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Zika Virus and Solid Organ Transplantation: Significant Pathogen or Harbinger of Things to Come?

Kotton, Camille Nelson MD, FIDSA, FAST

doi: 10.1097/TP.0000000000001179
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Zika virus is transmissible by blood transfusion, so what are the implications for organ transplantation?

1 Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Received 11 February 2016. Revision received 14 February 2016.

Accepted 16 February 2016.

The author declares no funding or conflicts of interest.

Correspondence: Camille Nelson Kotton, MD, Massachusetts General Hospital, Boston, 55 Fruit Street, Cox 5, Boston, MA 02114 (ckotton@partners.org).

The recent and rapid spread of Zika virus throughout the United States is concerning for clinicians caring for immunocompromised, vulnerable transplant recipients. Although an estimated 80% of those infected with Zika virus will be asymptomatic,1 it may be more problematic in immunocompromised hosts. Transmission could occur peritransplant as a donor-derived infection, either from the organ donor or from the donors of blood products (or even passed from the blood product donor(s) to the organ donor, and then to the organ recipient, as has been seen with HIV, West Nile, and other viruses).2,3 Posttransplant, transmission could occur from mosquitos in endemic regions, or via sexual transmission from an infected man,4 or from autochthonous (local) transmission in nonendemic areas via mosquitos, which would be relatively easy because the main mosquito vector Aedes aegypti can be found throughout much of the world, especially in tropical and subtropical regions.

Among arboviruses, Zika shares similarity with some more pathogenic flaviviruses, including yellow fever, dengue, West Nile, and Japanese encephalitis (hepatitis C is a more remote relative, also a Flaviviridae but within the genus Hepacivirus). Although previously active primarily in Africa (having been identified in the Zika forest of Uganda) then Asia, Zika appeared in Brazil in 2014, possibly transported there during the 2014 World Cup, or during the Va'a World Sprint, a canoe race in Rio that occurred shortly thereafter. The ready presence of the Aedes aegypti mosquito vector, as well as other Aedes species that could facilitate transmission, and a generally nonimmune population provided the “perfect storm” for rapid spread through the Americas, as shown in Figure 1. As of mid February 2016, within the United States only Puerto Rico (Organ Procurement and Transplantation Network/United Network for Organ Sharing region 3) has any reported disease activity; on December 31, 2015, the Puerto Rico Department of Health reported the first locally acquired case of Zika virus disease, with 29 subsequent confirmed cases.6

FIGURE 1

FIGURE 1

Clinically, Zika usually presents with fever, rash, joint pain, or conjunctivitis; myalgias, and headache may also be present. The incubation period is usually several days to a week. Among the most concerning possible associations are microcephaly in newborns and Guillain-Barre syndrome.7,8 The clinical presentation may well be altered in transplant recipients. Given that the predominance of disease has generally been in regions without transplant programs and other cohorts of immunocompromised patients, we do not know much about the anticipated clinical presentation. Although there have been few reports of chikungunya in transplant recipients, dengue has been reported in small series; a report from earlier this year concluded that “its presentation seems to be similar to that seen in immunocompetent patients.”9

Treatment for all flaviviruses remains in the domain of supportive care, because there are not yet directly acting antiviral therapies. Intravenous immunoglobulins are sometimes given to transplant recipients with viral infections (eg, parvovirus, adenovirus, cytomegalovirus); in the case of Zika infection, consideration should be given as to the sources of the IVIG, because optimally, it might need to be from a population that had some exposure to Zika virus to convey some protective immunity.

Diagnostics remain somewhat challenging and are available primarily in central reference laboratories.10 There are no currently commercially available diagnostic tests for Zika virus disease. In the United States, Zika virus testing is performed at the CDC Arbovirus Diagnostic Laboratory and a few local or state health departments. Reverse transcriptase-polymerase chain reaction (RT-PCR) on serum (a method of nucleic acid testing) may be positive during the first week after the onset of symptoms, when viremia is most likely. After the first week of illness, virus-specific IgM and neutralizing antibodies usually develop, although serologic response is often diminished in transplant recipients and may be no different with Zika virus. Serologic cross-reactivity with related flaviviruses (eg, dengue and yellow fever viruses) is common; plaque reduction neutralization testing can discriminate between cross-reacting antibodies in various flavivirus infections by measuring virus-specific neutralizing antibodies.

Screening transplant donors for Zika viremia via RT-PCR in a timely fashion would be very challenging in the near interim, given the need to transport specimen to a central reference laboratory, and likely slowed turnaround times. Serologic screening of donors is likely to be similarly challenging and less useful, given that it may not reflect a risk of transmission. In addition, there may be deficiencies in both RT-PCR testing and serology during the high-risk initial days of illness (the “window period” that provide false diagnostic security). To prevent donor-derived infection, epidemiologic screening seems most useful. Viremia is estimated to last roughly 7 to 10 days, such that in nonendemic areas, it may be effective to defer donors who have been out of the region or country in the past month.11 A guidance document developed by the OPTN/UNOS Ad Hoc Disease Transmission Advisory Committee, suggests “donor deferral should be considered if there is history of travel to Zika-endemic areas in the 28 days prior to donation. In the case of potential living donors with Zika infection, donation should be deferred where possible.”12 Shedding in urine and semen4 seems to be longer, but remains ill-defined; 1 study of 6 Zika patients noted urinary shed for at least 10 days, and approximately 30 days in 1 patient.13 The impact of this on kidney donors remains to be determined, but could suggest a higher risk of transmission even after a deferral period.

After transplant, prevention would include avoiding travel to or mosquito bites (especially daytime bites) in endemic regions, as well as unprotected sexual activity with men who have traveled to such regions and may be shedding virus in semen.4 In addition, those with acute illness should avoid further mosquito bites to prevent autochthonous transmission. In general, immunocompromised hosts tend to shed viruses longer, such that ill transplant recipients may provide for a longer period of transmission. Transfusion of blood products from at-risk individuals should also be avoided; many blood-banking programs are in the process of reviewing epidemiologic screening protocols. Canada recently implemented a temporary deferral period for blood donors, “anyone who has travelled outside of Canada, the continental United States and Europe will now be temporarily ineligible to give blood” for 21 days.14 Similarly, the American Association of Blood Banks has issued a guidance document stating “Blood collection facilities should implement self-deferral for travel to Mexico, the Caribbean, or Central or South America during the 28 days before donation.”15

The potential impact of any major viral infection on transplant outcomes can be significant, both peritransplant and posttransplant. We will likely see an impact on the use of donors with possible Zika virus exposure and increased morbidity and mortality in transplant recipients who develop disease. Viral infections can abrogate graft tolerance; whether Zika will increase rejections rates (either directly, or due to lowering of the immunosuppressive regimen to help clear infection) remains to be seen.

In the past decade, there have been significant concerns about the migration of other geographically restricted viral infections, including West Nile, dengue, chikungunya, and Ebola, and their impact on solid organ transplantation.3,16 With increasing global travel, environmental warming and El Niño, and an increased number of immunocompromised hosts living in endemic regions, we should expect to see a greater impact of more novel and previously geographically restricted diseases. Although the full influence of Zika on solid organ transplantation remains to be determined, it may well represent a paradigm for future infectious disease issues impacting solid organ transplantation.

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