The 2021 Zika outbreak in Uttar Pradesh state of India: Tackling the emerging public health threat

Introduction

Zika virus (ZIKV) is a positive-sense single-stranded RNA virus belonging to the Flavivirus family. It is responsible for an arboviral disease transmitted by bites of the female Aedes aegypti (primary vector ¹ ) and Aedes albopictus (secondary vector) mosquitoes amongst other Aedes species, sexual contact, vertical transmission from mother to fetus, blood transfusion, and organ transplantation. The majority of urban transmission is thought to be mediated by the Aedes mosquitoes. ZIKV was discovered in Uganda in 1947. ¹ Between 1969 to 1983, Zika spread had extended to Asia, as the virus was detected in mosquitoes in India, Malaysia, Indonesia, and Pakistan. According to the World Health Organization (WHO), the first recorded outbreak of Zika was reported from the Island of Yap in 2007. A large-scale outbreak was then reported from the French Polynesia in 2013. Subsequently, another outbreak was reported from Brazil in March 2015. On the 1st February 2016, the WHO designated ZIKV infection and its associated neurological disorders as a Public Health Emergency of International Concern (PHEIC). The African and the Asian are the two major lineages of ZIKV identified through ZIKV genetic analyses. ² In India, the first case was reported from Gujarat in November 2016 when a 34-year-old female was found ZIKV positive at B.J. Medical college, a tertiary care hospital in Ahmedabad. ³ Next, a positive case was reported from the Krishnagiri district of Tamil Nadu in June 2017. Subsequently, two outbreaks occurred in the states of Rajasthan and Madhya Pradesh in 2018. Thereafter, cases were reported from Kerala and Maharashtra in July 2021. The latest outbreak is of 150 cases of ZIKV disease (as of 24th November 2021), reported from Uttar Pradesh (UP), of which 139 were from Kanpur district alone (Figures 1 and 2).

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Figure 1.

Timeline of Zika outbreaks in India.

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Figure 2.

Locations of Zika outbreaks in India.

Most patients with acute ZIKV infection are either asymptomatic or have just mild symptoms. In symptomatic cases, the most common signs and symptoms include maculopapular rash, conjunctivitis, low-grade fever, headache, arthralgia, myalgia, and retro-orbital pain. In areas that are endemic to dengue and chikungunya, these symptoms are hard to differentiate. ZIKV infection is suspected to cause a number of neurologic diseases including Guillain-Barre syndrome (GBS), acute myelitis, meningoencephalitis, and congenital anomalies such as microcephaly in infants born to ZIKV positive mothers. ⁴

Discussion

The index case was a 57-year-old Indian Air Force (IAF) officer who presented with a high fever, skin rashes, and muscle and joint pains. His blood sample was found positive by RT-PCR testing at the National Institute of Virology (Pune, India) on 23rd October 2021. Subsequently, Kanpur emerged as the epicenter of the state‘s very first Zika outbreak.

Following the detection of the first case, active surveillance was carried out in a 3 km radius of Chakeri area of Kanpur (where the patient lived); with a focus on close contacts, individuals exhibiting symptoms of ZIKV infection, and pregnant females.

Multiple batches of mosquito and larvae samples were collected from the localities with confirmed cases and sent for testing to the National Institute of Malaria Research (NIMR), New Delhi. Genetic sequencing confirmed the presence of ZIKV-RNA in one of the mosquito samples. Aedes aegypti and Aedes albopictus were found to be in the highest concentration among mosquito species circulating in Kanpur. Also, the findings suggested a marked increase in mosquito densities compared to the previous year – this is expressed as the number of mosquitoes per man-hour-catch. A surge in mosquito density, from 0.66 to 1.06 per 10 man-hours was noted; indicating the presence of Aedes mosquito in 2–3% of the houses of the studied area. ⁵

Pregnant women living in this area were traced and screened regardless of their symptom status. Taking cognizance of the current situation and complications of Zika infection, the health authorities laid out a plan to monitor pregnant females. Any who presented with fever even once would be monitored till delivery. Second level ultrasound would be used to monitor the development of the fetus, in order to detect microcephaly as early as possible. ⁶

A number of factors may be responsible for the outbreak in UP, namely: (a) the similarities of ZIKA with dengue and chikungunya, virtually endemic there, (b) the state-wide distribution of the vectors, Aedes aegypti and Aedes albopictus, (c) geographical conditions conducive for mosquito-borne diseases with a sudden increase in vector density, (d) immunologically ZIKV naive populations exposed to a global travel upsurge after lifting of COVID travel restrictions.

The co-circulation of DENV, CHIKV, and ZIKV should be considered a serious public health concern. All these arboviruses use Aedes aegypti and Aedes albopictus for completing their transmission cycle. They also share certain early clinical manifestations. A systematic review including 34 studies from ten countries reported significant co-infection of Zika with dengue and chikungunya (among arboviruses). ⁷

A few studies describe that Indian mosquito strains have a lower susceptibility threshold for ZIKV. ⁸ It is also difficult to diagnose Zika infection early by serology because of its very high cross-reactivity with dengue virus.

The serious significance of ZIKV is its known sexual and vertical transmission that puts pregnant women and their fetuses at risk. ZIKV attacks the placental tissue inducing vascular damage and apoptosis of the barrier resulting in impaired placental function. Transplacental transmission is most common in the first trimester. ⁹ The syncytiotrophoblast cells, macrophages, and fetal endothelial cells allow entry and replication of the virus. ¹⁰ Altered perfusion and decreased oxygen permeability of the placenta leading to fetal hypoxia is the reason behind poor fetal development. The most important sign of congenital Zika infection is microcephaly which may be associated with decreased brain tissue and a specific pattern of brain damage. On neurological imaging, ventriculomegaly and cerebral calcification can be seen. Damage to the eye resulting in ocular abnormalities and increased muscle tone resulting in restricted body movements and joints with limited range of motion in the infant are other common findings. ¹¹

Pregnant women in an area with recent Zika virus transmission need to be tested for infection and serial fetal ultrasound scans are advised to look for signs of congenital infection. Obviously, advice to avoid traveling to Zika prevalent areas and to guard against mosquito bites is mandatory.

In the adult, neurological complications of ZIKV infection mainly include Guillain Barré syndrome, meningo-encephalitis, transverse myelitis, seizures, and stroke. ¹⁰

Prediction of an outbreak through vector surveillance and enhanced surveillance of people visiting ZIKV endemic areas, if properly implemented could have prevented an outbreak in the state of Uttar Pradesh. Lack of public health awareness about ZIKV and the inability to ramp up sample collection and testing resulted in delayed containment of the outbreak. Implementation of stringent control strategies is the need of the hour as the probability of future outbreaks cannot be dismissed owing to the conducive entomological and geographical conditions in the state.

Vector control strategies listed under the National Vector Borne Disease Control Program (NVBDCP) should be strictly implemented. These include source reduction, personal protective strategies (bed nets, repellents), space spraying with chemicals (e.g. malathion), and mechanical, chemical, and biological measures for mosquito and larva control. Some biocontrol measures which can be used in India to keep a check on mosquito population in areas with high vector density are:

Incompatible insect technique: Introduction of Wolbachia bacteria in mosquito populations reduces the lifespan of vectors. When an infected male mates with a normal female mosquito, no offspring is produced owing to the phenomenon of cytoplasmic instability. When an infected female mates with a normal male, Wolbachia infected offspring take birth. ¹²

Blood borne transmission can be prevented by performing screening tests and Zika virus testing should be made mandatory for blood donors in areas of outbreak. The surveillance of acute neurological illness should be strengthened and coordinated with more focus on adult surveillance in contrast to Polio where the pediatric population is focused.

Health workers providing antenatal services at ground level should be trained to recognize the symptoms early and notify the higher centers. All pregnant women should be tested in Zika endemic areas; they should be informed of the risks of congenital zika syndrome with infographics in local languages. Head circumference of the newborn should be measured by health care workers providing neonatal care and cases with microcephaly should be included under surveillance.

Directions for future

Setting up laboratories equipped with RT-PCR testing for surveillance of people in areas with high vector density should be made mandatory. Clustered regularly interspaced short palindromic repeats (CRISPR) based assays can be used for rapid detection of ZIKV in body fluid samples and for spotting the minutest mutations in the viral RNA. It can also be used for primary screening of pregnant females in endemic areas as it is quick, sensitive, and cost-effective.

The virus like particle (VLP) technology offers a promising immunization strategy against Zika for mass vaccination of the affected population, including childbearing women. Primary goal of immunization is to prevent Congenital Zika Syndrome so the vaccine should prevent intrauterine transmission in women of childbearing age; it should also prevent sexual transmission by providing mucosal protection. It should avoid the potential of antibody dependent enhancement (ADE) of disease among flavivirus infections. Recently, multiple VLP vaccine candidates have demonstrated excellent efficiency and do not cause ADE between ZIKV and flaviviruses.

Antivirals targeting specific genomic domains of ZIKV RNA like NS1 should be developed with the primary goal to prevent placental transmission of the virus. A study found increased Caspase-3 activity in ZIKV infected neural cells which induced cell apoptosis. Caspase inhibitor, Emricasan can be used as a neuroprotective agent as it inhibits Caspase-3 in infected cells. ¹⁴ The virus has been found to target human neural progenitor cells (hNPCs) and attenuate their growth, resulting in a growth pattern similar to that of microcephalic brains. ¹⁵

Entomological surveillance should be done on a regular basis to assess the geographical distribution of ZIKV in India. Improved approach aimed at fostering public health awareness and strict implementation of surveillance and control strategies is crucial to controlling the spread of ZIKV. These measures if properly followed can markedly reduce the risk of ZIKV outbreaks in the future.