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   Table of Contents      
REVIEW ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 3  |  Page : 122-130

ZIKA virus disease: An update


Senior Resident, Department of Community Medicine, VMMC and Safdarjung Hospital, New Delhi, India

Date of Web Publication7-Oct-2016

Correspondence Address:
Dr. Anika Sulania
JA-23, UGF, Khirki Extension, Malviya Nagar, New Delhi - 110 017
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-7438.191666

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  Abstract 

Zika virus is responsible for causing Zika virus disease (ZVD), is another vector borne disease which is being linked to the sudden rise of microcephaly in few states of United States of America and the cases of Guillain-Barré syndrome in French Polynesia. Looking at the cases and the relation between congenital malformations found in children of women who were suffering from ZVD, it has been declared as public health emergency of international concern by World Health Organization in February 2016 and now it has become important local public threat with impending pandemicity. Case fatality though is not very high but number of suffering individuals crossed 5 lakh alone in Brazil and still increasing. The symptoms are similar to Dengue virus disease or Chikungunya virus disease.

Keywords: Birth defects, epidemics, Flavivirus, microcephaly, surveillance, Zika virus


How to cite this article:
Sulania A. ZIKA virus disease: An update. MAMC J Med Sci 2016;2:122-30

How to cite this URL:
Sulania A. ZIKA virus disease: An update. MAMC J Med Sci [serial online] 2016 [cited 2019 Oct 19];2:122-30. Available from: http://www.mamcjms.in/text.asp?2016/2/3/122/191666


  Introduction Top


Zika virus disease (ZVD) is a mosquito-borne arbovirus infection caused by Zika virus (ZIKV), a Flavivirus from the Flaviviridae family spread via a type of mosquito called Aedes mosquito, namely Aedes aegypti and Aedes albopictus which is also responsible for spreading diseases such as dengue, chikungunya, and yellow fever.[1],[2],[3]

Problem statement

According to the WHO, since 2007, 52 countries and territories have reported the transmission of ZIKV [Figure 1] and [Table 1]. Out of those, 33 countries have reported ZVD in 2015-2016 alone, more than double the number only 1 month ago.[4] Lao People's Democratic Republic is the latest to report autochthonous transmission of ZIKV. France, Italy, and the United States of America have reported locally acquired ZIKV infection in the absence of any known mosquito vector.[5]
Figure 1: Countries and territories with autonomous transmission of Zika virus, 2007-2016

Click here to view
Table 1: Countries and territories with autochthonous transmission of Zika virus, 2007-2016[4]


Click here to view


Till date, more than 5 lakh cases were detected in Brazil alone followed by Columbia with 20,297 cases. Since there is a wide geographical distribution of the mosquito vector, a lack of immunity among population in newly affected areas, and the high international travel, ZIKV has the potential for further international spread.


  TIMELINE: History of Zika Virus Disease Top


In 1947, for the 1st time, ZIKV was isolated in a rhesus monkey in Zika forest, Uganda in the rhesus macaque population.[1],[2],[3]

In 1948, for the 2nd time, the virus was isolated from the mosquito Aedes africanus in Zika forest in Uganda only. Since then, sporadic outbreaks have been reported in humans, and a variety of mosquitoes have been confirmed on the basis of serological survey performed in Africa and Asiatic population [Figure 2]. It was believed that a continuous sylvatic cycle was maintained in nonhuman primates and mosquitoes.[6],[7]
Figure 2: Spread of zika virus in world

Click here to view


In 1952, the 1st ZIKV human infection was confirmed in East Africa by the existence of neutralizing antibodies in human sera along with many other diseases such as Bwamba fever and West Nile fever.[8]

In 1966, the 1st confirmed case was recorded in South East Asian region.[9]

In the 1970s, serological surveys were performed in Asia, and the neutralizing antibodies in humans were found in countries such as India, Pakistan, Thailand, Philippines, and Malaysia.[2],[9]

In 2007, the first vast recognized ZIKV outbreak was noted in Yap islands of the Federated States of Micronesia located in the Pacific Ocean. Illness with clinical features of rash, conjunctivitis, and arthralgia were noted and later confirmed due to ZIKV transmitted by Aedes mosquitoes; in this case, it was primarily Aedes hensilli.[10]

In 2014, in French Polynesia, it was found again and the alleged suspected vector found responsible for ZVD was A. aegypti, which is widespread in the tropics and subtropics, and A. albopictus. However, Aedes polynesiensis was also considered to be one of the vectors. Clinical presentation again was that of any viral fever, with mild fever, maculopapular rash, conjunctivitis, and arthralgia. Roughly, 11% of the population suffered in this outbreak. Guillain-Barré syndrome (GBS) was reported for the first time in a few patients following ZIKV infection. The incidence rate of GBS cases during the ZIKV outbreak was approximately 20-fold higher than expected, given the size of the French Polynesia (FP) population and the established incidence rates of GBS (1-2/100 000 population per year).[11],[12]

In 2015 (November) and continuing, the Pan American Health Organization (PAHO) in 2015 issued an alert regarding ZIKV transmission in North Brazil.[13] Since the origin of the disease was unknown, It was again considered to be vector transmitting disease causing outbreak and spread rapidly. Along with ZVD, clustering of microcephaly cases was found. Although a causal relationship between in utero exposure to ZVD and occurrence of microcephaly or adverse pregnancy outcome is yet to confirm, it is declared as Public Health Emergency of International Concern (PHEIC) by the WHO.


  Epidemiological Determinants Top


Agent factor

Agent


ZIKV is a positive, single-stranded RNA encoding a polyprotein. The virus falls in the family Flaviviridae and the genus Flavivirus. Other members of this genus are yellow fever virus, dengue virus (DENV), West Nile virus, and several other viruses, which may cause encephalitis. Estimated size of ZIKV is 30-45 nm in diameter. The virus may be preserved up to 6 months in 50 % Glycerol and up to 30 months after drying. It is susceptible to anesthetic ether, and the thermal death point is 58°C for 30 min.[14]

Phylogenetically, there are two main lineages of ZIKV, the African lineage and the Asian lineage.[15],[16],[17]

In Africa, the virus maintains a sylvatic cycle involving mainly monkeys and several Aedes mosquitoes[15] whereas the Asian lineage is found to be spreading and causing human-to-human transmission in Pacific islands and South America involving Aedes mosquito as the main vector.

Asiatic lineage was found to be having high NS1 codon adaptation index values, i.e., it is more predisposed to adaptive change, which could effect and increase translational efficiency in humans and increased viremia in patients, as observed for Lassa virus.[18]

Source of infection

Humans are the primary host for disease transmission. Nearly 80% of the people infected with ZIKV are asymptomatic.[2],[10]

Host factors

Population mobility


It has been reported that the tourism is intense between Brazil and Europe, and this could be responsible for the transmission of ZVD.[19]

Pregnancy

Special precautions need to be taken in pregnancy as the virus is thought to be teratogenic.

Environmental factors

Seasons


According to the WHO, because of EL-Nino weather effect, there are more chances of increase and expansion of favorable breeding sites,[20] which is one of the reasons for continuing of the outbreak in American regions up to May 2016.

Temperature, humidity, and rainfall

These factors are responsible for mosquito vector's growth and development which will in turn result in direct increase in the spread of disease.

Altitude

One of the vectors of transmission, A. Albopictus, is known to explore higher altitude for the transmission of the diseases such as chikungunya.

This is also one of the reasons of spreading ZIKV to other regions.[21],[22],[23]

Vector

Aegypti mosquito is well adapted for urban areas.[21],[22],[23] Although the main vector is Aegypti, many other mosquitoes are found to be responsible for the transmission of ZIKV.


  Mode of Transmission Top


Vector-borne diseases

At present, ZVD is transmitted by the Aedes mosquitoes with no other mosquito involved in transmission; however, Faye et al. reported a long list of mosquito species from which ZIKV strains were isolated, including several species of Aedes and Anopheles coustani, Mansonia uniformis, and Culex perfuscus.[24],[25]

This has now been confirmed with the widespread of the ZIKV disease ZVD, underscoring the potential for ZIKV to spread globally, similar to DENV and chikungunya virus (CHIKV),[26] as shown in [Figure 3].
Figure 3: Distribution of Zika and chikungunya viruses before 2005 and their expansion worldwide in Oceania between 2005 and 2015[14]

Click here to view


The history of ZIKV resembles that of CHIKV, an alpha virus.[27] Similar to ZIVK, CHIKV was also first isolated from Africa in 1952, followed by sudden epidemic in India and Southeast Asia between the 1950s and 1980s, before it disappeared epidemiologically.

In 2004, CHIKV re-emerged in East Africa and spread to Asia again before spreading worldwide. CHIKV, similar to DENV, now circulates in all inhabited continents, evolving to a global public health problem in the past decade.

It has been predicted that the ZV is adaptable with frequent genetic changes in NS1 gene codon and it can involve other mosquito species.[27]

Sexual transmission

It is also considered to be one of the ways of transmission of ZVD. The virus was found to be positive in semen of those who were suffering from ZVD.[27],[28],[29],[30]

Blood transmission

Molecular screening was used to detect the ZIVD among blood donors during FP outbreak and it was found to be 2.8% blood donors who were asymptomatic at the time of donation, tested positive for acute ZIKV infection.[31]

Perinatal transmission

Possible routes can be transplacental, during delivery, during breastfeeding (as the presence of ZIKV is detected in breast milk by reverse transcriptase-polymerase chain reaction [RT-PCR]) in the child, and by close contact between the mother and her newborn (saliva samples of mothers also came out to be positive for ZIKV.[32]

Incubation period

The incubation period according to CDC Atlanta (the time from exposure to symptoms) for ZVD is not known, but it is likely to be a few days to a week.[33] As quoted by Ioos et al., the incubation period ranges from 3 to 12 days.[34]

Extrinsic incubation period

In mosquito vector A. aegypti, the EIP is reported to be >15 days.[35]


  Pathogenesis and Clinical Features Top


Clinical features of ZVD are that of any other arboviral infection including dengue and chikungunya viral disease such as low-grade fever (<38.5°C) and general nonspecific symptoms such as myalgia, asthenia, and headaches; and at times, maculopapular rash often spreading from the face to the body or conjunctival hyperaemia or bilateral nonpurulent conjunctivitis or both transient arthritis/arthralgia with possible joint swelling mainly in the smaller joints of the hands and feet.

Symptoms are mild with illness lasting from several days to 2-3 weeks. However, severe features requiring hospitalization are rare with only 20% of the population exposed to ZKV develops symptoms.[10],[35],[36],[37]

Infection may go unrecognized or be misdiagnosed as dengue, chikungunya, or other viral infections giving fever and rash. Asymptomatic infections are common as described with Flavivirus infections such as dengue and West Nile fever.[10],[33] In addition, the clinical features of the ZDV are similar to dengue fever or chikungunya fever which are endemic diseases in the Asiatic region along with lack of laboratory support (to diagnose ZVD), resulting in nil reporting of ZVD.

With the mild signs and symptoms, ZVD is now thought to be associated with the development of microcephaly, GBS, and possibly other neurological defects as suggested by clustering of these cases around the area where active transmission of ZVD is taking place, i.e., in and around Brazil and French Polynesia,[38] hence the reason to declare it Public Health Emergency of International Concern (PHEIC).[39]

Microcephaly

According to the WHO, microcephaly is defined as a head circumference equal to or lower than two standard deviations (SDs) below the mean (≤−2SD) for age and sex or about less than the second percentile (PAHO).[40] Head circumference that falls below −3 SD is sometimes referred to as severe microcephaly. It can be acquired microcephaly when developed after birth, but there is no evidence that if a child caught ZVD during birth will develop acquired microcephaly or not.

The average number of cases reported of microcephaly in Brazil is consistently below 200 till 2015 [Figure 4].[41]
Figure 4: Microcephaly cases in Brazil spike

Click here to view


Between mid-2015 and January 30, 2016, 4783 suspected cases of microcephaly were reported, including newborn and fetal losses, almost 20 times higher than the previous years. Out of these cases, 36.2% were confirmed for the presence of ZVD. Rest cases are under investigation. The rate is high enough to strongly suspect the link between the two.[42]

Along with microcephaly, ophthalmic findings such as gross macular pigment mottling and foveal reflex loss and neuroretinal atrophy were found in children suffering from microcephaly along with the history of suffering from probable ZIKV in antenatal period in mothers.[43]


  Guillain-Barré Syndrome Top


In GBS, nerves get infected causing lower, bilateral, and symmetrical sensorimotor development deficit. The annual incidence of GBS is estimated to be between 0.4 and 4.0 cases per 100,000 inhabitants per year. In North America and Europe, GBS is more common in adults and increases steadily with age. During 2013-2014 outbreaks in FP, the incidence of GBS increases along with ZVD, giving hypotheses of the development of GBS in adults found to be suffering from ZVD.[36],[44],[45] At present, the cases were also reported in countries such as Brazil, Colombia, El Salvador, Suriname, and Venezuela.

Prenatal or perinatal complications of ZIKV infections have not been described in the literature. There is some evidence that perinatal transmission can occur, most probably transplacental or during the delivery of a viraemic mother.[14],[18] ZIKV transfusion-derived transmission is theoretically possible as 3% of the asymptomatic blood donors (42/1 505) were found positive for ZIKV by PCR during the ZIKV outbreak in French Polynesia from November 2013 to February 2014.[13] The presence of a viable virus was detected in semen more than 2 weeks after recovery from an illness consistent with ZIKV infection.[19] The possible cases of sexual transmission of ZIKV have been reported.[19],[20] However, the three modes of transmission described above have rarely been reported to date.


  Virus Isolation and Serology Top


Both molecular and serological tests are used to diagnose the presence of ZIKV infection. For detecting the presence of ZIKV infection, the following table provides details:



In few researches, urine samples were also tried to detect the presence of ZIKV by detecting ZIKV RNA by RT-PCR which might be useful because as compared to serum sample, higher titers for longer durations were found in urine sample, although large-sampled cohort studies are yet to be performed to verify these findings.[46]

Treatment

Since it is considered to be self-limiting illness, the treatment modalities focus on symptomatic illness.

Prevention and control of zika virus

The measures are directed toward the following:

Vector control

Knowing that the virus can involve other mosquito species also, directing control measures toward all the vectors per se is important. Many guidelines are released in detail about mosquito control measures by the WHO and CDC.[47]

Vaccines

Although vaccines are available for several other Flaviviruses such as yellow fever virus, Japanese encephalitis virus, and more recently DENV, ZIKV vaccines are yet to develop. Recently, the development of a vaccine "ZIKVAC" was acclaimed by one of the Indian companies Bharat Biotech International in February 2016. The firm is working in the development of two types of vaccine; one is recombinant and another is killed one. Animal trials have been started for both the vaccines, however it is said that it still take 15-18 months to launch the vaccine for use.[48]

Other measures

Other preventive measures include isolation under bed nets during the incubation period, using personal prophylactic measures such as wearing of full-sleeve shirts and full pants, light-colored clothing, use of mosquito repellent creams, and sleep under mosquito nets.

  • Environmental measures include detection and elimination of mosquito breeding places. Moreover, regular emptying, cleaning, or covering water-holding containers to eliminate mosquito breeding places.


In addition, specific recommendations were issued about protection from mosquito bites, such as keeping doors and windows closed or screened, wearing trousers and long-sleeved shirts, and using authorized repellents during pregnancy.[49]

Special precautionary guidelines

For travelers


Advising travelers visiting affected areas to take individual protective measures to prevent mosquito bites all day round.

There are three types of travel notice recommended by the CDC [Table 2].
Table 2: Three types of travel notice as recommended by the Centre for Disease Control


Click here to view


Hence, those who travel to or are planning to travel to ZIKV-infected area are recommended to follow a travel notice (Level 2-Practice Enhanced Precautions).

Pregnancy

Since ZVD is known to cause teratogenic effect with adverse pregnancy outcome, it has been recommended that pregnant women in any trimester should avoid traveling to the ZV-affected area and those who cannot avoid traveling to such places should strictly follow the guidelines to prevent mosquito bites during their journey. ZIKV usually remains in the blood of an infected person for only a few days to a week. If a woman suffering from ZVD conceived after the virus is cleared from her body then infant will not get infected by ZVD. There is currently no evidence that ZIKV infection poses a risk of birth defects in future pregnancies. A women contemplating pregnancy, who has recently recovered from ZIKV infection, should consult her health-care provider after recovery.

Infants with possible congenital ZIKA virus infection[48],[50]

A detailed history of pregnant women traveling or residing in ZV-affected area should be taken. Both pediatrician and the obstetrician should work together to identify such children and monitor them. Testing for the presence of ZV infection is only recommended for infants born with microcephaly or intracranial calcification. Also, additional detailed clinical evaluation and follow-up are recommended. Potential exposure of ZIKV in an infant is confirmed by RT-PCR on infant serum (recommended) or plasma collected from the umbilical cord and serological assays.

The presence of ZIKV has been detected in breast milk, but transmission through mother's milk has not been reported.[33]


  Case Definition for Zika Virus Disease Top
[51]

Suspected case

A person presenting with rash and/or fever and at least one of the following signs or symptoms:

  1. Arthralgia
  2. Arthritis
  3. Conjunctivitis (nonpurulent/hyperemic).


Probable case

A suspected case with:

  1. The presence of IgM antibody against ZIKV
  2. An epidemiological link.


Confirmed case

A person with laboratory confirmation of recent ZIKV infection:

  1. The presence of ZIKV RNA or antigen in serum or other samples (e.g., saliva, tissues, urine, whole blood)
  2. IgM antibody against ZIKV positive and PRNT90 for ZIKV.



  Indian Status Top


India is prone to ZIKV disease transmission as the vectors, mainly A. aegypti, are known to cause infections such as dengue and chikungunya. In addition, birth rate of the country is high so the consequences can be grave as ZIKV affects fetuses, as warned by the WHO. Currently not even a single case that has been reported, has been found positive for ZVD.

Just the day after announcing ZVD as a PHEIC by the WHO, the Government of India had released many guidelines for the prevention of the disease.[52]

Guidelines oriented toward the following issues

  1. Fact sheet for ZVD
  2. Do and don'ts list as follows:
    • For preventing/controlling mosquito breeding, removing all potential sources of water collection, covering tanks and other containers, and using larvivorous fishes in artificial ponds
    • For personal protection, use bed nets and personal protective measures
    • For managing fever, use paracetamol
    • Do not allow water to stagnate in and around houses or in any artificial container.
  3. Travel advisory for ZVD (trade or travel restrictions not recommended yet) instructs guidelines such as canceling/deferring nonessential travel to the affected areas and to use strict personal protective measures to prevent mosquito bites, and in case of febrile illness reporting to the nearest health facility. The National Centre for Disease Control (NCDC), New Delhi would be the nodal agency, and RT-PCR test would remain the standard test. Currently, for laboratory support, only two national laboratories are available, i.e., the NCDC, New Delhi and the National Institute of Virology, Pune, and the government is planning to put six more laboratories to cater to the emergency situations.[53]
  4. Guidelines on ZVD following epidemic in Brazil and other countries of America are as follows:
    1. Enhanced surveillance:
      • Community-based surveillance - integrated disease surveillance program to collect data on clustering of febrile illness and seek primary cases. Moreover, clustering of cases of microcephaly in newborns and GBS in adults.
      • International airports/ports - To display signage and maintain isolation rooms.
      • Rapid response team shall be activated at central and state surveillance units.
      • Laboratory diagnosis with RT-PCR would remain the standard treatment.
    2. Risk communication - Increased awareness and enhanced vigilance.
    3. Vector control - Enhanced integrated vector management.
    4. Travel advisory
    5. Nongovernmental organizations (NGOs)
      • In close interaction with NGOs and other Indian/state, professional bodies, etc., to sensitize clinicians both in government and private sectors about ZVD.
    6. Co-ordination with international agencies
      • Seeking/sharing information with the International Health Regulations' (IHR) focal points of the affected countries and must be in constant touch with the WHO for updates on the evolving epidemic.
    7. Research - Identify the research priorities and take appropriate action.
    8. Monitoring on a regular basis.



  Current Epidemic and Response Top


The WHO on February 1, 2016, declared ZVD as public health emergency on the basis of clustering of cases of microcephaly and neurological disorders, and their possible association with the ZIKV, in accordance with the IHR (2005), based on the presence of evidence of Zika's link to thousands of recent birth defects in Brazil. A global response unit was set up and in the statement the WHO also said "since the vector Aedes mosquito is found abundantly in Africa, parts of southern Europe and many parts of Asia, particularly South Asia." Also, because of high birth rate in Africa and Asia, it could spread to these regions and cause high morbidity.[42],[54]

Recommendations under PHEIC are to call for standardized and enhanced surveillance of microcephaly in the areas of known ZIKV transmission to increase research into the etiology, precautionary measures to prevent arboviral infection, stronger surveillance of ZIKV infection with the rapid development and sharing of diagnostics suitable for seroprevalence studies; improved communication about the risks of outbreaks of Zika and other arboviruses; guidance to be available to pregnant women.

The prioritized tools to fight the ZIKV spread in near future are as follows:[55]

  • Traditional tests along with multiplex tests for " Flavivirus".
  • Killed vaccine preparations for reproductive age women.
  • Vector-controlling innovative methods to control mosquitos' population.



  Conclusion Top


Although the causal relationship between ZIKV infection and the various neurological manifestations has not been established till now, still based on the facts available, there is an urgent need to strengthen surveillance for this emerging virus and for pending epidemics.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Abstract
Introduction
TIMELINE: Histor...
Epidemiological ...
Mode of Transmission
Pathogenesis and...
Guillain-Barr...
Virus Isolation ...
Case Definition ...
Indian Status
Current Epidemic...
Conclusion
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