challenges to the transplant community, necessitating recalibration and re-purposing of already scarce resources.
Prevention of transmission of SARS-CoV-2 by achieving vaccine induced herd immunity was considered the holy grail. A two-dose m-RNA vaccine directed against the spike protein of the SARS-Cov-2 introduced under the Emergency Use Authorization (EUA) in December 2020, was 94% effective in general population. However, it was found to induce antibody response in only 35-55% of the transplant population, leaving a large percentage susceptible to effects of COVID-19. Further complicating the situation remains the fact that the antibody levels required to prevent acquisition of COVID-19 or development of severe disease are not known, and vaccine immunity appears to wane over time, more rapidly so in transplanted individuals. Considering these, the CDC revised their vaccine guideline, and now requires a total of three doses of primary series of m-RNA vaccine followed by a booster with hopes to induce a sustainable level of anti-COVID-19 immunity. The experience so far reveals the vaccine is highly effective in preventing severe disease requiring hospitalization and death.
The approach to management of COVID-19 infection itself is multipronged and has continued to evolve over time. For the out of hospital transplant patients with a significant exposure to SARS-COV-2 or those with mild to moderate COVID-19, post exposure prophylaxis with a monoclonal antibody (REGEN-COV® casirivimab and imdevimab) directed against the spike protein of SARS-CoV-2 was effective against preventing severe COVID-19 related disease and hospitalization. However, the arrival of highly transmissible Omicron variant in November 2021, with its distinctive mutations in the spike protein rendered this monoclonal antibody ineffective for this indication. Then, in December 2021, FDA issued an EUA for AstraZeneca’s EVUSHIELD® (tixagevimab and cilgavimab) for pre-exposure prophylaxis (prevention) for those on immunosuppressive medications including transplant patients. EVUSHIELD® is a combination of two long-acting monoclonal antibodies directed against two separate domains of the spike protein of SARS-Cov-2. It provides effective prevention against COVID-19 for up to 6 months, and in studies has shown 77% reduced risk of developing COVID-19 when compared to placebo. At the Starzl Transplant Institute (STI), we offer EVUSHIELD® to all transplant patients as early as their index hospitalization for transplant surgery. Until recently, no oral antivirals were available for out of hospital treatment. On December 22, FDA issued EUA to two oral antivirals, Molnupiravir (LAGEVRIO®) and Ritonavir-boosted Nirmatrelvir (PAXLOVID®), for adults with mild to moderate COVID-19 who are within 5 days of symptom onset and who are high risk for progressing to severe disease. This was a long-awaited welcoming news for the transplant community.
For transplant patients hospitalized for COVID-19 infection, the 28-day mortality rates were as high as 21% before the widespread availability of vaccines and effective therapies. The risk of mortality appears to be associated with a disproportionately higher burden of underlying comorbidities often seen in transplant patients. The current management of hospitalized patients includes a reduction in immunosuppression, intravenous antivirals (Remdesivir, VEKLURY®), and a monoclonal antibody effective against the virus (Sotrovimab, XEVUDY®). High dose steroids and anti-IL6 drugs (Sarilumab, KEVZARA®) are administered to decrease systemic inflammation. Despite the above advances, the death rates in hospitalized COVID-19 patients requiring a breathing tube remains extremely high.
Besides the risks of severe illness, another significant challenge that transplants patients face is their inability to clear the virus leading to prolonged viral shedding and a high persistent test positivity rate. The subsequent requirement for isolation precludes them from resuming normal lives including getting back to work, leading to financial and mental health stresses. The prolonged isolation requirements also make delivery of traditional face to face clinical care at the transplant center extremely difficult. At STI, we have crafted an effective solution where a selected team chaperones the patient from entrance to designated sites of care within the transplant center where they can see their providers, get their blood work and other testing done while observing all precautions to prevent transmission. We have also strategically employed telemedicine to minimize transplant patients’ exposure to health care settings and avoid large congregations in clinic waiting areas.
From the transplant center and provider perspective, we have encountered unexpected COVID-19 positivity in candidates and/or living donors in immediate pre-transplant settings necessitating cancellation or postponement of transplant surgeries. Especially, earlier in the pandemic, we weathered several supply chain disruptions involving immunosuppressive medications causing some anxiety in the transplant community. In addition, the Great Resignation in the COVID era has impacted transplant teams in an unprecedented way by causing the departure of some experienced staff from the clinical, managerial, quality improvement and scheduling teams. We are working diligently to replace these individuals and minimize any disruptions to patient care.
Fortunately, we are beginning to see the light at the end of this long tunnel. Universal vaccination, masking and social distancing remain the cornerstones of any strategy to combat this deadly pandemic.
Puneet Sood, MD, MPH
Associate Professor of Medicine/Surgery
Medical Director, Kidney and Pancreas Transplantation Program
Thomas E. Starzl Transplant Institute