A review on zika virus: clinical aspects and therapeutic responses

The Zika Virus (ZIKV) happens to be one of the recent infections investigated after the Ebola pandemic. It is an arthropod-borne virus (arbovirus) within the family Flaviviridae class. ZIKV is an RNA virus with a single strand, enveloped, icosahedral, non-sectioned, positive sense. It is 40 nm wide and has an outer (E) envelope and a dense inner core. The ZIKV can be transmitted by two methods: human and human-to-human vectors. The vector transmission is by Aedes spp. Mosquitoes and diseases outside Africa are transmitted by Aedes aegypti. Originating in Nigeria in 1947 it was reported as a mild illness and from a rhesusmonkey. With a certain passage of time earned signi icant attention from healthcare organisations for the human population. Many clinical symptoms in adults in French Polynesia have been recorded, ranging from mild illness to severe neurological problems such as Guillain-Barré syndrome. Other symptoms include encephalitis microencephaly, meningoencephalitis, myelitis, paraesthesia, vertigo, facial and ophthalmological paralysis (photophobia and hypertensive iridocyclitis) and auditory manifestations. In this review, the clinical aspects and other therapeutic responses are studied here to understand the approach more treating symptoms arising with the infection of the Zika virus. Various complications have been studied in this review and diagnosis have been performed to identify the presence in the human body and also take clinical measures on alleviating the symptoms of the infected patients.


INTRODUCTION
Zika infection (ZIKV) is the most recent emanant infection after the Ebola pandemic. Before ZIKV was linked to mild disease, perhaps as it may have recently emerged as a signi icant threat to human well-being after six decades of sti ling movement, with apparent foetal anomalies, microcephalus, real neurological complications, and immune system issues, such as Guillain-Barré disorder (GBS). Zika infection is a lavivirus effectively transmitted by an infected Aedes aegypti, Aedes Africanus bite and also from Ae And Albopictus. Mosquitoes Hensilli. ZIKV is a mosquito-borne lavivirus in the positiveabandoned RNA community of Flaviviridae. It is strongly associated with a few different pathogens, including Dengue (DENV), yellow fever (YFV), West Nile (WNV), Japanese encephalitis (JEV), and tickborne encephalitis (TBEV) infections. Although ZIKV was initially con ined from a sentinel monkey at the Zika Forest Research Station in Uganda in 1981. (Singh et al., 2018) ZIKA Virus/ZIKA Fever Zika fever, or simply Zika lu, is an infectious disease caused by the Zika virus. Most cases do not have any side effects but appear to be mild and similar to dengue fever when present. Symptoms can include fever, red eyes, joint pain, cerebral pain, and maculopapular rash. Some propose that dengue fever and Chikungunya fever may recognise zika fever via increasingly noticeable oedema, no severe cerebral pain and discomfort, and a milder level of thrombocytopaenia. Zika fever is typically self-constraining with most clinical manifestations resolving fully within 3-7 days. No death, hospitalisation or haemorrhagic complications were recorded during the Yap Island outbreak. Zika fever-related rash usually improves in the irst week, but can last up to 14 days and maybe pruritus (Ioos et al., 2014;Gulland, 2016).
Zika infection is an arthropod-borne lavivirus transmitted by mosquitoes. ZIKV is a singlestranded RNA virus, enveloped, icosahedral, nonsectioned, positive sense. The lipid envelope is secured with thick projections which consist of a glycoprotein layer and envelope. Zika virus disease is transmitted by Aedes mosquitoes mainly by bite. When a person is infected with a mosquito bite, the Zika infection can be detected in their blood for a few days or in some individuals for longer.

EPIDEMIOLOGY
In 1953, the human disease caused by Zika was irst detected in Nigeria, when three sick people were established to have a viral infection. In April 1947, a febrile sentinel rhesus monkey (Rhesus 766) irst discovered Zika forests in Uganda. ZIKV was derived from the serum of a 10-year-old Nigerian girl who developed fever and headache in 1954. It is estimated that an epidemic in French Polynesia in 2013 and 2014 involved 32,000 people who had been tested for suspected Zika virus infection. In February 2014, the irst occurrence of human ZIKV infection occurred during the annual Tapati Festival in Easter Island, Chile, in the western hemisphere of the globe starting from French Polynesia. In Thailand, East Malaysia, Cambodia, the Philippines and Indonesia, sporadic cases of Zika have been reported.
In April 2007, there was a study of Zika epidemic outside Africa and Asia, on Yap Island in Micronesia. The episode was also reported in 2014 in South and Central America and 2015 in Mexico. The epidemic of Zika was inally revealed in Texas, the United States and Europe. Thus, the World Health Organisation (WHO) pronounced it on "a public health emergency of international concern" 1 February 2016 (Musso et al., 2014;Hasan et al., 2019).  (Miner and Diamond, 2017), (Table 1).

PATHOGENESIS
ZIKV is an RNA virus with a single strand, enveloped, icosahedral, non-sectioned, positive sense. It is 40 nm wide and has an outer (E) envelope and a dense inner core. The ZIKV can be transmitted by two methods: human and human-to-human vectors. Transmission of vectors is by Aedes spp. The transmission of mosquitoes and infections outside Africa is through Aedes aegypti. ZIKV reproduces the mosquito vector's midgut and salivary cells in the epithelial coating. It shows up in the currently contagious mosquito saliva with a set period of approximately ive days. The vector immunises the infection into the skin of the human host during a blood meal. The infection can contaminate the Langerhans epidermal keratinocytes, ibroblasts and cells. It is predicted that the pathogenesis of the infection continues with drainage to the lymph nodes and bloodstream. Flaviviruses replicate in the cytoplasm, but antigens of Zika have been detected in infected nuclei. ZIKV replication works on an unsusceptible antiviral reaction and produces type I interferon in the cells infected. Autophagosomal production is correlated with upgraded virus reproduction, the prompted articulation of antiviral antigen clusters (RIG-1, MDA-5, and TLR3) capable of discerning pathogen-associated molecular patterns after skin ibroblast disease was observed. ZIKV caused an autocephalous programme conirmed in the infected ibroblasts by the existence of autophagosome-like vesicles. In the critical process of Zika fever, the lymphocytes are activated. Following viral transmission, E glycoprotein promotes viral connection to the host cell receptors. This is followed by endocytic take-up, nucleocapsid uncoating, and viral RNA discharging into the cytoplasm. The antigen has been expressed in the nucleus of host cells as a noticeable contrast between various laviviruses. This will explain Zikarelated complexities.
Human-to-human transmission of ZIKV by transplacental route, spillage of the infection by a trophoblastic plug, the spread of the infection in an amniotic sac during formation or delivery by an infected mother to her newborn. Sexual methods have been reported in human-to-human transmission, and blood transfusion research has also been carried out in Brazil. Sexual transmission occurs when a person has a severe Zika disease, which is especially signi icant when the partner is pregnant due to the neurological results on the foetus. Second, placental ZIKV infection causes placental de iciency and restricts growth and microcephalus. (Musso and Gubler, 2016;Foy et al., 2011).

TRANSMISSION
Can transmit the Zika virus to humans by: Zika is transmitted essentially via the Aedes aegypti female mosquito, which is often aggressive during the day. The mosquitoes have to feed into laying eggs from the blood. The infection has likewise been con ined from various arboreal mosquito species in the sort Aedes, for example, A. Africanus, A. apicoargenteus, A. furcifer, A. hensilli, A. luteocephalus, and A. vittatus, with an irrelevant time of incubation of about ten days in mosquitoes (Diagne et al., 2015).
Zika can be spread to the sexual partners by individuals; the majority of cases realised include spread from symptomatic men to women. ZIKV may persist in semen for a time, with more than six months of recognised viral RNA. The infection replicates in human testis, where it infects many cell types, including testicular macrophages, peritubular and germ cells, sperm precursors.
Female genital discharges -Zika RNA infection was recognised during symptomatic disease in female genital tract secretions (through endocervical swabs and cervical body luid). Besides, zika infection RNA was identi ied in cervical luid 14 days after the initiation of disease when it was not identi iable in urine or blood for a long time.
Infection with zika can be transmitted via vertical (or mother-to-kid) transmission, during pregnancy or delivery. During pregnancy, an infection was linked to improvements in the neuronal development of the unborn child. Severe disease movements have been related to microcephalus development in the unborn child, although mild infection may trigger adult neurocognitive disorder (Venturi et al., 2016;Murray et al., 2017).
As of April 2016, two cases of blood transmission from Zika were entirely accounted for, both from Brazil, following which the US Food and Drug Administration (FDA) recommended screening for four weeks for blood donors and other high-risk donors.

CLINICAL FEATURES
Approximately 80 per cent of ZIKV is asymptomatic. Symptomatic infections are distinguished by a febrile self-constraining disease that usually goes on for 3-12 days and is linked with maculopapular rash, arthralgia, which affects the small joints of the hands and feet, conjunctivitis, back pain and headache. The skin rash starts blurring precipitously within two days, and fever begins to resolve within three days, and the rash continues. Some less usual clinical highlights include vomiting, diarrhoea, stomach pain, mucous layer ulcerations, uveitis and palatal petechiae.
Following utero infection, extreme ZIKV can be seen leading to neurological complications, especially microcephalus and Guillain-Barre syndrome (GBS), characterised by ascending paralysis and polyneuropathy, multi-organ failure, and thrombocytopenia and purpura. Infection with ZIKV causes encephalitis, meningoencephalitis, myelitis, paraesthesia, vertigo, facial paralysis and ophthalmological symptoms (photophobia and hypertensive iridocyclitis) and auditory. ZIKV can also damage the eye and cause uveitis in adults, which can be blinding. ZIKV disease affects up to 15 per cent of patients with conjunctivitis, possibly because of direct contact with the eye. In people with a variety of eye disorders, including retinal mottling, lens subluxation, and optic neuritis, congenital ZIKV infection can also cause sensory hearing loss and visual impairment. (Fauci and Morens, 2016;Olson et al., 1981).
5. Anomalies of the eyes in children with Zikarelated microcephalus, such as the retina or optic nerve defects, which in later life can cause blindness that destroys myelin or the protective covering of nerve ibres, gradually leading to loss of vision and weakness to the point of paralysis.

Guillain-barré syndrome (GBS) in adults
GBS is a rare, rapid-onset of paralysis. It is an immune system syndrome, and its regularly activated by an infection a few days to weeks earlier. The irst instance of Zika infection complicated by GBS was accounted for French Polynesia in March 2014. Guillain-Barré disorder (GBS) is the most well-known reason for acute laccid paralysis in healthy newborn children and kids. GBS happens worldwide with a yearly frequency of 0.34 to 1.34 cases per 100,000 people matured 18 years or less. In all age groups, males are affected about Fast serum lactate dehydrogenase, aminotransferase aspartate, gglutamyltransferase, C-reactive protein, ibrinogen and ferritin levels 1.5 times more frequently than females. Two-thirds develop the neurological symptoms in patients with acute in lammatory demyelinating polyradiculopathy (AIDP), the most common form of GBS, two to four weeks after what initially appears to be a benign respiratory or gastrointestinal infection. The prevalent manifestations of GBS at the presentation in children are pain and gait dif iculty. The primary modalities of treatment for Guillain-Barré syndrome incorporate plasmapheresis and administration of intravenous immune globulin. (Barbi et al., 2018;Oehler et al., 2013).

Congenital Zika syndrome in neonates
Congenital Zika syndrome is a group of congenital disabilities related to Zika during pregnancy. The congenital anomalies associated with maternal rubella infection during pregnancy include sensorineural hearing loss, eye defects, cardiac anomalies and neurological effects including intellectual disability, ischemic brain damage and microcephalus.
Microcephalus is a small head size clinical inding for gestational age and sex and is indicates the crucial issue with brain development. Guidance Centers for Disease Control and Prevention (CDC) Suggested were microcephalus be identi ied as an occipitofrontal diameter below the third gestational age and sex percentile. (Coelho and Crovella, 2017;Jaenisch et al., 2015) Characterise microcephaly with qualifying terms 1. Borderline microcephaly -Occipitofrontal circumference (OFC) between 2 and 3 Standard deviations (SD) lower than average for age, sex and gestation 2. Moderate microcephaly -OFC between 3 and 5 SD less than normal for age, sex and gestation 3. Severe microcephaly -OFC ≥5 SD less than mean for age, sex, and gestation.

Microcephaly has two primary mechanisms
1. Lack of brain growth or irregular brain development associated with a developmental insult during the induction phase and signi icant cellular migration; this type of microcephaly is thought to result from a reduction in the number of neurons generated during neurogenesis; the forebrain is most severely affected (e.g., holoprosencephaly) 2. Injury or insult to a previously normal brain (sometimes called secondary microcephaly); this type of microcephaly is thought to result from reduced dendritic processes and synaptic interactions.

ZIKA-Related Death
In late November, three ZIKV-related deaths were reported in Brazil (two adults with a neurological disorder and one infant, 1. Adult male with chronic lupus erythematous corticosteroid, rheumatoid arthritis and alcoholism 2. A 15-year-old girl with sickle cell disease who was born with fever, respiratory distress, jaundice and hepatosplenomegaly 3. A neonate microcephalus, foetal anasarca, and polyhydramnios that died within ive minutes of birth.

Diagnosis
ZIKV does have two forms of determination. The primary form contains both the infection characteristics as well as the viral sections, to identify ZIKV RNA, viral proteins, and live infection, respectively, RT-PCR, immunoassay, and virus isolation were made. The second diagnostic method is focused on the identi ication of the antibodies caused by ZIKV infection. RT-PCR and immuno histo chemical testing were useful in detecting Zika infection in foetal tissue loss and newborn infants who died after birth. Furthermore, the use of ultrasonography to diagnose microcephalus depends on clinical and technological considerations, and ultrasonography is undoubtedly not a too delicate tool to discern microcephalus (Buckley and Gould, 1988;Foo et al., 2017).

Virus Isolation
Intracerebral mouse immunisation was performed the primary isolation of Zika infection, considered as the reference examine for isolation of arboviruses. Zika infection can be re ined from blood, urine, saliva, and semen among human clinical examples.

Molecular Assay
Reverse transcriptase PCR (RT-PCR) is highly sensitive and accurate, and is known as the ZIKV diagnostic "gold standard." For example, the Food and Drug Administration (FDA) has af irmed one assay, Cobas Zika test (Roche), which is a subjective nucleic acid analysis to screen for Zika RNA infection in blood donors.

Serological Assays
The present serology assay is based on the identi ication of antibodies to structural laviviral proteins. Antibodies were not routinely explored for serological assays against non-structural viral proteins.
The key drawback of the existing serological assays is the cross-reactivity of various antibodies resulting from lavivirus infections. Various serological tests, including complimentary ixation, haemagglutination inhibition, immuno luorescence (IF) assay, ELISA and neutralisation tests, can be used to detect anti-Zika virus antibodies.

Prevention
There are currently no con irmed antibodies/vaccines for four illnesses with lavivirus. On ZIKV may be applied both inactivated and live attenuated virus/vaccine antibodies. These are YFV (live attenuated), TBEV (inactivated), JEV (inactivated and live attenuated) and DENV (recombining live-attenuated chimeric). For instance, 1 per cent sodium hypochlorite, 2 per cent glutaraldehyde, 70 per cent ethanol, 3 per cent -6 per cent hydrogen peroxide and 3 per cent -8 per cent formaldehyde are known to be susceptible to disinfectants. ZIKV inactivates potassium permanganate and ether. The best form of prevention is avoiding or repelling mosquitoes, preventing bites of mosquitoes by wearing long sleeves and boots, using insect repellents and staying indoors as possible (with air conditioning, window/door screens and mosquito nets to reduce the contact between mosquitoes and humans). Insect repellents that contain N, Ndiethyl-m-toluamide should be added for pregnant and lactating women older than two months. At the point outbreak occurs, blood donation should be suspended immediately. At the hour of pregnancy returned men should continue to use condoms with pregnant sex partners anywhere. (Shan et al., 2016;Oster et al., 2016).

Treatment
There is no available ZIKV approved therapeutic or preventive medicine. Patients with asymptomatic or uncomplicated Zika fever frequently do not need medication. Two strategies for antiviral production of ZIKV may be followed. The irst is to re-target existing medicinal drugs recently developed for ZIKV treatment for other symptoms of the disease. Few antiviral drugs have shown ef icacy in cell culture. When identifying inhibitors, It would be necessary to check if the compound concentration required for the anti-ZIKV effectiveness could be achieved in patients. The second approach is to build actual ZIKV-infection and replication inhibitors. Both viral infection and Viral enzyme assays can also be used to separate inhibitor compound libraries. They may also develop therapeutic antibodies for the treatment of ZIKV disease.
Zika fever treatment is helpful and includes acetaminophen for lu, migraine, or myalgia. Antiin lammatory drugs (Aspirin) should not be used in children with thrombocytopenia and Reye disease due to the risk of bleeding . As a consequence of the increased danger of hemorrhagic disease, non-steroidal anti-in lammatory drugs are likewise not recommended. Enough rehydration should be applied to minimise luid loss. Neurological complications analysis, particularly GBS, is important for the irst remedy of immunoglobulins intravenous.
Virological and foetal ultrasound tests to avoid ZIKV and fetal microcephalus or intracranial calci ica-tions should be administered to pregnant women with Zika fever-like side effects during or within 14 days of transmission to ZIKV (Gonzalez et al., 2016;Petersen et al., 2016). After delivery, the serum should be collected from the umbilical cord, or directly from the neonate within two days of birth for RT-PCR, IgM, or potentially neutralising antibodies to ZIKV.

CONCLUSION
Zika infection is a mosquito-transmitted lavivirus irst detected in monkeys in Uganda in 1947. It was remembered later by citizens in Uganda and the United Republic of Tanzania in 1952. There have been records of an epidemic of Zika infection in Africa, the Americas, Asia and the Paci ic etc. The future of the zika epidemic is uncertain, and the ZIKV epidemic has risen as an unprecedented global well-being crisis since the rapidly rising ZIKV epidemic may end up being an extensive and severe impairment in a generation of newborns (microcephaly) in children, including Guillain-barré syndrome in adults. The infection is transmitted through a mosquito vector, even though different non-mosquito methods of spread are also known. Therefore, preventive measures, including vector control, prevention of insect bite, utilisation of condoms, keeping away from travel to ZIKV endemic areas, assume a signi icant role.