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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 25  |  Issue : 2  |  Page : 67-72

Pathogenesis, diagnostic challenges and treatment of zika virus disease in resource-limited settings


1 Department of Medicine, Jos University Teaching Hospital, Jos, Nigeria
2 Department of Paediatrics, Jos University Teaching Hospital, Jos, Nigeria
3 Department of Medical Microbiology, Jos University Teaching Hospital, Jos, Nigeria
4 Department of Obstetrics and Gynaecology, Jos University Teaching Hospital, Jos, Nigeria

Date of Web Publication19-Jul-2018

Correspondence Address:
Nathan Yakubu Shehu
Department of Medicine, Jos University Teaching Hospital, Jos
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/npmj.npmj_36_18

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  Abstract 

The association of Zika virus (ZIKV) infection with congenital malformation and neurological sequelae has brought significant global concern. Consequently, the World Health Organization (WHO) declared it “a public health emergency of International concern” on 1 February, 2016. A critical review of its pathogenesis would lead to a better understanding of the clinical features and the neurological complications. This review is based on literature search in PubMed/Medline, Google Scholar and the WHO, http://www.who.int. This include all relevant articles written in English published through June 2018, with subject heading and keywords such as Zika, ZIKV, Zika pathogenesis, diagnosis of Zika, Zika Nigeria, Zika Africa and Zika resource-limited settings. Following ZIKV infection, viraemia ensues targeting primarily the monocytes for both the Asian and African strains. ZIKV infection by an African strain appears to be more pathogenic, in early pregnancy tends to result in spontaneous abortion. Whereas an Asian strain tends to be less pathogenic and more chronic, this allows the pregnancy to continue, ultimately resulting in congenital malformations. There is no routine laboratory diagnosis of ZIKV infection in resource-constrained countries. Serologic tests should be interpreted with caution since there can be cross-reactivity with other flaviviruses, especially in Africa where the burden of infection with flaviviruses is comparatively high. There is a paucity of well-equipped laboratories for comprehensive ZIKV diagnosis. It is imperative to strengthen the health systems, improve health workforce and diagnostic capacity of such settings.

Keywords: Africa, diagnosis, pathogenesis, Zika


How to cite this article:
Shehu NY, Shwe D, Onyedibe KI, Pam VC, Abok I, Isa SE, Egah DZ. Pathogenesis, diagnostic challenges and treatment of zika virus disease in resource-limited settings. Niger Postgrad Med J 2018;25:67-72

How to cite this URL:
Shehu NY, Shwe D, Onyedibe KI, Pam VC, Abok I, Isa SE, Egah DZ. Pathogenesis, diagnostic challenges and treatment of zika virus disease in resource-limited settings. Niger Postgrad Med J [serial online] 2018 [cited 2018 Dec 14];25:67-72. Available from: http://www.npmj.org/text.asp?2018/25/2/67/237086


  Introduction Top


Zika virus disease (ZVD) has recently generated significant concern globally. The recent outbreaks have become a major challenge due to a change from its earlier known spectrum of clinical features to the neurologic complications that are now seen.[1] Zika virus (ZIKV) was first isolated by Dick, Kitchen and Haddow in 1947 in albino mice using blood of rhesus monkey found in Zika forest of Uganda. It is transmitted by the Aede s species of mosquito.[2],[3] In 1952, human infection was demonstrated by the presence of neutralising antibody, and in 1964, the virus was isolated from humans in Uganda.[4],[5] Subsequently, until early 2007, Zika spread remained confined to Africa and Asia.[6],[7],[8] ZIKV infection in Nigeria was first reported in 1954.[9] Sero-epidemiologic studies done between 1971 and 1975 in Oyo State, Nigeria showed 31% Zika prevalence. In 2016, Zika seroepidemiologic study in North Central Nigeria found the anti-ZIKV positive rate of 6% for immunoglobulin M (IgM) and 4% for Immunoglobulin G (IgG).[10] In April 2007, there was a report of Zika outbreak outside Africa and Asia, in Yap Island of Micronesia.[11] In addition, Zika outbreaks were also reported from New Caledonia, French Polynesia, Easter Island and the Cook Islands in 2013 and 2014.[12] Furthermore, the outbreak was reported in South and Central America in 2014 and in Mexico in 2015.[13] Zika outbreak was eventually reported in Texas, the United States of America and Europe.[14] Brazilian health authorities reported 2400 suspected cases of Zika associated microcephaly and 29 mortalities.[15],[16],[17] Consequently, the World Health Organization (WHO) declared it “a public health emergency of International concern” on 1 February, 2016.[18]

The challenge of ZVD diagnosis in resource-constrained settings, especially in Africa is enormous. ZIKV presents with a mild acute febrile illness similar to several common acute febrile illnesses in the tropics. ZVD diagnosis with a reverse transcription polymerase chain reaction (RT-PCR) must be interpreted with caution based on the sample used and interval of symptoms onset and date of specimen collection. Bingham et al. found that only 56% of Zika RT-PCR was isolated from serum samples within 5 days of symptoms onset compared to 95% of urine samples collected on the same date.[19] Therefore, negative PCR does not rule out Zika infection. In addition, serological tests for virus specific IgM and neutralising antibodies may cross react with other flaviviruses.[19] Some of these flaviviruses such as dengue and yellow fever are also relatively common in Nigeria.[20],[21],[22],[23]


  Methodology Top


This literature review was carried out between May 2016 and June 2018 using electronic databases, including Google Scholar, PubMed/Medline, and the WHO, http://www.who.int. We searched and analysed all relevant articles written in English published through June 2018, with the following subject heading and keywords: 'Zika', 'Zika virus', 'Zika pathogenesis', 'Diagnosis of Zika', 'Zika Nigeria', 'Zika Africa', 'Zika resource-limited settings'.


  Pathogenesis Top


ZIKV is an enveloped, icosahedral, non-segmented, positive sense, single-stranded RNA virus.[24] It is 40 nm in diameter with an outer envelope (E) and a dense inner core. Its genome consists of a single-stranded positive-sense RNA molecule with 10794 kb of length with 2 flanking non-coding regions (5′ and 3′ NCR) and a single long open reading frame encoding a polyprotein: 5′-C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-3′, that is cleaved into capsid (C), precursor of membrane (prM), envelope and seven non-structural proteins (NS).[25] The envelop glycoprotein is the major antigenic determinant of ZIKV.[26] Zika belongs to the family flaviviridae and phylogenetic analysis has shown that it has three lineages: West African (Nigerian cluster), East African and Asian.[27] In 2016, partial ZIKV E gene sequence was done from a ZIKV RT-PCR-positive individual in North-central Nigeria (GenBank accession number MF926508/Nigeria/2016), this is the fifth ZIKV reported sequence data from Africa till date.[10] Phylogenetic analysis revealed that it belonged to the West African lineage.[10] ZIKV can be transmitted through two principal means: Vector to human and human-to-human. Vector transmission is by Aedes spp. mosquitoes and virus transmission outside Africa is exclusively via Aedes aegypti.[6] However, in Africa ZIKV has been isolated in Aedes africanus, Aedes aegypti, Aedes albopictus, Aedes apicoargenteus, Aedes luteocephalus, Aedes vitattus, Aedes taylori, Aedes dalzieli, Aedes hirsutus, Aedes metallicus, Aedes unilinaetus, Aedes opok and Aedes furcifer.[28] Furthermore, the virus has been detected in Mansonia uniformis, Culex perfuscus and Anopheles coustani mosquitoe.[29]

ZIKV replicates in the epithelial lining of midgut and salivary cells of the mosquito vector. After a variable period of about 5 days, it appears in the mosquito saliva which is now infectious. During blood meal, the vector inoculates the virus into human host skin. The virus may then infect the epidermal keratinocytes, the fibroblast and the Langerhans cells.[9],[30],[31] Subsequently, viraemia ensues and the primary target for of ZIKV is monocytes for both the Asian and African strains.[32] Monocytes have the potential to infiltrate immune sanctuary sites such as the brain, testes and placenta.[33] The immunological profile of ZIKV infection with the African lineage has a classical/intermediate monocyte mediated M1-skewed inflammation, whereas the Asian lineage has non-classical M2-mediated immunosuppression. Following viral transmission, viral attachment to the host cellular receptors is facilitated by E glycoprotein. This is followed by endocytic uptake, uncoating of the nucleocapsid and viral RNA are eventually released into the cytoplasm.[34] In stark contrast to other flaviruses, its antigen has been demonstrated in host cell nucleus.[35] This may explain the spectrum of developmental complications associated with Zika.

Human to human transmission of ZIKV can occur perinatally through the following mechanisms: Via transplacental route, leakage of the virus through the trophophlastic plug, diffusion of the virus into the amniotic sac during formation, or during delivery by an infected mother to her newborn.[36],[37] In addition, human-to-human transmission has been reported through sexual means and there was also a report of transmission through blood transfusion in Brazil.[38],[39] Sexual transmission occurs when a person has acute Zika infection, this is particularly important when the exposed partner is pregnant because of the possible neurological consequences on the foetus. ZIKV is neurotropic; it crosses the blood-brain barrier of the foetus and attaches to the neuronal cells of the brain. The viral RNA integrates its genome into neuronal cells, causing apoptosis and ultimately leads to interference with neuronal development, neuronal proliferation and migration.[6] Second, placental infection by ZIKV causes placental insufficiency and might contribute to growth restriction and microcephaly.[6] A recent hypothesis assumes that the pathogenesis of microcephaly might be related to Zika-induced liver injury which causes accumulation of metabolites such as Vitamin A. Vitamin A toxicity is also known to cause microcephaly and other adverse neuronal outcome.[40]

The neuropathology of ZIKV infection has been clearly demonstrated in the Asian strain. However, microcephaly has not been demonstrated following the African Zika strain infection. Interestingly,in vitro studies have confirmed the higher virulence of the African strain with higher viral replication and cell lysis in both neuronal and non-neuronal cells.[41] More than 30 laboratory-based studies have suggested that the African strains of Zika are capable of causing the same, or worse, damage to cells in the central nervous system (CNS), and reproductive and immune systems as the Asian strains circulating in the Americas.[42] It could be that Zika infection by an African strain in early pregnancy leads to spontaneous abortion, while infection with an Asian strain would be less destructive and more chronic, hence allowing the pregnancy to continue. This ultimately results in congenital malformations.[43] The immune response to ZIKV infection is similar to other flaviviruses; IgM develops within a few days of onset of infection and may remain detectable for about 3 months.[44] IgG develops afterwards and remains in the circulation for years.[45]


  Clinical Features Top


About 80% of ZIKV infection are asymptomatic.[46] Symptomatic infections are characterised by a self-limiting febrile illness which usually lasts 4–7 days and is associated with maculopapular rash, arthralgia, especially affecting the small joints of the hands and feet, conjunctivitis, back pain and mild headaches. Within 2 days, the skin rash begins to fade spontaneously and within 3 days, fever starts to resolve and only few rash persists.[6] Other less common clinical features include nausea, diarrhoea, abdominal pain, ulcerations of mucous membranes, uveitis and palatal petechiae.[7],[8],[47]

Severe ZVD may be seen following in utero infection leading to neurological complications, notably microcephaly and Gullian-Barre syndrome (GBS). Meta-analysis showed that prevalence of ZIKV-associated GBS and microcephaly among all pregnancies were 1.23% (95% confidence interval [CI] = 1.17%–1.29%) and 2.3% (95% CI = 1.0%–5.3%), respectively.[48],[49] Other neurological manifestation seen include craniofacial disproportion, spasticity, seizures, irritability and brainstem dysfunction, feeding difficulties and ocular abnormalities.[50] Neonates with ZVD usually have intrauterine growth restriction; other features may include a transient diffuse rash, conjunctivitis and conjunctival injection. Ocular abnormalities such as focal pigment mottling, chorioretinal macular atrophy, optic nerve abnormalities, cataract, intra-ocular calcifications, microphthalmia, conjunctival injections, optic disc cupping, lens subluxation in addition to bilateral iris coloboma, foveal reflex loss, macular hypoplasia and scarring.[51]

Several foetal neuronal abnormalities have been demonstrated when ultrasound was done at 29 weeks gestation; this include brain atrophy, large cysterna magna, severe unilateral ventricular enlargement, corpus callosum and vermian dysgenesis, absence or redumentary thalamus, thin brainstem and pons calcifications involving frontal lobes white matter, caudate, lenticulostriatal vesssels and cerebellum.[12],[13] Neuroimaging (computed tomography and magnetic reasoning imaging) features commonly reported in newborns include enlarged cisterna magna, hypogenesis of corpus callosum, ventriculomegaly, delayed myelination, cerebellar and brainstem hypoplasia, calcifications in the junction between cortical and subcortical white matter and cortical malformations like polymicrogyria in the frontal lobes. Interestingly, abnormality of frontal lobe has not been reported in other congenital infections.[14]

Congenital Zika syndrome (CZS) refers to the range of abnormalities seen in neonates following Zika infection in pregnancy.[52] This include visual, hearing and other neurological abnormalities (including neuroimaging findings).[53] Complete cranial growth may be attained at 30 weeks,[54] Therefore, ZIKV infection in late pregnancy may not affect head size. The sensitivity of microcephaly in detecting probable or definite ZIKV infection is 83% (95% CI = 79–86). It has thus been suggested that microcephaly should not be a necessary criterion for diagnosis of CZS.[52] The Centres for Disease Control and prevention, the USA has described five features to define CZS which include: severe microcephaly with partially collapsed skull; specific pattern of brain damage including subcortical calcifications and decreased brain tissue; damage to the back of the eye, including macular scarring and focal pigmentary mottling of the retina; congenital contractures such as club foot or arthrogryposis and hypotonia which restricts foetal body movement soon after birth.[55] Routinely characterising this syndrome may be a challenge in resource constraint settings, with paucity of high cadre health workforce. Therefore, it is needful to develop a simple algorithm that low cadre health worker can readily identify. This is further compounded by challenge of confirming maternal Zika infection. Birth defects surveillance program in Atlanta for 2014 and North Carolina and Massachusetts in 2013–2014 found 2.86/1000 live births with one or more defects that met the 2016 CDC case definition for Zika surveillance.[56] 52% of the birth defects were brain defects or microcephaly, other defects include neural tube defects and other early brain abnormalities (31%); eye defects (11%); sequelae of CNS dysfunction (0.6%). There were 48% pregnancy losses and 66% preterm delivery (<37 weeks' gestation).[56] Between 2015 and 2018, in Brazil, there were 2952 CZS in a population of Population of 209,553,000.[57] This gives a CZS population prevalence of 0.001. On the African continent data are scarce regarding CZS. However, the scarce data does not definitively proof the absence of CZS.[42]


  Laboratory Diagnosis Top


The largely asymptomatic or mildly symptomatic nature of ZIKV infection makes laboratory testing important for diagnosis. Serologic test results should be interpreted with caution since there can be cross-reactivity with other flaviviruses, including in individuals who have been vaccinated against yellow fever or Japanese encephalitis.[58] Infections with flaviviruses such as Yellow fever and Dengue fever are common in Africa as well as vaccination against yellow fever which makes cross-reactivity a critical challenge in the interpretation of test results in these settings. Current algorithms proposes a combination of IgM tests followed by plaque-reduction neutralisation tests (PRNTs) in cases of positive or equivocal results for definite diagnosis.[45] If ZIKV IgM tests results are positive, equivocal or inconclusive, testing for neutralisation antibodies using PRNT should be performed to determine whether the ZIKV IgM reflects recent ZIKV infection or a false-positive result. A PRNT titre >10 should be interpreted as evidence of recent infection with ZIKV when the PRNT to the other flaviviruses tested is <10.[45]

The gold standard of ZIKV infection diagnosis is based on viral RNA detection from clinical specimens. Direct virus detection is only possible during the first 3–5 days after onset of symptoms.[59],[60] Saliva and urine specimens for viral genome detection by RT-PCR might be the best diagnostic specimen. Bingham et al. found that only 56% of Zika antigens were isolated from serum samples within 5 days of the onset of symptoms compared to 95% of urine samples collected on the same day.[19] It is important to use PCR assays that target both the Asian and African ZIKV lineages which target the conserved regions of the envelope gene or NS5 region.[61] This is to avoid false-negative results. It is also important to note that real-time reverse transcriptase polymerase chain reaction (rRT-PCR) negative results does not rule out Zika infection due to decay in viraemia over time and inaccuracy in reporting onset of Zika symptoms.[45] This challenge of clearly determining onset of Zika symptoms is particularly challenging in Nigeria and other settings that are resource constrained, where several tropical diseases may present with fever. It has been proposed that pan-flavivirus assays and sequencing analysis can be used as a surrogate for possible ZIKV infection.[62],[63] However, in settings with high flaviviral infections like Nigeria; this may be fraught with high false-positive making its clinical utility suboptimal. This is because ZIKV IgM enzyme-linked immunosorbent assay can provide false-positive results because of cross-reacting IgM antibodies against related flaviviruses or non-specific reactivity.[45] Dengue infection serology in some parts of Nigeria is between 2.3% and 44.4%.[20],[21] In 1986, there were 9800 cases of yellow fever with 5600 deaths in Oju, Benue state, Nigeria. Moreover recently, between 12 September 2017 and 21 February 2018, there were 87 confirmed yellow fever cases in seven States of Nigeria (Kwara, Kogi, Kano, Zamfara, Kebbi, Nasarawa and Niger).[22],[23] There is no routine laboratory diagnosis of Zika in Nigeria like in other resource constraint countries. In these countries, health systems are weak because of inadequate funding. There is a paucity of well-equipped laboratories for comprehensive ZIKV diagnosis. In addition, the out of pocket payments for health services in developing countries such as Nigeria is high,[64] making health workers to prioritise treatment over testing. It is imperative to strengthen the health systems, improve health workforce and diagnostic capacity of such settings.


  Treatment and Prevention Top


At the moment, no preventive medicines or vaccines are available. Since Zika presents asymptomatically or with mild symptoms, symptoms may be controlled with bed rest, intravenous fluids and acetaminophen.[65] The major challenge of Zika is the complication of infection, effort should be placed on antiviral agents, vaccines and other preventive measures. About 30 FDA approved antiviral agents have been evaluated and were found to have significant anti-Zika viral activity.[66] However, the antiviral effects were largely determined using the Asian strains. It is therefore important to determine this antiviral activity against African strains.

The general preventive measures include preventing mosquito bites and preventing sexual transmission. Measures of preventing mosquito bites include: wearing long sleeve shirts and long dresses, permethrin-impregnated clothes, indoor residual spraying of insecticide, screening of doors and windows against mosquitoes and other environmental control measures aimed at reducing or eliminating the breeding of mosquitoes.[65] Prevention of sexual transmission is particularly important when the sexual partner is pregnant. Sexual transmission can be prevented through abstinence or by using condom. Due to blood transfusion-related transmission, it is needful to provide affordable cost effective safe blood transfusion services in resource-constrained settings. This would include pre-donation screening to rule out possible Zika infection and cost-effective Zika serological test with high sensitivity. This is especially important in pregnant women requiring blood transfusion. There are several candidate vaccines at various developmental stages, some are live attenuated, inactivated and others are genetically engineered vaccine constructs. Among these vaccines, there is one that targets both Dengue and ZIKV.[67] It will be more helpful to develop multi-flavivirus vaccine that can be used in resource-limited settings with high and multiple flavivirus infections.


  Conclusion Top


ZIKV has caused global concern, especially because of its associated congenital malformations and neurological sequelae. It is pertinent to fully understand the pathogenesis of Zika including the African strain. The largely asymptomatic nature of the infection and lack of routine viral diagnostic facilities makes the establishment of true extent of infection a challenge while its largely asymptomatic course also means testing may not be a priority for health-care providers. However, because of the potentially serious consequence of infection and the need to differentiate ZVD from other tropical infections, development of cheap and easy to use tests should be pursued. As it stands, very few laboratories in resource-limited settings like Nigeria have the resources, equipment and workforce capacities to carry out rRT-PCR detection of Zika infections. Strong collaborations with well-equipped laboratories in developed countries should be accessed for confirmatory diagnosis of Zika infections while gradual capacity building should be encouraged in resource-limited settings. In addition, low cost highly specific Zika testing methods needed to be developed for use in resource-limited settings. Regular active surveillance of Zika is really needful in Africa to determine the burden and spectrum of the disease.

Acknowledgement

We are grateful to all members of the Zika research project: Prof. Marcus Panning, Prof. Stephen Oguche, Dr. Christopher Yilgwan, Dr. Simji S. Gomerep, Dr. Emmanuel T. Obishakin, Dr. Mark Okolo, Dr. Salamatu S. Machunga-Mambula, Dr. Dung D. Pam, Dr. Caleb J. Attah and Ewa J. Olugbo.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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