The Epidemiology， Clinical Characteristic，Transmission Potential and Control Measures of Zika Virus Infection

ALOTAIBIABDULLAHSAUDM　ALANAZIMANSOURRASHEDM　AHMADMEESAQ

【中圖分类号】R758 【文献标识码】A 【文章编号】2095-6851（2017）11-0-01

Introduction

Zika virus （ZIKV） is a single-stranded RNA virus， anarthropod-borne Flavivirus distributed throughout much ofAfrica and Asia.The virus is transmitted by Aedesmosquitoes and potentially by transfusion， perinatal and sexual transmission. The potential for spread into countries where Aedesmosquitoes are endemic is high. Concern hasbeen heightened further in the face of upcoming mass gatherings in regions where the virus iscurrently endemic， such as the Umrah and Haji pilgrimagesin Saudi Arabia， where local mosquito populations represent the potential for new outbreaks1. The current lackof specific treatments or vaccines and complications in diagnosis of ZIKV further underscorethe urgency of developing a global approach toresearching this virus.

International interest in the Zika virus （ZIKV） hasbeen sparked by the current outbreak in Braziland other countries in the Americas， which led thePan American Health Organization to issue an alertfor northeast Brazil on 7 May 2015. The World Health Organization （WHO） strongly suspects that the concomitance of a sharp increaseof microcephaly and/or GBS incidence in sevencountries in the Americas and the ZIKV out-break indicates a relationship. This possibilityhas led them to declare a Public Health Emergency of International Concern on February 1，20162.

History and Epidemiology

Zika virus was first isolated from afebrile sentinel monkey in the Zika forest in Ugandain1947 and subsequently from Aedes africanusmosquitoes in the same forest3. Isolationof ZIKV from Aedes africanus mosquitoes and otherAedes species including Aedes aegypti in Africa andMalaysia.Many other Aedes species， including Aedes luteocephalus， Aedes albopictus， Aedes furcifer， Aedes vittatus，Aedes taylori， Aedes dalzieli， Aedes hirsutus， Aedes. metallICUs， Aedes hensilii and Aedes unilineatus 3.

Since 1947， when Zika virus was first isolated in Uganda， it was confined for the

first60 years to an equatorial zone across Africa and Asia.However， it was not until

2007 that the virus was recognized as a clinically important pathogen capable of causing disease epidemics . The 2007 outbreak， on Yap Island in Micronesia， was the world's first major outbreak of Zika virus disease in humans. No hospitalization or deaths were reported during this outbreak， and the clinical features observed were similar to those described in earlier case reports： mild fever， malaise， headache， arthralgia and rash.During 2013 and 2014， the second and major ZIKV outbreak was reported in French Polynesia， the febrile cohort of Zika was estimated at 28，000 .endprint

Affected Countries by Recent Outbreak

AS of May 2015， ZIKV has spread to at least 20 countries in the Americas. As of July 2016， ZIKV has been reported in 65 countries whereas microcephaly and other neural defects have been documented in 13 countries.There was increase in incidence of Guillain-Barré syndrome have confirmed in 15 countries. ZIKV was reported in Brazil， Caribbean， several Central and South American states by May 2015. About 30 000 cases of ZIKV infection were confirmed in Brazil by 30 January， 2016. A recently published study reported 1 474 cases of the Guillain-Barré syndrome and 164 237 confirmed and suspected cases of ZIKV disease from Bahia， Venezuela， Brazil， the Dominican Republic， Honduras， Colombia， and Suriname during April 1， 2015， to March 31， 2016 4. Recent report by Defense Armed Forces Health Surveillance Branch released on 25th January confirmed 198 346 cases of ZIKV and 2 569 cases of microcephaly during January 2015 to January 2017 in Western Hemisphere countries .

VIROLOGIC CHARACTERISTICS

ZIKV has single-stranded positive-sense RNA genome about 10.7 kb in length enclosed in a capsid and surrounded by a membrane. Single polypeptide that is encoded by the genome of Zika virus experience post translational chopping done by viral and host proteases leading to formation of seven non-structural proteins that are NS1， NS2A， NS2B， NS3， NS4A NS4B， NS5 along with three structural proteins such as envelope （E）， pre-membrane （prM）， and capsid （C）.

On the based nucleotide sequences，there are three lineages of ZIKV according to NS5 gene：（1） East African （one strain examined），（2） Asian （one strain examined），（3） and West African （three strains examined）. While based on phylogenetic analysis of entire genomes， two genetic lineages exist for ZIKV that corresponds to Asian and African geographical areas. African strains are further categorized into two groups： （1） Nigerian cluster MR766 prototype cluster （isolated in Uganda） whereas， （2）Asian clade is also classified into two groups Malaysian and Micronesian strains.

Transmission Dynamics of ZIKV

There are many routs for the transmission of the Zika virus to human， such as

1-Vector Transmission

ZIKV is an arthropod-borne virus （arbovirus） that is transmitted bymosquito vectors， with two distinct transmission cycles： （i） a sylvatic cycle，involved in themaintenance of ZIKV betweennon-human primates and arboreal mosquitoes in forests； and （ii） anurban cycle， involved in the transmission of ZIKV between humansand urban mosquitoes in towns .endprint

In an urban cycle， the transmission of ZIKV is believed to be mediatedpredominantly by two Aedes species mosquitoes： Aedes. aegypti， recognizedby a bright lyre-shaped dorsal pattern with white bands on itslegs， and Aedes. albopictus， characterized by a single longitudinal dorsalstripewithwhite bands on its legs.Both Aedes aegypti and Aedes albopictus are usually active during daylighthours andare widelydistributed throughout the tropical and subtropical regionsof the world. But Aedes albopictus also present incool temperate regions.

2-Transmission Through Blood

Blood-borne transmission of Zika virus has been reported，about 2%–8% blood donors were tested positive for ZIKV during French Polynesia outbreak.In Brazil，two more cases of ZIKV were reported by the transfusion of blood .AABB （American Association of Blood Banks） has declared ZIKV as high risk agent and introduced precautionary measures such as NAT （nucleic acid test） or pathogen inactivation of blood products to control transfusion-transmitted ZIKV. Blood safety authorities have been alerted regarding The post-transfusion Zika fever was reported in 42 out of 1505 in recipient from blood donors positive for ZIKV by PCR 5.

3-Transmission Through Breast Milk

ZIKV has been detected in breast milk of three lactating mothers and two of three newborns showed symptoms of ZIKV. More evidence is still needed to support this conclusion of transmission of ZIKV through breast milk and other perinatal transmission routes6.

4-Transmission Trough Saliva

ZIKV has been isolated from the salivary sample of person by cell-culture with febrile illness who had returned from Dominican Republic to Italy on January 2016. About 29 days after the onset of symptoms， viral load was found to be higher in saliva and urine than in blood . During the largest ZIKV outbreak of French Polynesia that occurred from October 2013 to March 2014， 1067 salivary and blood samples （only blood， only saliva or both samples together） were collected from 855 patients and were tested for ZIKV using RT-PCR. Results showed that ZIKV was more frequently confirmed in saliva samples than blood samples. For 182 individuals with both samples collected， tests were positive for 16 （8.8%） in blood while negative in saliva whereas tests were positive for 35 （19.2%） in saliva while negative in blood.

5-Transmission Through Urine

The presence of Zika virus in urine is supported by many evidences of the research.During the acute phase of Zika virus infection， five saliva samples and nine urine samples were collected from nine patients and tested by RT-PCR， RT-qPCR， and NAT-Zika in Rio de Janeiro. ZIKV was isolated one from saliva and one from urine sample. Viral load was found to be higher in urine samples than saliva samples.endprint

6-Sexual Transmission

There are several evidences that show sexual transmission of ZIKV is possible. In outbreak of French Polynesia that occurred in December 2013， high ZIKV RNA load was confirmed in semen of patient 7.The New York City （NYC） Department of Health and Mental Hygiene （DOHMH） was reported that the transmission of ZIKV from female to male is possible because a women returened from ZIKV epidemic area and rRT-PCR of woman， was positive for ZKIV. During the condom-less intercourse ZIKV transferred to male.

7-Vertical Transmission

There are lot of evidences that provide basis of vertical transmission of ZIKV and its association with fetal brain development. During French Polynesia epidemic in 2013， two cases of ZIKV have been documented and in Brazil outbreak in 2015， pregnant women found to deliver babies with congenital teratogenic disorders specially microcephaly

ZIKV was confirmed in Brazilian woman during 8th week of pregnancy and also detected in amniotic fluid during 17th week of pregnancy in Spain.

Pathogenesis

There is insufficient data available to understand the pathogenesis of ZIKA virus. The

AXL， DC-SIGN， TIM-1 and Tyro entry/adhesion factors allow the entry of ZIKA virus.After the eatery， immature dendritic cells， epidermal keratinocytes， and human dermal fibroblasts have been found to be permissive to ZIKV infection. TheReplication of ZIKV triggers an antiviral immune response and produce type I interferon in infected cells8. During the acute phase of ZIKA infection， T cells such as （Th1， Th2， Th9， and Th17） are activated.

According to one study，there is infection in radial glial cells of dorsal ventrICUlar zone in response to intraperitonial injection of ZIKV strain in pregnant mice. Therefore， significant reduction of cortex founder cells in neonates was observed after vertical transmission of Zika virus which leading to brain anomalies in fetus . Brazilian ZIKV （ZIKVBR） strain has been shown to cause birth defects such as intrauterine growth restriction and microcephaly. ZIKVBR cross the placenta， target cortical progenitor cells， induce cell death and impair neurodevelopment . ZIKV promotes cells death by inhibiting cell-cycle progression and cause death of human cortical progenitor cells （hCNPCs） .

Clinical Manifestations of Zika Virus Disease

Incubation Period

Incubation duration is usually between （3–12） days.Approximately 25% of infected patients develop symptoms （2–10） days after illness9.endprint

Signs and Symptoms

Symptoms associated with ZIKV infection arevariable. It is asymptomatic in up to 80% ofcases， and when symptoms do occur，they are typically mild and non-specific.The symptoms typically occur approximately2 to 12 days after the mosquito bite， presenting mostcommonly with fever， maculopapular rash， conjunctivitis， andjoint pain， and the clinical illness lasts for several days to aweek. Other symptoms include muscle pain and headache， butabdominal pain， nausea， diarrhea， mucus membrane ulceration，and pruritus are rarely observed10.According to Pan America Health Organization （PAHO）， commonly reported clinical symptoms in ZIKV infected individuals of America are exanthema （skin rash） and mild fever often accompanied by joint or muscle pain as well as conjunctivitis whereas， autoimmune and neurological complications.The Zika infection is more serious as it is associated with two neurological conditions：

1-Microcephaly

About 4 000 cases of microcephaly were reported in Brazil with ZIKV infection and this incidence is 20-fold more than 2010 to 2014. Microcephaly has been considered as an irreversible and most serious neurological complications caused by ZIKA virus. According to evidences of study， the virus has been found in the placenta and amniotic fluid of mothers and in the brains of newborns. The first domestic case of microcephaly in fetus was observed in Hawaii on January 15， 2016， whose mother had lived in Brazil. After that many other cases of microcephaly in new born were reported in Texas， Illinois， and Florida in women who were back from international tour 11.

2-Guillain-Barre Syndrome

Guillain-Barre syndrome is an autoimmune disease inwhich the immunesystemattacks the peripheral nervous system， causing tingling，muscle weakness， paralysis， and even death. Previously， this neuromuscular complicationhad been associated with infection by other arboviruses，such as DENV and chikungunya virus .The temporal and geographic association ofZIKV with Guillain-Barre syndrome was initially observed during the2013–2014 outbreak reported in French Polynesia andsubsequently during the2015–2016 outbreak in the Americas. During the previousFrench Polynesia outbreak， the incidence of Guillain-Barre syndromewas estimated to be ～20-fold higher than its basal incidence of 1–2cases per 100，000 population per year .

Laboratory Diagnosis of Zika Virus

There is no widely available test for Zika infection. In most people， diagnosis is based on clinical symptoms and epidemiological circumstances （such as Zika outbreak in the patients area or trips to areas where the virus is circulating）. Diagnostic tests for ZIKV infection include ：endprint

1-Polymerase Chain Reaction

Nucleic acid detection by reverse transcript-polymerase chain reaction （RT-PCR） targeting the non-structural protein 5 genomic region is the primary means of diagnosis. It is useful in the first 3-5 days after the onset of symptoms.

2-Serological Test

An ELISA has been developed to detect IgM to ZIKV only after five days. Because it is closely related to dengue and yellow fever， it may cross-react with antibody tests for those viruses.

3-Neuclic Acid Amplification Test

Nucleic acid amplification test （NAT） for detection of viral RNA can also be performed.

4-Plaque Reduction Neutralization Test

The Plaque reduction neutralization assay generally has improved specificity over immunoassays， but may still yield cross-reactive results in secondary Flavivirus infections.

Management of Zika Virus Disease

There is presently no vaccine and no specific antiviraltreatment for ZIKV infection. Treatment is often supportive，and symptoms can be generally treated with fluids， rest andoral analgesics and antipyretics （e.g.， acetaminophen） for feverand pain relief， while aspirin and others non-steroidalanti-inflammatory drugs （NSAIDs） should be used only whendengue has been ruled out because of the risk of bleeding.However， NSAIDs are not typically used during pregnancy12.

Control Measures for the Prevention of ZIKV

1-Elimination and control of Mosquitoes

Avoid allowing standing water in outdoor containers so that they do not become mosquito breeding sites， avoid accumulating garbage， use mosquito nets in windows and doors.

2-Prevention of Mosquito Bite

During the first week of ZIKV infection， the infected patientshould avoid further mosquito bite because the ZIKV canbe found in the blood and pass from an infected person to amosquito. Consequently， an infected mosquito can then spreadthe virus to another person. Preventing further mosquito bitecan be accomplished by using insect repellent， wearing longsleevedshirts and long pants， and treating clothing with

permethrin. However， insect repellent should not be used onbabies younger than 2 months of age.

3-Public Awareness about Zika virus and Mosquitoes

Peoples should be made aware about the disease and its preventive measures. They should take the basic precautions to protect themselves from the disease.

References

1.Elachola H， Gozzer E， Zhuo J， Memish ZA. A crucial time for public healthpreparedness： Zika virusand the 2016 Olympics， Umrah， and Hajj.Lancet2016；387（10019）：630—2.endprint

2.Musso D， Nhan T， Robin E， Roche C， Bierlaire D， Zisou K，et al. Potential for Zika virus transmission through bloodtransfusion demonstrated during an outbreak in FrenchPolynesia， November 2013 to February 2014. EuroSurveill2014；19（14）：20761.

3.Dick GW， Kitchen SW， Haddow AJ. Zika virus. I. Isolat-ions and serological specificity. Trans R Soc Trop Med Hyg1952；46（5）：509—20.

4.T. Dos Santos， A. Rodriguez， M. Almiron， A. Sanhueza， P. Ramon， W.K. de Oliveira， et al.Zika virus and the Guillain-Barré syndrome-case series from seven countriesNew Engl J Med， 375 （16） （2016）， pp. 1598–1601

5.D. Musso， T. Nhan， E. Robin， C. Roche， D. Bierlaire， K. Zisou， et al.Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia， November 2013 to February 2014.Euro Surveill， 19 （14） （2014）， p. 2076.

6.S. Colt， M.N. Garcia-Casal， J. Pena-Rosas， J.L. Finkelstein， P. Rayco-Solon， Z.W. Prinzo， et al.Transmission of Zika virus through breast milk and otherbreastfeeding-related bodily-fluids： A systematic review. PLoS Negl Trop Dis， 11 （4） （2017）， p. e0005528.

7.D. Musso， C. Roche， E. Robin， T. Nhan， A. Teissier， V.M. Cao-LormeauPotential sexual transmission of Zika virus.Emerg Infect Dis， 21 （2） （2015）， pp. 359–361.

8.R. Hamel， O. Dejarnac， S. Wichit， P. Ekchariyawat， A. Neyret， N. Luplertlop， et al.Biology of Zika virus infection in human skin cells.J Virol， 89 （17） （2015）， pp. 8880–8896.

9.C. Zanluca， V.C.A. de Melo， A.L.P. Mosimann， G.I.V. dos Santos， C.N.D. dos Santos， K. LuzFirst report of autochthonous transmission of Zika virus inBrazil. Mem Inst Oswaldo Cruz， 110 （4） （2015）， pp. 569–572.

10.Ministry of Health New Zealand. Zika virus. Last updated： February 12，2016. Ministry of Health NZ Website. http：//www.health.govt.nz/yourhealth/conditions-and-treatments/diseases-and-illnesses/zika-virus

11.D.R. Lucey， L.O. GostinThe emerging Zika pandemic： enhancing preparednessJama， 315 （9） （2016）， pp. 865–866.

12.Petersen EE， Staples Erin， Meaney-Delman D， et al. Update： interim guidelines for pregnant womenduring a Zika virus outbreakdUnited States， 2016. MMWR Morb MortalWkly Rep 2016；65：30e3.endprint