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Healio
Issue: March 2016
ByThomas M Yuill, PhD
ByDonald Kaye, MD, MACP
March 15, 2016
8 min read
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Zika virus: Much more than advertised

Issue: March 2016
ByThomas M Yuill, PhD
ByDonald Kaye, MD, MACP
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Zika virus was first isolated from a sentinel monkey in the Zika Forest of Uganda in 1947. For many years following its discovery, Zika was not considered a significant public health threat. Between 1951 and 1981 there was serological evidence of Zika virus infection in people from Uganda, Tanzania, Egypt, the Central African Republic, Sierra Leone and Gabon as well as parts of Asia, including India, Malaysia, the Philippines, Thailand, Vietnam and Indonesia. Clinically, these cases of febrile disease were less severe than dengue or chikungunya virus infections, but similar. The situation changed in 2007 during an outbreak on Yap Island, Federated States of Micronesia, with 59 probable cases and 49 laboratory-confirmed cases, and with 73% of the island’s population probably infected.

Figure 1. Female Aedes aegypti mosquito in the process of acquiring a blood meal from a human
host.

Source: James Gathany, CDC.

 

Off and running

In 2013, the picture changed again when a significant outbreak in French Polynesia began, ending with 11% of the population affected. There were 8,750 suspected and 383 confirmed cases, but there were 32,000 visits to health care facilities in a 5-month period. Outbreaks of Zika virus infection spread to the Cook Islands, New Caledonia and then to Chile’s Easter Island. The Zika virus responsible for the Easter Island outbreak was shown to be closely related to the virus from French Polynesia. A 2014 study showed that of 37 viruses isolated in Africa and Asia, there are three main lineages of Zika virus — two from Africa and one from Asia. The Asian lineage was the one that appeared in French Polynesia. The three lines likely originated in Uganda around 1920. These Pacific Ocean outbreaks indicated clearly that the virus could move quickly over fairly long distances via viremic individuals to isolated localities where there were populations of Aedes vector mosquitoes. The French Polynesia outbreak gave some indication that Zika virus infections might cause more than just a 2- to 7-day, self-limiting, low-grade fever (< 38.5°C), transient arthritis/arthralgia with possible joint swelling (mainly in the smaller joints of the hands and feet) and maculopapular rash (often starting on the face and then spreading throughout the body), conjunctival hyperemia or bilateral nonpurulent conjunctivitis with general, nonspecific symptoms such as myalgia, asthenia and headaches. During the 2013-2015 outbreak, clinicians reported the appearance of central nervous system malformations in at least 17 fetuses and infants. That led health care workers in French Polynesia to hypothesize that Zika virus infection during the first or second trimester of pregnancy might be associated with these abnormalities. Also during this outbreak, there were 42 cases of Guillain-Barré syndrome (GBS). Of these 42 registered GBS cases, 24 (57%) were male, and 37 (88%) had signs and symptoms consistent with Zika virus infection.

Thomas Yuill

The most significant geographic jump of all occurred at the end of February 2015, when the health departments of the Brazilian states of Bahia, Maranhão, Pernambuco, Rio Grande do Norte, Paraiba and Sergipe reported cases of rash with low-grade fever or no fever, with or without headache, pain or joint swelling and muscle pain. Dengue and chikungunya virus infections were ruled out. All cases recovered uneventfully. There were similar cases in Rio de Janeiro. The surprise came in May, when the first cases of Zika virus infection were laboratory-confirmed in Bahia and then in Rio Grande do Norte as well — the first cases ever in the Western Hemisphere. On May 15, 2015, Brazil’s Ministry of Health announced that Zika virus was circulating in the country. The Instituto Evandro Chagas, the national virus reference laboratory, announced that tests on samples from 16 people were preliminarily positive for Zika virus. Of these, eight were from Bahia and eight from Rio Grande do Norte. The virus was off and running in Brazil, and as of early February has reached 22 states and the Federal District.

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Donald Kaye

How did the virus get to Brazil? It is suspected that in 2014, when Brazil was the venue for the FIFA World Cup and the Va’a World Elite & Club Sprint Championships canoe races, a viremic individual brought the virus into the country. Many areas of Brazil had abundant populations of Aedes aegypti mosquitoes, the Zika virus vector capable of transmitting another flavivirus — dengue virus — to more than 1 million victims annually. The Brazilian population was essentially completely susceptible to Zika virus infection since the virus had not circulated there before. The speculation is that after virus introduction, during one of these international sporting events, transmission smoldered undetected until enough cases appeared at the same time to get the attention of health care providers and health officials. Brazilian researchers concluded that the virus was imported from French Polynesia.

There were no epidemiological or ecological barriers to virus spread within Brazil, nor to its dissemination into neighboring countries and on to those areas in South, Central and North America where A. aegypti was present. The virus next appeared in Colombia, spread there, and the case count has reached at least 13,500 by January. By late January, WHO reported that cases occurred in 25 countries and territories, including Barbados, Bolivia, Brazil, Colombia, Costa Rica, Curaçao, the Dominican Republic, Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Martinique, Mexico, Nicaragua, Panama, Puerto Rico, Paraguay, Saint Martin, Suriname, the U.S. Virgin Islands and Venezuela. Brazil has had the most cases by far.

Zika’s association with microcephaly, other conditions

In September 2015, clinicians in northeast Brazil began to see an increase in infants born with microcephaly in the areas where Zika virus was circulating, raising concern that the two were related. Zika virus RNA was detected in amniotic fluid of two women bearing fetuses with microcephaly. Zika virus RNA was found in the tissues of one microcephalic newborn who died shortly after birth. Later, additional Brazilian samples were taken from two pregnancies ending in miscarriage and from two infants with microcephaly who died shortly after birth. All four cases were positive for Zika virus infection, indicating that the infants had become infected during pregnancy. The Ministry of Health became concerned about fetal infections and set up a task force to investigate the situation. A registry was established for microcephaly — defined as a newborn’s head circumference being at least 2 standard deviations below the mean by gestational age and sex — among women infected by Zika virus during pregnancy. From August to October 2015, researchers studied 35 infants with microcephaly born in eight of Brazil’s 26 states. Their mothers had been in localities where Zika virus was being transmitted during their pregnancies. Of these 35 cases, 25 were classified as severe microcephaly (head circumference more than 3 SDs below the mean), 17 had at least one neurological abnormality, and of 27 who had neuroimaging studies, all had abnormalities. However, it was not stated if there was serological or virological evidence that the mothers had been infected with Zika virus during pregnancy. This situation prompted the release of new alerts by the Ministry of Health, as well as the European Centre for Disease Prevention and Control and the CDC concerning the possible association of microcephaly with the recent outbreak of Zika virus infection. However, while these agencies stated that there was a strong association between Zika virus infection in pregnant women and microcephaly, none indicated a definite causal relationship. Interestingly, Colombia has not reported microcephaly cases. Perhaps there have not been enough infections in pregnant women there for microcephalic fetuses or newborns to occur. Prospective studies are needed to confirm causality.

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By way of follow-up, Brazilian researchers looked at 4,180 suspected cases of microcephaly reported since October 2015. Of these cases, 732 had intensive analysis. Of these, 462 were excluded because they did not meet the criteria for microcephaly or because they were not due to maternal infection. This left 270 cases due to maternal infection. Zika virus was found in six of these infants, but the test used was insensitive as it would only show positive results during the acute phase of the infection. Although cases of microcephaly have increased over previous years, these findings suggested that in utero Zika virus infection may not have been the only etiological agent responsible for all of them. Prospective studies by a team of medical specialists continue in Salvador, Bahia state in Brazil, which are expected to provide further insight into Zika virus infections and congenital effects.

Congenital abnormalities were not restricted to microcephaly. In January, examinations of three microcephalic children showed cerebral calcifications and unilateral ocular findings involving the macular region and loss of the foveal reflex. In one child, well-defined macular neuroretinal atrophy was detected.

Future challenges

What to do next? The U.S. Public Health Service indicated that the country must prepare for the arrival of Zika virus. There are already several cases of individuals infected among the 20 affected countries in the Americas who have become ill in the U.S. Although only one Zika virus-infected person in four or five becomes ill, because of the potential danger of fetal infection, the CDC has cautioned pregnant women or those planning to become pregnant to avoid travel to areas of Zika virus transmission. Development of Guillain-Barré syndrome in infected people is also a potential problem. Small areas of focal virus transmission may occur in the U.S. following its introduction in those areas where A. aegypti occurs in the Southeast across to southern Texas, New Mexico, Arizona and now in Southern California. However, air conditioned buildings and screened windows reduce the risk for exposure to bites of these mosquitoes. The potential role of the Asian tiger mosquito, A. albopictus, as a Zika virus vector in the U.S. and elsewhere is undefined. Laboratory studies conducted in Singapore showed that it is an efficient vector. The geographic distribution of this mosquito is much wider in the U.S. than A. aegypti. Vector control is difficult because these mosquitoes live in very close association with people. Spraying or fogging only eliminates adult mosquitoes, but a new crop emerges from breeding sites. Since any water catchment that persists for several days can serve as a breeding site, finding and eliminating all of them or treating them with larvicides is extremely difficult. The introduction of genetically modified mosquitoes that result in offspring failure is promising and being tested now in Brazil.

There have been three cases of apparent sexual transmission from a convalescent male to his female partner. The epidemiological significance of sexual transmission is unknown. Availability of approved Zika vaccines is years away. The virus will certainly continue to spread and is very likely to become endemic in the Americas. This may present a challenge for the safety of blood and blood products. At present, testing for Zika virus infection in the U.S. is available in the CDC’s Arbovirus Diagnostic Laboratory and some state health departments. Also, let us remember, the Olympics are coming to Brazil this summer.

  • For more information:
  • Thomas Yuill, PhD, is a ProMED-mail viral diseases moderator and professor emeritus, department of pathobiological sciences and department of forest and wildlife ecology, University of Wisconsin-Madison.
  • Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

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