Haemorrhagic Fevers Transmitted by Vectors in the Neotropics

During the past 20 years there has been a dramatic emergence and re-emergence of epidemic of haemorrhagic vector-borne-disease (VBD) that have been caused by viruses believed to be under control such as dengue, yellow fever, Venezuelan equine encephalitis, Saint Louis Virus, Arenavirus, hantavirus or viruses that have extended their geographic distribution such as West Nile and Rift Valley fever. Bacteria like Leptospira and Rickettsia have also re-emerged.


Introduction
During the past 20 years there has been a dramatic emergence and re-emergence of epidemic of haemorrhagic vector-borne-disease (VBD) that have been caused by viruses believed to be under control such as dengue, yellow fever, Venezuelan equine encephalitis, Saint Louis Virus, Arenavirus, hantavirus or viruses that have extended their geographic distribution such as West Nile and Rift Valley fever. Bacteria like Leptospira and Rickettsia have also re-emerged.
Many reports have demonstrated the changing global and tropics epidemiology. The population growth, urbanization, human activities, and even climate variability all help to a continual fluctuation in the epidemiology of several haemorrhagic fevers transmitted by vectors in the tropics.
Haemorrhagic fevers produced by bacterial or virus share many general features. Those infectious agents are arthropod-borne cause many haemorrhagic fevers. For some viral haemorrhagic fevers, person-to-person transmission may occur through direct contact with infected blood or secretions. Infectious agents are transmitted by arthropod like mosquitoes and ticks. Animal reservoirs are usually wild rodents, however, pets, domestic livestock, urban mice, monkeys, and other primates may also provide as intermediate hosts.
The term viral hemorrhagic fever describes a potentially fatal clinical syndrome characterized by an insidious onset of nonspecific signs followed by bleeding manifestations and shock. The haemorrhagic fever syndrome is also characterized by a combination of a capillary leak syndrome and bleeding diathesis. The clinical manifestations and even histopathological findings are pretty similar and difficult to make a differential diagnosis (Table 1, Figure1). In the tropics where endemic haemorrhagic fevers are frequent that is a big concern.
This chapter gives an overview of the epidemiology and ecology of haemorrhagic fevers transmitted by vector taking place exclusively in the neotropics, hence it shows the principal clinical syndromes associated to vectors.

Common VBD in the tropics transmitted by arthropods and rodents
Etiological agents of HF affect humans on all continents. Most but not all agents causing HF are arboviruses, with transmission to humans resulting from an arthropod bite. However, animal reservoirs are generally rats and mice, but domestic livestock, monkeys, bats and other primates may also serve as intermediate hosts. Population growth, urbanization, human activities, and even climate change all contribute to a continual flux in the epidemiology of many HF transmitted by vectors arboviruses.
Haemorrhagic fevers share many clinical common features. Infectious agents that are arthropod-borne (usually mosquitoes and ticks) cause many viral hemorrhagic fevers. Some viral hemorrhagic fevers, person-to-person transmission may occur through direct contact with infected patients, their blood, or their secretions and excretions.

Flaviviral hemorrhagic fevers
Dengue is the mainly significant arboviral disease of humans with over half of the world's population existing in areas of risk. The occurrence and scale of epidemic dengue have augmented considerably in the last 40 years as the viruses and the mosquito vectors have both extended geographically in the tropical regions of the world in particular across South-east Asia, Africa, Western Pacific and tropics areas of the Americas, (Figure 2).
Dengue and Yellow fever are the prototype virus of the Flaviviridae, Dengue is a mosquitotransmitted viral disease very common in tropical areas of South America. The virus is transmitted mainly by Aedes aegypti, this mosquito is peridomestic and breeds in artificial containers around human settlements. The vector has a great preference feed for humans, which is a reason for the success disease; Dengue mainly is an urban disease and has no social class preferences. Dengue has two clinical presentations: dengue fever and hemorrhagic dengue. There are four dengue serotypes classified as 1, 2, 3, 4.
Dengue fever is supposed to generate about 230 million infections worldwide every year, of which 25,000 are lethal. Worldwide incidence has increasing swiftly in new decades with some 3.6 billion people, over half of the world's population, currently at risk, primarily in cities and villages centres of the tropics and subtropics. Demographic and community changes, in particular urbanization, globalization, and augmented worldwide journey, are most important contributors to the get higher incidence and geographic extension of dengue infections.
In modern lifetimes, the proliferate of unprepared urbanization, with related unsatisfactory housing, overcapacity and weakening in water, sewage and waste management systems, has produced model circumstances for enlarged diffusion of the dengue virus in tropical urban areas. Age frequency of dengue has been distributed in a broad ages either in adolescents or adults. In addition, the advance of tourism in the tropics has led to a boost in the number of tourists who become infected, mainly adults.
Symptoms and risk factors for dengue haemorrhagic fever (DHF) and severe dengue differ between children and adults, with co-morbidities and incidence in more elderly patients associated with greater risk of mortality. Treatment options for DF and DHF in adults, as for children, centre round fluid replacement (either orally or intravenously, depending on severity) and antipyretics. Further data are still needed on the optimal treatment of adult patients.
Because Dengue is endemic in the most tropical countries, the disease is overdiagnosed, therefore, many other hemorrhagic fevers as leptospirosis, hantavirus, arenavirus, rickettsiosis, Venezuelan equine encephalitis, chikungunya virus and malaria are erroneously diagnosed as dengue. Those diseases are clinically indistinguishable from dengue and other vector borne diseases and confirmatory diagnosis needs the employ of proficient laboratory tests that are difficult to pay for developing countries. Consequently, the endemic diseases above mentioned in developing countries remains mostly unidentified. Recent surveillance suggests that Venezuelan equine encephalitis, it may represent up to 10% of the dengue burden in neotropical cities, or tens-of-thousands of cases per year throughout Latin America.
On the other hand, yellow fever remains an important cause of mortality and morbidity in several South American countries like Colombia, Venezuela, Guyana, Ecuador, Peru, Bolivia and Brazil (Figure 2). The mosquitoes of Haemagogus and Sabethes are the main vectors in the rain forest, in contrast, Aedes aegypti in the urban areas cause YF.
YF has two different cycles: one endemic or sylvan cycle involving monkeys and epidemic urban cycle rare in South America. The frequented endemic sylvan YF constitutes to great source for introducing into urban environment. Despite the serious public health that YF represents, many South American countries abruptly discontinued YF campaigns.

Hantavirus
The hantaviruses are a group of emerging rodent-borne pathogens (family Bunyaviridae; Genus Hantavirus) that are etiologic agents for hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. HFRS is associated with rodents of the family Muridae, subfamilies Murinae and Arvicolinae; HPS is associated with rodents of the subfamily Sigmodontinae. Since the identification of HCPS in USA in 1993, a huge number of cases of HPS and an rising number of hantaviruses and rodent reservoir hosts have been identified in Central and South America (Figure 2). Epidemiologic studies have demonstrated important differences in frequency of infection with hantaviruses in both human and rodent host populations. Antibody prevalences in rodent and human populations may vary from less than 1% to more than 40%. Currently, more than 1500 cases of HCPS have been reported and more than 15 genetically distinct variants of hantaviruses, all associated with sigmodontine rodents, have been identified throughout the Americas.
Hantaviruses have been documented in South America from Argentina, Chile, Paraguay, Uruguay, Bolivia, Brazil, Peru, and Venezuela, and in Central America from Costa Rica and Panama.
Patients with HCPS typically present a short febrile prodrome of 3-5 days. In addition to fever and myalgias, early symptoms include headache, chills, dizziness, non-productive cough, nausea, vomiting, and other gastrointestinal symptoms. Malaise, diarrhoea, and lightheadedness are reported by approximately half of all patients, with less frequent reports of arthralgias, back pain, and abdominal pain. The mean duration of symptoms before hospitalization is 5.4 days. Remarkable hematologic result included a high white-cell count with augmented neutrophils, myeloid precursors, and atypical lymphocytes.
Several characteristics distinguish Latin American HCPS cases from the classical HCPS described for the first time in the USA. These include a variation in severity of disease from moderate and self-limiting to severe, the demonstration of person-to-person transmission, and a somewhat higher incidence of extrapulmonary clinical manifestations in the South American form of HCPS. Nevertheless, hantaviruses in the Americas is still far from complete knowl-odgement. The factors involved in the dynamics of these viruses in nature, their establishment and transmission within host populations and from hosts to humans, and the variable pathology of these viruses in humans are complex. It is likely that more hantaviruses will be described in the future, and much more data will be required in order to describe the diversity and evolution of this group of pathogens. Latin America, as the centre of diversity for Sigmodontine rodents and their hantaviruses is presented with the unique opportunity as well as the challenge of being center stage for continued studies of the dynamics of hantaviruses in natural host populations and the links of host and virus to human populations.

Arenavirus
The Arenaviridae is a miscellaneous RNA viruses and contains the etiologic agents of some emerging zoonoses that are characterized by high case-fatality rates. Rats and mice (murids) are the main reservoirs of the arenaviruses. So far, six arenaviruses are reported to produce human disease: Guanarito (causes Venezuelan hemorrhagic fever), Junin (Argentine hemorrhagic fever), lymphocytic choriomeningitis (lymphocytic choriomeningitis), Lassa (Lassa fever), Machupo (Bolivian hemorrhagic fever), and Sabiá (human disease from Brazil).
The recognized arenaviruses in the Americas are hosted by rodents of the family Cricetidae; with the exception may be hosted by a bat (genus Artibeus, family Phyllostomidae). Pichindé virus, hosted by Oryzomys albigularis, was described from animals in the Pichindé Valley near Cali, Colombia, Guanarito virus, is also hosted by Zygodontomys brevicauda, the short-tailed cane mouse, causes Venezuelan hemorrhagic fever in the Venezuelan state of Portuguesa. This state borders on Colombia, and Z. brevicauda is a common species in Caribbean Colombia.

South American hemorrhagic viruses
Four members of the Tacaribe complex produce acute disease in humans: Junin, Machupo, Guanarito, and Sabiá viruses. Junin virus, the mainly considerably studied of the South American hemorrhagic fever viruses, is the agent of Argentine hemorrhagic fever. The disease disproportionately affect men, probably because of the job-related risk linked with agricultural work. The mouse Calomys musculinus is recognized the primary host of Junin virus.
Guanarito virus, the agent of Venezuelan hemorrhagic fever, mainly affects rural populations and has a restricted geographic circulation. Venezuelan hemorrhagic fever has been described close to the Portuguesa province in northwestern Venezuela, an intensively agricultural area. In 1989, previous to its detection as a dissimilar an hemorrhagic disease, irregular cases of Venezuelan hemorrhagic fever were probably mistaken diagnosed as dengue fever. Remarkably, deforestation and human intrusion into rodent environment may have resulted in augmented human contact to infected rodents and a concurrent enhance in human illnesses. The reservoir of Guanarito virus is a short-tailed rodent called Zygodontomys brevicauda and Sigmodon alstoni. We emphasize that many New World arenaviruses are likely cross-reactive to the antigens we used; recovery and sequencing of viral RNA will be essential to fully characterize these viruses. Hemorrhagic fever of arenaviral origin should be included in the differential diagnosis of tropical fevers, at least in studied region.
As the human population of the rural Department of Córdoba and adjacent areas of the tropical Caribbean coast.
Besides the hemorrhagic South American virus described above, the principal old world arenavirus are the Lymphocytic choriomeningitis virus (LCMV) and Lassa virus. LCMV has a global spreading, which coincides with the geographic dispersion of its major host, the everpresent house mouse (Mus musculus). LCMV is a cause of acute aseptic meningoencephalitis and congenital malformations of the CNS and eye. People with a decreased immune system and women in the first or second trimester of pregnancy are at enlarged probability of developing severe disease. Mainly inhabitants are most likely to be infected by rodents in their homes; because population of Mus musculus are much larger in tropical countries, infections with LCMV in humans, may be frequent. Hence, deprived sanitation and other natural conditions facilitate mice incursion of human settlements.
In Europe and USA, peaks in the summer and fall are likely because more mice are entering homes. It is really unknown the incidence of infection in humans in different countries with lymphocytic choriomeningitis virus, but mainly experts believe the disease is not well known or underrecognized or underreported. The seroprevalence of lymphocytic choriomeningitis in different countries is between 0% and 60%. Vague clinical signs, demanding diagnostic problems, because require of knowledge on physicians and public health workers to put together recognition of lymphocytic choriomeningitis virus infections and its role diseases in humans.
Regarding Lassa fever is a significant cause of febrile disease in West Africa; it is projected about 100,000 to 300,000 cases and numerous deaths linked to Lassa virus. The cases are primarily reported from hyperendemic or endemic foci in the West African countries of Guinea, Liberia, Nigeria, and Sierra Leone.

Leptospirosis
It is a bacterial zoonotic disease that affects both humans and animals. Humans become infected through direct contact with the urine of infected animals or with a urine-contaminated environment. Leptopira is the bacteria belong to Spirochetaceae family transmitted directly or indirectly from animals to humans, who can suffer severe hemorrhagic, hepatic/renal and pulmonary disease. The bacteria enter the body through cuts or abrasions on the skin, or through the mucous membranes of the mouth, nose and eyes. Person-to-person transmission is rare. In the early stages of the disease, symptoms include high fever, severe headache, muscle pain, chills, redness of the eyes, abdominal pain, jaundice, haemorrhages in the skin and mucous membranes, vomiting, diarrhoea, and rash.
There are 20 known Leptospira species and hundreds of serovars, some of which belong to different species. Because there are pathogenic and non-pathogenic leptospira, it is basic to identify the pathogenic serovars of leptospires and their potential reservoirs to focus control strategies.
Pathogenic Leptospira spp are chronically maintained in renal tubules of a wide range of wild and domestic mammals and enzootic cycles are maintained by direct contact with infected urine or indirect contact with contaminated soil or water. More than 260 pathogenic serovars have been serologically identified and grouped in to 24 serogroups which have adapted to different animal species. Although some animal species may act as maintenance host for some serovars, they can also be incidental hosts from other serovars which may result in a range of clinical symptoms which is dependent upon the infecting strain, the geographical location and the hosts' immune response. Leptospirosis is a rural and occupational disease, which is considered to be an emerging zoonotic disease. In tropical and subtropical areas the transmission of leptospires is increased during heavy rainfall resulting in flooding, as well as poor sanitation and high host biodiversities, and has therefore become a major public health problem in these areas.
Outdoor and agricultural workers (rice-paddy and sugarcane workers for example) are particularly at risk but it is also a recreational hazard to those who swim or wade in contaminated waters. In endemic areas the number of leptospirosis cases may peak during the rainy season and even may reach epidemic proportions in case of flooding because the floods cause rodents to move into the city.
Prevention strategies of human leptospirosis include wearing protective clothing for people at job-related risk and evading of swimming in water that can be polluted. Leptospirosis control in animals dependent on the serovar and animal species, the management infection can be done by vaccination and rodent controls (24,26).

Rickettsiosis
The genus Rickettsia includes bacteria Gram-negative in obligate association with eukaryote cells. A number of species have been identified in various terrestrial arthropods, and more recently in leeches and amoeba. Usually, pathogenic rickettsiae were classified into two groups: the typhus group (TG), composed of Rickettsia prowazekii and Rickettsia typhi, vectored by lice and fleas, respectively; and the spotted fever group (SFG), composed of more than 20 species mostly vectored by ticks. Other rickettsiae have shown antigenic and genetic particularities that preclude their inclusion in either the TG or SFG, such as Rickettsia bellii and Rickettsia canadensis, reported in ticks from the american continent.
Many Rickettsia species cause diseases in humans and animals, to which they are vectored by lice, fleas, ticks, or mites. Most of the recognized pathogenic Rickettsia species are classified into the SFG, which includes agents of spotted fever rickettsioses in humans in different parts of the world, vectored by ticks. During the last decades, there has been an increasing number of new Rickettsia species of unknown pathogenicity, mostly isolated from ticks. Some of them, previously considered non-pathogenic, were recently shown to be pathogenic to humans, such as the SFG Rickettsia slovaca, Rickettsia aeschlimannii, Rickettsia massiliae, and Rickettsia monacensis in Europe. In addition, R. parkeri, an 'old' SFG organism first reported in ticks in the 1939 was shown to be pathogenic 65 years later. These facts indicate that any novel described Rickettsia from invertebrate hosts, especially ticks, should be regarded as potentially pathogenic for humans.
In Latin America, several Rickettsia species (belonging mostly to the spotted fever group) pathogenic for humans or with unknown pathogenicity have been reported. Rickettsia rickettsii, the etiological agent of the most severe spotted fever in the world, has been reported in Amblyomma cajennense ticks in Brazil, Colombia, Panama, and Mexico and in Amblyomma aureolatum ticks in Brazil, (Figure 2

Malaria
The etiologic agent of malaria is a parasite denominated Plasmodium, which is transmitted by means of the bites of infected Anopheles mosquitoes. The genus Plasmodium includes species of malaria, vivax, falciparum. Malaria is may be a main cause of morbidity and mortality in the tropics with Plasmodium falciparum responsible for the common of the disease burden and P. vivax being geographically most broadly circulated cause of malaria.
In the human body, the parasites reproduce in the liver, and then infect red blood cells. Symptoms of malaria consist of fever, headache, and vomiting, and usually show between 10 and 15 days after the mosquito bite. If not treated, malaria can rapidly turn into life-threatening by disturbing the blood provide to vital organs (30). In Africa and Latin America, the parasites have showed resistance to a several of malaria medicines. Means interventions to control malaria include: prompt and effective drug treatment; apply of insecticidal nets by people at risk; indoor residual spraying with insecticide to manage the vector mosquitoes, transgenic mosquitoes manipulated for resistance to malaria parasites and biological control of mosquitoes.
Malaria remains one of the world's serious health problems with 1.5 to 2.7 million deaths yearly; these deaths are mainly among children and pregnant women in sub-Saharan Africa. Of connotation, more people are dying from malaria today than 30 years ago. It seems to be the vector, the female anopheline mosquito is changing its behaviour or adapting to human activity such as creating new mosquito breeding sites. Hence, the impact of augmented population, and people displaced by violence can boost the incidence and proliferation of malaria. Furthermore, the difficulty of drug resistance by the parasites to almost all currently available antimalarial drugs.
Finally, most of the hemorrhagic tropical diseases describe above, can be also classified as neglected tropical diseases. Those represent some of the most common infections of the poorest people living in developing countries. Because they primarily affect the marginalized poor as well as preferred indigenous populations and people of African descent, the tropical hemorrhagic diseases in the Latin American and African countries are predominantly ignored diseases.
There is also misdiagnosis of hemorrhagic diseases in the tropics, mainly because the weak epidemiology and public health system in developing countries. The maximum disease problem of hemorrhagic diseases, such as leptospirosis, rickettsiosis, malaria and hantavirus infections, have first require scale-up of accessible funds or the advance of new measures instruments in order to accomplish control (32). The total elimination is implausible in the tropics, for that reason require and inter-disciplines efforts as social services, community education and environmental interventions.

Conclusions
The tropical hemorraghic fevers in the neotropics is a group of debilitating viral, bacterial and parasitic infections, that are very common aetiology of illness of the poorest people living in developing countries as Latin America. During the past 20 years there has been an intense emergence and re-emergence of epidemic of haemorrhagic vector-bornedisease (VBD) that have been produced by viruses supposed to be under control such as dengue, yellow fever, Venezuelan equine encephalitis, Saint Louis Virus, Arenavirus, hantavirus or viruses that have prolonged their geographic distribution such as West Nile and Rift Valley fever. Bacteria like Leptospira and Rickettsia have also re-emerged. Haemorrhagic fevers produced by bacterial or virus share many general features. Those infectious agents are arthropod-borne cause many haemorrhagic fevers. For some viral haemorrhagic fevers, person-to-person transmission may occur through direct contact with infected blood or secretions. Infectious agents are transmitted by arthropod like mosquitoes and ticks. Animal reservoirs are usually wild rodents, however, pets, domestic livestock, urban mice, monkeys, and other primates may also provide as intermediate hosts.
Disease difficulties following from infection by these agents are common; the most tremendous manifestations include circulatory instability, augmented vascular permeability, and diffuse haemorrhages among them. Thus, the clinical manifestations and even histopathological findings are extremely comparable and challenging to make a differential diagnosis. Finally, in the Latin American the etiologic agents described in this chapter are disseminated in almost all countries, with exception of Uruguay.