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Zika Virus-associated Ocular and Neurologic Disorders

The Emergence of New Evidence

Şahiner, Fatih*; Siğ, Ali Korhan MD*; Savaşçi, Ümit†; Tekin, Kemal MD‡; Akay, Fahrettin MD§

Author Information

From the *Department of Medical Microbiology, Gulhane Medical Faculty, University of Health Sciences, and †Department of Infectious Disease, Gulhane Training and Research Hospital, University of Health Sciences, and ‡Department of Medical Microbiology, Gulhane Training and Research Hospital, University of Health Sciences, and §Department of Ophthalmology, Atatürk Training and Research Hospital, Katip Çelebi University, İzmir, Turkey.

Accepted for publication April 17, 2017.

The authors have no funding or conflicts of interest to disclose.

Address for Correspondence: Fatih Şahiner, Department of Medical Microbiology, University of Health Sciences, Gulhane Medical Faculty, Kecioren, Ankara, Turkey. E-mail: [email protected].

The Pediatric Infectious Disease Journal: December 2017 - Volume 36 - Issue 12 - p e341-e346
doi: 10.1097/INF.0000000000001689
  • Free

Abstract

Zika virus (ZIKV) was first identified in Uganda in 1947 during a surveillance study on yellow fever. The virus was known as an infectious agent that was confined to the tropical areas of Africa and Asia, until the last decade.1,2 Only a few cases had been reported in the literature until the first ZIKV outbreak, in which 185 clinically compatible cases were described in Yap Island, Micronesia, in 2007.3,4 In 2013, a second outbreak occurred in French Polynesia (FP) where it was estimated that approximately 32,000 people were infected at that time.5,6 In 2014, the virus spread across the Pacific islands (e.g., Cook island, New Caledonia and Easter Island).4 ZIKV infections have now affected greater than a million people and is a global public health problem after outbreaks were reported in South and Central America in 2015. The World Health Organization (WHO) declared ZIKV outbreaks to be an international emergency and a serious global public health problem in February 2016.7 ZIKV then occurred in North America in 2016, initially via imported cases and subsequently as a result of local transmission.8,9

ZIKV has attracted intense interest because of the possibility of its association with severe autoimmune and neurologic disorders.7,10–12 A limited number of studies (an average of less than 1 per year) had been conducted on this virus until the outbreaks of 2007 and 2013 because the ZIKV infection was typically asymptomatic, or presented with mild symptoms, and no report had described a severe infection or poor prognosis before the 2013 FP outbreak.4 Numerous aspects of this virus remain unclear, although new information is constantly emerging (over 1000 articles have been published in 2016). In recent studies, Guillain–Barre syndrome (GBS), microcephaly, intracranial calcifications and abnormal ocular manifestations have been attributed to ZIKV, and the association between these abnormalities and ZIKV infection are currently under investigation.10,11,13–15

ZIKV

ZIKV is a member of the Flaviviridae family and the Flavivirus genus and was named after the Zika Forest, near Kampala, Uganda, where it was first isolated.1,16 According to genomic studies, ZIKV has a close similarity to the Spondweni, Kedougou and Bagaza viruses and has 2 major lineages, namely, African and Asian.4,17 In some studies, the African lineage has been evaluated as 2 subtypes—the West African (Senegal–Nigeria) and East African (Uganda) lineages.18

EPIDEMIOLOGY

The data obtained from virologic and seroprevalence studies, as well as sporadic cases since the 1950s to the present have shown that ZIKV has a wide geographic spread that includes Asia, Africa, the Pacific Islands, Central and South American Countries and the Caribbean and, recently, North America.8,9,19 According to the WHO and Centers for Disease Control and Prevention (CDC) data, the virus has today reached more than 70 countries or territories, predominantly in South and Central America.8,9 It is believed that imported cases and mosquito movement play a significant role in the spreading of ZIKV between regions. One suggestion is that cultural festival participants brought ZIKV to Easter Island from FP.20 Imported cases may also have been significant in spreading ZIKV from FP to New Caledonia, the Cook Islands and South America.18,20–22 Another hypothesis is that the newly emerged virus arrived in Brazil during the football World Cup competition in 2014.20 The ZIKV type circulating in Brazil was identified as being of the Asian lineage, and it is believed that this lineage originated in the Pacific Islands.22,23

TRANSMISSION

Transmission of ZIKV predominantly occurs via mosquito vectors (the Aedes genus of the Culicidae family).4 Intrauterine transmission via infections that occur during pregnancy is also common.12,24,25 Therefore, during the Brazilian outbreak, viral RNA was detected in the amniotic fluid samples and brain tissues of some infants and aborted fetuses with microcephaly after their mothers had been infected by ZIKV during pregnancy.10,12,13 Viral RNA was isolated from mother’s milk in several studies.24,26 However, the mechanisms of transplacental and perinatal virus transmission and its frequency have not yet been clarified. Sexual contact, blood transfusion or bodily fluids (eg, saliva, urine, semen and tears) are thought to be other possible transmission routes.27–31 In a new case report, ZIKV infection occurred in a person caring for an infected individual via secondary nonsexual transmission (direct contact).32 In addition, in November 2016, the WHO stated that ZIKV transmission, other than via the mosquito-borne route, had been reported from 12 different countries in America, Europe and Oceania since February 2016.9 This infection is actually a zoonosis, and the other proposed that transmission route is via the bites of monkeys and other nonhuman primates.33 A recent systematic review, in which 53 papers were analyzed, demonstrated that the available evidence of infection via breast milk and urine is contradictory, and the available data reporting infection via saliva, animal bites, transplantation, needle stick injury and laboratory studies are inconclusive.25

CLINICAL MANIFESTATIONS

ZIKV Disease

ZIKV infections are generally asymptomatic and progress subclinically, but clinical symptoms that are similar to those of other arbovirus infections may occur.16 Symptomatic disease occurs in approximately 20% of people with ZIKV infection.34 These symptoms are usually mild, and may present with acute onset of fever, maculopapular rash, arthralgia or conjunctivitis, and acute symptoms typically resolve within 4–7 days.4,34 Other common symptoms include edema in the extremities, retro-orbital pain, dizziness, headache and myalgia. Rare symptoms include digestive problems (abdominal pain, diarrhea and constipation), mucosal ulcerations (aphtha), pruritus and postauricular lymphadenopathy.4,17,35 However, the clinical and epidemiologic pattern of ZIKV infections changed in the last decade; in 2013, an increase in the incidence of autoimmune and neurologic diseases was observed in FP after the ZIKV outbreak,11 and in 2015, similar data were reported from Brazil.10,36,37 These reports have continued to increase to date; an increased incidence of GBS, possibly associated with “ZIKV infection,” has been reported from 19 different countries or territories, and neurodevelopmental malformations potentially associated with “congenital ZIKV infection” have been reported from 28 different countries or territories.9 These disorders, which have been attributed to the Asian lineage, are discussed in detail below.

Guillain–Barré syndrome

GBS is a rare autoimmune disease that occurs when an individual’s own immune system damages the nerve cells and sometimes causes muscle weakness or paralysis.38 A possible association between GBS and ZIKV was initially suggested during the outbreak in FP in 2013, at which time the incidence of GBS increased by 20.11 In the latter epidemic, autoimmune and neurologic diseases were identified in 74 people who have symptoms compatible with ZIKV infection and 42 of whom had GBS.7 However, the authors could not prove an association between this increase in incidence and ZIKV infection, only that it occurred concurrently. Nevertheless, they asserted that simultaneous circulation of serotypes 1 and 3 of the dengue virus may have contributed to the increasing incidence of GBS29 because seroneutralization tests showed that all 42 cases were positive for dengue and ZIKV infection.7 However, this association is not surprising because GBS may occur after other viral infections. Moreover, in November 2013, a laboratory-confirmed ZIKV infection complicated by GBS was described in detail in a woman in her early 40s.11 In February 2015, the WHO published a final report stating that the incidence of GBS had likely increased by 5–6 times since 2015 in some regions of Brazil.37 A further WHO report, published in November 2016, described an increase in incidence of GBS and/or GBS cases with confirmed ZIKV infection cases in 19 different countries, including Brazil, Colombia, The Dominican Republic, El Salvador, French Guiana, FP, Guadeloupe, Guatemala, Honduras, Jamaica, Venezuela, Mexico and Panama.9

Microcephaly and Neurodevelopmental Delays

Congenital microcephaly can be caused by genetic conditions, some teratogenic agents or some infections that occur during pregnancy.10 It is generally a lifelong problem and can range from mild to severe; in some cases, it can even be life threatening. ZIKV has recently been associated with microcephaly and some neurodevelopmental disorders, but the prognosis for infants with congenital ZIKV infection is unknown. The initial alert regarding a possible association between ZIKV infection and microcephaly emerged from Brazil, in September 2015.10 This has led to great concern because this number corresponds to a 20-fold increase in the incidence of microcephaly compared with the previous year. In the following period, 7830 suspected cases were reported to the Brazilian Ministry of Health by June 4, 2016, almost all of which were in northeastern Brazil.39 After the Brazilian alert, FP conducted a retrospective evaluation and found that 17 microcephaly cases had been reported during the ZIKV epidemic in this region where the average annual number of microcephaly cases is 0–2.36 A recent CDC report has shown that the risk of microcephaly development is estimated at 1%–13% in the first trimester of pregnancy in cases of maternal ZIKV infection.40 As of November 2016, 2352 microcephaly and/or central nervous system malformation cases potentially associated with congenital ZIKV infection had been reported from 28 different countries or territories; 2159 cases in Brazil, 58 in Colombia, 31 in the United States, 15 in Guatemala, 14 in Martinique, 14 in French Guiana and 61 in others.9 In congenital ZIKV infection, the commonly occurring neurodevelopmental abnormalities are as follows: intracranial calcifications, ventriculomegaly and neuronal migration disorders (lissencephaly and pachygyria), severe cortical malformations, cerebellar hypoplasia, abnormal hypodensity of the white matter and other anomalies, including congenital contractures and deformities of the foot (clubfoot).10,36,39 Some of the remarkable data from the ZIKV studies are summarized in Table 1.

T1
TABLE 1.:
Neurologic Disorders That are Possibly Associated With ZIKV Infection (2013–2016)

The Japanese encephalitis virus, which is closely related to ZIKV, can cause encephalitis, and the West Nile virus, belonging to the same genus, can lead to some invasive neurologic infections, such as meningitis–encephalitis.17 In 1952, ZIKV infection developed in the brain of intraperitoneally infected mice, suggesting that ZIKV crosses the blood-brain barrier.41 Approximately 20 years later, in 1971, in a mouse model, newborn and 5-week old mice were intracerebellarly inoculated with ZIKV, and expansion in astrocytes and pyriform cell destruction was observed in the hippocampus.42 In addition, the presence of virions in the endoplasmic reticulum of neurons and astrocytes was shown.42 Recent experimental studies have shown that, after passing through the placenta, the virus disrupted neural progenitor development and led to microcephaly in mice,43 impaired growth in human neurospheres and brain organoids,44 resulted in intrauterine growth restriction and microcephaly in mice fetuses and led to an increase in cell death by apoptosis and autophagy by targeting human cortical progenitor cells (in vitro), resulting in impaired neurodevelopment.45 In addition, another recent study, using single-cell RNA sequence analysis, showed that the Axl receptor is the ZIKV entry receptor in neural stem cells, and that the candidate viral entry receptor Axl is highly expressed by human radial glial cells, astrocytes, endothelial cells and microglia in the developing human cortex and by progenitor cells in the developing retina.46

Ocular and Ophthalmologic Manifestations

Before discussions of an association between some ocular manifestations and ZIKV began, it was known that West Nile virus, which is a flavivirus closely related to ZIKV, causes neurologic disease and retinal lesions in humans.52 Like other neurotropic flaviviruses, ZIKV may reach the eyes from the brain, the first site invaded by the virus, by retrograde transport via the optic nerve tract or may spread in a hematogenous manner across the blood-retinal barrier.53

Nonpurulent conjunctivitis is one of the most common ocular diseases in symptomatic ZIKV infections, and it occurred in 55%–63% of patients in the Yap Island and FP outbreaks.16 Unlike previously published data, in a study conducted in Brazil in 2015, conjunctivitis was not observed during pregnancy in 23 women with symptoms compatible with ZIKV infection.54 Therefore, it has been concluded that conjunctivitis occurs in only 10%–15% of ZIKV-infected individuals and may not be an important clinical finding in the differential diagnosis of ZIKV infection.53

Our knowledge of other possible ophthalmologic abnormalities (summarized in Table 2) that are possibly associated with ZIKV infections is based on case reports and case series, particularly those published over the last year. A recently published article showed that the rate of ocular abnormalities in ZIKV-infected infants (1–6 months) was very high for this age group, and retinal lesions differed from other congenital infections that have previously been described in the literature.54 However, some points have not been clarified, such as whether the eye disorder alone occurs without microcephaly in ZIKV infection, as this can be shown only by screening infants who are without microcephaly and who are born of mothers with symptomatic and asymptomatic infections during pregnancy.54 In recent studies, ZIKV-induced uveitis has been described in humans and experimental animal models.14,53 In one such investigation, ZIKV-associated conjunctivitis, as well as panuveitis and infection of the cornea, iris, optic nerve and the cellular compartments of the retina, was described in a mouse model.53 In the same study, high levels of ZIKV RNA and infectious virus were detected in the eye, and detectable viral RNA was observed in the tears and lacrimal glands associated with acute uveitis in immunodeficient adult mice. These data show that the ocular and neurologic systems can be seriously affected by the ZIKV.

T2
TABLE 2.:
Ocular Manifestations That are Possibly Associated With ZIKV Infection

DIAGNOSIS

ZIKV infections are associated with several diagnostic difficulties. For example, the clinical pattern of the infection is generally asymptomatic or moderate and has a similarity with other arboviral infections (eg, Chikungunya and Dengue, etc.) and coinfections with these viruses complicate diagnosis.17,19 Further problems include the occurrence of cross reactivity with other members of the Flaviviridae family in serologic tests, the short duration of the viremic period and intrauterine diagnostic difficulties.17,21 Laboratory diagnosis of the infection is based on the use of the following methods in individuals showing clinically compatible symptoms: detection of viral IgM and IgG antibodies from a person’s serum or cerebrospinal fluid (CSF), confirmative differential diagnosis using the plate-reduction neutralization test method, detection of viral antigens from tissue samples using immunohistochemical methods and detection of viral RNA by reverse transcriptase polymerase chain reaction (RT-PCR) in bodily fluids (eg, serum, CSF, amniotic fluid, urine, semen and saliva) or tissue samples (placental and fetal).1,4,16,17,24,29 Reproduction of ZIKV in cell cultures, primarily Vero cells and Aedes albopictus C6/36 cell lines, and genotyping-sequence analysis are other diagnostic approaches that are used for diagnostic confirmation or in research studies.19,22,27 In-house serologic and molecular tests were previously used in the diagnosis of ZIKV infection, but newly developed commercial RT-PCR tests (such as Altona, Germany; Genesig, United Kingdom; MyBioSource, United States; Genekam, United States and FastTrack, Luxembourg), commercial enzyme-linked immunsorbent assay (ELISA) tests (Euroimmun AG, Germany; MyBioSource, United States) for ZIKV IgG and ZIKV IgM detection and the immune fluorescence antibody test (Euroimmun AG, Germany) are today used instead.19

Detailed evaluation must be conducted with regard to infants with microcephaly or intracranial calcification that has been detected prenatally or during birth and whose mothers were potentially infected with ZIKV during pregnancy (either by travelling to or residence in, an area with autochthonous ZIKV transmission). Cross-reaction with other flaviviruses often occurs in serologic tests; therefore, diagnosis of ZIKV infection generally depends on detection of viral RNA from blood samples. If less than 7 days have passed since the first symptoms began, when the patient is in the viremic period, molecular methods are the first choice of diagnostic tool, and viral RNA can be detected by RT-PCR from blood samples. In addition, the virus can be isolated using cell culture techniques during this period.4,34 The viremic period usually lasts for a few days (3–5 days after the first symptoms begin), although it is prolonged in some cases.4 The virus can be detected in saliva and urine specimens more frequently, and sometimes for longer, than in blood samples.28,31 Therefore, viral RNA from CSF, urine or saliva samples can be investigated by RT-PCR as a possible alternative in routine diagnostic practice.4,30,31 RT-PCR for ZIKV on fixed and frozen tissues, and histopathologic examination with immunocytochemical staining of the placenta and umbilical cord, should also be considered.34

TREATMENT

There is no available approved specific treatment or vaccines for ZIKV. Symptomatic treatments are recommended for suspected ZIKV infections, after more severe conditions, such as malaria, dengue and bacterial infections, have been excluded.34 Treatments are often supportive and include rest, analgesics, antipyretics and liquid replacement. Acetaminophen is preferred in cases of high fever. Physicians must especially avoid using aspirin and other nonsteroid anti-inflammatory drugs until Dengue virus infection has definitely been excluded, because of the coagulation pathologies.57 New treatment methods are currently under development, and some of these are in clinical trials. Researchers have recently shown that a human mAb (ZIKV-117) could neutralize infection of the ZIKV strains corresponding to African, Asian and American lineages in cell culture and in mice, including during pregnancy.58 In addition, experimental studies on the possible effects of some antivirals are continuing and have revealed the following: Azithromycin reduces viral proliferation and the cytopathic effects of ZIKV in glial cell lines and human astrocytes,59 sofosbuvir efficiently inhibits replication and infection of several ZIKV strains in multiple human tumor cell lines and human neuronal stem cells,60 adenosine triphosphate analogs can efficiently inhibit ZIKV RNA-dependent RNA polymerase61 and flavonoids have an inhibitory effect on the NS2B-NS3 protease of ZIKV.62

PREVENTION

Every person who lives in a ZIKV infection area, or travels to such an area and has still not been infected (including pregnant woman), is at risk of infection. The main method of prevention is to avoid mosquito bites and eradicate mosquitoes.4 The CDC recommends that particular protection methods should be established for pregnant women.57 In addition, it is recommended that pregnant women (in any trimester) postpone any plans to travel to ZIKV transmission zones.

Vaccine Studies

In February 2016, the WHO declared ZIKV to be a public health emergency of international concern because of the possible relationship between ZIKV infections and the extraordinary cluster of microcephaly and other neurologic complications.7 The number of affected people has reached millions in a short time. The availability of vaccines against several members of the Flaviridae family, including Dengue, yellow fever and Japanese encephalitis, has encouraged pharmaceutical companies to develop protective vaccines against ZIKV. Although there is no approved protective vaccine against the ZIKV infection, over 20 institutions are making efforts in this respect.63

The current understanding of protective immunity against ZIKV is limited.23 A recent study showed immunogenicity of a purified inactivated virus vaccine and a plasmid DNA vaccine (DNA-prM-Env vaccine) in Vero cells and in mice.64 The same researchers subsequently administered 3 different vaccines (purified inactivated, DNA based and adenovirus serotype 52 vector based) to nonhuman primates, with successful results.65 Immediately after these studies, a different group of researchers announced that they had developed 2 vaccines against ZIKV and that the immunogenicity of these vaccines had been shown in C57BL/6 mice.66 One of these is a prototype subunit vaccine, which is a recombinant ZIKV E vaccine delivered intradermally, and the other is based on adenovirus serotype-5 vector expressing codon-optimized ZIKV E antigen. In another study, a novel, synthetic, DNA vaccine targeting the premembrane and envelope proteins of ZIKV was introduced.67 According to the study results, the vaccine generated antigen-specific cellular and humoral immunity and had neutralization activity in mice models. Moreover, the Food and Drug Administration recently approved the launch of a phase I trial of a synthetic DNA plasmid vaccine (GLS-5700).63 The results of a recently published study revealed that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated mRNA encoding the premembrane and envelope glycoproteins elicited potent and durable neutralizing antibody responses in mice and nonhuman primates.68 Most of these studies are in preclinical development, and new reports consistently continue to add to these.

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    Keywords:

    Zika virus; vaccines; ocular; neurologic; pregnancy

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