MED-NERD
Zika virus
Outline:
- Overview
- Epidemiology
- Transmission
- Symptoms
- Complications and Effects
- Diagnosis
- Differential diagnosis
- Treatment and Management
- Prevention and Vaccination
- References
Overview:
Zika virus (ZIKV) is a single-stranded positive-sense small enveloped RNA virus belonging to Flaviviridae genus in the Flaviridae family. The size of the genome is nearly 10.8 kilobases. Flaviviruses consist of about 70 viruses transmitted mainly by mosquito or tick vectors (mosquito-borne viral disease), but can also be transmitted sexually, vertical transmission, and by blood transfusion. This group of viruses includes: yellow fever virus (YFV), dengue virus (DENV), West Nile virus (WNV), tick-borne encephalitis virus, Japanese encephalitis virus (JEV), St. Louis encephalitis, Rio Bravo virus, the Modoc virus, Langat virus, and Powassan virus. A polyprotein is encoded from its RNA and then cleaved into envelope, capsid, non-structural proteins, and pre-membrane. Regulating host antiviral response and inducing host cell death may be mediated by untranslated RNA produced by the virus. ZIKV was first identified in 1947 in a rhesus monkey in zima forest in Uganda and Kampala from Africa. The virus has caused several outbreaks over the last decade and is still considered an important pathogen in specific regions in which the virus is a threat. Symptoms include rash, headache, fever, myalgia, arthralgia, and conjunctivitis.
Epidemiology:
-In 1947: First described in 1947 in Africa.
-In 1960s: ZIKV spread to Asia and sporadic cases were found.
-From 1960s to 1980s: Rare, mild, sporadic cases were found in Africa and Asia
-In 2007: The first viral outbreak in Yap islands, Micronesia, Pacific, and about 75% of population was infected.
-In 2013-2014: The second viral outbreak in French Polynesia, Pacific, infecting approximately 50% of population.
-In May 2015: The largest viral outbreak and nearly a pandemic occurred in North-eastern Brazil, peaked in Region of Americas, Pacific Regions, the coast of West Africa territories. More than 70 countries were affected and about 1.62 million people were infected. It was found to be associated with Guillain-Barré syndrome in July 2015. ZIKV was associated with microcephaly in Brazil reported in October 2015.
-In 2016: A viral outbreak in Latin American and Caribbean nations, infecting about 440,000–1300,000 people in Brazil. ZIKV was reported as actively transmitted disease in 60 nations and territories. On February 1, 2016, the World Health Organization (WHO) announced ZIKV as a public health emergency.
-From 2017 to 2018: Outbreaks of ZIKV have declined in the Americas region. This may be explained by herd immunity (most of the population have been infected in some regions such as Brazil).
-In 2019: By July, ZIKV was transmitted to about 87 countries and territories and reported in : Americas, Africa including Ethiopia, South-East Asia, and Western Pacific Regions, it was also found in France
-ZIKV has not been reported in almost 61 countries although the Zika mosquito vector is present in these regions.
- Ae. aegypti highly transmit the disease compared to Ae. albopictus which is the primary potential mosquito vector in Europe.
-Causes of rapid transmission include:
•The climate, humidity, and temperature in tropical regions helps the transmission and circulation of Aedes mosquito .
•Lack of defences in newly infected regions and when a new virus is transmitted.
-ZIKV is still circulating and is considered a threat that may cause outbreaks in specific regions.
Transmission:
Mosquito-Borne Transmission:
It is the main mode of transmission of ZIKV. ZIKV can be transmitted by Aedes mosquitoes; Aedes aegypti, Aedes albopictus, Aedes hensilli on Yap Island, Aedes polynesiensis in French Polynesia, and Aedes africanus. Ae. aegypti, that is present in tropical areas, transmits the disease more than Ae. albopictus which was reported in Gabon in 2007 and in France as sporadic cases. Usually, the bite of Aedes mosquitoes is during the day, it peaks during early morning and late evening. Chikungunya, dengue, and yellow fever can be transmitted by the same mosquito. Moreover, it may be isolated from domestic mosquito, Culex quinquefasciatus.
Vertical transmission:
ZIKV can be transmitted during pregnancy from mothers to foetuses (Maternofoetal transmission) causing severe congenital malformations. It occurs in about 20-30% of infected pregnant women. Transmission occurring in the first trimester of pregnancy is associated with higher risk of Congenital Zika Syndrome (CZS). Isolating the virus from foetal brain, amniotic fluid, and serum of babies after infection confirms this mode of transmission. Transmission via breastmilk is controversial and the WHO has not prevented breast feeding for infected mothers.
Sexual transmission:
ZIKV has been detected in the semen of infected patients. It is considered the only arbovirus transmitted sexually. The virus can be transmitted from both sexes but mainly from male to female.
Contact with Infected Body Fluids:
This mode of transmission is not proven yet however; ZIKV can be detected in saliva and urine which is useful when obtaining blood samples is difficult.
Blood transfusion:
ZIKV can be easily transmitted from asymptomatic blood donors to blood recipient. The virus can present in the blood of infected patients for about two months. Approximately, 3% of blood donates were positive for the virus. Transmission via blood transfusion has been reported in Brazil with 2 cases being reported.
Transmission in solid organs transplantation:
This may be a mode of transmission, but is not confirmed yet. According to the US guidelines, transplantation should be prevented when there is a suspected case of ZIKV-positive donor, taking into consideration the risks and benefits of donation.
See: Ebola virus
Symptoms:
Most cases of ZIKV infection are mild or asymptomatic as in 1960s–80s. More than 80% of patients are not detected. The incubation period is about 3-14 days and symptoms usually last from2 to 7 days. Approximately, 20-25% of cases develop these symptoms: fever, retroocular headache, malaise, skin maculopapular rashes, non-purulent conjunctivitis, arthralgia (involving the small joints of the hands and feet), asthenia, and myalgia . Other symptoms include: diarrhoea, vomiting, abdominal pain, loss of appetite, hematospermia, and oedema.
The rash usually appears within the first week and lasts several days or weeks with the following criteria: fine maculopapular, may be pruritic, with diffuse distribution, and involves face, trunk, as well as extremities including palms and soles. Commonly, patients recover completely and quickly.
Complications and Effects of ZIKV infection:
Targets of the virus include: foetus embryonic cells, the forebrain-specific human neural progenitor cells, and the brain organoids embryonic leading to cell necrosis.
ZIKV in infants and children:
Congenital Zika Syndrome (CZS) is a severe malformation developed as a result of infection of foetus that consists of the following neurological anomalies : foetal hydrops, arthrogryposis, structural brain anomalies, and ocular anomalies. It clinically manifests as swallowing disorders, microcephaly (which occurs in about 4-6% of cases), and hypertonia. It occurs in about 5-14% of infected pregnant women. The outcome of the syndrome is poor and occurs in average age of 30 months. Prenatal exposure to ZIKV may result in developmental injuries even without congenital symptoms. A study has shown that developmental injuries in children exposed to ZIKV in the third trimester were higher than in the first trimester which was known to have the worst complications.
Microcephaly:
In 2015, 1248 new cases of microcephaly were reported. In 2016, the number increased to 4180 with 270 confirmed cases of microcephaly. Vertical transmission of ZIKV is associated with ophthalmologic abnormalities:
•Chorioretinal macular atrophy
•Macular pigment mottling
•Optic nerve head hypoplasia
•Optic nerve double-ring sign
•Loss of foveal reflex
In Brazil, a study of 35 infants with microcephaly born between August and October 2015 showed that the mothers of all 35 during pregnancy had lived in or travelled to areas of ZIKV. ZIKV RNA has been detected in placental and foetal tissue and amniotic fluid in different cases of neurological malformations.
Other complications during pregnancy, include stillbirth, foetal loss, preterm birth.
ZIKV in adults:
As a result of neurotropism of the virus, neurological complications may occur including: myelitis or Guillain-Barré syndrome, meningoencephalitis. In every 10,000 ZIKV infection cases, 2-3 cases have Guillain-Barré syndrome which is associated with higher morbidity rate and cranial neuropathy and is characterized by muscle weakness and sometimes paralysis due to nerve cell damage. Some patients may have renal pathology which may remain subclinical except in immunocompromised patients. Rare severe complications of ZIKV include blood disorders (bleeding, bruising or slow blood clotting).
In general, hospitalization needed in severe cases is uncommon and mortality rate is low.
Effect on male fertility:
ZIKV may persist in male genital tract. Acute ZIKV infection may decrease the total sperm count by 50% at day 60 after infection. The virus was found in semen with reduced sperm count. ZIKV may modify the transcriptional profile of Sertoli cell (responsible for spermatogenesis) which in turn support ZIKV replication. ZIKV may cause damage the reproductive male system by promoting cell death in spermatogonia. More studies are required to confirm this effect on male fertility.
Diagnosis:
Diagnosis is mainly based on clinical symptoms and epidemiological circumstances and some tests are used to confirm the diagnosis.
Serologic Testing:
Detection of Zika virus RNA is done using nucleic acid amplification test (NAAT). The first week of infection is characterized by high viremia and represents the highest sensitivity of NAAT. A positive serum NAAT within 7 days of symptom onset suggests acute ZIKV infection. If NAAT results are negative, testing for virus-specific immunoglobin M (IgM) can be performed using enzyme-linked immunosorbent assay (ELISA). Detection of antibodies is associated with false-positive results due to cross reaction with other flaviviruses especially dengue virus. Protein biomarkers may be used to differentiate between these viruses. In 2018, a study showed that protein array tested was nearly 90% effective in differentiation between ZIKV and dengue virus. ZIKV RNA may be detected in urine for more than 10 days.
Negative ZIKV RT-PCR or other serologic test
does not rule out the diagnosis.
Prenatal ultrasound and amniocentesis may be used to diagnose congenital ZIKV infection. There is no specific time for conduction of ultrasound, but abnormalities have been detected in 2nd and 3rd trimester of pregnancy based on limited case reports. ZIKV may be transiently present in amniotic fluid, therefore absence of RNA via NAAT does not rule out congenital infection. The sensitivity and specificity of amniocentesis for detection of congenital ZIKV infection is unknown.
Differential diagnosis:
-Dengue: Characterized by higher fever and severe muscle pain. Warning signs include bleeding.
-Alphavirus infection including: chikungunya, Barmah Forest, Mayaro, Ross River, sindbis, and o’nyong-nyong viruses.
-Chikungunya: Characterized by higher fever and more severe joint pain in hands, feet, knees, and back.
-Leptospirosis
-Rickettsia
-Malaria
-Rubella, Measles
-Group A Streptococcus (GAS) Infections
-Enterovirus
-Parvovirus B19 Infection, Adenovirus
-Yellow Fever
-Coronavirus Disease 2019 (COVID-19)
Treatment and Management:
Majority of patients recover without requiring treatment. No specific antiviral treatment is available for ZIKV infection. Management is mainly supportive including: rest, analgesics, antipyretics, and fluids to prevent dehydration. Acetaminophen may be used for fever and pain. Antihistamines can be used for pruritic rashes. Until dengue and other flavivirus infections can be ruled out, Non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided due to the risk of haemorrhage. Researchers work on development of drugs that may be used in ZIKV infection.
Prevention and Vaccination:
No effective vaccine is available against ZIKV infection. Examples of developed vaccines include : inactivated virus vaccine, lipid Nano-particle encapsulated mRNA vaccines, recombinant protein subunit vaccine, DNA vaccines expressing pre-membrane and envelope proteins, live-attenuated vaccines, and virus-like particles. This represents a challenge as none of these vaccines has been licensed yet.
Other preventive measures :
Mosquito-Control is the main preventive measure against ZIKV.
-Personal protection include: wearing light-coloured clothing covering most of the body.
-Physical barriers: screens, window, closed doors, applying insect repellent to skin or clothing that contains IR3535, icaridin, or DEET.
-Sleeping during the day or early evening should be under mosquito nets.
-Eliminate mosquito breeding sites ( e.g., removing standing water in flower pots, covering water storage containers)
- Using larvicides and insecticides may be recommended to reduce mosquito populations.
-Travellers to endemic areas should take the previous precautions to avoid being infected.
-The USA has applied testing of blood donations for ZIKV RNA with exclusion of positive donations.
-The WHO has recommended practicing safer sex (using condoms) or abstinence of sexual activity in the following conditions:
• For 6 months in males and 2 months in females returning from endemic areas of ZIKV.
• Pregnant females during the entire period of pregnancy.
-Establishing health and education programs to increase awareness about ZIKV infection.
References:
(1) Pielnaa P, Al-Saadawe M, Saro A, Dama MF, Zhou M, Huang Y, Huang J, Xia Z. Zika virus-spread, epidemiology, genome, transmission cycle, clinical manifestation, associated challenges, vaccine and antiviral drug development. Virology. 2020 Apr;543:34-42.
https://www.sciencedirect.com/science/article/pii/S0042682220300210?via%3Dihub
(2) Masmejan S, Musso D, Vouga M, Pomar L, Dashraath P, Stojanov M, Panchaud A, Baud D. Zika Virus. Pathogens. 2020 Oct 28;9(11):898.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692141/
(3) Zika Virus, World Health Organization (WHO).
https://www.who.int/news-room/fact-sheets/detail/zika-virus
(4) Zika virus disease, European Centre for Disease Prevention and Control (ecdc).
https://www.ecdc.europa.eu/en/zika-virus-disease
(5) Zika virus, National Health Service (NHS).
https://www.nhs.uk/conditions/zika/
(6) Zika, Pan American Health Organization (PAHO).
https://www.paho.org/en/topics/zika
(7) Christian KM, Song H, Ming GL. Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System. Annu Rev Neurosci. 2019 Jul 8;42:249-269.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523638/
(8) Zika virus, Centers for Disease Control and Prevention (CDC).
https://www.cdc.gov/zika/about/index.html
(9) Bhagyashri D Navalkele, MD, MBBS ,Miriam T Levine, MD,Pranatharthi Haran Chandrasekar, MBBS, MD, Zika Virus Differential Diagnoses.Medscape.
(10) Sirohi D, Kuhn RJ. Zika Virus Structure, Maturation, and Receptors. J Infect Dis. 2017 Dec 16;216(suppl_10):S935-S944.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853281/
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