This annex deals with the pathogens and diseases transmitted by mosquitoes to humans and animals. The main arbovirus infections of humans in the diverse regions of the world are summarised. More details are given on the dengue virus including its four viral serotypes, the range of symptoms affecting humans, the past and current epidemics of dengue (mainly vectored by Aedes aegypti and other aedine species) including its increasing spread over the past fifteen years. Few elements are also provided on virus transmission to animals by Ae. aegypti, and on vertical transmission.
Safety Assessment of Transgenic Organisms in the Environment, Volume 8
OECD Consensus Document of the Biology of Mosquito Aedes aegypti
Harmonisation of Regulatory Oversight in Biotechnology
Annex B. Human and animal health affected by mosquitoes
Abstract
Pathogens and diseases
An arthropod-borne virus or arbovirus is defined as a virus that is maintained in nature principally through biological transmission between susceptible vertebrate hosts by haematophagous arthropods; arboviruses multiply and produce virus in the vertebrate host, multiply in arthropod tissues, and are passed on after a period of extrinsic incubation to other vertebrates once again by the bites of an arthropod (PAHO, 1979). Most arboviruses fulfil the criteria laid down in this definition, but the group is very heterogeneous, containing viruses which, because they have not been fully classified on morphological or physicochemical grounds, are included among the arboviruses for convenience. There are currently 490 known arboviruses and this very large group contains representatives from several different viral families, the most important of which are the families Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae and Rhabdoviridae (Bishop et al., 1980; Rehle, 1989).
The extrinsic incubation period (EIP) is the time necessary for the development of arbovirus in the arthropod host. If the female mosquito longevity is lower than the viral EIP, then the potential for vector transmission is reduced. Average EIP is 15 days at 25°C and 6.5 days at 30°C (Chan and Johansson, 2012).
By definition, arboviruses have at least two different hosts, a vertebrate and an invertebrate arthropod, although many arboviruses have complex life-cycles involving several different vertebrates, and some are capable of transmission by more than one species of vector. All arboviruses, with perhaps very few exceptions, are current or potential zoonoses maintained in nature principally by wild animals and birds.
They have evolved to a state of mutual tolerance or symbiosis with their reservoirs. Since arboviruses rely only on virus production in the vertebrate host for successful transmission, disease in this host would be a disadvantage. Therefore, arboviruses seldom cause recognisable disease in maintenance hosts, and when disease is apparent in man or domesticated animals, it is only overt sign of the presence of these viruses.
Over 80 viruses produce significant human disease which ranges from mild febrile illness, which may or may not be accompanied by a skin rash and sometimes by polyarthritis, to severe and often fatal encephalitis or haemorrhagic fever. The same virus may produce different disease patterns in different subjects and illness often has a biphasic pattern. Mild fever, often not recognised, occurs during the initial viraemic stage. This may be followed by more serious symptoms, at which stage viraemia may have ceased and immunological responses, including antibody formation, have occurred. Frequently, only a small proportion of persons infected with potentially encephalitogenic arboviruses in epidemics develop encephalitis in this second phase. The great majority of infections do not develop past the first phase, which may even be asymptomatic.
Virus infection vectored by mosquitoes
There are 66 members in the flavivirus group, of which 31 are mosquito-borne. 26 flaviviruses can cause human disease but several of them have produced only laboratory-acquired infections or isolated cases of disease in man (Table A B.1). The range of clinical manifestations produced by flaviviruses is similar to those of the alphaviruses – febrile illnesses with or without a rash, or encephalitis. In addition, yellow fever, Kyasanur Forest disease, Omsk haemorrhagic fever, and dengue virus can cause haemorrhagic symptoms. Only those viruses which produce substantial prevalence are discussed in detail.
The International Committee on Taxonomy of Viruses (ICTV) has assigned the dengue virus (DENV) to the genus Flavivirus, of the Flaviviridae family. Based upon biological, immunological and molecular criteria, there are four viral serotypes, namely DENV-1, DENV-2, DENV-3 and DENV-4, which have different antigenic characteristics and serology (Boshell, 1995; Klungthong et al., 2004). Each serotype creates specific lifelong immunity against homologous reinfection, as well as short-term cross-immunity against the other serotypes, which can last several months (Leitmeyer et al., 1999; Monath, 2004). Each serotype has been subdivided into several genotypes (clades): three genotypes for DENV-1 (I, II and III) although two other clades named IV and V have been proposed, six genotypes for DENV-2 (American, Asian/American, Asian I, Asian II, Cosmopolitan and Sylvatic), four for DENV-3 (I, II, III and IV) although a fifth has also been proposed (V) and finally four for DENV-4 (I, II, III and Sylvatic) (Holmes, 2006).
Classic dengue fever affects both adults and older children. Following an infective mosquito bite, there is an incubation period of five to eight days followed by the sudden onset of acute fever, which often becomes biphasic, with a severe headache, pain behind the eyes, backache, chills and generalised pain in muscles and joints. A maculopapular rash generally appears on the thorax between the third and fifth day of illness and may spread later to the face and extremities. Lymphadenopathy, anorexia, constipation and altered taste sensation are common. Occasionally, petechiae are seen on the dorsal surfaces of the feet and the legs, hands, axillae and palate late in the illness. In young children, upper respiratory tract symptoms predominate and dengue fever is rarely suspected. The illness generally lasts for about ten days, after which recovery is usually complete, although convalescence may be prolonged. Laboratory findings reveal leukopenia, a mild thrombocytopenia, and slight lymphocytosis (Brathwaite et al., 2012).
Concerning the dengue haemorrhagic syndrome, fever, upper respiratory symptoms, headache, vomiting and abdominal pain may be present in the initial phase of the disease. Myalgia and arthralgia are uncommon. These symptoms (which are not severe enough for confinement) may last two to four days and many recover without any further symptoms. However, in a proportion of these cases, the initial phase is followed by an abrupt systemic collapse with hypotension, peripheral vascular congestion, petechiae, and sometimes a rash. Different degrees of shock may be evident, with the patient often restless, sweating, and febrile, clammy extremities, and a hot, feverish trunk. The fourth and fifth days are critical and purpura, ecchymoses, epistaxis, haematemesis, melaena, coma, convulsions and severe shock indicate a poor prognosis. Should the patient survive this period, however, recovery is usually complete. Laboratory studies often reveal thrombocytopenia, a prolonged bleeding time, an elevated prothrombin time, a raised haematocrit, hyperproteinemia and a positive tourniquet test. The liver is often enlarged, soft, and tender (Brathwaite et al., 2012). Several hypotheses have been proposed to explain why DENV now causes devastating epidemics, although it previously caused relatively mild illness. The two principal proposals are that either there is an unusual response to infection in the host, or there is an increase in the virus’ virulence. Haemorrhagic manifestations are thought to be due to secondary infection with different DENV, with a critical interval of six months between the two infections. The first infection probably sensitises the patient, whereas the second appears to produce an immunological catastrophe (WHO, 2009).
Table A B.1. Some important arbovirus infections of humans in geographic regions of the world
1. WHO recommends that vaccine against dengue should only be used after testing on individuals to assess whether they have ever been exposed to the infection. (WHO Website, 2018)
Source: Adapted from Evans, A.S. (Ed.) (1982), Viral Infections of Humans: Epidemiology and Control. Second Edition, Plenum Medical Book Company, New York and London.
Dengue virus serotypes, health effects and epidemics
The dengue disease may be endemic (which is often undiagnosed) or epidemic. In the Americas, there have been four epidemics during the 1963-83 period. The first epidemic in 1963 was caused by DENV‑3 in the Caribbean and Venezuela. The second was in 1969, caused by DENV-2, affecting the Caribbean islands and also Colombia. The third epidemic began in 1977 in Jamaica, was caused by DENV-1 and affected more than 60 000 inhabitants, spreading to other Caribbean islands, Mexico, Central America, and Venezuela (Figueroa et al., 1982). In 1981 the fourth epidemic, resulting from DENV-4, began in Saint Barthélemy (French Antilles) and spread to other Caribbean Islands and Belize (PAHO, 2005).
Puerto Rico was seriously affected during all four epidemics, and after relatively high dengue activity in 1981 and 1982, the first epidemic of dengue in Brazil in 50 years began. Most countries reported only sporadic cases during 1983, however, Colombia, El Salvador and Mexico had significant localised outbreaks in 1983 (PAHO, 2005). Ae. aegypti reinfestation (1971-99) was caused by the failure of eradication programmes leading to increased dispersal of the mosquito and DENV circulation and a corresponding clear increase in the number of outbreaks over the 2000-10 period. During 2010, more than 1.7 million dengue cases were reported, with 50 235 severe cases and 1 185 deaths (Brathwaite et al., 2012). The epidemic seemed to continue extending globally in the following years; in 2015, the total number of suspected or laboratory-confirmed dengue cases notified to WHO for the Americas, South-East Asia and Western Pacific regions, exceeded three million (Figure A B.1).
Figure A B.1. Number of suspected or laboratory-confirmed dengue cases notified to WHO, 1990‑2015
a. AMRO: WHO Regional Office for the Americas
b. SEARO: WHO Regional Office for South-East Asia
c. WPRO: WHO Regional Office for the Western Pacific
Source: WHO (2018), Programmes – Dengue Control – Epidemiology Page, Website, www.who.int/denguecontrol/epidemiology/en/.
Zika virus infection
Zika virus (ZIKV) belongs to Flavivirus genus of the Flaviviridae family and it is transmitted to humans by mosquitoes (Gould and Solomon, 2008). However, sexual transmission between humans is another potential form of infection (Moreira et al., 2017). In 2015, ZIKV was shown to be associated with microcephaly and birth defects in children exposed in utero following infection of mothers during their pregnancy in Brazil (Zanluca et al., 2015; Calvet et al., 2016; Mlakar et al., 2016). Other studies evidenced the link between ZIKV infection during pregnancy and congenital cerebral malformations in newborns as microcephaly and other dysfunctions (Besnard et al., 2016; Driggers et al., 2016), and this was experimentally supported (Cugola et al., 2016). Moreover, the infection consequences in newborns can cause a range of different pathologies, which were described as the congenital Zika syndrome (Martines et al., 2016). ZIKV may additionally be associated with other neurological complications affecting adults, such as Guillain-Barré Syndrome (Dos Santos et al., 2016). Beyond to newborn disorders, the main symptoms of ZIKV infection are maculopapular rash, fatigue, lethargy, asthenia, fever, arthritis, arthralgia, myalgia, conjunctivitis and headache. The suspected patients can be submitted to RT‑PCR assays or serological tests to confirm the ZIKV infection (Musso and Gubler, 2016).
The recent burden of Zika virus outbreaks in many countries is alarming. Although the virus is known since 1947 when it was first isolated from a sentinel Rhesus monkey exposed in the Zika Forest (Uganda) (Dick, Kitchen and Haddow, 1952), fewer reports of human infections were described until 2007. In that year, a ZIKV outbreak was first registered in Yap Islands, Federated States of Micronesia and since then, subsequent epidemics were reported in several islands in different Pacific regions between 2013 and 2014. This fast geographic expansion of the viral distribution was achieved in the Americas in 2015, causing important epidemics, mainly in Brazil. Currently, autochthonous transmission of ZIKV is occurring in many countries around the world where potential mosquito vectors are endemic (Musso and Gubler, 2016). The ZIKV emergent scenario caught the attention of the main health authorities mainly because congenital microcephaly and other neurological disorders in newborns were correlated with ZIKV infection in pregnant women, as described above. The WHO declared a state of public health emergency of international concern during almost the entire year of 2016 and launched a document named “Zika Strategic Response Plan” to guide the viral prevention and management by the national governments and communities where activities related to detection, prevention, research, care and support were recommended. This strategical document is constantly updated to provide the key information and progress achieved against ZIKV infections (WHO, 2016).
Entomological studies have demonstrated that Brazilian and other American populations of Ae. aegypti and Ae. albopictus mosquitoes are competent to ZIKV, but they present different levels of susceptibility (Chouin-Carneiro et al., 2016). Moreover, well-known laboratory strains of Ae. aegypti also show vector competence to this pathogen, which can sustain vector-pathogen studies to clarify the interactions between this virus and its invertebrate host (Costa-da-Silva et al., 2017). Recently, a field study demonstrated the occurrence of naturally-infected Ae. aegypti in the city of Rio de Janeiro (Brazil), confirming the species potential to transmit ZIKV to humans (Ferreira-de-Brito et al., 2016). The entomological surveillance in endemic regions is an essential activity to monitor the circulation of ZIKV and the potential of new outbreaks to occur.
Ae. Aegypti other characteristics
Transmission to animals
In addition to being a vector for human pathogens, Ae. aegypti is capable of spreading disease among animal species that associate with humans, such as cattle and dogs. Ae. aegypti female mosquitoes are capable of the mechanical transmission of lumpy skin disease virus (LSDV) from infected to susceptible cattle (Chihota et al., 2001). Canine heartworm is transmitted by Ae. aegypti to dogs, which are companion animals frequently associated with the home environment.
Vertical transmission
The virus is transmitted to humans through the bite of the mosquito Ae. aegypti as principal vector and Ae. albopictus as a secondary vector. The mechanism of transmission of the virus that occurs most commonly involves the human-to-mosquito-to-human cycle.
However, it has been observed that vertical transmission of the virus can occur whereby infected females naturally transmit the virus to their progeny (transovarial transmission), the virus being in this case transmitted to the next generation without an intervening human host. Vertical transmission allows the virus to persist in nature during adverse weather conditions that limit mosquito reproduction, resulting in the appearance of virus-infected mosquitos once desiccated eggs hatch following a subsequent rainfall. Thus, vertical transmissions in vectors could play a role in the endemic maintenance of the viruses. Vertical transmission of dengue viruses in Ae. aegypti is documented by several studies (see below) and appears to vary with the vector geographical strains and virus serotypes (Rodhain and Rosen, 1997).
The first findings suggesting that transovarial transmission of DENV can occur in nature was reported by Khin and Than (1983). In this study, DENV-2 serotype was recovered from three of 123 pools of Ae. aegypti larvae (6 200 specimen) collected from water containers in Rangoon, Myanmar; the virus was also isolated from two of the 76 pools (7 730 mosquitoes) of male Ae. aegypti collected as larvae and reared in the laboratory to adults. In Trinidad and Tobago, the isolation of DENV-4 from adult Ae. aegypti reared from eggs and larvae collected in nature was documented by Hull et al. (1984): the virus was recovered in one out of the 158 mosquito pools tested from 10 different localities (10 957 adults processed for virus isolation), giving further evidence that transovarial transmission of DENV occurs in nature. In southern India, DENV-2 and DENV-3 were detected in vertical transmission to males in summer months when dengue infections were high in humans, suggesting how DENV adopted a novel strategy of surviving adverse climatic conditions (Thenmozhi et al., 2000). In Juchitán and Tuxtepec, Oaxaca, Mexico, vertical transmission of DENV in Ae. aegypti mosquitoes was recorded in two endemic localities. Although the presence of DENV in larvae could not be demonstrated, DENV- 2, - 3 and -4 serotypes were detected in four out of 43 pools of in-cage born mosquitoes (Günther et al., 2007). In Acapulco, Guerrero, only two (0.9%) of 226 pools of Ae. aegypti adults (one pool of adults emerged from field-collected larvae, and another of indoor-collected adults) were positive for DENV-1. This appears to be the first report of evidence on the vertical and transovarial transmission of DENV-1 in field-caught Ae. aegypti in Mexico (Martínez et al., 2014).
References
Alfred, S.E. and J.R. Paul (1984), Viral Infections of Humans: Epidemiology and Control. Second Edition, Plenum Medical Book Company, New York and London.
Besnard, M. et al. (2016), “Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia”, Euro Surveillance, Vol. 21, No. 13.
Bishop, D.H. et al. (1980), “Bunyaviridae”, Intervirology, Vol. 14, No. 3-4, pp. 125-143.
Boshell, J. (1995), “El dengue” [Dengue], Innovación y Ciencia [Innovation and Science], Vol. 4, pp. 46‑50.
Brathwaite, D.O. et al. (2012), “The history of dengue outbreaks in the Americas”, the American Journal of Tropical Medicine and Hygiene, Vol. 87, No. 4, pp. 584‑593.
Calvet, G. et al. (2016), “Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study”, Lancet Infectious Diseases, Vol. 16, No. 6, pp. 653-660.
Chan, M. and M.A. Johansson (2012), “The incubation periods of dengue viruses”, PLoS ONE, Vol. 7, No. 11: e50972.
Chihota, C.M. et al. (2001), “Mechanical transmission of lumpy skin disease virus by Aedes aegypti (Diptera: Culicidae)”, Epidemiology & Infectection., Vol. 126, No. 2, pp. 317-321.
Chouin-Carneiro, T. et al. (2016), “Differential susceptibilities of Aedes aegypti and Aedes albopictus from the Americas to Zika virus”, PLoS Neglected Tropical Diseases, Vol. 10, No. 3: e0004543.
Costa-da-Silva, A.L. et al. (2017), “Laboratory strains of Aedes aegypti are competent to Brazilian Zika virus”, PLoS One., Vol. 12, No. 2: e0171951.
Cugola, F.R. et al. (2016), “The Brazilian Zika virus strain causes birth defects in experimental models”, Nature, Vol. 534, No. 7606, pp. 267-271.
Dick, G.W., S.F. Kitchen and A.J. Haddow (1952), “Zika virus. I. Isolations and serological specificity”, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 46, pp. 509–520.
Dos Santos, T. et al. (2016), “Zika Virus and the Guillain-Barré Syndrome - Case Series from Seven Countries”, New England Journal of Medicine, Vol. 375, No. 16, pp. 1598-1601.
Driggers, R.W. et al. (2016), “Zika virus infection with prolonged maternal viremia and fetal brain abnormalities”, New England Journal of Medicine, Vol. 374, No. 22, pp. 2142-2151.
Ferreira-de-Brito, A. et al. (2016), “First detection of natural infection of Aedes aegypti with Zika virus in Brazil and throughout South America”, Memórias do Instituto Oswaldo Cruz, Vol. 111, No. 10, pp. 655-658.
Figueroa, R.M. et al. (1982), “Dengue epidemic in Honduras, 1978-1980”, Bulletin of the Pan American Health Organization, Vol. 16, No. 2, pp. 130‑137.
Gould, E.A. and T. Solomon (2008), “Pathogenic flaviviruses”, Lancet Infectious Diseases, Vol. 371, No. 9611, pp. 500-509.
Günther, J. et al. (2007), “Evidence of vertical transmission of dengue virus in two endemic localities in the state of Oaxaca, Mexico”, Intervirology, Vol. 50, pp. 347-352.
Holmes, E.C. (2006), “The evolutionary biology of dengue virus”, Novartis Found Symposium, Vol. 277, pp. 177‑187.
Hull, B. et al. (1984), “Natural transovarial transmission of dengue 4 virus in Aedes aegypti in Trinidad”, the American Journal of Tropical Medicine and Hygiene, Vol. 33, pp. 1248-1250.
Khin, M.M. and K.A. Than (1983), “Transovarial transmission of dengue 2 virus by Aedes aegypti in nature”, The American Journal of Tropical Medicine and Hygiene, Vol. 32, pp. 590-594.
Klungthong, C. et al. (2004), “The molecular epidemiology of dengue virus serotype 4 in Bangkok, Thailand”, Virology, Vol. 329, pp. 168-179.
Leitmeyer, K.C. et al. (1999), “Dengue virus structural differences that correlate with pathogenesis”, Virology, Vol. 73, No. 6, pp. 4738-4747.
Martines, R.B. et al. (2016), “Pathology of congenital Zika syndrome in Brazil: A case series”, Lancet, Vol. 388, No. 10047, pp. 898-904.
Martínez, N.E. et al. (2014), “Natural vertical transmission of dengue-1 virus in Aedes aegypti populations in Acapulco, Mexico”, Journal of the American Mosquito Control Association, Vol. 30, No. 2, pp. 143-146.
Mlakar, J. et al. (2016), “Zika virus associated with microcephaly”, New England Journal of Medicine, Vol. 374, pp. 951–958.
Monath, T. (2004), “Dengue: The risk to developed and developing countries”, Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, pp. 2395-2400.
Moreira, J. et al. (2017), “Sexually acquired Zika virus: A systematic review”, Clinical Microbiology and Infection, Vol. 23, No. 5, pp. 296-305.
Musso, D. and D.J. Gubler (2016), “Zika virus”, Clinical Microbiology and Infection, Vol. 29, No. 3, pp. 487-524.
PAHO (2005), Number of Reported Cases of Dengue and Dengue Hemorrhagic Fever (Dhf), Region of the Americas (by Country and Subregion), Pan American Health Organization, Washington, DC.
PAHO (1979), Dengue in the Carribean, 1977, Proceedings of a Workshop Held in Montego Bay, Jamaica, 8-11 May, 1978, PAHO Scientific Publication 375, Pan American Health Organization, Washington, DC.
Rehle, T.M. (1989), “Classification, distribution and importance of arboviruses”, Tropical Medicine and Parasitology, Vol. 40, No. 4, pp. 391-395.
Rodhain, F. and L. Rosen (1997), “Mosquito vectors and dengue virus vector relationships”, in Gubler, D.J. and G. Kuno (eds), Dengue and Dengue Hemorrhagic Fever, CAB International, New York, pp. 45–60.
Thenmozhi, V. et al. (2000), “Natural vertical transmission of dengue viruses in Aedes aegypti in southern India”, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 94, pp. 507.
WHO (2018), Programmes – Dengue Control – Epidemiology Page, Website, World Health Organization, Geneva, www.who.int/denguecontrol/epidemiology/en/.
WHO (2016), Zika Strategic Response Framework and Joint Operations Plan, Zika Strategic Response Plan Quarterly Update 2016, World Health Organization, Geneva, www.who.int/emergencies/zika-virus/quarterly-update-october/en/.
WHO (2009), Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition, World Health Organization, Geneva, www.ncbi.nlm.nih.gov/books/NBK143163/.
Zanluca, C. et al. (2015), “First report of autochthonous transmission of Zika virus in Brazil”, Memórias do Instituto Oswaldo Cruz, Vol. 110, pp. 569–572.