Public Health Challenges of the Zika Virus Outbreak: A Neurologist’s Perspective

Though it been nine years since Zika virus emerged in a major outbreak in the Yap Islands and over a year since its emergence in South America, Zika continues to cause symptoms in thousands of people leading to devastating neurological consequences including congenital birth defects and Guillain Barre Syndrome (GBS) in some. Over the last six months, the virus has rapidly spread across Central and South America and the Caribbean, now with local Zika virus transmission also identified in the Southern United States, Western Africa, and Southeast Asia. Seven months ago, the World Health Organization (WHO) declared the cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, a Public Health Emergency of International Concern1. Since this declaration, there has been a rapid rise in the number of countries with mosquito-borne transmission. Seventy-two countries now report local mosquito-borne transmission, with 11 countries reporting evidence of person-to-person transmission of Zika virus2.

Evidence suggests that there is an etiological link between Zika virus and neurological effects, including GBS and congenital birth defects3-4. The number of countries with evidence of neurological manifestations of Zika virus has increased significantly since February 2016, with 18 countries reporting an increased incidence of GBS and/or laboratory confirmation of Zika virus infection among GBS cases. Though Brazil and French Polynesia were the only countries reporting an increased number of microcephaly cases and other congenital malformations at the beginning of February 2016, there are now 20 countries reporting microcephaly and other central nervous system (CNS) malformations possibly associated with Zika virus infection. Unfortunately, given the rapid spread of the virus over the last several months, these numbers are expected to rise.

The pace of scientific discovery has been impressive with the rapid development of mouse models to elucidate neuropathogenic mechanisms, and clinical trials ongoing evaluating the safety of candidate Zika virus vaccines5-6. In contrast, public health efforts to prevent, monitor, and control the spread of Zika virus have had minimal effects in halting Zika’s global spread. Efforts have been severely affected by the lack of funding support, and in the United States, Congress departure for summer recess without securing necessary emergency funds to combat Zika virus. Beyond the lack of funding, recent global health security crises, including the ongoing Zika virus outbreak and recent Ebola epidemic, have illustrated how rudimentary our current global public health systems are in recognizing and containing epidemics. The effective implementation of measures to ensure global health security requires strengthening day-to-day detection, response, and prevention programs that can be scaled up on a global scale rapidly if needed. Though ensuring individual countries are able to detect, investigate, diagnose and rapidly contain infectious disease outbreaks is essential, public health systems for identifying and monitoring emerging diseases solely led by national or sub-national government agencies often demonstrate varying strategies. Countries’ responsibility in monitoring and reporting diseases are also affected by the fear of economic and political consequences, such as the loss of tourism and trade due to the imposition of travel restrictions. Therefore, global oversight is needed to monitor disease outbreaks which cross national boundaries.

The importance of response monitoring was emphasized in the Strategic Response Framework recently published by the World Health Organization (WHO), where a number of important indicators on surveillance, response and research were delineated7. A weekly situation report published by the WHO reports the number of countries with cases of Zika virus, including the neurological complications of microcephaly and GBS and provides important real-time information on countries affected by Zika virus8. The Pan American Health Organization (PAHO) also publishes a weekly epidemiological report, with country-specific data on trends in Zika virus infection as well as neurological manifestations including congenital malformations and GBS9. Though, many variables are not reported including the number and percentage of countries with laboratory capacity, and the population covered by available laboratory testing, including the number of symptomatic pregnant women. The WHO and PAHO should be commended on their efforts to build laboratory capacity in Zika endemic regions. A report on the challenges of implementing such measures would be incredibly valuable, especially for regions at risk of endemic Zika virus.

One of the cornerstones of communicable disease surveillance is the reporting and confirmation of cases seen by healthcare professionals. In order for healthcare providers to recognize and report clinical manifestations, clear, uniform case definitions must be available. Varying case definitions in the context of Zika virus may lead to challenges in understanding the global impact of Zika virus and its serious complications. For example, the case definitions of microcephaly in the context of Zika virus differ by WHO and the United States Center for Disease Control (CDC). The WHO published guidance on the assessment of microcephaly in the context of Zika virus and define microcephaly as a head circumference of two standard deviations or more below the mean for age and sex. Severe microcephaly is defined as a head circumference of more than three standard deviations below the mean for age and sex10. For term neonates (37-42 weeks), it is recommended that WHO Child Growth Standards for size at birth be used to interpret measurements. If accurate gestational age is known, Intergrowth-21 Size at Birth Standards are preferred11. The United States CDC defines microcephaly as a head circumference at birth less than the 3rd percentile for gestational age and sex according to Intergrowth-21 chart, or if head circumference at birth is not available, head circumference less than the 3rd percentile for age and sex within the first six weeks of life12. The challenges of having different case definitions has been pointed out in a commentary in the New England Journal of Medicine— “we have some concern regarding diagnostic criteria for microcephaly in fetuses and newborns exposed to the virus. According to the CDC recommendation that microcephaly should be defined as an occipitofrontal circumference below the third percentile, nearly 3% of newborns would be categorized as having microcephaly. In Brazil, where there are 3 million live births per year, the application of this definition would result in nearly 90,000 infants being labeled as having microcephaly — a far greater number than any studies to date would indicate….a comparison of prevalence with the use of such radically different criteria will lead to grossly inappropriate conclusions”13. In a recent publication on congenital Zika virus syndrome in Brazil, in which 1501 live births were investigated, microcephaly case definitions adopted by the Brazilian Ministry of Health were noted to have changed three times since November 201514. Importantly, authors from the Brazilian case series note that the high cutoffs for head circumference adopted early in the epidemic made an unexpected contribution to the understanding of Zika virus congenital syndrome, as about one in five definite or probable cases had head circumferences in the normal range, and would not have been enrolled had more specific cutoffs been used15. Authors conclude that the finding of several newborn babies with neuroimaging abnormalities despite normal sized heads suggests that the initial focus on microcephaly was too narrow. Indeed, there is growing recognition of the importance of defining the spectrum of congenital manifestations associated with Zika virus, rather than focusing on microcephaly as a defining clinical feature of Zika virus infection. This transition is long overdue, as microcephaly is a clinical sign of in utero insult, and existing evidence highlights the wider range of congenital abnormalities associated with the acquisition of Zika virus infection in utero. In addition to microcephaly, other manifestations include craniofacial disproportion, brainstem dysfunction, ocular abnormalities, hearing abnormalities, and findings on neuroimaging such as calcifications, cortical disorders and ventriculomegaly16. Increasing public and healthcare sector knowledge regarding Zika virus congenital syndrome is imperative, and developing a comprehensive case definition including neurodevelopment assessment strategies in infants with in utero exposure are urgently needed.

In adults, Zika virus is linked to the development of GBS, and associated with other neurological manifestations including myelitis and meningoencephalitis17-19. The importance of understanding the neurological spectrum of Zika virus infection has important implications both in our understanding of the neurovirulence of Zika virus infection and in clinical management. Fundamentally, accurately describing the spectrum of neurological manifestations around Zika virus is based on a thorough bedside neurological assessment and availability of ancillary testing including neuroimaging and neurophysiology testing. In many Zika endemic regions, there is a major deficiency in the neurological healthcare workforce, with a particular deficiency of pediatric neurologists20. Building a stronger neurological workforce globally is needed, though the first important step in the context of the ongoing epidemic is to train generalists, emergency medicine physicians, and intensivists in basic pediatric and adult neurological assessment and management strategies relevant to the potential effects of Zika virus on the nervous system. GBS is a potentially deadly neurological condition, though evidence based guidelines exist on the appropriate management of patients. The infrastructure to optimize care according to evidence-based standards in many Zika-endemic regions has not been published including access to intensive care units, ventilator support, and immunotherapy.

The WHO and CDC have recently developed guidance on screening, assessment and management of neonates and infants with in utero exposure to Zika virus which contains important recommendations on short and long-term follow-up of children in areas of Zika virus transmission21-22. Monitoring including developmental and neurological assessments, hearing and vision assessments, and psychosocial support to mothers and caretakers are delineated. Alongside these recommendations, a pragmatic toolkit would be useful for healthcare providers. Access to high quality, low cost, and effective medications including antiepileptic drugs are required and addressing how to provide rehabilitation care in Zika endemic countries would be useful. The numbers of patients with neurodisabilities requiring long-term occupational, physical, and cognitive rehabilitation care will continue to grow. Pragmatically addressing how governments will provide long-term care for disabled populations affected by Zika virus should be occurring concurrently as unfortunately, the number of infants requiring long-term occupational, physical and cognitive rehabilitation care is expected to rise.

The global public health emergency of the ongoing Zika virus outbreak has several fundamental challenges. The fact that the virus remains silent in many individuals, with delayed severe neurological sequelae in some is proving to be a major public health challenge. Monitoring for possible neurological consequences is complex as laboratory testing may not be able to accurately show prior viral infection. Developing mechanisms to monitor and treat patients affected by the Zika virus requires improvements in the access to neurological care and supportive services in many endemic regions. The consequences of the neurological manifestations of Zika virus will be life-long for many patients, as well as caregivers, communities, and countries whose health systems are ill-equipped to provide adequate socioeconomic support. As scientific advances on Zika virus are made, public health efforts should keep pace, with rapid updates and implementation guidelines on surveillance, diagnostic, and management strategies. Efforts require an organized, collaborative and rapid global response, that provides pragmatic and consistent advice to the healthcare sectors and the public.

References

  1. Hartl G, Lindmeier C, Jasarevic T WHO statement on the first meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika virus and observed increase in neurological disorders and neonatal malformations. In: WHO Media centre, 2016 [online] Available at: http://www.who.int/mediacentre/news/statements/2016/1st-emergency-committee-zika/en/. Accessed July 29, 2016
  2. Situation Report: Zika Virus, Microcephaly, Guillain-Barré Syndrome. World Health Organization, July 28, 2016. [online] Available at: http://apps.who.int/iris/bitstream/10665/246261/1/zikasitrep28Jul2016-eng.pdf?ua=1Accessed July 29, 2016.
  3. Broutet N, Krauer F, Riesen M, et al. Zika Virus as a Cause of Neurologic Disorders. N Engl J Med 2016;374:1506-1509
  4. Rasmussen SA, Jamieson DJ, Honein MA, et al. Zika virus and birth defects—reviewing the evidence for causality. N Engl J Med 2016;374:1981–7
  5. Miner JJ, Cao B, Govero J, et al. Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell. 2016;165(5):1081-91
  6. Zika Virus. National Institute of Allergy and Infectious Disease. [online] Available at: https://www.niaid.nih.gov/topics/zika/researchapproach/Pages/vaccineResearch.aspx. Accessed July 29, 2016
  7. Zika Strategic Response Plan. World Health Organization, 2016. [online] Available at: http://apps.who.int/iris/bitstream/10665/246091/1/WHO-ZIKV-SRF-16.3-eng.pdf?ua=1&ua=1. Accessed July 29, 2016
  8. Zika virus situation reports, World Health Organization, 2016 [online] Available at: http://www.who.int/emergencies/zika-virus/situation-report/en/. Accessed July 20, 2016
  9. Regional Zika Epidemiological Update (Americas): Zika virus – Incidence and trends. Pan American Health Organization, 2016 [online] Available at: http://www.paho.org/hq/index.php?option=com_content&view=article&id=11599&Itemid=41691〈=e. Accessed July 28, 2016
  10.  Screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero. Rapid Advice Guideline, World Health Organization, 2016 [online] Available at: http://apps.who.int/iris/bitstream/10665/204475/1/WHO_ZIKV_MOC_16.3_eng.pdf. Accessed July 28, 2016
  11. Screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero. Rapid Advice Guideline, World Health Organization, 2016 [online] Available at: http://apps.who.int/iris/bitstream/10665/204475/1/WHO_ZIKV_MOC_16.3_eng.pdf. Accessed July 28, 2016
  12. Congenital Microcephaly Case Definitions, Centers for Disease Control and Prevention [online] Available at: http://www.cdc.gov/zika/public-health-partners/microcephaly-case-definitions.html
  13. Zika Virus. N Engl J Med 2016; 375:293-295.
  14. França GV, Schuler-Faccini L, Oliveira WK, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet. 2016.
  15. Costello A, Dua T, Duran P, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Organ. 2016;94(6):406-406A. doi: 10.2471/BLT.16.176990.
  16. Mécharles S, Herrmann C, Poullain P, et al. Acute myelitis due to Zika virus infection. Lancet. 2016 2016;387(10026):1481.
  17. Carteaux G, Maquart M, Bedet A, et al. Zika Virus Associated with Meningoencephalitis. N Engl J Med. 2016 Apr 21;374(16):1595-6
  18. Zika Virus May Now Be Tied to Another Brain Disease. American Academy of Neurology, 2016. [online] Available at: https://www.aan.com/PressRoom/home/PressRelease/1451. Accessed July 15, 2016.
  19. Atlas: Country resources for neurological disorders. Mental Health, World Health Organization [online] Available at: http://www.who.int/mental_health/neurology/epidemiology/en/. Accessed July 15, 2016.
  20. Diagnostic Tests for Zika Virus. Center for Disease Control and Prevention [online] Available at: http://www.cdc.gov/zika/hc-providers/types-of-tests.html. Accessed July 20, 2016
  21. Screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero. Rapid Advice Guideline, World Health Organization, 2016 [online] Available at: http://apps.who.int/iris/bitstream/10665/204475/1/WHO_ZIKV_MOC_16.3_eng.pdf. Accessed July 30, 2016
  22. Clinical Guidance for Healthcare Providers Caring for Infants & Children, Center for Disease Control and Prevention [online] Available at: http://www.cdc.gov/zika/hc-providers/infants-children.html. Accessed September 10, 2016.

Acknowledgements

I would like to thank Dr. Gretchen Birbeck for reviewing the manuscript.

Kiran T. Thakur, MD

Department of Neurology, Columbia University Medical Center, New York, NY

More Posts