Does the Zika virus, a single-stranded RNA-enveloped arthropod borne flavivirus, represent a challenge for blood transfusion?
Flavivirus transmission occurs through blood transfusion (viz. phylogenetically related West Nile Virus and dengue virus) and there are two suspected Zika transfusion-transmitted cases in Brazil.
So, that and other evidence led the authors of a recently published paper in the Lancet to answer “yes.” (1)
The initial Zika virus isolate emerged from a rhesus macaque in 1947. Believed not to cause human disease, it remained obscure until the 2013/14 French Polynesian outbreak that involved 32,000 persons and an increased frequency of Guillain-Barre cases. In 2015, it reached the Americas, in Brazil. By September, 2015 healthcare workers noted an increased frequency of infants with microcephaly born in areas where Zika was prevalent. Through December, 2015 more than 1.3 million suspected Zika cases occurred in Brazil; more than 4300 microcephaly cases were reported by mid-February, 2016. Currently, Zika affects many in South American and Caribbean countries. (2-4) (see figure 1 from reference 3)
Aedes aegypti and, to a lesser extent, Aedes albopictus mosquitos transmit Zika. (see figure 2 from reference 5 ) A. aegypti feeds primarily on humans and bites multiple people in a single blood meal. Both A. aegypti and A. albopictus bite during the daytime. A. aegypti resides in tropical and sub-tropical regions while A. albopictus’ distribution extends to temperate areas. (see figure 3 from reference 2)
- aegypti is endemic in Puerto Rico, U.S. Virgin Islands, parts of continental U.S., and Hawaii. In contrast, the West Nile Virus is transmitted by Culex mosquitos.
Zika transmissions occur, also, congenitally, prenatally, and sexually; the latter via semen in which the virus may persist for more than 60 days. Transmission through blood transfusion reportedly occurred in two cases in Brazil. Other possible transmission routes include laboratory accidents, breast milk, and bites from infected animals.
Approximately 20% of infected persons develop symptoms that occur 3 days to 12 days after infection. Viremia extends from 2 days to 11 days after symptoms with a viral load up to 8.1 X 10(6) copies per mL. Clinical symptoms include non-purulent conjunctivitis, a pruritic, macular or papular rash, arthralgia, low grade fever, headache, retro-orbital pain, edema, vomiting, or a combination of these. Symptoms resolve, generally, within two weeks. (2-4) Severe neurologic sequelae include acute motor axonal Guillain-Barre Syndrome (6) (see figure 4 from reference 6), microcephaly in up to 30% of the fetuses of women infected between 7-13 and possibly 18 weeks of gestation (7), and acute myelitis.
Diagnostic testing includes detection of viral nucleic acid by RT-PCR and detection of IgM antibodies. Viremia is transient and results may be negative 5-7 days after symptom onset; serologic cross-reactive results occur in those with previous dengue infections, recipients of yellow fever or Japanese encephalitis vaccines, or those infected with other flaviviruses. Plague reduction neutralization tests (PRNT) help resolve the diagnosis. Noting that Zika virus RNA is unlikely to be detected in serum beyond the first week and that Zika virus RNA can be detected in urine for at least two weeks after symptom onset, the CDC now recommends that Zika virus rRT-PCR be performed on urine collected less than 14 days after symptom onset in patients suspected of having Zika. (8)
Measures to avoid mosquito bites effectively prevent infection. However, to date, no evidence shows effectiveness of vector-control interventions to interdict Zika transmission. (5) Recently, the Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) issued guidance for protecting workers from occupational exposure to the Zika virus. (9) Vaccine development is in progress, but caution is raised by in vitro experiments showing more severe clinical courses in those with pre-existing dengue antibody (which may cross react with Zika). (10) Clinical management is supportive. Aspirin and nonsteroidal anti-inflammatory drugs should be avoided until dengue is ruled out. For women in Zika active areas, delaying pregnancy is advised. Pregnant women in non-Zika active areas are advised to avoid travel to Zika endemic regions. Fetal ultrasound should be considered for pregnant women with positive or inconclusive test results. Men who reside or travel to areas with active Zika transmission and who have a pregnant partner should use condoms during sex. (3)
During the French Polynesian outbreak, 42 (2.8%) of 1505 asymptomatic blood donors were RT-PCR positive for Zika; 11 donors described a Zika-like illness 3-10 days post-donation. (11) As of May 12, 2016 there were 279 pregnant women with laboratory evidence of possible Zika infection who resided in Zika infected U.S. territories, travelled to Zika active areas, or became infected in the U.S through sexual transmission. (12) Since 80% of infected persons have no symptoms, this report suggests infected persons reside in the U.S. who would potentially qualify as blood donors.
As such, current FDA guidelines for blood donors (13) recommend for areas without active Zika transmission:
- Deferral for 4 weeks after resolution of Zika symptoms
- Defer for 4 weeks for donors with Zika-like symptoms that arise within 2 weeks of departure from a Zika active area
- Defer for 4 weeks after last sexual contact with a man who had Zika or travelled/resided in Zika active area 3 months prior to sexual contact
- Defer for 4 weeks after departure from Zika active area
For areas with active Zika transmission, FDA recommends:
- Obtain blood and blood components from areas of U.S. without active Zika
- Or, collect blood components locally and test blood donations with an FDA-licensed blood screening test [use of tests under an investigational new drug (IND) application may be permitted]
- Or, collect and prepare platelets and plasma locally if pathogen reduction technology is used with an FDA-approved device [use of devices under investigational device exemption (IDE) may be permitted]
- Donor deferral as for areas without active transmission
If a donor reports Zika-symptoms post-donation and that product has been transfused, FDA recommends that blood establishments advise the recipient’s physician regarding the potential need for monitoring the recipient for a possible Zika infection.
The Council of State and Territorial Epidemiologists (CSTE) issued consensus recommendations for notification of blood collection organizations and blood banks of local Zika transmission on May 5, 2016. (14) They stated that transmission is likely to be relatively localized and that the CDC web site (http://www.cdc.gov/Zika/geo/) will be the mechanism for Zika transmission communication.
Since Zika is active in Puerto Rico, local blood collection ceased on March 1, 2016 with blood shipped to Puerto Rico from the continental U.S. Following introduction of Roche Molecular Systems nucleic acid testing (NAT) under IND, local blood collections resumed on April 2, 2016. Pathogen reduction for locally collected apheresis platelets is in progress. Collections ceased in the U.S. Virgin Islands on January 22, 2016 and on February 18, 2016 in American Samoa. (15)
At this time, the February 2016 FDA guidelines for safeguarding the blood supply remain in effect. One blood center in Texas announced that it will test all blood donors for Zika under IND regulations. It is likely that pathogen reduction implementation for platelets and plasma will expand and additional blood centers will implement testing under IND. Eventually a licensed test will become available. Zika is under active investigation and new information and scientific breakthroughs are eagerly anticipated.
- Musso D, Stramer SL, Busch MP. Zika virus: a new challenge for blood transfusion. Lancet 2016;387:1993-94.
- Peterson LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med 2016;374:1552-63.
- Plourden AR, Bloch EM. A literature review of Zika virus. Emerg Infect Dis 2016;22 (July) doi: 10.3201/eid2207.151990
- Sampathkumar P, Sanchez JL. Zika virus in the Americas: a review for clinicians. Mayo Clin Proc 2016;91:514-21.
- Haug CJ, Kieny MP, Murgue B. The Zika challenge. New Engl J Med 2016;374:1801-03
- Watrin L, Ghawche F, Larre P, et al. Guillain-Barre syndrome (42 cases) occurring during a Zika virus outbreak in French Polynesia. Medicine 2016;95:e3257
- Rasmussen SA, Jamieson DJ, Honein MA, Peterson LR. Zika virus and birth defects- reviewing the evidence for causality. New Engl J Med 2016;374:1981-87.
- CDC. Interim guidance for Zika virus testing of urine-united States, 2016. MMWR early release May 10, 2016 doi: 10.15585/mmwr.mm6518e1
- OSHA-DTSEM FS-3855 4/10/2016
- Paul LM, Carlin ER, Jenkins MM, et al. Dengue virus antibodies enhance Zika virus infection doi: 10.1101/050112
- Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill 2014; 19(14).pii:20761
- CDC. Possible Zika virus infection among pregnant women-United States and Territories. MMWR early release May 20, 2016 doi: 10.15585/mmwr6520e1
- FDA. FDA recommendations for donor screening, deferral, and product management to reduce the risk of transfusion-transmission of Zika virus. Guidance for industry, February 2016 and March 2016 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance/default.htm
- CSTE. Consensus recommendations for notification of blood collection organizations and blood banks of local Zika transmission. May 5, 2016.
- Vasquez AM, Sapiano MRP, Basavaraju SV, et al. Survey of blood collection centers and implementation of guidance for prevention of transfusion-transmitted Zika virus infection-Puerto Rico, 2016. MMWR 2016;65 early release, April 8, 2016
Author: Jay Menitove, MD