Much has been learned about COVID-19 since the White House declared it to be a national emergency on March 13, 2020. Researchers have conducted thousands of studies that have characterized myriad aspects of the disease, including populations at high risk for infection and predictors of disease severity and outcomes. Particular interest has centered on solid organ transplant (SOT) recipients, who are prone to infection because of the immunosuppressive medications they must take to prevent organ rejection.
Some of the latest research findings, including those presented at the 2021 American Transplant Congress (ATC) in June, document an evolution in the understanding and management of COVID-19 in this patient population.
Shift in Therapies
In a study presented at the ATC, for example, Madeleine R. Heldman, MD, and colleagues at the University of Washington in Seattle, demonstrated a shift in therapies as the pandemic progressed. In their analysis of 946 SOT recipients hospitalized with COVID-19, they compared medications prescribed during an early period in the pandemic (patients diagnosed up to June 19, 2020) and a late period (patients diagnosed during June 20 to December 31, 2020).1 Between the early and late period, the proportion of patients treated with hydroxychloroquine plummeted from 60% to 1%, Dr Heldman reported. Remdesivir use jumped from 9% to 52% of patients and corticosteroid use increased from 11% to 62% of patients. Patients diagnosed in the late period had significant 32% decreased odds of 28-day mortality compared with those diagnosed in the early period after adjusting for comorbidities, according to Dr Heldman. “This provides indirect evidence that novel therapies for COVID-19 may [positively] impact SOT recipients,” she said.
In a separate study of 157 SOT recipients presented at the congress2, investigators from the Miami Transplant Institute of the University of Miami-Jackson Health System in Miami, Florida, concluded that remdesivir and convalescent plasma are safe to use in SOT recipients. Of the 157 patients, 64 (40.8%) and 41 (26.1%) received remdesivir and convalescent plasma, respectively. Liver function test abnormalities developed in 5 (7.8%) of the remdesivir recipients, but none of the patients required cessation of treatment, according to Anmary Fernandez, MD, a transplant infectious disease fellow who reported study findings. She and her colleagues observed no infusion reactions among patients who received convalescent plasma. Acute rejection occurred in 2 patients (4.9%) within 9 days after infusion, but this rate was similar to that of patients who did not receive the plasma, Dr Fernandez said.
Transplant infectious disease specialist Robin K. Avery, MD, professor of medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, who was not involved with these studies, said the research findings are encouraging.
“There had been questions early on in the pandemic as to whether these newer therapies were going to be okay for transplant recipients, like whether remdesivir was going to be okay for patients with renal dysfunction or [on] dialysis [and] whether convalescent plasma was going to cause alloimmune responses and rejection later on,” Dr Avery told Renal & Urology News. “This [study by Dr Fernandez and colleagues] and some other studies have underscored the fact that these therapies seem to be safe in our organ transplant recipients.”
SOT Recipients At Risk for Severe Disease
Zeroing in on which therapies are effective for SOT recipients with COVID-19 is critical because the disease course in these individuals can be particularly severe. For example, an analysis of retrospective data from the TANGO International Transplant Consortium by Leonardo V. Riella, MD, of Massachusetts General Hospital in Boston, and colleagues found that 44 (30%) of 145 kidney transplant recipients (KTRs) hospitalized with COVID-19 in March and April 2020 died after a median follow-up of 10 days following hospital admission for COVID-19.3 Acute kidney injury (AKI) developed in 46% of cases, and respiratory failure requiring intubation occurred in 29% of cases. The study, which was described during the American Society of Nephrology’s 2020 Kidney Week conference, included 9697 KTRs followed at 11 transplant centers, of whom 145 (1.5%) were hospitalized with COVID-19. Of the 145 patients, 55% were older than 60 years and 65% were male. The median time since receiving a transplant was 5 years. Only 16% had received a transplant less than 1 year from presentation.
Novel epidemiologic findings also emerged in recent studies. A study by Gaurav Agarwal, MD, of the University of Alabama at Birmingham, and colleagues revealed that kidney transplant recipients are at higher risk for COVID-19 than other SOT recipients.4
In a study of 19,031 SOT recipients, of whom 2183 tested positive and 16,848 tested negative for SARS-CoV-2, 71.8% of patients who tested positive had a kidney transplant compared with 57.4% of those who tested negative.
SOT recipients who tested positive were significantly more likely to have hypertension (86.7% vs 81.1%), diabetes (64.5% vs 59.0%), coronary artery disease (71.2% vs 67.6%), chronic kidney disease (76.3% vs 70.2%), and peripheral vascular disease (28.5% vs 23.2%), Dr Agarwal’s team reported. Hispanic or Latino patients were significantly more likely to test positive vs negative (17.3% vs 10.4%).
The study also characterized complications in SOT recipients following a COVID-19 diagnosis: 13.7% experienced major adverse cardiac events, 3.8% had graft rejection, and 3.4% had graft loss during the study period, according to the investigators.
Novel Research Approach
Besides stimulating research that has provided information that can guide management decisions, the pandemic spurred innovation in how research itself is conducted. For example, transplant surgeon Dorry L. Segev, MD, PhD, professor of surgery and epidemiology at Johns Hopkins University, described to ATC attendees how he and colleagues conducted large-scale COVID-19 vaccine studies with SOT recipients while keeping participants safe.5
“We launched this study during what was the third wave of the pandemic in the United States,” he said. “It was dangerous for transplant patients to leave the house, let alone go to a health care center, enroll in a study, do exams, do lab work, and things like that.”
The mRNA vaccines became available for use in the United States in December 2020. Knowing that SOT recipients would be scattered across the country, his team used social media to openly enroll any transplant recipient who wanted to participate and who had access to the vaccine starting in December. “By March, we were already able to quantify responses to the vaccine,” Dr Segev related.
Thousands of patients participated in the study “and we’ve never met any of them in person,” Dr Segev said. “Everything has been done online, over the phone, remotely.”
One of the novel approaches used in conducting the study was to send patients automated blood collection devices they could attach to their upper arm and painlessly draw about 200 microliters of blood. The team made an instructional video to educate patients how to use the devices. Patients would then use a return mailer to send the devices containing the sample back to Johns Hopkins.
Dr Segev and colleagues originally published findings from these studies in research letters in JAMA, one on March 15 and another on May 5. These reports described the effects of the first dose and second dose, respectively, of the 2 FDA approved mRNA vaccines (Moderna and Pfizer-BioNTech) in SOT recipients without a prior COVID-19 diagnosis. The vaccines are designed to stimulate an immune response to the spike protein of SARS-CoV-2, the novel coronavirus that causes COVID-19. At the congress, Dr Segev reported updated findings from larger numbers of patients.
The March 15 research letter discussed findings from 436 transplant patients, of whom 76 (17%) had detectable antibodies at a median of 20 days after receiving the first vaccine dose.6 The updated findings, based on 1112 patients, showed that 208 (19%) developed antibodies at a median of 21 days after the first dose.
The May 5 report described results from 658 patients, of whom 357 (54%) had detectable antibodies at a median of 29 days after the second dose. Updated findings from 873 patients showed that antibodies developed in 495 (57%) at a median of 30 days after the second dose.7
Based on the latest findings, Dr Segev concluded that the mRNA vaccines are safe in SOT recipients, but they elicit poor anti-spike protein antibody responses. SOT recipients, he said, may be at higher risk for COVID-19 despite vaccination, but he cautioned that the studies only looked at antibody response, which at best is a surrogate measure of protection against SARS-CoV-2 and may not accurately reflect patients’ level of protection.
The Pandemic’s Lessons
The Johns Hopkins COVID-19 vaccine studies, which were designed in response to the exigencies presented by the pandemic, have shown what can be achieved by streamlining large-scale studies, Dr Avery said. Investigators were able to get answers more quickly by enrolling patients online, providing ways for patients to send in blood samples by mail, and communicating remotely. This is important because “the whole thing with pandemic science is the faster we get answers, the better we can implement interventions for these patients,” she said.
Transplant recipients typically are excluded from initial randomized trials of new treatments, and the pandemic underscored the need to find out quickly which therapies are effective in this population, she said.
Physicians learned a lot about managing immunosuppression in SOT recipients hospitalized with COVID-19, such as the need to withhold mycophenolate to allow the immune system to control the virus, Dr Avery noted. “However, we’ve also learned that you need to have some immunosuppression on board because you still want to mitigate the inflammatory phase [of COVID-19].”
Another consequence of the pandemic was that transplant center physicians and nurses became more adept at managing larger numbers of transplant recipients as outpatients to avoid exposing them to possible infection during in-person visits, she said. They have gained proficiency in the use of telehealth encounters and remote monitoring, she said.
“We’ve learned a lot from this pandemic,” Dr Avery said. “My hope is that on a societal level we are better prepared in terms of hospital resources, ability to ramp up production of drugs and vaccines rapidly, and things of that nature.”
1. Heldman MR, Kates OS, Rakita RM, Lease ED, Fisher CE, Limaye AP. Trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic. Presented at: ATC 2021 held June 4-9, 2021. Abstract 99.
2. Fernandez A, Anjan S, Chandorkar A, et al. Clinical outcomes of solid organ transplant recipients treated with remdesivir and convalescent plasma for Covid-19 at the largest transplant center in the United States. Presented at: ATC 2021 held June 4-9, 2021. Abstract 21.
3. Riella LV, Mothi SS, Akalin E, Cravedi P.COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium. Presented at: Kidney Week 2020 Reimagined virtual conference, October 19 to 25. PO0765.
4. Agarwal G, Vinson A, Dai R, et al. COVID-19 in solid organ transplantation: results of the National COVID Cohort Collaborative (N3C). Presented at: ATC 2021 held June 4-9, 2021. Abstract 126.
5. Segev D. A US-wide study of COVID vaccine safety, immune response, and durability in 3000 transplant patients. Video presentation at the 2021 American Transplant Congress on June 6, 2021.
6. Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021;325:184-1786. Published online March 15, 2021. doi:10.1001/jama.2021.4385
7. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204-2206. Published online May 5, 2021. doi:10.1001/jama.2021.7489