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Update to Chapter 233: Arthropod-Borne and Rodent-Borne Virus Infections

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The Zika virus pandemic continues to spread throughout Central and South America and the Caribbean, and it includes cases exported from endemic locales to the continental United States and to other nations. Because Zika virus is currently causing an epidemic in Puerto Rico and has been imported into the fifty United States and the District of Columbia by 934 arriving travelers (as of 2 July 2016), many primary care and other providers will be faced with diagnosing cases, and many additional providers will need to counsel patients about actual risks and unfounded fears. As the pandemic is still actively evolving, information about the pandemic and options for diagnosis, treatment, and prevention will likely also require frequent updating.

History and Global Events

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The ongoing Zika epidemic in the West African nation of Cabo Verde now has been associated with the same Zika virus strain that is circulating in the Americas, suggesting that the virus was probably exported to Cabo Verde from Brazil or another nation in the Americas. This means that Zika virus has literally spread entirely around the globe to arrive in the area of its presumed origins, West Africa, and that Zika has made the last 10,000-mile leg of that journey, from the islands of the South Pacific to West Africa, in about 2 years or less.

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With the exception of dengue, no other arthropod-borne virus has ever expanded so far geographically—and no arbovirus, including dengue, has spread so far so quickly. The reasons for the sudden and explosive emergence of Zika virus are not known, since the virus has existed in Africa and parts of Asia/Southeast Asia for decades without causing recognized outbreaks. Likely cofactors in this explosive spread include human movement (air, boat, and land travel of millions of people), population susceptibility, and high prevalences of the principal vector mosquito, Aedes aegypti, in increasingly crowded urban settings. The possibility that the virus could have mutated to spread more efficiently has been debated; however, it is noteworthy that Zika strains circulating in the Americas appear genetically similar to older strains not associated with geographic spread. Zika virus has recently been isolated from Aedes albopictus mosquitoes; however, the role of this alternative vector in Zika spread has yet to be determined.

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As of 2 July 2016, 40 countries in the Americas are experiencing ongoing local Zika virus transmission. In recent months, Zika has caused local epidemics in the U.S. Commonwealth of Puerto Rico and in the U.S. Territories of the United States Virgin Islands (USVI) and American Samoa. The epidemic in Puerto Rico has been widespread (an estimated 106,000 infections to date, representing all areas of the island); considerable national resources are now being applied to control it, and to prevent complications such as congenital defects in fetuses and babies of infected pregnant women. In addition to the 934 cases of travel-associated Zika virus disease in the continental United States including the District of Columbia, Puerto Rico, the USVI, and American Samoa have together reported 2020 locally acquired and 6 travel associated cases. Among >530 Zika-affected pregnancies reported in all of these areas combined, birth defects have so far been seen in 7 live births and in 5 instances of pregnancy loss.

Zika Complications

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It has become clear that Zika infection of pregnant women is associated with a range of birth defects including microcephaly, cerebral calcifications, visual defects, arthrogryposis, limb reduction defects, and many other problems, as well as later-onset problems in infants who did not have obvious defects detected in utero or at birth. These include delayed development, seizures, feeding problems, and persistent crying. The scope and incidence of these problems is currently being intensively studied; however, many questions remain unanswered.

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Available data have not yet quantified the risks of Zika virus in pregnancy, although two relatively robust studies have estimated incidences of severe birth defects of all types in Zika-infected pregnant women at between about 1% and 29%. As would be expected from experiences with other viral teratogens, especially rubella, studies are beginning to suggest that the most severe birth defects, including profound microcephaly, tend to result from first-trimester or early second-trimester Zika infections. One study reported the incidence of microcephaly in 1–13% of fetuses of women infected during the first trimester of pregnancy (Johanssohn et al, 2016). Clinical data and experimental primate data suggest that pregnant Zika-infected women may be viremic for longer periods than nonpregnant infected women or infected men; however, it is not known whether this is due to altered immunity in pregnancy or, as seems more likely, persistent infection of the fetus.

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Ten countries in the Americas have reported cases of microcephaly or other fetal malformation potentially associated with Zika infection of pregnant women; the vast majority of these cases have been in Brazil. Despite a large burden of Zika virus infection, Colombia has so far reported very few cases of birth defects despite extensive investigations; however, additional Zika-birth defects may soon be seen in Colombia now that that country’s epidemic has been ongoing for 9 full months. Although some Colombian babies who were potentially exposed to Zika infection in the second or third trimesters have now been delivered as healthy babies, other babies potentially exposed in the first trimester are just now coming to term, e.g., those potentially exposed between October 2015, when Colombia’s epidemic began, and December 2015. The true incidence of birth defects in women in Colombia infected during pregnancy will be forthcoming within the next few months.

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Neurologic complications associated with Zika epidemics continue to be reported at relatively low frequency, estimated at about 1 per 4000 Zika infections for Guillain-Barré syndrome. Another possible immune-mediated complication, acute disseminated encephalomyelitis (ADEM), has been linked to Zika infection at an apparently lower but indeterminate frequency.

Zika Virology

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All RNA viruses mutate as they spread through populations of new hosts; therefore it is not surprising that Zika strains in the Americas are diversifying during the current pandemic. The Americas strain genome, closely related to Pacific Zika strains from 2014, appears to differ slightly from a strain causing the 2007 Yap (Federated States of Micronesia) epidemic, and is even more different in genetic sequence than older Asian and African strains. Nevertheless, there is no evidence that the pandemic virus has evolved new phenotypic properties that facilitate spread. As phylogenetic and epidemiologic studies are completed, more information should become available. Fortunately, current research tests and diagnostic tests to detect virus, viral RNA, and antiviral antibody are capable of identifying all current Zika virus strains.

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Several recent publications have noted that monoclonal antibodies to dengue virus enhance in vitro the infection of FcR-bearing cells by Zika virus. This has led to speculation that dengue immunity may make people more susceptible to Zika infection, or even more susceptible to severe Zika disease, including birth defects in infants of infected pregnant women. However, the phenomenon of immune enhancement (antibody-dependent infection enhancement, or ADE) is a universal in vitro phenomenon among the flaviviruses (Morens, 1994) and does not necessarily indicate risk to infected people. ADE is widely suspected of being involved in the occurrence of severe dengue diseases (dengue hemorrhagic fever and dengue shock syndrome) upon sequential dengue infection with different dengue serotypes (Halstead, 2007); however, antibodies to other flaviviruses, such as Japanese encephalitis virus, do not appear to put people at risk of severe dengue disease even though they mediate ADE in in vitro assays. Around the globe, millions of people live in areas supporting circulation of multiple flaviviruses without showing evidence of increased risk of clinical severity. Questions concerning Zika risks in dengue immune persons can only be answered by large-scale, prospective epidemiologic studies.

Viral and Vector Ecology

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As noted, Zika virus has been isolated from Aedes albopictus mosquitoes in the Americas; however, the potential role of this alternative vector remains to be determined. The issue is of special importance to the United States, since Aedes albopictus is much more widely distributed in continental States than is Aedes aegypti, potentially increasing the risk that returning infected travelers could ignite small local outbreaks in U.S. cities and towns. Although Aedes mosquitoes may be at least transiently prevalent in 40 of the United States and in parts of Canada (Hahn et al, 2016), it is believed that risks of local outbreaks in the continental United States are substantial only within certain areas of Texas, Louisiana, and Florida.

Pathogenesis and Natural History, Including Viral Transmission

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Although the great majority of Zika infections result from human–mosquito–human transmission, Zika virus has also been transmitted sexually from men to women and from men to men, via blood transfusion, and via laboratory accident. The precise level of risk of sexual transmission from infected men has not yet been accurately measured. Investigations in Brazil have proposed that sexual transmission may contribute significantly to overall virus transmission; however, evidence to this effect is scant. In the United States, only 13 instances of sexual transmission have been reported to the Centers for Disease Control and Prevention (CDC). Presumably because the testes are an “immunologically privileged” site, Zika virus or Zika virus RNA may remain in the testes of infected men for many weeks, including infected men who may not know they have been infected. There is little evidence that prolonged testicular infection is harmful to infected men; however, such men may potentially transmit the virus to their sexual partners, including pregnant women or women trying to conceive. This poses an additional level of risk to these women and makes comprehensive counseling concerning safe sexual practices important.

Clinical Picture

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The clinical picture of Zika disease remains that of a typical, often mild, “dengue-like” illness with rash, fever, conjunctival injection, myalgia, and arthralgia. The inapparent to apparent infection ratio, widely cited as being about 5:1, has varied from study to study; however, all studies find more inapparent (asymptomatic, or with mild symptoms that do not lead to recognition of Zika disease) than apparent cases. Some studies have claimed that symptomatic disease (e.g., illness with rash) in pregnant women is more likely to lead to fetal infection; however, many of those data have been generated by retrospective methods, and babies with apparent congenital Zika infection have been delivered by women who did not have recognized Zika infection. Although most flavivirus infections that produce a rash are associated with rash-associated pruritus, there have been many anecdotal reports of patients with uncharacteristically severe Zika pruritus. Petechial enanthem on the hard palate also has been reported; its frequency is unknown. In addition to deaths from birth defects and neurologic complications, rare Zika deaths have been reported, possibly due to coincidence or to unrelated underlying conditions.

Diagnosis/Differential Diagnosis

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Although several new diagnostic tests have recently become available in the United States under Emergency Use Authorization, the same diagnostic problems of specimen timing and interpretation of results remain. Infection may be confirmed by viral isolation or PCR detection of viral RNA only during a narrow window of time (approximately 7 days) subsuming the acute illness, with an additional week of detection provided by testing urine. Determination of past infection by detecting antibody remains an often complicated endeavor, particularly in patients who have had past flavivirus exposures to natural virus infection or vaccines. Interpretation of flavivirus serologic test results by experienced flavivirologists is desirable, as the many complexities involved may confuse clinicians and commercial lab personnel.

Management of Pregnant Women, Women Seeking to Become Pregnant, Male Sexual Partners of Such Women, and Fetuses/Babies Who May Have Been Exposed to Zika infection

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CDC has continued to release frequent and updated information that supports management and counselling of women and of couples who have been, or may become, exposed to Zika virus. As recommendations have frequently changed with newly available information, it is desirable for practitioners to consult the CDC website (www.cdc.gov/zika/) regularly. Other recommendations have been made by the Pan American Health Organization and World Health Organization, and by other national and professional agencies. Recommendations address different types of exposures including exposures of women living in epidemic areas, exposures of women and couples who may travel to epidemic areas, and exposures of women living in the continental United States who may be exposed to infected sexual partners. The most important goal of counseling is to apply multiple available approaches to protect women from Zika infection while pregnant, including the interval of pregnancy between conception and pregnancy determination, and the period of 2–3 weeks before conception.

Prevention and Control

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As noted, Zika is currently spreading epidemically in Puerto Rico, the USVI, and American Samoa; within the coming year small local outbreaks of autochthonous transmission are anticipated in certain areas of the continental United States. Because no vaccine or effective drug is likely to be available within the next 1–2 years (if then), prevention must depend upon community and governmental efforts (education and counseling, vector control, diagnosis of infection) and personal protection undertaken by individuals. CDC has recently released a comprehensive Draft Interim Response Plan (www.cdc.gov/zika/) that represents a framework for Zika control at the national, state, and local level. In coming months, there remains an important role for practitioners in counselling and educating patients, who may be confused by the many complexities of Zika (Plourde, Bloch, 2016) and by the continually evolving information reported in the media as the pandemic progresses, and as hundreds of scientific studies are completed and reported.

References

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Hahn  MB  et al.: Reported distribution of Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus in the United States, 1995-2016 (Diptera: Culicidae). J Med Entomol, 2016
[PubMed: 27282817]
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Halstead  SB: Dengue. Lancet 370:1644, 2007
[PubMed: 27362784]
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Johanssohn  MA  et al.: Zika and the risk of microcephaly. N Engl J Med, 2016
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Morens  DM: Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 19:500, 1994
[PubMed: 7811870]
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Plourde  AR, Bloch  EM: A literature review of Zika virus. Emerg Infect Dis 22:1185, 2016
[PubMed: 27070380]