Transplant medicine contends with organ shortage and pandemic-related disruptions
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Transplant medicine and the field of transplant infectious diseases have faced numerous disruptions and challenges during the COVID-19 pandemic, according to experts.
“The number of transplants declined transiently during the height of the COVID-19 pandemic but are now at the pre-pandemic level and growing overall,” Sarah Taimur, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, told Healio | Infectious Disease News.
Despite incredible challenges brought on by the pandemic and organ shortages, there continue to be exciting developments in transplant ID, including transplants from donors with HIV and hepatitis C, xenotransplantation, and new therapies. We touched base with experts in the field and asked about these issues and more.
COVID-19 ‘trumped everything’
Like many areas of medicine, transplant ID was disrupted by the COVID-19 pandemic. The disease itself has become the subspecialty’s No. 1 issue, according to Michael G. Ison, MD MS, chief of the NIH’s Respiratory Diseases Branch.
“It has kind of trumped everything in the field,” said Ison, who was previously a medical professor of infectious diseases and organ transplantation surgery at the Northwestern University Feinberg School of Medicine.
Because transplant recipients are at an increased risk for COVID-19 and may have a suboptimal immune response to vaccination, they have been prioritized in guidance for COVID-19 vaccines and booster shots.
“There are strategies to improve response to vaccines, but so far, no ‘magic bullet’ has been identified,” Ison said.
The results of a systematic review and meta-analysis of more than 6,100 solid organ transplant recipients found that only 8.6% and 34.2% had a serologic response after one or two doses of COVID-19 vaccine, according to findings published last year in the journal Viruses. A third dose raised that rate to only 66%.
“The vaccines have been a game-changer for the general population and for transplant recipients, although, unfortunately, some of our transplant recipients are not generating robust responses to the vaccines. They still are quite vulnerable to COVID-19,” said Christine Durand, MD, a transplant ID physician at Johns Hopkins University School of Medicine.
Antivirals come with their own challenges, according to Durand. Paxlovid, for example, is difficult to prescribe for transplant recipients because of drug-drug interactions, and there is still a need for an oral antiviral for this patient population, she said.
However, monoclonal antibodies, which were hugely successful for the nontransplant population, have also been beneficial for transplant recipients, according to Durand.
An early study that assessed the first 73 solid organ transplant recipients at the Mayo Clinic to receive infusions of bamlanivimab or casirivimab-imdevimab for the treatment of mild to moderate COVID-19 found that no patients required mechanical ventilation, died or experienced rejection.
More recently, a single-center retrospective study examined the effectiveness of casirivimab-imdevimab or sotrovimab for kidney transplant recipients infected with the omicron variant of SARS-CoV-2 and found that only two of the 47 patients were hospitalized to receive oxygen and none died or required ICU admission within 30 days.
“Unfortunately, the virus evolves so quickly that [mAbs] tend to only be of benefit for short time frames,” Durand said, “but they certainly have saved many lives [among] our transplant recipients.”
Taimur said transplant practitioners must keep up with CDC guidance and work with patients to ensure they are up to date on their COVID-19 vaccines, including boosters.
“COVID-19 remains an infection to contend with in relation to organ donors and recipients,” she said.
‘One of our most challenging issues’
The United States is in the midst of an organ shortage crisis, which the pandemic exacerbated, according to experts.
“Particularly for transplant patients, COVID-19 had an outsized impact on multiple fronts, including reducing the number of transplants being done transiently at the beginning of the pandemic” because organs from donors with SARS-CoV-2 were underutilized, Ison said.
Durand recalled that living donor transplantation was shut down when COVID-19 “first came on the scene” and remained that way while the field worked to get its footing during the initial surges.
According to a study published in The Lancet in May 2020, there was a more than 51% decline in deceased donor transplantations in the U.S. in the early months of the COVID-19 pandemic as hospitals diverted resources and staff to respond to the initial surge in cases. The decrease was driven mostly by declines in kidney transplants, researchers found.
More than 104,000 people in the U.S. are currently waiting for a transplant, with one new person added to the national list every 10 minutes on average, according to the Health Resources & Services Administration (HRSA). There were around 42,000 transplants performed in the U.S. in 2022.
“The organ shortage is still one of our most challenging issues,” Durand said.
In March, the HRSA announced a new initiative to improve access to donor organs, including a proposal to more than double the agency’s budget for organ procurement and transplantation to $67 million.
‘Great advancements’
There have been advancements in recent years in who can donate organs, which could help expand the donor pool, Durand said. This includes transplanting organs from donors with HCV or HIV to recipients with or without HCV or HIV.
“In 2018, we were just at the beginning of that practice with a couple of successful pilot studies in kidney transplantation,” she said. “Since then, that’s expanded outside beyond kidney transplantation and liver transplant transplantation to also include heart and lung transplantation.”
In 2016, 3 years after the HIV Organ Policy Equity Act made it legal for transplantation between people with HIV, a surgical team at Johns Hopkins performed the first HIV-positive-to-HIV-positive kidney transplant in the U.S. and what was believed to be the first HIV-positive-to-HIV-positive liver transplant in the world.
A federal advisory committee recommended in January that HHS remove a requirement that allows HIV-to-HIV kidney and liver transplants only in the context of a study, which would move the practice beyond research and into standard clinical practice.
“There’s been just a huge expansion of that practice across organ types and across the country,” Durand said.
Another potential solution for the organ shortage is xenotransplantation — or transplanting organs from other species into humans.
“There’s been a lot of interest in that as a new strategy to expand the donor pool,” Durand said.
Last year, researchers in The New England Journal of Medicine outlined the first heart transplant from a genetically modified pig into a human. The recipient, a 57-year-old man with nonischemic cardiomyopathy, died just over 2 months after the procedure, which was hailed as a milestone. Further examination revealed that the man’s death was “not consistent with typical rejection.” Additional studies are underway to understand what happened.
Taimur mentioned xenotransplantation as an emerging hot topic in transplant ID. The FDA cautions that although the potential benefits are “considerable,” xenotransplantation also comes with the risk for potential infection “with both recognized and unrecognized infectious agents and the possible subsequent transmission to their close contacts and into the general human population.”
“Of public health concern is the potential for cross-species infection by retroviruses, which may be latent and lead to disease years after infection,” the FDA said. “Moreover, new infectious agents may not be readily identifiable with current techniques.”
There also have been advancements in the therapeutic armamentarium available for transplant ID, according to Ison.
“We have a bunch of new antifungal medications that are either approved — such as rezafungin, ibrexafungerp and fosmanogepix — or pending approval, like olorofim, that will give us new options for patients with fungal infections, particularly some fungal infections for which we have very limited therapeutic options, and we now have two drugs that are effective for prevention and treatment of cytomegalovirus (CMV) with a different toxicity profile from other currently available agents,” said Ison.
The new CMV drugs are critically important for transplant recipients because CMV — a common virus that is normally kept dormant by T cells — is one of the most common post-transplant infections, Durand noted.
One newer agent used to treat CMV is maribavir, which the FDA approved in November 2021 as the first drug to treat adults and children with post-transplant CMV infections that do not respond to other available antivirals.
Before the approval, researchers assessed maribavir in a phase 3, open-label study of hematopoietic stem cell and solid organ transplant recipients with CMV with or without resistance. They randomly assigned participants in a 2:1 ratio to receive maribavir twice daily or investigator-assigned therapy — valganciclovir/ganciclovir, foscarnet or cidofovir — for 8 weeks, with 12 weeks of follow-up.
Significantly more participants in the maribavir group achieved CMV clearance at the end of 8 weeks (55.7% vs 23.9%; P < .001), and rates of treatment-emergent adverse events were similar between the groups (97.4% vs. 91.4%), with fewer patients in the maribavir arm discontinuing treatment due to adverse events (13.2% vs. 31.9%).
“The approval of maribavir has given us a novel therapy for refractory and resistant CMV in which we previously had to rely on toxic foscarnet,” Ison said.
Additional options may also be available soon, including new indications for letermovir. Although the drug has already been approved for prophylaxis of CMV infection in seropositive adult allogeneic hematopoietic stem cell transplant recipients, studies have shown that it effectively prevented CMV disease among kidney transplant recipients with fewer side effects than valganciclovir.
In a study that was presented at IDWeek last year, 601 patients were randomly assigned to receive letermovir or valganciclovir within a week of a kidney transplant. Results showed that 10.4% of patients treated with letermovir developed CMV within a year of the transplant compared with 11.8% of patients treated with valganciclovir. Additionally, the incidence of drug-related adverse events was 19.9% in the letermovir group compared with 35% in the valganciclovir arm.
The FDA’s target action date for the approval of letermovir for the prevention of CMV in high-risk kidney transplant recipients was June 5.
“That will be a huge step forward in the field for one of the most common infectious complications that we see with a less toxic drug,” Durand said.
The FDA is expected to decide by Sept. 7 on whether to update the approval of letermovir to extend its use from 100 to 200 days for the prevention of CMV in allogeneic hematopoietic stem cell transplant recipients.
“We continue to gain insight into infectious diseases in relation to organ donors and recipients, and we have continued to improve our ability to diagnose infections in organ donors and manage donor-derived infections in recipients, making organ transplantation progressively safer,” Taimur said.
‘Left a bit behind’
Ison said challenges that arose during the COVID-19 pandemic highlighted an important issue that has not been effectively addressed: In the next pandemic, will transplant recipients be left behind again?
“If you think about a lot of the key things that allow the general healthy patient population to move on from the pandemic — such as vaccines and effective antivirals — the transplantation population is at a disadvantage,” he said. “They don't have great vaccines to protect them. Some of the antivirals can't be safely used in many transplant patients. This means that they may not have great options both for prevention and for treatment of breakthrough infections.”
He said studies examining COVID-19 vaccine responses among transplant recipients did not begin until over a year after the vaccines were authorized, and the same is true for mAbs.
“We were extrapolating data and not including this patient population” in studies, Ison said. “How well can these patients be protected?”
Transplant recipients were also “left a bit behind” in the mpox outbreak, Ison said.
“We're starting to see more breakthrough infections, so perhaps there may need to be a different approach to mpox,” Ison said, adding that it is possible that transplant recipients could have gotten vaccinated against mpox and thought they were protected when in fact they were underprotected, just as they were against COVID-19. There have not been enough studies to say for sure, according to Ison.
“We need a good framework to figure out in future pandemics how we can improve the outcomes and study of the disease among transplant recipients,” he said.
References:
- Avery RK, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciab988.
- Durand CM, et al. Am J Transplant. 2022;doi:10.1111/ajt.16205.
- FDA approves first treatment for common type of post-transplant infection that is resistant to other drugs. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-common-type-post-transplant-infection-resistant-other-drugs. Posted Nov. 23, 2021. Accessed May 15, 2023.
- FDA. Xenotransplantation. https://www.fda.gov/vaccines-blood-biologics/xenotransplantation. Accessed May 26, 2023.
- Fernandes G, et al. Kidney Med. 2022;doi:10.1016/j.xkme.2022.100470.
- Griffith BP, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2201422.
- Han SH, et al. Int J Med Sci. 2021;doi:10.7150/ijms.62621.
- HSRA announces organ procurement and transplantation network modernization initiative. https://www.hhs.gov/about/news/2023/03/22/hrsa-announces-organ-procurement-transplantation-network-modernization-initiative.html. Published March 22, 2023. Accessed May 26, 2023.
- HRSA. Organ donation statistics. https://www.organdonor.gov/learn/organ-donation-statistics. Accessed May 26, 2023.
- Limaye A, et al. Abstract LB2307. Presented at: IDWeek; Oct. 19-23, 2022; Washington (hybrid meeting).
- Loupy A, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31040-0.
- Sakuraba A, et al. Viruses. 2022;doi:10.3390/v14081822.
- Werbel WA, et al. Am J Transplant. 2023;doi:10.1016/j.ajt.2023.03.014.
- Yetmar ZA, et al. Open Forum Infect Dis. 2021;doi:10.1093/ofid/ofab255.
For more information:
Christine Durand, MD, can be reached at ChristineDurand@jhmi.edu.
Michael G. Ison, MD MS, can be reached at Michael.Ison@nih.gov.
Sarah Taimur, MD, can be reached at newsmedia@mssm.edu.
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