Clinicians battle infections in solid organ transplantation

Several recent high-profile cases of HIV transmission from donor to recipient after a solid organ transplantation sent ripples through the infectious diseases community. In early 2013, rabies was transmitted to three individuals who received solid organs from a single donor. Each of these cases has been described in peer-reviewed literature, and many of them were covered by mainstream media.

In March, The American Journal of Transplantation published a supplement with a comprehensive series of papers devoted to all facets of infection in this patient population, including the most common infections that occur, how prevention and containment methods have improved in recent years and what can be done for both the donor and recipient to minimize risk. Researchers addressed the role of prophylaxis and immunosuppressive medications along with broader political implications under the transplant umbrella. In addition, they examined ways to minimize risk of infection in living and deceased donors and in recipients of the organs.

Peter Chin-Hong, MD, MAS, professor of medicine, director of the pathways to discovery program in clinical and translational research, and the director of transplant and immunocompromised host infectious disease service at the University of California San Francisco, discussed the general state of affairs in an interview with Infectious Disease News.

“In the past several years, there has been increasing attention to these infections,” he said. “Two years ago, we first became aware of a case involving a brother who gave a kidney to a sister. The brother had been tested several months before the transplantation, but contracted HIV in the interim. This led to new guidelines around when living donors are tested, and brought transplant infections to the forefront in the clinical community.”

The community has learned that these infections are relatively easy to see when the donor has a bacterial infection before transplant, according to Chin-Hong. Serologic and molecular testing allow clinicians to find many infections and successfully treat them.

“However, what has become apparent is that there is a whole host of organisms in donors who are otherwise healthy,” he said. “Dormant viruses are in their organs, and it may not be evident prior to transplantation that the donor was infected. This is the main clinical challenge we face.”

Beyond the clinic, Chin-Hong cited two significant obstacles to more overall success in the field: shortages of organs and increasing incidence of multidrug-resistant infections. Infectious Disease News spoke to a cross section of experts about these and other challenges faced by transplantation specialists.

Anticipated vs. unanticipated infections

Michael Green, MD, MPH, chair of the Ad Hoc Donor Transmission Advisory Committee at the United Network for Organ Sharing (UNOS), said donor-derived infections historically have been classified as those that are anticipated and those that are unanticipated.

“Anticipated donor-derived infections are attributable to a number of different pathogens, which historical experience has taught us are so common as to be expected,” Green said. “Anticipated donor-derived infections are characterized by the fact that testing of potential organ donors can identify the presence of potential pathogens in the recipient prior to acceptance of and subsequent implantation of donor organs.”

Rigorous efforts to catalog these infections have allowed organ centers and potential recipients to understand the risks in any given organ and to take necessary steps for prevention.

Unanticipated infections are those that testing of the donor failed to identify. Sometimes this occurs because test results came back after transplantation, and other times the organs simply were not tested for such pathogens due to time constraints or a lack of risk for that particular infection in the donor.

Often, according to Green, “There is literally no time to test donors for every potential risk.”

Green said the most frequently occurring anticipated donor-derived infection is cytomegalovirus (CMV). Michele I. Morris, MD, associate professor of clinical medicine and director of the immunocompromised host section in the division of infectious diseases at the University of Miami Miller School of Medicine, agreed.

“While we generally see bacterial or fungal infections common to hospitalizations or ICU stays, CMV remains the most common complication in transplants,” she said.

A critical factor in the development of CMV is whether the recipient has been exposed to the disease. Patients who have never had the disease who receive an organ from a donor who has are at increased risk, as are those who have had it previously, according to Morris.

“If the recipient is positive for CMV before transplant, it may reactivate during immunosuppression,” she said. “The good news is that in the last decade or so, we have gotten better at preventing this, particularly in the early post-transplant period.”

Morris said these improvements have had the bonus effect of helping to prevent colitis, pneumonia or other more serious complications.

“They have been given prophylaxis, so by the time they get CMV, they’re in a little better shape and can better fight end organ disease,” she said.

For the most part, bacterial infections are generally the most common types that occur in solid transplant recipients. The usual complications that apply in a surgical setting also apply in the transplant setting, according to Morris. Potential transplant recipients usually have been hospitalized for a long time and are therefore at greater risk for hospital-acquired infections.

Beyond bacteria and CMV, it is important to note, too, that specific infections are more likely to attack specific organs. For example, Farinas and colleagues conducted a retrospective cohort study to determine incidence rates and risk factors for mediastinitis in heart transplant recipients. They evaluated 48 cases from six centers in Spain.

“The incidence of [mediastinitis] after [heart transplantation] has not changed in the last 2 decades,” Farinas and colleagues concluded. “Gram-positive remain the most frequent causative organisms.”

Mortality was most frequently attributed to recurrence of the infection, the presence of nosocomial infection, sepsis and poor general condition at diagnosis, according to their findings.

Morris said fungal infections frequently occur in lung, heart and liver recipients. Despite the anticipated nature of many of these infections, completely preventing them is unrealistic, according to most experts.

“Donors and recipients are screened for infection that reside dormant in the body that may reactivate with immunosuppressive drugs,” Morris said. “But it’s almost impossible to catch everything.”

Emily Blumberg, MD, program director of the infectious disease fellowship and director of transplant infectious diseases at the University of Pennsylvania, concurred. “For each organ and organism, we are trying to individualize the approach for each patient,” she said. “We are trying to maximally utilize the organs we have while eliminating as many risks as we can, but there is no one size fits all.”

Part of the issue, according to Michael G. Ison, MD, MS, associate professor in the divisions of infectious diseases and organ transplantation at the Northwestern University Feinberg School of Medicine and medical director of transplant and immunocompromised host infectious diseases service at the Northwestern University Comprehensive Transplant Center, is that people from certain parts of the world, particularly the United States, are more global than others.

“More people in the US have emigrated or been on vacation in a wider part of the world, which obviously might expose them to a broader range of pathogens,” Ison said. “While we test all patients for HIV and hepatitis, we can screen people for Chagas’ disease if they have been in a region endemic to that infection or coccidiomycosis if they’ve been in the Southwest, for example. We can base our screening on the experiences of the patient.”

Screening

Although additional screening has the obvious benefit of detecting more infections, more testing may not be the obvious solution to transplant infections, according to Blumberg.

“We can’t test all individuals and organs for all diseases,” she said. “It is expensive and a burden on the system.”

Chin-Hong said it would be preferable to find ways to use tests more wisely and effectively or, better yet, use better tests.

“Assays with inadequate specificity are causing us to put red flags on organs that are perfectly safe to use,” Chin-Hong said. “People die waiting. We could be using more organs, or using the ones we have more effectively.”

Blumberg and Chin-Hong said most serologic screening tests assume a proportion of false-positive or negative results when the organ is tested. This contributes to organ wastage.

It may simply be a matter of weighing risks, according to Chin-Hong.

“We know this organ might be infected, but we also know that we can treat that infection,” he said. “You have to make these choices.”

According to Chin-Hong, more widespread use of polymerase chain reaction testing might be a solution. “We see about a 3% to 5% rate of false-positives for HIV and hepatitis B and C tests,” he said. “We can improve on that with available technology.”

A further complicating factor is that different approaches are required for living vs. deceased donors. The brother-sister transmission of HIV — and other incidents like it — taught the clinical community that the timing of testing living donors is critical. Ison said screening these donors should include three separate processes. The first is a diligent review of the donor’s medical and social history; the second is a physical examination; and the third is the necessary blood work.

For living donors, all of this is possible or at least easier than it can be for deceased donors, in which uncertainty can come into play and the window of usefulness of the organ closes quickly.

“For example, if a college student dies suddenly and is an organ donor, the parents or even the friends might not be able to paint an accurate picture of what that person has been up to recently,” Ison said. “Also, if the deceased was involved in another health system, all pertinent information might not be available to the system where the recipient is.”

Prophylaxis and treatment

Similar to screening, more is also not necessarily better when it comes to preventing post-transplantation infections. One of the risks transplant specialists deal with is that patients are often on so many drugs that they can mask serious infections that may be developing.

“Post-transplant patients are often treated with steroids or other immunosuppressants, which can prevent fevers from occurring,” Morris said. “It is easy to miss an infection if there is no fever.”

Overall, though, Morris said infectious disease practitioners need to consider any change in clinical status as a potential sign of infection, including nonspecific symptoms such as decreased appetite or weakness, or signs such as lowered blood pressure or transient confusion.

Green said effective prevention strategies have been developed for anticipated infections, and treating unanticipated infections, although challenging, is possible.

“The potential efficacy of such interventions will clearly vary by the type of pathogen, the timing of notification and the intensity of immunosuppression being used in exposed recipients,” he said. “While the latter might be adjusted to minimize risk of infection-related disease, this must be balanced against the risk of developing rejection if immunosuppression is reduced.”

Although there are accepted therapies for many infections, the research community continues to investigate options. Barron and colleagues conducted a study to evaluate whether anidulafungin (Eraxis, Pfizer) is as safe and effective as caspofungin in treating invasive fungal infections in patients with hepatic insufficiency or liver transplantation.

In the transplant cohort, 33 patients were treated with anidulafungin and 33 were treated with caspofungin. Fourteen percent of patients in the anidulafungin group experienced a fivefold increase in liver function vs. 10% in the caspofungin group. Anidulafungin also yielded shorter hospital stays.

It may benefit the clinical community to pay attention to results such as these. Similarly, in another study, Lopez-Medrano and colleagues also found invasive pulmonary aspergillosis to carry a high mortality rate in a cohort of kidney transplant recipients. Among 38 case patients, 20% had aspergillus colonization in the respiratory tract before transplantation. Aspergillus fumigatus was the most commonly reported species. Despite treatment with voriconazole, liposomal amphtericin or combination therapy, a 52% mortality rate was observed. Shorter time from transplant to invasive disease (P=.04), bigger lung nodules diameter (P=.01), ICU admission (P=.01) and higher dose of steroids just after invasive disease (P=.03) were the key factors associated with mortality.

“A higher index of suspicion for an earlier diagnosis and a more aggressive withdrawal of immunosuppression in early-onset [invasive pulmonary aspergillosis] might improve the prognosis,” the researchers concluded.

For Green, the best prevention, in a macro sense, is the sharing of information and experiences about transplantation and infection. This will allow clinicians to make better-informed decisions.

Prophylactic measures generally do not affect the chance that the recipient will reject the organ, according to Green.

“A potential exception to this would be preventive strategies against the Epstein-Barr virus, where reduction in immunosuppression is a central part of the approach to preventing disease,” he said. “In this case, immunosuppression is pre-emptively reduced in organ recipients with subclinical infection to prevent progression to development of symptomatic disease.”

Conversely, clinicians frequently reduce immunosuppression when treating infections after the organ has been transplanted.

“Accordingly, there is always a risk of superimposed rejection when immunosuppression is reduced,” Green said. “Clinicians caring for organ recipients with infection need to balance these risks.”

On timing

Another critical factor in the success or failure of organ transplantation is understanding the time frame of the infection process. Ison said he thinks of transplant infections as occurring in three different time frames: within 30 days of transplantation, and then within 6 months, and then after 6 months.

“The infections we see at those points are markedly different,” he said. “Within the first 30 days or so, the majority of infections we see are the same as in any surgical patient, such as pneumonia, bacteremia from catheters, [urinary tract infections].”

Ison said pre-existing or latent infections that originated in the recipient or donor make up the balance.

“Infections that are incubating in the recipient at the time transplant occurs manifest in post-transplant, often within 3 to 5 days,” he said.

Moving beyond the early post-transplant period, peak immunosuppression can lead to opportunistic infections, according to Ison. “We see Listeria, Aspergillis, reactivation of latent infections such as hepatitis,” he said.

The use of prophylactic drugs may modulate the timing and frequency of these opportunistic infections, he said.

“The third type of infections occur after 6 months,” Ison said. “These are frequently community-acquired infections. Colds and influenza, pneumonia, UTIs, anything that would make another person sick happen more easily in these patients.”

Others have considered variations on this schedule.

Buke and colleagues retrospectively evaluated a cohort of 161 adult patients who underwent heart transplantation to determine the rate of fungal infections and mortality in the post-transplant setting. They focused on four time periods slightly different from those outlined by Ison: within 30 days; 31 to 90 days; 91 to 180 days; and beyond 180 days.

Results indicated 36 positive cultures in 27 patients. There were seven fungal infections in the first and second periods, four in the third and 10 in the fourth period. Nine patients died of pneumonia, two died of pyelonephritis and one from a bloodstream infection. The most frequently occurring pneumonia was Aspergillus spp.

“It is concluded that, the rate of mortality due to fungal infections were high,” the researchers wrote. “Most of the invasive aspergillosis cases occurred between 31st days and 90th days and was highly fatal (80%). Non-Candida albicans isolates predominated.”

Similarly, Rabin and colleagues conducted a retrospective cohort study of 360 heart transplant patients to determine rates of invasive fungal disease. Of 23 proven or probable cases, 13 occurred within 3 months of transplantation. The addition of muromonab-CD3 (Orthoclone OKT3, Janssen-Cilag), antithymocyte globulin or daclizumab (Zenapax, Hoffmann-La Roche) to standard corticosteroid induction therapy increased infection rates, according to the results. The researchers concluded that enhanced immunosuppression may increase invasive fungal disease incidence, which was highest within 3 months of transplant. They, too, suggested increased vigilance in the post-transplantation setting.

Morris summed up the question of timing from a clinical perspective: “You can’t wait until an infection occurs because they can develop very quickly from CMV viremia to pneumonia or something more serious,” she said.

Beyond the clinic

Chin-Hong said the HIV case drew attention to these infections, and concrete steps have been taken as a result.

“People are doing more sensitive diagnostic tests at the outset,” he said. “More broadly, the Disease Transmission Advisory Group is now a committee. We now have UNOS to manage guidelines.”

The first act of UNOS was to set up a surveillance system. “I’m in New Orleans, there is an organ in San Francisco, but that organ has rabies,” Chin-Hong said. “There wasn’t any good place to report this. Now there is. The system of communication has been formalized.”

The organization and subcommittee follow up on each report, according to Blumberg. “This information is then put into the larger context of what happens in the US on an annual basis,” she said.

The result is that clinicians have gathered a great deal of information on all manner of transplant infections. However, Blumberg said the system is still far from perfect.

“Any potential donor-derived transmission event is supposed to be reported to UNOS, but that doesn’t always happen because in some cases we expect it and in some cases the donor derivation is not recognized,” she said, noting that CMV goes unreported because it is an expected complication of transplantation. “Also, many of the reports that come in don’t turn out to be real donor-derived infections.”

Blumberg pointed to the papers in the American Journal of Transplantation Infectious Disease Guidelines in the March 2013 supplement. The body of research should serve as a reference point for clinicians treating transplant infections, according to Blumberg.

“We added a section on ventricular assist devices and a section on West Nile virus, we updated the findings on arenaviruses,” she said, further noting that provisions for dealing with Chagas’ disease are included. “People need to understand who to test and who not to test for these infections.”

Debate on the issue is not limited to the infectious diseases or transplantation communities. “The wildest thing going on right now is at the House of Representatives level,” Chin-Hong said. “It involves knowingly transplanting HIV-infected organs to recipients with HIV. In South Africa, where the prevalence of HIV is so much higher, this is already happening, and it is saving lives of people with HIV who are dying of other things or organ failure.”

One area where the federal government and regulatory agencies have failed to appropriately deal with is MDR infections.

For Ison, the failure of drug companies to develop new drugs has forced the system to continue to deal with treatable infections.

“The pipeline is rather weak and rather dry for addressing this problem,” he said. “A good example is norovirus, which goes away in a few days in a healthy person. In the transplant population, prolonged shedding and diarrhea affect renal function and cause much larger problems. But because it’s not a long-term illness in healthy populations, there is not a huge investment to develop antivirals.”

Chin-Hong agreed: “We have limited options to treat Acinetobacter baumannii, Klebsiella and other infections, in transplant populations or otherwise,” he said. “People in the transplant population are more heavily exposed to health care settings and antibiotics and are therefore at higher risk for these infections which can be resistant to multiple available antibiotics.”

Unlike some others in the field, Chin-Hong said he is guardedly optimistic about the prospects for the development of antimicrobials.

“There are mechanisms in place to make the development of these drugs more attractive to the industry, even if the profit margins are narrow,” he said, adding that time will tell if this proves true.

Ison called the failure to develop antimicrobials a societal problem, as is the overwhelming shortage of available organs. This problem, according to Chin-Hong, involves individual choice.

“Culturally, in the US, we want people to have individual decisions,” he said. “In other more socialist countries, organ donorship is an opt-out policy, rather than an opt-in policy. A lot of people might want to donate organs, but don’t know that they can, or simply didn’t opt in. It would be better, too, if everyone is an organ donor until they say no.”

Chin-Hong is not optimistic that the system will change, though.

“What we have is here to stay,” he said. “And a by-product of this is going to be medical tourism, with people going to China or India to get organs. Those countries are not regulated the same way, and recipients may bring different infections back into the US.”

In general, though, experts such as Morris agree that progress is being made, overall, in the prevention of transplantation infections in the United States. “We are making great progress in screening and treatment,” she said, adding that her hope is tempered.

“Even before infections develop, though, the biggest challenge for organ transplant candidates is that we have 118,000 people on organ waiting lists, and most of them will die before they even get a transplant,” she said. “We need to get more donor organs available to these people.” – by Rob Volansky

References:

Am J Transplant. 2013;13:1–371. onlinelibrary.wiley.com/doi/10.1111/ajt.2013.13.issue-s4/issuetoc. www.icaac.org/images/ICAAC2013_FinalProg
PDF_PSmall.pdf Barron MA. #T-807.
Presented: ICAAC 2013; Sept. 10-13; Denver.
Buke C. #T-809. Presented: ICAAC 2013; Sept. 10-13; Denver.
Farinas M. #T-823. Presented: ICAAC 2013; Sept. 10-13; Denver.
Lopez-Medrano. #T-812. Presented: ICAAC 2013; Sept. 10-13; Denver.

For more information:

Peter Chin-Hong, MD, can be reached at: peter.chin-hong@uscf.edu.
Michael Green, MD, MPH, can be reached at: Michael.green@chp.edu.
Michael G. Ison, MD, MS, can be reached at: 645 N. Michigan Ave. Suite 900, Chicago, IL 60611; email: mgison@northwestern.edu.
Michele I. Morris, MD, can be reached at: mmorris2@med.miami.edu.

Disclosures: Blumberg, Chin-Hong, Farinas, Green, Ison and colleagues report no disclosures. Barron reports multiple relationships with Pfizer and Merck. Buke and colleagues report no disclosures. Munoz (Lopez-Medrano) reports being on the speaker’s bureau of Astellas, Pfizer, Gilead, Merck and Novartis. Morris reports research funding from or advisory roles with Astellas, Pfizer, Novartis, Optimer and Roche.

Should the FDA allow HIV-infected organs to be transplanted into individuals with HIV?

There is no question that we should allow transplantation from eligible HIV-positive donors to eligible HIV-positive individuals.

My research team and I initiated, and have been strong advocates of, the HOPE Act (HIV Organ Policy Equity Act). Strong evidence supports the feasibility of this practice, including excellent outcomes from HIV-to-HIV transplants in South Africa, as well as excellent outcomes of transplants in HIV-positive individuals in the NIH-sponsored United States clinical cohort study. In addition, we estimated that hundreds of such organs would be available if this were a possibility. Put another way: every year, while people are dying on the transplant waiting list, we are throwing away perfectly viable organs for transplantation, just because of an antiquated law that was written before we even knew that HIV was the virus responsible for AIDS, at a time where AIDS was a death sentence. The landscape for HIV has changed dramatically, and we need to allow medical care of HIV-positive individuals with end-stage organ disease to evolve accordingly.

Dorry Segev, MD, PhD, is an associate professor of surgery in the division of transplantation at Johns Hopkins School of Medicine. Disclosure: Segev reports no relevant financial disclosures.

 

Closely monitored clinical trials on the safety and efficacy of transplanting HIV-positive organs into HIV-positive recipients need to be performed, and that is what the FDA should support.

In order for that to happen, NOTA has to be amended … and the change in the law (which currently prohibits organ procurement from HIV-positive recipients) is close to being passed (has made it through congress with bipartisan support). But there are potential issues regarding the transmission of a more "virulent" strain of HIV that is resistant to cART – although with increasing cART options this is less likely to be a problem. In South Africa, the HIV-positive donors who have been utilized have come from treatment-naïve donors, making the risks of transmitting a resistant strain lower. In addition, since the donor organ may be a reservoir for HIV, there is always a concern that the long-term function may be impacted. In the NIH trial that has been completed, clinical evidence of recurrent HIV nephropathy has not been seen, but again the long-term impact of the reservoir is unknown. Most importantly, any opportunity to increase the pool of donor organs should move forward – since all potential kidney transplant recipients (without living donors) are waiting up to 8 years for a transplant, and for patients with HIV, access to HIV-positive organs will likely reduce that time to less than 1 year. Similarly, for liver transplant recipients, the chance to get an organ before significant deterioration may be their only chance to get a liver transplant.

Peter G. Stock, MD, PhD, is a professor of surgery, surgical director of the Kidney and Pancreas Transplant program, surgical director of the Pediatric Renal Transplant program and program
co-director of the Pancreatic Islet Cell Transplant program
at University of California San Francisco. Disclosure: Stock reports no relevant financial disclosures.