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Zika and Hearing Loss

2016; Lippincott Williams & Wilkins; Volume: 69; Issue: 12 Linguagem: Inglês

10.1097/01.hj.0000511123.79295.d0

2333-6218

Gordon Glantz,

Mosquito-borne diseases and control

Figure: iStock Photo/bakhtiar_zeinThe United States is bracing for the northward trek of a potential calamity from South America, except it is not a hurricane. It is a virus called Zika. ZIKV is spread not by wind, but by mosquitoes, and hearing loss is one of its many debilitating results. As of October 2016, more than 25,000 people in the U.S. and its territories have contracted the Zika virus according to the CDC http://bit.ly/2ekEHpe. Zika has caught enough attention for Congress to allocate $1.1 billion to fight the spread of the disease, with a ripple effect of states and cities preparing for signs and, more importantly, of medical researchers rushing to develop vaccines and diagnostic tests.Figure: James Bale, Jr., MDFigure: Kristen Healy, DPhil, MPHDoctors on the front lines—such as James Bale, Jr., MD, professor of Pediatric Neurology at the University of Utah School of Medicine, and Kristen Healy, DPhil, MPH, assistant professor of Medical Entomology and Public Health Entomology at Louisiana State University (LSU)—are wary of long-term effects of the virus and caution that researchers remain in the learning phase in the fight against Zika. “I was hired at LSU in 2013, specifically to work with mosquito control programs in the state. When I started, there was a need to help programs address the West Nile virus. Now the issue is the Zika virus. I think it is safe to say that mosquitoes and mosquito-borne diseases are going to be an annual concern,” said Healy. “Unfortunately, there is still much we do not know about Zika virus. And given that it is also sexually transmitted adds a new layer onto the transmission potential of the virus. Therefore, there is the potential to see some localized transmission.” The proverbial bullet may have been dodged at the Rio Olympics. As the World Health Organization (WHO) reported no cases as a result of the Games, simple warnings against pregnant women traveling to risk areas like Brazil will ring hollow. Just as Florida is often the first to be hit by storms, as seen most recently with Hurricane Matthew, it is also where retirees spend the winter months, families travel to Disney World, and baseball teams and fans flock to for spring training. It could be the first American state, with its warm climate and swamps that breed mosquitoes, to feel the full wrath of Zika. “That's going to be the challenge, getting rid of the mosquitoes,” said Bale. “Now we are learning about sexual transmission, so that's a new challenge. It's a potentially huge problem, affecting the southern states and then moving north. We are talking about the potential for several million. We are already seeing it in Florida. The CDC is worried about how it plays out, if it spreads in that way.” HEARING LOSS CONFIRMED What is known is that Zika causes microcephaly, defined by the CDC http://bit.ly/2ektSDK as “a birth defect where a baby's head is smaller than expected when compared to babies of the same sex and age” in the fetuses of infected pregnant women.Figure: Mariana Leal, PhDAs confirmed by Mariana Leal, PhD, who was a first-hand witness to the genesis of Zika in Brazil, hearing loss is one of many lasting side effects in surviving infants. “Considering the hearing loss subject, if we fail to identify soon the hearing problem, this will bring irreversible impact for the child's language development,” said Leal, the ENT head chief of Agamenon Magalhães Hospital (AMH), which is a reference center for audiological health in the state of Pernambuco. “The first cases of microcephaly were detected in our state in September. As a reference hospital, we were invited to evaluate the first babies diagnosed with microcephaly from the hearing (loss) perspective.” “It seems to be real,” added Bale, who sees similarities between Zika and Rubella (German Measles; a vaccine was developed in 1969 after a pandemic earlier in the decade). “There are a couple of studies, and it's not surprising at all. That's the most difficult part. There is not a way to prevent it. And the question is, ‘What's the full spectrum?’” “I don't think it will take 10 years (like Rubella, before a vaccine), but that's a good example, a good model. I look at Rubella, and it may be similar in the way it plays itself out. [Rubella] was one of the major causes of nerve deafness. It's a tough problem to know how it will damage the inner ear. [Rubella] was the most common cause of non-genetic hearing loss. Will Zika become the most common? We are continuing to learn more and more about the full spectrum of it.” A YEAR IN THE TRENCHES Leal's timeline of Zika research dates back to October 2015. “The Brazil Ministry of Health reported an unusual increase in cases of microcephaly in the state of Pernambuco in the northeast of Brazil,” she said. “These patients had imaging studies suggestive of congenital infection, characterized by the presence of calcifications, ventriculomegaly, and disorders of cortical development.” By the next month, the Flavivirus Laboratory at the Oswaldo Cruz Institute indicated that the Zika virus genome was detected through RT-PCR in amniotic fluid samples of two pregnant women from Paraíba, a neighboring state of Pernambuco, where fetuses have been diagnosed with microcephaly through ultrasound exams. In the same month, the Brazilian Ministry of Health declared they had accepted the relationship between the increase in occurrence of microcephaly and ZIKV infection through the detection of ZIKV by molecular biology in tissue samples of a newborn who died in the state of Ceará. The State Health Department of Pernambuco, followed by the Brazilian Ministry of Health, created the first protocol to diagnose and evaluate microcephaly and established AMH as the reference center for evaluating audiology impact. By February 2016, Leal said the relationship of ZIKV and microcephaly was confirmed and published in the New England Journal of Medicine, sparking laboratory testing from March to July (2016;374[10]:951 http://bit.ly/2ekz3TU). In September, based on the research from Leal's group in Brazil, the CDC published http://bit.ly/2ekv9KW the first article on hearing loss in infants with congenital Zika infection. Since then, the quest for a more expansive grasp on the situation continues, as Leal admits that her team is still going through this topic every day to learn more. “We found about six percent of sensorineural hearing loss among 70 children with microcephaly and laboratory evidence of congenital Zika virus infection,” said Leal, adding that sensorineural hearing loss should be considered part of the spectrum of clinical findings associated with congenital Zika virus infection, which “should be considered a risk factor for hearing loss in auditory screening programs.” Since it is not known that all infected newborns will develop immediate hearing loss, Leal cannot stress enough the importance of screening, adding that “even children who have normal initial screening tests should receive regular follow-up, because onset of hearing loss could be delayed and the loss could be progressive, as in other congenital infection like cytomegalovirus (CMV).” She added: “The importance of hearing screens focuses on identifying hearing loss early. Catching problems sooner rather than later can make a big difference in a child's language development. Language skills are learned before the age of 3 years, because hearing and learning language are closely tied together. The brain scans allow doctors to identify the pattern of ZIKV infection characterized by brain calcification at the junction between cortical and subcortical white matter associated with other malformations of cortical development, as recently published by Brazilian researchers in medical literature.” A WORK IN PROGRESS While it is known that Zika damages the inner ear, Leal's team has yet to pinpoint the particulars. “The exact location of the inner ear damage is not known yet,” she said. “Further research have to be conducted, but it will probably take some time.” As for the different measurements that doctors have performed so far, such as audiogram, otoacoustic emissions, and auditory brainstorm responses (ABR), Leal explained what has been deployed and the ongoing results. “Besides the instruments used for other organs damaged (such as ophthalmic, neurologic, and imaging evaluations), we have performed behavior audiometry, imitanciometry, click ABR, frequency-specific ABR (with tone bursts),” she said. “The click ABR is used for screening evaluation; the frequency-specific ABR and behavioral audiometry for diagnostic confirmation. Otoacoustic emissions are not in our protocol, because this test is less sensible for retrocochlear hearing loss, which can be the case in Zika-infected newborns. “We found sensorineural hearing loss in 5.8 percent of children with macrocephaly, using frequency-specific ABR. The behavioral audiometry was consistent with the electrophysiologic tests. But we must consider that the behavioral responses can be affected by the neuromotor development abnormalities that are present in these children. Moreover, there is some delay in oral language development. “It is already well-demonstrated that this virus has strong neurotropism. But it is still not known if the auditory lesions are in the central or peripheral nervous system or in the sensory organ.” LOOKING AHEAD With the money allocated by Congress, much hope rests on developing a vaccine soon. In February, the Brazil Ministry of Health signed the first international agreement for the development of a vaccine against the Zika virus. This research will be carried out in conjunction with the Brazilian government and the University of Texas. Meanwhile, researchers like Healy are receiving grants to monitor and control the population of mosquitoes in the battle against the spread of the disease. “We have several grant-funded projects in our laboratory,” said Healy. “In particular, we are working on projects assessing temperature-dependent development rates in mosquitoes and how temperature relates to larvicide efficacy in mosquitoes. Our goal is to provide recommendations to mosquito control on which larviciding products they should use at different times of the year.” An overwhelming concern is the potential for those with less severe cases to develop hearing loss later in their childhood. “There are studies looking at less affected cases—kids with secondary hearing loss and late onset hearing loss,” said Dr. Bale. “That's clearly the uncertain part about this, because we may not know until they are school-age. There are some good longitudinal studies on the most severely affected more than mild hearing loss.” “We are following children who were diagnosed with congenital Zika syndrome (CZS), children with and without hearing loss, to find out the evolution,” Leal said. “Our group is involved in a cohort study and in the future, we hope to identify the potential development of hearing loss in children with CZS and those who have asymptomatic ZIKV infection. Knowing that children with other congenital infections such as CMV can develop delayed hearing loss, we can't leave out this possibility for ZIKV and for this reason, we are attentive and following those children with periodic re-evaluation.” One of the many unanswered questions is why some cases are more severe than others. The answer could be a vital tool in research to combat Zika. “It's just the tip of the iceberg right now,” said Bale. “It probably has something to do with our immune systems and how we respond. Do we know the answer? No. We don't understand it yet. What's going to happen? Right now, it's anybody's guess.”