Vector-borne diseases are human infections transmitted by arthropods like mosquitoes, ticks, bugs, and other flies like sandflies and black flies. These insects are cold-blooded and sensitive to climatic factors like temperature, rainfall, and humidity. The name arbovirus is an acronym denoting arthropod-borne viruses, which are a group of RNA viruses that develop chiefly in arthropods (mainly in the hematophagous members of the group such as mosquitoes and ticks) and are maintained in nature by continuous transmission to and between susceptible vertebrate hosts via the biting habits of the said arthropods. A brief classification of the clinically significant arboviruses causing human and animal disease is outlined in Table 1.
The burden of these diseases is highest in tropical and subtropical areas, and they mostly affect the populations living in disadvantaged conditions. Distribution of vector-borne diseases is determined by a complex set of demographic, environmental, and social drivers such as global travel, trade, and unplanned urbanization. Weather plays an important role in the distribution, and abundance of these infections by influencing the vector density, intensity, and temporal pattern of vector activity (particularly biting rates) throughout the year; and rates of development, survival, and reproduction of pathogens within vectors.
Every year more than a million deaths are recorded worldwide due to arboviral diseases such as dengue, yellow fever, Japanese encephalitis (JE), chikungunya fever, Zika fever, West Nile fever, (transmitted by mosquitoes), and tick-borne encephalitis (transmitted by ticks). Arboviral diseases, thus, represent a significant emergent threat to human health (contributing to more than 17% of annual infectious disease burden) across the globe, the scope of which is likely to expand in the future given the current trends in the driving factors mentioned above.
MOSQUITO-BORNE ARBOVIRAL DISEASES
Dengue fever (DF) is one of the most common vector-borne viral diseases affecting humans worldwide. It is among the leading causes of acute febrile illness (AFI) in developing countries.
The etiological agent responsible for DF is the Dengue virus (DENV) – a positive sense single-stranded RNA (ssRNA) virus belonging to the genus Flavivirus of the family Flaviviridae. DENV consists of four distinct serotypes (DENV 1-4), infection due to a serotype typically leads to lifelong immunity against the infecting serotype; however, infections due to heterologous serotypes may lead to severe clinical manifestations due to antibody-dependent enhancement.
Aedes aegypti and Aedes albopictus are the primary vectors involved in disease transmission. Both vectors are day-feeding and container-inhabiting mosquitoes that thrive in warm tropical climates with Ae. aegypti having a greater preference for the urban environment compared to Ae. albopictus which mostly inhabits rural regions. Though Ae. aegypti is considered to be a more efficient vector and is associated with most infections, Ae. albopictus is known to have a better cold tolerance and is more geographically widespread.
Since the mid-twentieth century, there has been an alarming increase in both the incidence and geographical range of dengue. Several coinciding drivers are thought to contribute to this process, including climate change and rapid urbanization in developing countries. The rapid expansion of cities coincided with changes in water use patterns and the growth of the automobile industry, both of which provided potential oviposition sites and larval habitats for Ae. aegypti (in the form of water in plastic storage containers and unused automobile tyres).
The first epidemics of DF in India were recorded in 1963-1964, along the eastern coast of India. The disease spread to most of southern India and cities in northern India, such as Delhi and Kanpur. Eventually, the entire sub-continent was involved in subsequent epidemics leading to hyper-endemicity (i.e., co-existence of all the four serotypes of DENV) in most areas. DF cases in most parts of the country show a moderate to strong positive association with the total rainfall.
The typical incubation period for DF ranges from 3-10 days. The disease usually begins with a febrile phase associated with sudden high-grade fever lasting for 2-7 days, followed by a critical phase of defervescence with increased capillary permeability, reduced platelet counts, and increased hematocrit. This phase may also be associated with dengue warning signs and/or deterioration of clinical condition to shock, disseminated intravascular coagulation, and/or multi-organ dysfunction. A final phase of recovery of clinical parameters lasting 2-3 days occurs in most cases.
A wide array of available diagnostic tests have been evaluated for the diagnosis of DF. These include direct methods such as the isolation of DENV (in Vero cell lines), detection of the non-structural (NS1) antigen via enzyme-linked immunosorbent assay (ELISA) or immunochromatographic tests (ICTs), and viral genetic material detection using nucleic acid amplification tests (NAAT). Indirect methods include commercial serological assays detecting immunoglobulin M (IgM) (IgM Antibody Capture/MAC-ELISA-based platforms) and IgG against DENV. Direct methods have a high success when samples are collected during the early phase of the disease (i.e., within 4-5 days of symptom onset) whereas antibodies are usually detectable by 3–5 days after the onset of illness, being detectable in 80% and 99% of patients by days 5 and 10, respectively. However, the sensitivity of these tests may vary in primary and secondary dengue (with multiple NS1 detection assays showing decreased sensitivity in detecting secondary dengue infections). This may be of diagnostic significance in a country like India, where secondary dengue is thought to contribute up to 43% of the total dengue burden; this proportion is much higher in many states of southern India, including Andhra Pradesh, Tamil Nadu, and Karnataka.
In general, virus isolation and NAAT have a much higher specificity than antibody-based serologic tests but are also more cumbersome and technically demanding. Tests such as the Plaque Reduction Neutralization Test (PRNT) may be used to distinguish between DENV and other flaviviruses in IgM-positive patients.
The World Health Organization (WHO) classifies DF as dengue and severe dengue based on clinical deterioration during the critical phase of the illness, along with a list of warning signs indicating possible deterioration (severe abdominal pain, persistent vomiting, etc.). Treatment of DF is largely supportive in nature and illness phase dependent. Antipyretics and oral fluid replacement is the mainstay of management in patients without warning signs, whereas those with warning signs may require careful inpatient monitoring for 24–48 h. Infusions of crystalloids or colloids may be required in patients with shock. Blood transfusion and/or platelet replacement may be needed in patients with severe hemorrhage and/or thrombocytopenia, respectively.
Although multiple dengue vaccine candidates are currently in late stages of development, as of 2021, the only version commercially available is CYD-TDV-a tetravalent, live-attenuated, chimeric vaccine made by Sanofi Pasteur, approved in December 2018 in the European Union, for the prevention of DF caused due to all the four DENV serotypes and marketed under the name Dengvaxia. It is currently licensed in 20 countries such as Singapore, Brazil, and Philippines for individuals between 9 and 45 years of age residing in endemic areas. However, it is not yet approved and available in India.
JE virus (JEV), belonging to the family Flaviviridae, is transmitted by Culex tritaeniorhynchus, Culex vishnui, and Culex pseudovishnui group. The zoonotic cycle between Culex mosquitoes, pigs, and wading birds (the vector, amplifying host, and reservoir host, respectively) serves as a mode of infection. Humans are incidental dead-end hosts who can get infected but cannot transfer the virus to another transmission vector because of short-lived and low viremia. JEV is the main cause of viral encephalitis with approximately 68,000 clinical cases per year in Asia. The case-fatality rate among those with encephalitis can be 30% even though JE is mostly asymptomatic. About 30%–50% of those with encephalitis have permanent neurologic or psychiatric sequelae.
As per the WHO, major outbreaks of JEV happen once in 2–15 years. The transmission of JEV intensifies during monsoons due to an increase in vector population and is seen in agricultural areas of intensive paddy cultivation. Following an outbreak, safety measures are taken to quarantine pig herds and reduce mosquito breeding. However, the virus can remain dormant until the upcoming monsoon, when the outbreak may reoccur due to the negligent implementation of the aforementioned safety measures. JE was clinically diagnosed at Vellore, in Tamil Nadu, in 1955, for the first time in India. After this, multiple disease outbreaks were reported in India: Bankura in 1973, Gorakhpur in 1978, etc., Lapeyssonnie and Gopalakichenin reported the serological evidence of the JEV disease in Pondicherry in the early 1950s. After that, major outbreaks have been reported often in Cuddalore and Tiruchirapalli districts of Tamil Nadu and Pondicherry. JEV exists as a single phenotype encompassing five different genotypes: G-I, G-II, G-III, G-IV, and G-V, based on E protein gene and their nucleotide homology; further, three distinguishable subtypes (a, b and c) are there within G-I. Genotype III is the most commonly isolated JEV strain in India, followed by genotype II.
Laboratory diagnosis of JE is generally done by testing cerebrospinal fluid (CSF) or serum to detect virus-specific IgM antibodies. IgM antibodies against JEV are detectable after 3 to 8 days of illness and can persist for up to 3 months or longer. IgM antibodies may occasionally reflect a past infection or prior vaccination. The test should be repeated on a convalescent sample if IgM against JEV is not detected in a serum sample collected within 10 days of illness onset. Confirmatory neutralizing antibody testing should be performed in case of detection of virus-specific IgM antibodies. However, this type of testing is only carried out by the Centers for Disease Control and Prevention (CDC) and certain specialized reference laboratories around the world. The guidelines, as set by the National Vector Borne Disease Control Programme (NVBDCP) for the laboratory confirmation of a suspected case of JE, require the detection of IgM antibody against JE in serum and/or CSF, a fourfold difference in IgG in paired sera, virus isolation or antigen detection from brain tissue by immunofluorescence, or the detection of JEV nucleic acid by polymerase chain reaction (PCR).
Laboratory confirmation of JEV infection by methods such as reverse transcriptase PCR (RT-PCR), Plaque Reduction Neutralization Test, and virus isolation are time-consuming, costly, and technically demanding with respect to equipment complexity and manpower training. Moreover, other important concerns for the detection of the whole virus by laboratory isolation include the safety and health of the personnel involved in the assays, as JEV is highly contagious and poses a risk of laboratory-acquired infections. Hence, virus isolation requires an elaborate Biological Safety Level-3 (BSL-3) laboratory setup with specialized Personal Protective Equipment (PPE). For a rapid, sensitive, and specific detection of JEV, biosensors provide the biggest advantage as they can be helpful in point of care diagnostics.
The specificity of assays such as JEV MAC-ELISA could be low in certain areas where multiple flaviviruses co-circulate due to the cross-reactivity of IgM antibodies to conserved, immunogenic epitopes on the flavivirus envelope protein. Nucleic acid amplification, histopathology, immunohistochemistry, and viral culture on autopsy tissue samples are useful for post-mortem diagnosis as well.
As there is no cure for the disease, treatment focuses entirely on relief from clinical signs and symptoms and supportive care.
Chikungunya virus (CHIKV) is an RNA virus under the genus Alphavirus, of family Togaviridae, responsible for causing chikungunya fever which is transmitted by the blood meal of infected mosquitoes, such as Aedes aegypti and Aedes albopictus, to human beings. An important determinant of the epidemic potential is vector population density, which is linked to the seasonal activity in the weeks between spring egg hatching and autumn egg diapause.
In the Kenyan language, “chikungunya” means “it contorts or bends up” which point towards the stooping posture of the patient caused by unbearable joint pain due to arthritis. Symptoms such as fever, headache, joint pain, and rash usually begin after 2-6 days of incubation. A significant outbreak of Chikungunya fever was documented in India in 1963 at Kolkata, 1965 at Pondicherry and Chennai in Tamil Nadu, 1973 at Nagpur and Barsi in Maharashtra, Rajahmundry, Visakhapatnam, and Kakinada in Andhra Pradesh. Subsequently, plenty of sporadic outbreaks continued to be recorded in India. Following a quiescence of 32 years, CHIKV re-emerged in India in 2005. The re-emergence is believed to have resulted from novel viral mutations and a new vector. The CHIKV has undergone a novel mutation (E1-A226V) where valine replaces alanine in the 226 position of the E1 glycoprotein gene, leading to a change in vector preference. The increased affinity of the mutated virus for Ae. albopictus compared to Ae. aegypti can be explained by the aforementioned mutationz.
In India, at present, diagnostic facilities are available at the National Institute of Virology (NIV), Pune and National Institute of Communicable Diseases, Delhi. Diagnosis of CHIKV can be done by detecting IgM/IgG antibodies by ELISA, viral isolation, and real-time RT-PCR assays targeting the nsP1 gene. The primary laboratory test used to diagnose CHIKV infection is the detection of CHIKV or viral RNA in serum collected within the first 5 days after symptom onset followed by the CHIKV-specific IgM MAC-ELISA, which has higher sensitivity. Laboratory confirmation of chikungunya is of most importance in areas where dengue is epidemic, due to similar clinical presentation of both the diseases. The diagnostic sensitivity and specificity of the NIV CHIK MAC ELISA kit by CDC, Colorado (CO), USA is 95% and 98%, respectively.
Johnson et al. in an evaluation of nine commercially available CHIKV IgM detection assays, observed that the performance of Abcam ELISA, Euroimmune ELISA, Euroimmune indirect immunofluorescence test, and InBios ELISA was comparable to each other and superior to the other kits evaluated. The sensitivity, specificity, and accuracy of these kits were as follows: Abcam ELISA (100%, 97%, 99%, respectively), Euroimmune ELISA (100%, 100%, 100%, respectively), Euroimmune indirect immunofluorescence test (92%, 100%, 96%, respectively) and InBios ELISA (100%, 100%, 100%, respectively).
There is no specific treatment for the disease, and fatalities are rare. Symptomatic management can ease disease manifestations, and recovery usually occurs after 2 weeks of illness. Prevention is centered primarily on vector control; no vaccine is currently available.
It is an acute hemorrhagic disease first discovered in Africa, caused by the Yellow fever virus of the genus Flavivirus, belonging to Flaviviridae. Tropical areas of Africa and Central and South America are endemic to the disease. Epidemic outbreaks of yellow fever occur when the virus is introduced into areas of high population and vector density, where the majority of individuals have little to no immunity (due to either poor vaccination coverage or lack of prior exposure).
The yellow fever virus is transmitted by mosquito genera such as Aedes, Haemagogus, and Sabethes which breed in a variety of habitats such as domestic (areas in and around houses), wild (implying jungle habitats), and semi-domestic (which can include both the aforementioned locations). There are 3 types of transmission cycles:
- Sylvatic yellow fever: The primary reservoir of this infection are those monkeys in tropical forests, bitten by wild mosquitoes of Aedes and Haemagogus species, which then transmit the virus to other monkeys. Sometimes the infected mosquitoes can bite the people who are trespassing or laboring in the forest; this can lead to yellow fever in humans
- Intermediate yellow fever: Semi-domestic mosquitoes that can breed in both jungle and household habitats infect both monkeys and people. It is the commonest cause of outbreaks in Africa. It has a higher transmission rate than the sylvatic cycle due to increased contact between mosquitoes and people. Nearby villages in a locality can have outbreaks at the same time
- Urban yellow fever: High density of Aedes aegypti mosquitoes in heavily populated areas can cause large epidemics where infected people transmit the virus via mosquitoes to people without immunity due to poor vaccination coverage.
No case of yellow fever has been reported from India to date. India possesses a tropical climate resembling Africa along with a heavy distribution of the vector Ae. aegypti, which puts the country at a high risk of developing yellow fever outbreaks in the future. There are plenty of reasons put forth to explain the absence of yellow fever in India, such as strict measures for international travelers, including vaccination for yellow fever 10 days prior to travel to an endemic country and a quarantine period of 6 days in case of unvaccinated individuals (6 days being the maximum incubation period for the disease). The Breteau index or Aedes aegypti index surrounding 0.4 km of an airport should be less than one.
Clinically, an elevation in the level of serum transaminases is observed within 2-3 days of infection. A diagnosis of yellow fever is dubious when there is a preponderance of AST relative to ALT, which is the opposite of what is typically expected in cases of viral hepatitis. Laboratory diagnosis by the method of nucleic acid amplification of yellow fever virus from blood can be confirmatory up to 5 days of viremia. After day 5, serological detection of IgM and IgG antibodies specific for yellow fever is mandatory;, however cross-reactivity may be seen with other flaviviruses such as dengue virus. Post-mortem diagnosis on autopsy can be confirmed by biopsy of tissues within 24 hours, followed by immunohistochemistry.
Currently, no specific antivirals are available for the treatment of yellow fever. Supportive treatment with specific care to treat dehydration, fever, renal and hepatic failure improves patient outcomes. The most important mode of prevention of yellow fever involves vaccination in endemic areas and for travellers to endemic areas. According to CDC recommendations, the live-attenuated yellow fever virus 17D vaccine (YF-17D vaccine) is advised for individuals aged 9 months – 59 years who either live or are travelling to regions with a high risk for yellow fever activity, or travelling to countries requiring an “International Certificate of Vaccination or Prophylaxis” (ICVP) for entry. Yellow fever transmission in urban areas can be lowered by eradicating mosquito breeding areas by using larvicides in water storages and places where there is a collection of standing water.
Zika virus disease
Zika virus (ZIKV) disease has attained global prominence fairly recently. In March 2015, when Brazil recorded a large outbreak of infections associated with fever and rash, ZIKV was soon implicated as the etiologic agent. Over the subsequent months, an association of the infection with Guillain-Barré syndrome (GBS) and microcephaly was uncovered (in July and October 2015, respectively), finally culminating in WHO declaring the outbreak a Public Health Emergency of International Concern on February 1, 2016.
ZIKV is a positive sense ssRNA virus belonging to the genus Flavivirus of the family Flaviviridae. The virus was initially identified in 1947 in monkeys residing in the Zika forest of Uganda. The first documented case in humans was reported in 1954 from Nigeria. ZIKV infections were initially considered to be restricted in geographical distribution until large outbreaks of infection occurred in the Pacific islands and South America, beginning in 2007. In India, the Indian Council of Medical Research (ICMR) has carried out sentinel surveillance for ZIKV through its network of laboratories starting from 2016. As a result, the first sporadic cases were detected in Tamil Nadu and Gujarat in 2016-2017. Subsequently, outbreaks were reported in Madhya Pradesh and Rajasthan in 2018. The most recent of such outbreaks were reported from Kerala in May 2021, followed by the states of Maharashtra and Uttar Pradesh in the ensuing months.
Female mosquitoes of the genus Aedes (Ae. aegypti and Ae. albopictus) constitute the primary vector involved in disease transmissions like other arboviruses, such as those causing Dengue and Chikungunya. Non-human primates (NHPs) are thought to play the role of amplifying hosts in the sylvatic cycle. Other modes of transmission include blood transfusion, perinatal transmission, or via sexual intercourse. Of these, perinatal transmission poses a significant concern due to the associated birth defects. ZIKV has not been reported to be transmitted via breast milk.
Most ZIKV infections in humans are thought to be asymptomatic. Symptomatic infections have an incubation period ranging from 3-14 days and are characterized by non-specific manifestations of low-grade fever, myalgia, arthralgia, and headache along with maculopapular rash and conjunctivitis. The disease was long considered to be benign and self-limiting. However, neurological complications such as GBS were noted in those infected during the ZIKV outbreak in French Polynesia in 2013. Attention to the link between ZIKV infection and microcephaly was drawn following an alarming increase in the incidence of the latter in Brazil's Northeast region, during the 2015 outbreak. Macular and chorioretinal abnormalities are also seen concurrently along with microcephaly in certain cases.
Virus isolation or viral genome detection in blood by real-time RT-PCR targeting the envelope (E) gene, performed within 5 days of illness onset, is the gold standard reference. However, ZIKV can also be isolated from saliva, amniotic fluid, urine, and semen. RT-PCR can be used to demonstrate the presence of ZIKV in neuronal tissues. Serological tests for antibody detection have been developed (e.g., the CDC developed the ELISA technique for IgM detection in 2007). However, the efficacy of these tests is offset by the high frequency of cross-reactions, especially in infections with related arboviruses. Currently, no serological tests are licensed in India for the diagnosis of ZIKV disease. Sentinel surveillance for ZIKV is carried out by subjecting a proportion of samples from the cases presenting with AFI to ZIKV PCR testing.
As of 2022, no licensed vaccine or specific antiviral is known to be effective against ZIKV, and treatment constitutes entirely supportive interventions.
TICK-BORNE ARBOVIRAL DISEASES
The discussion on tick-borne arboviral infections is largely confined to Kyasanur Forest Disease (KFD), the main tick-borne arboviral disease endemic in India, in this review. However, some of the other uncommonly encountered arboviral infections, including those resulting in encephalitis or fever with rash, that has been sporadically reported in the country are mentioned in Tables 2-4. Figures 1-4 illustrate the geographical distributions of commonly encountered arboviral diseases in India.
Kyasanur forest disease
KFD is an arboviral tick-borne disease mainly affecting monkeys but has recently been recognized as an emerging zoonosis in humans. The disease was first identified in 1957, following observations of monkey mortality in the forested area of Shimoga district, Karnataka, India, followed by cases of acute, hemorrhagic fever in nearby people.
KFD Virus (KFDV) is a positive sense ssRNA virus and a member of the genus Flavivirus of the family Flaviviridae. The virus is closely related to another tick-borne flavivirus – the Alkhurma Hemorrhagic Fever Virus, which is endemic in Saudi Arabia and Egypt.
In nature, the main vector for KFDV transmission includes hard ticks belonging to the genus Haemaphysalis (e. g. H. spinigera) which transmit the infection among wild non-human primates (NHPs) such as red-faced bonnet monkeys (Macaca radiata) and black-faced langurs (Semnopithecus entellus). However, the virus has a wide host range, and numerous other wild animal species can serve as natural reservoirs.
The annual incidence of KFD in India is around 400-500 cases yearly. KFD is endemic in the state of Karnataka, India, especially in the regions of Shimoga, Uttara Kannada, Chikkamagalore, Dakshina Kannada, and Udupi. Moreover, serological evidence also suggests the presence of KFDV and/or related viruses in other parts of India, including parts of the Kutch district, the Saurashtra region in Gujarat, and parts of West Bengal.
The incubation period of KFD in humans typically ranges from 3-8 days, beginning with a prodromal phase associated with sudden onset fever, chills, headache, and myalgia. Sometimes, it may be accompanied by lymphadenopathy, conjunctival suffusion, and hemorrhaging of eyes and mucus membranes. Recovery usually begins after two weeks of illness and is associated with a long convalescent phase; this may sometimes be complicated by a second phase consisting of neurologic manifestations-including severe headache, mental changes, tremors, and rigidity. Massive hemorrhage from pulmonary (leading to hemoptysis) and gastro-intestinal sites (leading to melena) is an important end-stage complication leading to mortality. The case fatality rate is reported to be approximately 3.4% and long-term sequelae are uncommon.
Isolation of KFDV is the gold-standard method for diagnosis and can be done on Baby Hamster Kidney-21 (BHK–21), Vero E6 cell lines, or in mice. Antibodies against KFDV can be detected in clinical samples by hemagglutination inhibition or neutralization tests; recently, MAC-ELISA platforms have been developed for IgM detection during the acute phase. RT–PCR assays targeting Flavivirus-specific NS5 region are highly sensitive and specific compared to conventional methods.
Treatment mainly consists of supportive measures and may involve early hospitalization and the infusion of intravenous fluids to combat hypotension. As of today, no specific antiviral agents are available for treatment. The health department of the State Government of Karnataka was involved in the development of a formalin-inactivated chick embryo fibroblast vaccine in the early 1990s, which is currently licensed and available in India. The vaccination strategy involves two doses administered a month apart, followed by booster doses after 6–9 months and subsequently every 5 years.
Given their history, arboviral epidemics will likely continue to emerge and expand to new geographical niches. In addition, animals constitute an enormous reservoir of potentially novel human arboviral infections, which might emerge via zoonotic spill-over. Thus, sustained interdisciplinary One Health-based approaches and strengthening of national programs such as NVBDCP for integrated vector management would be required to anticipate the occurrence as well as prevent or mitigate the severity of such outbreaks. Research initiatives focusing on surveillance systems, vector control, and diagnostic modalities must be prioritized. Finally, global alliances such as the Global Arbovirus Initiative, launched by the WHO in March 2022, may be required for the timely mobilization of resources on an international scale to combat arboviral disease.
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