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Most of the ZIKV cases are either in-apparent infections (about 80%) or mild ‘dengue-like’ syndrome.14 Symptomatic case usually presents with abrupt onset of mild fever, joint pain, headaches, retro-orbital pain, maculo-papular rash usually with itching, and conjunctivitis. Oedema of extremities, vertigo, myalgia and digestive disorder may also occur. These symptoms are usually mild and last for 2-7 days and the incubation period ranged 3-12 days.7,19 The cause of phobia about Zika is due to its suspected implication with increased neonatal microcephaly (as discussed), and other neurological conditions as Guillain-Barré syndrome.4,7
Laboratory diagnosis, Infection with ZIKV can be diagnosed by PCR or by IgG and IgM antibodies detection.7,20
Arboviruses are transmitted between arthropods (mosquitoes, ticks, sandflies, midges, bugs…) and vertebrates during the life cycle of the virus.8 Many arboviruses are zoonotic, i.e., transmissible from animals to humans.9,10 As far as we are aware, there are no confirmed examples of anthroponosis, i.e., transmission of arboviruses from humans to animals.9,10 The term arbovirus is not a taxonomic indicator; it describes their requirement for a vector in their transmission cycle.11,12 Humans and animals infected by arboviruses, may suffer diseases ranging from sub-clinical or mild through febrile to encephalitic or hemorrhagic with a significant proportion of fatalities. In contrast, arthropods infected by arboviruses do not show detectable signs of sickness, even though the virus may remain in the arthropod for life. As of 1992, 535 species belonging to 14 virus families were registered in the International Catalogue of Arboviruses.12 However, this estimate is continuously increasing as advances in virus isolation procedures and sequencing methods impact on virus studies. Whilst many current arboviruses do not appear to be human or animal pathogens, this large number of widely different and highly adaptable arboviruses provides an immense resource for the emergence of new pathogens in the future.
Despite the announcement of the successful eradication of smallpox in 1979, the last case of rinderpest in 2008 and the current campaigns to eradicate poliomyelitis and measles through mass-immunization programmes, we still face the prospect of emerging or reemerging viral pathogens that exploit changing anthropological behavioural patterns. These include intravenous drug abuse, unregulated marketing of domestic and wild animals, expanding human population densities, increasing human mobility, and dispersion of livestock, arthropods and commercial goods via expanding transportation systems. Consequently, the World Health Organization concluded that acquired immune deficiency syndrome, tuberculosis, malaria, and neglected tropical diseases will remain challenges for the foreseeable future.1 Understandably, the high human fatality rates reported during the recent epidemics of Ebola, severe acute respiratory syndrome and Middle East respiratory syndrome have attracted high levels of publicity. However, many other RNA viruses have emerged or reemerged and dispersed globally despite being considered to be neglected diseases.2,3 Chikungunya virus (CHIKV), West Nile virus (WNV) and dengue virus (DENV) are three of a large number of neglected human pathogenic arthropod-borne viruses (arboviruses) whose combined figures for morbidity and mortality far exceed those for Ebola, severe acute respiratory syndrome and Middle East respiratory syndrome viruses. For instance, for DENV, the number of cases of dengue fever/hemorrhagic fever is between 300–400 million annually, of which an estimated 22 000 humans die.4 Moreover, in the New World, within 12 months of its introduction, CHIKV caused more than a million cases of chikungunya fever according to Pan American Health Organization/World Health Organization, with sequelae that include persistent arthralgia, rheumatoid arthritis and lifelong chronic pain.5 Likewise, within two months of its introduction, to Polynesia, the number of reported cases exceeded 40 0006 and is currently believed to be approaching 200000 cases. Alarmingly, this rapid dispersion and epidemicity of CHIKV (and DENV or Zika virus in Oceania) is now threatening Europe and parts of Asia through infected individuals returning from these newly endemic regions. This is an increasingly worrying trend. For example, in France, from 1 May to 30 November, 2014, 1492 suspected cases of dengue or chikungunya fever were reported.7 Accordingly, this review focuses on the emergence or reemergence of arboviruses and their requirements and limitations for controlling these viruses in the future.
The recent epidemic of Ebola virus in Africa as well as the emergence of a hitherto unknown virus known as Middle East respiratory syndrome coronavirus (MERS-CoV), Bas-Congo virus in central Africa or of severe fever with thrombocytopenia syndrome virus (SFTSV) in China have repeatedly shown the global impact of emerging infectious diseases (EIDs) on economics and public health. These EIDs, more than 60% of which are of zoonotic origin, are globally emerging and re-emerging with increased frequency. Surveillance and monitoring of viral pathogens circulating in humans and wildlife and the identification of EIDs at an early stage is challenging. Many potential emerging viruses of concern might already be infecting humans or wildlife but await their detection by disease surveillance. In remote and underdeveloped regions of the world, often no attention is paid towards possible infectious disease cases until a threshold of serious cases and deaths appears in a cluster and certain epidemic properties are reached. Some viruses might just be overlooked at population levels until they spread or re-emerge and become epidemic in another region or time. An effective strategy in virus surveillance would need to survey simultaneously a wide range of viral types in a large number of human and wildlife individuals in order to detect viruses before spreading. For example, the EcoHealth Alliance within the surveillance program PREDICT seeks to identify new EIDs before they emerge or re-emerge. Therefore, wildlife animals that are likely to carry viruses with zoonotic potential, e.g., bats, rodents, birds and primates, are sampled frequently. However, collecting swabs or blood from sufficient numbers of wildlife individuals and the subsequent identification of viruses is challenging. The solution for overcoming this challenge might be presented by the disease vector itself. Blood feeding arthropods feed on blood from a wide range of hosts including humans, mammals and birds. Therefore, they act as “syringes”, sampling numerous vertebrates and collecting the viral diversity over space, time and species. Xenosurveillance and vector-enabled metagenomics (VEM) are surveillance approaches that can exploit mosquitoes to capture the viral diversity of the animal, human or plant host the mosquito has fed on (Figure 1). Xenosurveillance, a term introduced by Brackney et al., refers to the identification of viral pathogens from total nucleic acids extracted from mosquito blood meals, either by next-generation sequencing (NGS) or conventional PCR assays. Recent developments in NGS and viral metagenomics, which is the shotgun sequencing of viral nucleic acids extracted from purified virus particles, offer great opportunities for the characterization of the complete viral diversity in an organism or a population. VEM, a technique used to sequence purified viral nucleic acids directly from insect vectors, has already been used to detect both animal and plant viruses circulating in vectors. This review summarizes findings from xenosurveillance efforts as well as VEM studies using mosquitoes, since both approaches combine sampling of multiple individuals of blood-feeding arthropods with the high-throughput properties of NGS.
In recent years the spread of vector borne diseases has gained concern worldwide, especially in tropical and subtropical regions because of their recurring outbreaks. Some of these diseases have become endemic in many areas causing millions of cases every year. The most common of these diseases includes Malaria, Dengue and Chikungunya spread by mosquito bites. Malaria has been long recognized as a significant public health threat with around 212 million cases reported in 2015 alone. Malaria is caused by five different species of Protozoal parasite, Plasmodium. These include P. falciparum, P. ovale, P. malariae, P. vivax and P. knowlesi that are carried and spread by Anopheles mosquito [4, 5]. Dengue and Chikungunya are caused by viruses named Dengue virus (DENV) and Chikungunya virus (CHIKV) respectively. Both are spread by common mosquito vectors Aedes s p. Dengue viruses have four serotypes DENV-1, 2,3 and 4. As many as 400 million people are affected with Dengue every year. Chikungunya follows somewhat unique pattern of spread across the world, it has the potential to emerge and re-emerge, drastically affecting a population and then remaining undetected for years. In recent years many tropical countries have seen an unexpected rise and spread in cases of Dengue and Chikungunya.
These three vector borne diseases share an overlapping epidemic pattern with most cases reported from tropical regions of the world. Several studies have been published reporting co-circulation of Malaria, Dengue and Chikungunya [10, 11]. Apart from shared endemicity, the three diseases also share similar clinical presentation with febrility as the most common symptom. There are several distinguishing features also, like periodic increase and decrease of fever in Malaria, hemorrhagic conditions and depletion of platelet count in Dengue and severe arthralgia in case of Chikungunya infection [12, 13]. The cumulative burden of these infections has increased in recent times with frequent outbreak of Dengue and Chikungunya being reported from several parts of the world. Global travel and rapid urbanisation are important factors that have contributed in expansion of disease endemicity by introducing the vector population to exotic surroundings.
Simultaneous infections with more than one infectious agent complicate the diagnosis and course of treatment available. Due to the similar nature of initial symptoms for Malaria, Dengue and Chikungunya and overlapping endemicity, misdiagnosis of dual infection as monoinfection is a real possibility. Indeed several reports have been published reporting such scenarios. These arthropod borne diseases affect some of the poorest countries and in resource poor settings; clinician might rely on symptoms and endemicity for diagnosis, which might lead to underdiagnosis of cocirculating pathogens. Despite similar clinical presentation the course of treatment is entirely different for all three diseases. Malaria is treated using antimalarial drugs. In case of Dengue and Chikungunya no vaccine or drug is available and clinicians rely on supportive therapy [13, 16]. Any delay in either diagnosis or start of therapy for any of these infections could have fatal outcomes. Also, there is lack of sufficient information on how concurrent infections affect disease severity and outcome. Several studies have been published that report cases of concurrent infection with two of these pathogens and in rare instances concurrent infection with all three vector borne infections. Such reports have the potential to inform public health officials and clinicians about the prevalence, disease severity and treatment options available for concurrent infections. The purpose of the present review is to assess the prevalence of such infections by thorough search and analysis of published literature.
The Aedes mosquito-transmitted viral disease of humans, Zika, was originally identified in 1947 and is named after the rainforest in Uganda, East Africa, where it was first isolated from rhesus macaques.1 For close on 70 years, the prevalence of Zika infection was very low, such that prior to now it has attracted little interest apart from arbovirus and tropical medicine specialists. In the last several months, this scenario has changed dramatically, however, subsequent to a major Zika epidemic in over 35 countries in Latin America and the Caribbean.2 This includes an estimated 1,400,000 clinical cases in Brazil, from where the outbreak arose in early 2015,3 although questions regarding the accuracy of reporting have been raised.4 Furthermore, the World Health Organization (WHO) predicts that by the end of this year up to 4 million people across the Americas may be infected with the Zika virus.5 The impact on the vast majority of those people will be minimal, but particularly in infants the effect may be profoundly debilitating and long-lasting. Such is the extent of the issue, real and predicted, and the degree of concern that it has engendered globally, that on February 1, 2016 the International Health Regulations Emergency Committee of the WHO declared the Zika epidemic as “a public health emergency of international concern” and highlighted the importance of aggressive measures to reduce infection, especially of pregnant females and those of childbearing age.6 Subsequently, the US Centers for Disease Control and Prevention moved Zika to level 1 activation,7 the highest available state of response.
The incubation time for CHIKV is relatively short, requiring only 2–6 d with symptoms usually appearing 4–7 d post-infection. Vazeille et al. detected CHIKV in the salivary glands of Ae. albopictus only 2 d after infection. Upon infection, CHIKF tends to present itself in two phases. The first stage is acute, while the second stage, experienced by most but not all, is persistent, causing disabling polyarthritis. Characteristics of the acute phase include an abrupt onset of fever, arthralgia, and in some cases, maculopapular rash,. The acute phase causes such intense joint and muscular pain that makes movement very difficult and prostrates its victims,.
Ninety-five percent of infected adults are symptomatic after infection, and of these, most become disabled for weeks to months as a result of decreased dexterity, loss of mobility, and delayed reaction. Eighteen months after disease onset, 40% of patients are found to still have anti-CHIKV IgM,,,. The chronic stage of CHIKF is characterized by polyarthralgia that can last from weeks to years beyond the acute stage. CHIKV has been shown to attack fibroblasts, explaining the involvement of muscles, joints, and skin connective tissues. The high number of nociceptive nerve endings found within the joints and muscle connective tissues can explain pain associated with CHIKF,.
More than 50% of patients who suffer from severe CHIKF are over 65 y old, and more than 33% of them die. Most adults who suffer from severe CHIKF have underlying medical conditions,,. The other group that is disproportionately affected by severe CHIKV is children. Other complications associated with CHIKV, from most common to least common, include respiratory failure, cardiovascular decompensation, meningoencephalitis, severe acute hepatitis, severe cutaneous effects, other central nervous system problems, and kidney failure,,,,,,.
Similar to the etiological agents of yellow fever, Japanese encephalitis and dengue, Zika is a member of the Flavivirus genus of enveloped, positive sense, single-stranded RNA viruses.8 Compared to each of these close relatives, infection with which can be severely incapacitating for a person of any age, it is thought that approximately 80% of adults infected with Zika show no clinical manifestations.9 Hence, for several days after being bitten by an infectious mosquito, they may serve as asymptomatic carriers of infection. If a person is ill, the main symptoms may last for up to 1 week and are similar to but less severe than other related febrile illnesses – a mild headache, fever, myalgia, arthralgia, conjunctivitis, and maculopapular rash.10 The principal possible consequence of Zika infection, for which there is now claimed to be a causal link,11 occurs via congenital transmission from a pregnant female to her fetus in utero or newborn baby,10,12 the effects of which can be severe.13 In Brazil alone, the virus has been associated with over 4,000 cases of microcephaly,2 a previously uncommon condition that as a result of aberrant brain development produces babies with abnormally small heads and, in most cases, neurological impairment. In March 2016, Panama registered a baby born with microcephaly linked to the Zika virus, in what is thought to be the first such case outside Brazil during the current outbreak. The baby died within 4 hours and at postmortem examination the virus envelope protein was detected by enzyme-linked immunosorbent assay in the baby’s umbilical cord.14 Rarely, Zika is also associated with, but still not proven to be causally linked to, Guillain-Baré syndrome, a neural demyelination syndrome that is considered to be an autoimmune sequela of infectious disease.12,15
OHFV distribution is restricted to western Siberia (Figure 1). The main vector of OHFV is the meadow tick, Dermacentor reticulatus, which can also transmit the virus to humans. However, humans are mainly infected after contact with infected muskrats (Ondatra zibethicus) which are very sensitive to the infection and often succumb to the infection. Muskrats develop high viremia which can last for several weeks. Human infection occurs through contact with urine, feces, and blood. Secretion of OHFV in unpasteurized goat milk has been reported but no milk-borne outbreaks have been observed. The exact number of annual cases are uncertain because of misdiagnoses and unreported cases, but 165 cases were reported between 1988 and 1997. OHFV may cause a biphasic disease; the initial phase is characterized by high fever, bleeding from the nose, mouth, and uterus. Thirty to fifty percent of the cases experience a second phase characterized by high fever and reappearance of the symptoms from the initial phase. Case fatality rates range from 0.5 to 2.5%. No antiviral treatments are available against OHFV, instead treatment is focused on supportive care to minimize hemorrhage and other complications.
Bats and the viruses they harbor have been of interest to the scientific community due to the unique association with some high consequence human pathogens in the absence of overt pathology. Virologic and serologic reports in the literature demonstrate the exposure of bats worldwide to arboviruses (arthropod-borne viruses) of medical and veterinary importance. However, the epidemiological significance of these observations is unclear as to whether or not bats are contributing to the circulation of arboviruses.
Historically, a zoonotic virus reservoir has been considered a vertebrate species which develops a persistent infection in the absence of pathology or loss of function, while maintaining the ability to shed the virus (e.g., urine, feces, saliva). Haydon et al. extended this definition of a reservoir to include epidemiologically-connected populations or environments in which the pathogen can be permanently maintained and from which infection is transmitted to the defined target population. The significance of the relative pathogenicity of the infectious agent to the purported reservoir host has been debated. In the case of bats as a reservoir species, rigorous field and experimental evidence now exist to solidify the role of the Egyptian rousette bat (Rousettus aegyptiacus) as the reservoir for Marburg virus. Considering arboviruses, additional criteria must be met in order to consider a particular vertebrate species a reservoir. Reviewed by Kuno et al., these criteria include the periodic isolation of the infectious agent from the vertebrate species in the absence of seasonal vector activity, and the coincidence of transmission with vector activity. Further, the vertebrate reservoir must also develop viremia sufficient to allow the hematophagous arthropod to acquire an infectious bloodmeal in order for vector-borne transmission to occur. Bats have long been suspected as reservoirs for arboviruses, but experimental data that would support a role of bats as reservoir hosts for certain arboviruses remain difficult to collect. Here we synthesize what information is currently known regarding the exposure history and permissiveness of bats to arbovirus infections, and identify knowledge gaps regarding their designation as arbovirus reservoirs.
Among emerging zoonotic wildlife diseases, vector-borne infections pose a major challenge to public health both in terms of vector and pathogen abundance and diversity and of human and animal morbidity and mortality. Furthermore, the continuous discovery of new pathogens and the emergence of new epidemiological cycles, due for example to the invasion of new habitat by vector species, claim the need for a constant and intensified surveillance.
In general, vector-borne pathogens account for more than 17% of all infectious diseases, causing more than 700 000 deaths annually (https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases, accessed May 27, 2019). The burden of these diseases is highest in tropical and subtropical areas where especially mosquito-borne diseases disproportionately affect the poorest populations. In such areas, major outbreaks of dengue, malaria, chikungunya, yellow fever and more recently Zika have been afflicting populations, claimed lives and overwhelmed health systems. Other diseases such as Chagas disease and leishmaniosis affect hundreds of millions of people worldwide (https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases, accessed May 27, 2019).
Within the temperate areas of the northern hemisphere wildlife zoonoses carried by ticks pose the greatest challenge when compared to mosquito-borne infection. In general, reported cases of vector-borne infections have increased during the last 30 years in the northern hemisphere (Semenza and Suk, 2018). In Europe, the most challenging infections include Ixodes ricinus transmitted diseases such as Lyme borreliosis (LB) and Tick-borne encephalitis (TBE) with an average number of 85.000 and 16.000 cases reported annually respectively. Other tick-borne diseases with rising public health concern include rickettsiosis and Crimean-Congo Hemorrhagic Fever. Mosquito borne diseases of concern include viral infection induced by WNV, Usutu virus (USUV) and Chikungunya virus (CHIKV), while others (i.e. dengue virus, Plasmodium spp.) still represent a potential threat with few sporadic autochthonous episodes of local circulation, especially within the countries of the Mediterranean basin.
A similar trend has been reported for the USA where cases of mosquito-borne and tick-borne diseases have more than tripled since 2004, characterized by steadily increasing incidence of tick-borne diseases and sporadic outbreaks of domestic and invasive mosquito-borne diseases (Petersen et al., 2019).
Transmission of vector-borne pathogens is particularly sensitive to anthropogenic changes as they imply the interaction of three principal players: the pathogen, the vector (represented in many cases by an invertebrate) and a vertebrate host which can acquire and transmit the infection, if competent. Changes in vector-host interaction and in the vectorial capacity can determine a rise in infection hazard and disease incidence.
POWV is found in Russia and North America, and is the only TBFV present in America (Figure 1). It is transmitted by Ixodes scapularis, Ixodes cookei, and several other Ixodes tick species, to small and medium size mammals, whereas humans are accidental dead-end hosts. Milk-borne POWV transmission might also be possible since POWV virus has been found to be secreted in milk under experimental settings.
Although not much is known about POWV pathogenesis, recent studies in mice have found that tick saliva was important to enhance POWV transmission and the outcome of disease. Furthermore, it has been demonstrated that POWV infects macrophages and fibroblasts in the skin, shortly after the tick bite, also, other unidentified cells were shown to be infected. Interestingly, macrophages were found to be the primary target for POWV in the spleen, and in the CNS, which is the main target site for POWV infection, neurons have been shown to be the primary target for POWV in mice and humans.
During the last 10 years there has been an increase of POWV in the USA with approximately 100 reported cases. The recent rise in incidence could be due to increased surveillance and diagnosis of POWV, or it may represent a true emergence of the disease in endemic areas, or both. The incubation period ranges from 1 week to 1 month. The symptoms of POWV infection may include fever, headache, vomiting, weakness, confusion, seizures, and memory loss with a case fatality rate of 10%. Approximately half of the survivors experience permanent neurological symptoms, such as recurrent headaches, muscle wasting, and memory problems (https://www. CDC.gov). There are no antiviral treatments or vaccines available against POWV.
Zika virus is a new emerging mosquito-borne virus belonging to the Flaviviridae family of viruses (9). This family is comprised of 4 genera: Flavivirus, Hepacivirus, Pegivirus, and Pestivirus (10). Zika virus belongs to the Flavivirus genus, which antigenically and phylogenetically is related to the Spondweni virus (9, 11). Many important human pathogens are included in this genus, for instance, Dengue, West Nile, Yellow fever, tick-borne encephalitis, Japanese encephalitis, Murray Valley encephalitis and St. Louis encephalitis viruses. These viruses are associated with a range of infections from asymptomatic or self-limiting febrile infections to some fatal diseases such as hemorrhage, shock, meningitis, and encephalitis (12).
In Flaviviridae family, all members have enveloped viruses with a single-stranded RNA genome of positive polarity (10) which contained one open reading frame (ORF) with two flanking noncoding regions (at 5′ and 3′ end) (13). The genomes are 5′ capped without a 3′ poly (A) tail.
A polyprotein is coded by the ORF then processed into three structural proteins (the envelope (E), the capsid (C) and the precursor of the membrane (prM)) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (1, 12). The ssRNA is held within an icosahedral capsid shaped from 12-kDa protein blocks; the nucleocapsid is surrounded by a host-derived membrane contained two viral glycoproteins (14).
Similar replication strategies are employed by the members of Flaviviridae family despite significant differences in tissue tropism, transmission, and pathogenesis (10).
Zika infection is asymptomatic in 80% of cases. When symptomatic, it is typically described as a mild dengue-like illness, manifested by two or more of the following: sudden onset fever, conjunctivitis, arthralgias, and maculopapular rash (Figure 2). Myalgias and headache are also common. The WHO interim case definition describes suspected, probable and confirmed cases.12 Unlike in dengue, death from acute Zika virus infection is rare, but has been reported in a child with sickle cell disease in Colombia.13 The incubation period for Zika virus after a person is bitten by an infected mosquito ranges from 2–7 days, and may be up to 14 days. This is the reason for screening for risk factors within 14 days of symptom onset. The incidence of GBS or microcephaly appears to be similar between symptomatic and asymptomatic cases.
Patients should be assessed for pregnancy as well as for neurological symptoms and signs indicating possible GBS. While the situation is rapidly evolving, as of March 2016, laboratory testing is only available through the Centers for Disease Control and Prevention (CDC) and several state and territory health departments. Generally, testing is not recommended for asymptomatic persons, with the exception of pregnant women 2 to 12 weeks after travel to areas with ongoing Zika virus transmission.17 In symptomatic patients, serum should be obtained for polymerase chain reaction (RT-PCR), IgM, and IgG if within seven days of symptom onset. If more than seven days has elapsed, only IgM and IgG should be assessed; RT-PCR is not indicated.18 Note that serological cross reactivity may occur between Zika and other flaviviruses (e.g., dengue, yellow fever, St. Louis encephalitis, Japanese encephalitis, West Nile). Public health departments may decline to test if the clinical scenario is not suggestive of Zika virus or associated complications. In particular, due to the high cross-reactivity with related flaviviruses, serologic test interpretation is complex and can be difficult, leading to false positive results. Conversely, a negative Zika IgM or RT-PCR test result does not rule out Zika virus infection. Emergency clinicians should consult with public health experts to assist with interpretation of test results.
The global resurgence of dengue in endemic areas has been attributed to rapid population growth and urban expansion. Unplanned urban expansion leads to high densities of humans exposed to the mosquito vector Ae. aegypti. It also puts severe constraints on civic amenities, particularly water supply and solid waste disposal, thereby increasing the breeding potential of the vector species [4, 9]. Water that is left stored in the open can become a breeding ground for mosquitoes that carry dengue fever. Risk factors associated with dengue also include lacking mosquito control infrastructure and dengue vector control services. In addition, increased air travel and globalization of trade significantly contributed to the introduction of all dengue virus serotypes to most population centers of the world. Globalization and travel have also contributed to hyperendemic transmission of all four dengue serotypes throughout the tropics.
Changing dengue incidence and distribution have also been attributed to climate [22, 23]. Rainfall and temperatures affect the spread of mosquito vectors and virus transmission. Rising temperatures and changing rainfall patterns, two examples of climate change, have been linked to the expansion of the flight ranges of mosquitoes carrying malaria (Anopheles), dengue fever (Ae. Aegypti), and other tropical diseases. Climate change has been associated with increases in dengue incidence and distribution in Puerto Rico, Mexico, and Thailand.
Indeed, global warming is predicted to lead to an increase in global temperatures between 2 and 4.5 degrees' Celsius by the year 2100 and could have a perceptible impact on vector-borne diseases. Climate change is projected to lead to a substantial increase in populations at risk of dengue and could expose an additional two billion people to dengue transmission by 2080. Studies also predict that global climate change could affect sylvatic dengue virus (DENV) affecting wild animals, as compared to urban DENV circulation, and lead to cross-species transmission of DENV into humans. It is also conjectured that climate change and climate variability have the greatest adverse effect on small island states [28–30].
Members of the genus Orthonairovirus of medical and veterinary significance include Crimean Congo hemorrhagic fever virus (CCHFV) and Nairobi sheep disease virus (NSDV). CCHFV is transmitted by ticks in genera Rhipicephalus and Hyalomma. While neither live virus nor nucleic acid of CCHFV has been detected from bats, serologic evidence suggests past infection of populations of bats across a diverse geographic range. Further, bats are often parasitized by both soft and hard ticks, which occupy a diverse range of ecological niches in endemic countries. A 2016 seroprevalance study by Müller and colleagues examining 16 African bat species (n = 1,135) found that the prevalence of antibodies against CCHFV was much higher in cave-dwelling bats (3.6%–42.9%, depending on species) than foliage-living bats (0.6%–7.1%). They also screened 1,067 serum samples by RT-PCR, but all were negative for CCHFV nucleic acid. Experimental studies to assess the ability of bats to support replication of CCHFV have not been published.
Initial assessment was based on review of title and abstract of all studies. Full texts of potentially relevant studies were further analysed for coinfection prevalence data. Cross-sectional studies, retrospective analysis and case reports with full text availability and reporting data about any/all of the coinfections were included in the study. We excluded studies carried out in animals, reviews, letters, opinion pieces, grey literature, dissertations and conference abstracts.
Electronic databases of PubMed, WHO, CDC, Pan American Health Organization (PAHO), Google, and Cochrane library were extensively searched for ZIKV and mass gathering. It was done from 1947 till May 2016. The keywords emerging diseases, Zika virus, epidemiology, phobia, mass gathering, preparedness, surveillance were searched. Many articles were reviewed, scrutinized and critically appraised and the most relevant articles were utilized.
Depending on the purpose of the investigation, laboratory diagnosis of Zika virus can be conducted by virus isolation, antigen detection, viral RNA detection with molecular assays and anti-Zika virus antibodies detection with serological assays (35).
Since the beginning of modern virology in the 1950s, transmission electron microscopy (TEM) has been one of the most important and widely used techniques for the identification and characterization of new viruses. Two TEM techniques are usually used for this purpose: negative staining on an electron microscopic grid coated with a support film and (ultra) thin section TEM of infected cells, fixed, pelleted, dehydrated, and embedded in epoxy plastic. Negative staining can be conducted on highly concentrated suspensions of purified virus or cell culture supernatants. For some viruses, TEM can be conducted on contents of skin lesions (e.g., poxviruses and herpesviruses) or concentrated stool material (rotaviruses and noroviruses). For successful detection of viruses in ultrathin sections of infected cells, at least 70% of cells must be infected, and so either high multiplicity of infection (MOI) or rapid virus multiplication is required.
Viruses can be differentiated by their specific morphology (ultrastructure): shape, size, intracellular location or, for some viruses, from the ultrastructural cytopathology and specific structures forming in the host cell during virus replication. Usually, ultrastructural characteristics are sufficient for the identification of a virus at the level of a family. In certain cases, confirmation can be obtained by immuno-EM performed either on virus suspension before negative staining or on ultrathin sections. This requires virus-specific primary antibodies, which might be not available in the case of a novel virus. For on-section immuno-EM, OsO4 post-fixation must be omitted and the partially dehydrated sample must be embedded in a water-miscible acrylic plastic (usually LR White). The ultrastructure of most common viruses is well documented in good atlases and book chapters and many classical publications of the 1960s, 1970s, and 1980s. Several excellent reviews were recently published on the use of TEM in the detection and identification of viruses.
Zika virus (ZIKV) is a mosquito-borne virus from the genus Flavivirus in the family Flaviviridae and consists of two genetically distinct lineages: Asian and African. Other notable viruses within this genus include dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and yellow fever virus (YFV). Like most flaviviruses, the ZIKV is an enveloped virus with a capsid 50 nm in diameter and an RNA genome of approximately 11 Kb in length. The genome is translated as a single long open reading frame (ORF) and encodes ten proteins. This includes seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5), which mediate viral replication for synthesis of new viral particles, and three structural proteins (C, prM, and E), which comprise the capsid and play a key role in host immune evasion.
First identified in 1947 in the Zika Forest of Uganda, ZIKV infections in humans remained sporadic for 60 years, with very few cases reported, until April 2007 when the ZIKV caused an outbreak on Yap Island, Federated States of Micronesia. In 2013, the ZIKV was identified in French Polynesia and spread rapidly across the Pacific, including New Caledonia and Cook Islands. Coincidentally, during those outbreaks, the link between Guillain–Barré syndrome (GBS) and ZIKV was reported, raising concerns about the neurological tropism of the virus. In May 2015, the first case of ZIKV infection was reported in Brazil and the virus rapidly spread throughout the country and much of Latin America, causing the largest recorded epidemic of the virus to date. The Brazilian epidemic raised great international concern because of severe birth defects, including microcephaly, in neonates born to mothers infected by ZIKV during pregnancy.
ZIKV is transmitted mainly through the bite of infected mosquitoes from the genus Aedes, although other vectors may also be involved in the transmission. Additionally, other routes of ZIKV transmission have been identified, including blood transfusions, transplacental, perinatal, and sexual intercourse. ZIKV infection usually causes a self-limiting and a mild illness, where the majority of cases are asymptomatic and, when present, symptoms include fever, headache, rash, conjunctivitis, and arthralgia. In regions where there is a circulation of other arboviruses, such as DENV and chikungunya (CHIKV), the clinical diagnosis of ZIKV infection becomes extremely difficult because of common symptoms. Therefore, laboratory-based molecular diagnosis is of fundamental importance to correctly identify the etiologic agent.
Given the lack of approved vaccines and antivirals against ZIKV, a rapid and reliable point-of-care (POC) diagnostic test for detection of ZIKV is urgently required for control and prevention measures and to increase the diagnostic capacity of ZIKV-affected, mainly in low-resource areas. ZIKV infection is diagnosed in the laboratory by nucleic acid amplification tests or serological methods, including enzyme-linked immunosorbent assays (ELISA), plaque reduction neutralization tests (PRNT), and lateral flow assays (rapid tests). Currently, RT-qPCR is considered the gold standard method to detect ZIKV from patient and mosquito samples. Although RT-qPCR provides high-quality results, the test requires extensive sample preparation, RNA extraction, expensive equipment, and technical expertise to run and interpret the amplification of the viral RNA. Moreover, available serological methods are prone to produce false-positive results due to cross-reaction with other flaviviruses in circulation, such as DENV, and are therefore of limited value.
Loop-mediated isothermal amplification (LAMP) is a powerful alternative POC assay for the virus as it allows rapid, robust, and simple amplification of nucleic acid targets at a single and fixed temperature. The assay has many advantages over RT-qPCR, including rapidity, low cost, high sensitivity, and high specificity. LAMP results can also be easily read with the naked eye through color-based reporters that can be added to the reaction mixture. Importantly, the simple, single-temperature incubation allows LAMP reactions to be performed without expensive equipment, directly in the field. Since the 2015 emergence of the ZIKV in Brazil, many LAMP assays have been developed for diagnosis by research groups across the world. These diagnostic platforms based on LAMP have proven to be specific, sensitive and inexpensive POC tools that can be applied even in resource-limited regions of the world. Here we review the development and application of LAMP methods for the diagnosis of ZIKV and explore the next steps to bring this assay into mainstream use.
Zika virus (ZIKV) is an emerging mosquito-borne human-pathogenic flavivirus that has been mostly neglected due to its mild clinical manifestations and limited spread in restricted geographical regions in the first 60 years after its discovery.1 ZIKV was first isolated from the serum of a febrile sentinel rhesus macaque in 1947 in Zika Forest of Uganda.2 Between 1947 and 2006, <20 cases of human ZIKV infection were reported in the literature.1 These cases were geographically restricted in certain African (African lineage) and Southeast Asian (Asian lineage) countries. The first documented sizable outbreak of human ZIKV infection outside Africa and Asia occurred on Yap Island of the French States of Micronesia in 2007, during which 73% of the Yap population became infected.3 ZIKV then spread to other Pacific islands, and arrived in the western hemisphere in 2014 (Easter Island, Chile).4, 5, 6 Since then, many countries in the Americas have reported autochthonous cases of ZIKV infection. Brazil alone has reported an estimated 500 000–1 500 000 human cases of ZIKV infection in 2015.7 Although most patients with ZIKV infection are asymptomatic or have mild symptoms, life-threatening complications such as Guillain–Barré syndrome, thrombocytopenic purpura, and fatal disseminated disease in immunosuppressed hosts have been reported.1, 3, 8 Furthermore, preliminary epidemiological and virological data suggest that congenital ZIKV infection may be associated with microcephaly and other congenital anomalies in infected fetuses.9, 10, 11 The rapidly expanding epidemic and this suspected congenital ZIKV syndrome have led the World Health Organization to declare the ZIKV outbreak as a global public health emergency on 1 February 2016.12
The cause of the sudden emergence and rapid spread of ZIKV since 2007 is incompletely understood. A number of possible environmental factors have been proposed. First, globalization and urbanization have allowed ZIKV and its mosquito vectors to spread beyond their original geographical habitats. Second, major sport events including the World Cup and the Va'a World Sprint Championship canoe race in Brazil in 2014 might have provided an opportunity for infected travelers to introduce the virus to Latin America.13 Third, climate changes associated with El Niño in South America in 2015 on the background trend of global warming possibly facilitated the rapid spread of Aedes mosquitoes and ZIKV.14 Fourth, the increased awareness of and diagnostic capability for ZIKV infection likely led to the increased detection of this previously neglected disease. In contrast, little is known about the virological factors possibly associated with the apparent change in the spread of ZIKV after 2007. Although it has been shown that the epidemic strains are phylogenetically more closely related to the Asian than the African lineage of ZIKV, a comprehensive comparative analysis between the pre-epidemic and epidemic strains is lacking.15 In this study, we performed comparative genomic analysis of all the pre-epidemic and epidemic strains with complete genome or complete polyprotein sequences available in GenBank to identify possible viral factors associated with this rapidly emerging viral epidemic.
Chikungunya virus (CHIKV), a mosquito-borne pathogen listed by National Institute of Allergy and Infectious Diseases (NIAID) as a Category C Priority Pathogen that causes Chikungunya fever (CHIKF), has been spreading throughout Asia, Africa, and parts of Europe in recent times,,. CHIKV is an arthropod-borne virus (arbovirus) and is transmitted to humans primarily by Aedes aegypti, the infamous yellow fever propagator,. CHIKV infection is marked by severe joint pain, contorting its victims into unusual postures. The disease gets its name from the Kimakonde vernacular language of Tanzania and Mozambique, and the word chikungunya means “that which contorts or bends up” and translates in Swahili to “the illness of the bended walker”,,. In Africa, CHIKV is maintained in a sylvatic cycle among forest-dwelling Aedes spp. mosquitoes, wild primates, squirrels, birds, and rodents (Figure 1). In Asia, the disease is vectored by Ae. aegypti and Ae. albopictus
. Transmission in Asia occurs in an urban cycle whereby the mosquito spreads the disease from an infected human to an uninfected human, following an epidemiological pattern similar to dengue fever.
The 2005–2006 epidemic of CHIKV in La Reunion islands in the Indian Ocean, spurred the discovery of a new vector species, Ae. albopictus
. Wrecking over one-third of the island's population, this epidemic peaked its devastation between January and February 2006, when over 46,000 cases came into light every week, including 284 deaths,. Ae. albopictus is common in urban areas of the United States and is already flourishing in 36 states, raising grave concerns to the immunologically naive populace of the United States.
Accordingly, this review elaborately details the epidemiology and global expansion of CHIKV, describes its clinical features and pathogenesis and its symptoms and complications, and finally nominates a possible vaccine approach against CHIKV infection.
A wide range of infectious disease drivers can be grouped under this category, including climate change, land-use patterns, global trade and travel, migration, and so on. Climate change involves mean temperature increases in many parts of the world, as well as increased likelihood of adverse or even extreme weather events (11–13). Many infectious diseases are temperature sensitive as many vectors and pathogens are dependent upon permissive ambient conditions. There is thus a substantial body of research that collectively demonstrates that warming will increase the transmission of vector-borne diseases in the geographic ranges of their distribution (14–18). Changing temperature and precipitation patterns can affect the habitats and population growth of cold-blooded disease vectors, such as mosquitoes and ticks, as well as the replication rates of infectious diseases within their hosts, and even the rates at which disease-carrying vectors bite humans (18–20).
Among the best substantiated indicators of the observed effects of climate change on infectious disease is evidence of an altitudinal increase of malaria in the highlands of Columbia and Ethiopia (21) and of the northerly expansion of the disease-transmitting tick species, Ixodes ricinus, in Sweden (22). Many modelling studies project significant shifts in the transmission of vector-borne diseases such as malaria (23, 24), dengue (25), and Chikungunya (26) under climate change scenarios, but it is important to note that the extent of observed changes will depend on the presence or absence of mitigating measures, such as vector control or socioeconomic development (27, 28). Other examples of infectious diseases in Europe anticipated to be affected by climate change include West Nile virus (29), salmonella (30), campylobacter, and cryptosporidium (31, 32).
Land-use patterns, meanwhile, are a crucial driver of infectious disease emergence. It has been estimated that more than 60% of human pathogens are zoonotic (i.e. diseases of animals that can be transmitted to humans) (33). Many human land-use activities, including agriculture, irrigation, hunting, deforestation, and urban expansion, can cause or increase the risk of zoonotic and food- and water-borne diseases (33, 34). For example, one consequence of urban sprawl and deforestation is that wildlife may increasingly need to find new habitats in urban or abandoned environments, which could lead to increased human exposures to infectious pathogens. Meanwhile, the density of human population, also associated with increasing urbanisation, has also been shown to be linked to the emergence of many infectious diseases (35).
Intensified global trade and travel, not to mention migration, render political borders irrelevant and create further possibilities for global disease transmission (36–38). There are numerous examples of the arrival, establishment, and spread of ‘exotic’ pathogens to new geographic locations, including malaria, dengue, Chikungunya, West Nile, and bluetongue in recent years, aided by shipping or other trade routes (36). This process is facilitated when the environmental conditions in different parts of the world share common characteristics (36). Meanwhile, numerous vaccine-preventable diseases, such as polio, meningitis or measles, can also be introduced or reintroduced to susceptible populations as a consequence of international travel (39).