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Transplant ID: An emerging subspecialty
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Just 10 years ago, patients with HIV and end-stage renal disease were often sent home to die from Groote Schuur Hospital in Cape Town, South Africa, because of limited access to dialysis and a shrinking organ donor pool. Then, in a pioneering program, physicians at the hospital began transplanting kidneys from HIV-positive donors into HIV-positive recipients, starting with four successful transplants. They announced the new therapeutic approach in a six-paragraph letter to The New England Journal of Medicine.
“That trial was groundbreaking,” Emily A. Blumberg, MD, professor of medicine in the Perelman School of Medicine and director of transplant infectious diseases at the University of Pennsylvania, told Infectious Disease News. “But it probably could only be initiated in South Africa because, at the time, they couldn’t offer dialysis to HIV patients. The surgeon who started it, Elmi Muller, was really thoughtful in terms of trying to figure out how to help a group of people who were never going to get help otherwise.”
Among the first 27 recipients of organs from these HIV-positive to HIV-positive transplants, around three-quarters were still alive after 5 years, the physicians later reported. Since then, other countries, including the United States, have successfully transplanted kidneys and livers between HIV-positive people, and surgeons have even begun transplanting kidneys from hepatitis C-positive donors into HCV-negative patients and treating the recipients with direct-acting antivirals (DAAs).
Experts have said that these procedures, still in the experimental stages, could help solve an organ shortage crisis in the U.S. They are on the cutting edge of the relatively new field of transplant infectious diseases, a subspecialty in which physicians work with transplant teams to treat and manage infections in organ or stem cell recipients.
Infectious Disease News spoke with several experts about the growing subspecialty of transplant ID, including its potential to impact patients who have not undergone solid organ or stem cell transplantation. Experts described a burgeoning field of medicine full of unanswered questions.
“New things happen almost every year in this field,” Kieren Marr, MD, director of transplant and oncology infectious diseases and professor of medicine at Johns Hopkins University School of Medicine, said in an interview. “It’s really pretty amazing.”
An emerging subspecialty
As a subspecialty, transplant ID is in the early stages of development, making it an intriguing focus for medical students looking to enter an emerging field, experts said. A recommended curriculum for formal training in transplant ID has existed in the U.S. for only about 8 years.
According to Peter Chin-Hong, MD, Infectious Disease News Editorial Board member and professor of medicine at the University of California, San Francisco School of Medicine, the genesis of transplant ID as a medical subspecialty came from trying to treat donor-derived infections, and the need to address the safety of patients in these settings is one of the reasons that the field has grown so much.
“What really sealed the deal was stories of people who died getting hep C and HIV,” Chin-Hong said in an interview. “That showed the need for a group of providers with expertise in infectious diseases in the transplant setting.”
The need for more physicians trained in transplant ID is clear. In each of the past 5 years, the U.S. has set a record for the total number of transplantation surgeries. In 2017, 34,768 were performed from both deceased and living donors, a 3.4% increase over 2016, and the number of deceased organ donors reached 10,000 for the first time — in part because of the death toll of the opioid epidemic. But the need for organs still far outstrips demand, with more than 114,000 people in the U.S. waiting for an organ, according to the United Network for Organ Sharing.
Transplant ID subspecialists can play a role in keeping the organ supply robust, Chin-Hong said.
“There are times when non-ID people will see an infection and worry about it, but someone in transplant ID might jump in and say, ‘That’s actually very easily treatable. I would be fine taking that organ,’” he said. “We’ve become integral in the system of transplantation.”
To prevent organ rejection, transplant recipients take immunosuppressive drugs that leave them vulnerable to opportunistic infections. Recipients also may get infections from the donated organ. Because transplant ID is a relatively new field, best practices for treating infections in transplant recipients have still not been fully established. For instance, although cytomegalovirus (CMV) is the biggest opportunistic infection in solid organ transplantation and a common complication of hematopoietic stem cell transplantation (HSCT), experts are still learning how to optimize treatment.
“That’s one of the joys of [transplant ID]. People are very energized,” Chin-Hong said. “Some might disagree, but it’s almost like the early days of HIV. It’s kind of ill-formed and there are a lot of questions still to be asked.”
In 2010, Transplant Infectious Diseases published the first recommended curriculum for subspecialty training in transplant ID. Written by a working group from the American Society of Transplantation Infectious Diseases, it included clinical, laboratory and research components that should be covered in an additional 1 year of training. At Johns Hopkins, Marr said that a specialized transplant ID fellowship was created about 10 years ago, offering trainings for 6 months to 2 years, depending on how much clinical exposure the fellows want, how much training they have received already and how much research they want to undertake. Blumberg said transplant ID fellows at Penn typically spend about 1 year of their fellowship on transplant ID training. At Northwestern University, enough students were interested in transplant ID that the school created an ad hoc program for them, which will soon become a formal program, according to Michael G. Ison, MD, medical professor of infectious diseases and organ transplantation surgery in the university’s Feinberg School of Medicine.
“The field has grown significantly in terms of numbers,” Ison said. “When I went to my first transplant ID group at the American Transplant Congress in 2004, there were probably 15 to 20 people in there. Now it’s 450 transplant ID people who are members, and we basically bust at the seams at the annual meeting.”
There are ways that practicing ID clinicians can receive education in transplant ID, too. According to Marr, some clinicians come to Johns Hopkins for as little as 2 weeks for transplant ID observerships. But Marr and Chin-Hong both said more guidance is needed to help ID clinicians who are already in practice who might want to take care of transplant patients.
“Similar to HIV, you need to see a certain number of patients to maintain excellence in the field because it’s very specific information that can become outdated if you’re not seeing enough patients,” he said.
Important pathogens
There are currently no good estimates on the percentage of transplant recipients in the U.S. who develop infections. According to Marr, numerous factors may increase the risk for infection, including underlying disease, organ rejection and corresponding needs for immune suppression. Patients may have several infections at a time.
“Longitudinal studies show that most people get some type of infection. Some people get multiple infections. Risks are complex, and we continue to work toward prevention,” Marr said.
CMV, a common but normally dormant virus, is particularly problematic after transplant. By adulthood, about half the U.S. population has been infected with CMV, but the virus is usually kept in check by T cells, Marr explained.
“Once you give someone a drug that releases those T cells from keeping that virus in check, they can get a terrible disease — an infection that doesn’t occur when your immune system is right, and everything is working well,” she said.
Antivirals can prevent CMV in both solid organ and stem cell transplant recipients, but physicians continue to learn when to use the drugs, based on diagnostic monitoring or predicted risks. Until recently, physicians have had few options, but new drugs are being developed. Recent results from a randomized phase 3 trial showed that the antiviral drug letermovir was highly effective at preventing CMV in seropositive patients who underwent HSCT, leading the FDA to approve the drug late last year.
Transplants are on the rise, but as the U.S. population ages, more patients especially need HSCTs — mostly bone marrow transplants — for diseases like leukemia and lymphoma, Chin-Hong said. In terms of infections, the risks for these patients generally differ by region. Blumberg said fungal pathogens like aspergillosis are a common concern in the Northeast, whereas coccidioidomycosis, or valley fever, is problematic in dry areas of the Southwest.
“Interestingly, working in the solid organ population doesn’t totally prepare you for the stem cell population and vice versa,” she said. “There are some very different issues related to conditioning versus surgical concerns versus immune reconstitution in the post-transplant setting.”
In terms of respiratory infections, Ison said influenza, respiratory syncytial virus (RSV) and parainfluenza are the three viruses that transplant ID physicians focus on the most. According to findings from a recent study, in which Blumberg participated, influenza vaccination and preliminary treatment with antivirals are associated with a significant reduction in influenza-associated mortality among transplant recipients and should be emphasized as strategies to improve their outcomes.
Findings presented at IDWeek last year indicated that high-dose influenza vaccine is preferable to standard-dose vaccine in adult solid organ transplant recipients, but Ison said there are insufficient data to suggest that high-dose or adjuvanted vaccines are superior, so standard-dose vaccines are still recommended. It is also recommended that health care workers and close contacts such as family members be fully immunized, particularly against influenza.
Oseltamivir and zanamivir are recommended for treatment of influenza in organ recipients, but there are limited options for RSV — ribavirin being the only approved treatment — and no approved treatment for parainfluenza, Ison said. Once pneumonia develops in these patients, outcomes tend to be very poor.
“The risk for having a severe infection, particularly pneumonia, is much higher in the transplant setting, particularly for lung or stem cell patients because of the specific alteration of their immunity and involvement of the lung in the case of lung transplant settings,” Ison said. “While it will oftentimes cause mild, self-limited infections in other populations, it can present with aggressive infections leading to pneumonia and death in a sizeable portion of lung transplant patients.”
Organ recipients are at risk for many other infections — for instance, the Epstein-Barr and BK polyoma viruses, which are significant causes of infection in kidney transplant recipients.
Timing plays an important role in determining the types of infections that threaten organ recipients. In the first month, for instance, recipients are at risk for nosocomial and donor-derived infections. Later, latent or community-acquired infections are more common.
Rare diseases are sometimes transmitted through donor organs, such as in 2016 when researchers reported that two kidney transplant recipients in China had likely died from rabies after they received organs from a deceased donor infected with the disease. Two other patients who received transplanted corneas from the same infected donor survived after receiving rabies prophylaxis.
“I think over the last decade or so we’ve really done a good job of defining the epidemiology of donor-derived infections,” Ison said. “But ways to help mitigate those either through planned, optimized testing is clearly an area where there is need.”
According to a recently published literature review in The New England Journal of Medicine, thanks to improved diagnostic tests, organs from high-risk donors — such as those who use injection drugs — can now be screened faster and more accurately for transmissible infections that may have been missed by earlier tests. Such organs were traditionally avoided because of the risk for infections from an unseen disease.
Antimicrobial resistance
Another area of focus in transplant ID — and one that impacts other aspects of medicine — is antimicrobial resistance.
According to research, organ transplant recipients are often colonized by multidrug-resistant organisms (MDROs), leaving them vulnerable to resulting infections. In a recently published study in Clinical Infectious Diseases, researchers reported that 67% of liver transplant recipients at one hospital were colonized with MDROs and many suffered subsequent MDRO infections.
Complications that arose after transplant surgery — including prolonged hospital stays — were associated with MDRO colonization and subsequent infection, suggesting that nosocomial infection with MDROs — particularly vancomycin-resistant enterococci — played an important role, the researchers said.
Like other areas of medicine, Ison said antibiotic resistance has increased significantly over time in patients undergoing transplantation surgery, who probably face a greater threat from multidrug-resistant bacteria than patients who are not undergoing transplantation surgery because they are frequently exposed to the health care setting and are prescribed more antibiotics.
He said learning how to manage multidrug-resistant infections in transplant recipients can have a positive impact on nontransplant patients.
“If we figure out how to best manage complex patients, [that] would be beneficial,” he said. “The management of multidrug-resistant bacteria in the transplant setting is an area of high priority and need, in part because of work in the nontransplant setting.”
Expanding the organ donor pool
For years, HIV-positive patients waited for HIV-negative organs just like every other patient on the organ donor waiting list, while organs from donors with HIV were discarded. Transplant surgeons from Johns Hopkins began a push to repeal the ban of transplanting HIV-infected livers and kidneys into HIV-infected recipients in 2010. The HIV Organ Policy Equity (HOPE) Act of 2013 made it legal to transplant HIV-infected organs in the U.S. In 2016, Johns Hopkins performed the first HIV-positive to HIV-positive kidney transplant in the U.S. and what was then thought to be the first HIV-positive to HIV-positive liver transplant in the world. (Months later, physicians in England disclosed in a letter to The New England Journal of Medicine that they had performed an HIV-positive to HIV-positive liver transplant on a patient in 2011.)
The demonstration that HIV-positive transplantation surgery was safe and effective provided evidence of a potential untapped source of organs for HIV-positive patients with end-stage organ failure.
HIV transplants are legal in the U.S. only as part of a research study. Transplanting organs from HCV-positive donors to HCV-negative recipients is not against the law outside of a study, but Blumberg said many physicians performing these procedures at U.S. centers firmly believe that they should be done as part of a research project because there is still so much to learn.
“We’ve done a lot of [them] at our center and we’ve learned a lot. There are things we are still learning,” she said. “We don’t know what the optimal duration of therapy is. We don’t know what the long-term outcomes are going to be. We don’t know if results will be different based on the different organs. There have been some limited data that suggest that hepatitis C may behave differently in different organs, so I think there’s a lot we still don’t know.”
In March, physicians from Johns Hopkins reported that the first 10 HCV-negative patients to receive kidneys from HCV-positive donors as part of the EXPANDER trial were free of infection after 1 year. Before that, a group at Penn reported that all 10 patients enrolled in the THINKER trial, in which HCV-negative patients received kidneys from HCV-positive donors, had been cured of their resulting infection within 12 weeks.
The NIH announced in May that it was sponsoring the first large-scale clinical trial to track the outcomes of HIV-positive to HIV-positive kidney transplants in the U.S. Recipients will be evaluated for HIV-related complications, such as HIV superinfection, in which recipients are infected with more than one strain of the virus.
“This study offers a chance to improve the health of those living with HIV, and increase the overall supply of transplantable organs,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in a statement.
Impact on ID clinicians
Experts agreed that transplant ID has become a vital subspecialty in medicine — one that can have an impact on patient care for ID clinicians.
“Over a couple of decades, it’s become clear that general ID docs need to know more about the medically immunosuppressed,” Marr said. “Even if you’re not a card-carrying transplant ID subspecialist, you’re going to see these folks in many academic and community hospitals because of our increasing dependence on biologic immunosuppression. More and more there are people who come to Hopkins for training in our transplant and oncology infectious disease program so that they can become more comfortable caring for people with complex immunosuppression.”
Ison said shedding light on the subspecialty can encourage ID clinicians in smaller or private hospitals that do not have transplant ID programs but see sick transplant patients to refer these patients to a transplant center or call a transplant ID colleague for help.
“Transplant programs are recognizing the benefit of transplant infectious disease physicians, [who] can take over responsibility for patients with infections,” Ison said. “They have expert content knowledge and have been shown to improve the outcomes of their patients.”
Chin-Hong agreed, adding that the knowledge and experience that transplant ID specialists gain from treating infectious diseases that occur frequently in patients who receive transplants but are relatively rare in other patient populations — such as CMV, aspergillosis and mucormycosis — make these physicians an asset to other providers.
“We become experts in patient safety that can be generalized to other areas,” he said. – by Gerard Gallagher
- References:
- Avery R, et al. Transpl Infect Dis. 2010;doi:10.1111/j.1399-3062.2010.00510.x.
- Durand CM, et al. Ann Intern Med. 2018;doi:10.7326/M17-2871.
- Goldberg DS, et al. N Engl J Med. 2017;doi:10.1056/NEJMc1705221.
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- For more information:
- Emily A. Blumberg, MD, can be reached at blumbere@pennmedicine.upenn.edu.
- Peter Chin-Hong, MD, can be reached at Peter.Chin-Hong@ucsf.edu.
- Michael G. Ison, MD, can be reached at mgison@northwestern.edu.
- Kieren Marr, MD, can be reached at kmarr4@jhmi.edu.
Disclosures: Blumberg, Chin-Hong, Fauci and Ison report no relevant financial disclosures. Marr reports sitting on adviosry boards for Amplyx, Chimerix and Cidara, having equity in MycoMed Technologies and recieving a research grant from Merck.