**4. Factors that increase dengue severity, cases and co-infection classification**

Most of dengue infections are subclinical or asymptomatic. Dengue epidemics were presented in Cuba in 1981 and 1987, and most cases of dengue shock and hemorrhagic dengue were mainly found in white population than in afro-descendants [16]. In studies carried out in Brazil and El Salvador, it was found that the African descent was a protective factor in dengue hemorrhagic manifestations [16]. In a dengue outbreak in Santiago de Cuba in 1997, it was found that hemorrhagic dengue cases were reported more frequently in patients aged between 15 and 39 years old. Additionally, they found a history of asthma in a 16.5% of the cases [17]. The WHO estimates that, by 2030, the diabetes mellitus will have been the 7th leading cause of death. A study carried out for evaluating the influence of diabetes mellitus and its relation to clinical manifestations of dengue, indicated higher risks of dengue symptoms potentially fatal within patients developing diabetes mellitus [18]. Other risk factors such as sickle-cell disease, uremia, allergies, hypertension, chronic renal failure may enable disease severity [1]. Regarding age, the lower compensation capacity of capillary plasma extravasation in children increases dengue shock risk. It has been observed that serious dengue cases were continuously presented in primary infections from breastfeeding babies whose mothers were developing immunity to some dengue serotype. The non-neutralizing antibodies produced by cross reaction during a primary infection or passively obtained from a mother to newborns are adhered to epitopes of dengue virus infections facilitating the entry of cells to Fc-receptors. This may contribute to a person's viral load increase resulting in strong immune response that includes inflammatory mediators [19]. Cytosines may enable plasma extravasation. In secondary infections, memory T-cells caused by previous reactions to dengue activate, replicate, produce cytosines and die of apoptosis. This can be correlated with disease severity [16]. The patient's background is important when ruling out other causes of this disease, for instance, other flavivirus presence like YFV, Saint Louis encephalitis virus (SLEV), Zika virus (ZIKV), WNV. Alphavirus like Chikungunya (CHIKV), Mayaro virus (MAYV), Venezuelan Equine Encephalitis virus (VEE), Bunyavirus like Oropouche virus (OROV), group C virus, Guaroa virus (GROV), Influenza virus, arenavirus, filovirus as well as other microorganisms can cause the disease with symptoms with similar symptoms such as malaria, Leptospirosis, typhoid fever, rickettsia diseases, etc. [1]. Dengue infections with different serotypes as well as the sequence of these infected patients may influence on the severity of the disease. In a study carried out in Singapore, between 2005 and 2011, febrile adult patients found in DENV-1 cases that were associated with dengue hemorrhagic fever (adjusted RR = 1.74) and severe dengue (adjusted RR = 2.1) were assessed, while DENV-2 had a low risk of dengue hemorrhagic fever (adjusted RR = 0.5) [20]. A special attention should be given to the clinical features of this disease in order to learn differences that lead to the identification of microorganisms causing the disease. It was found that there were no elevated hematocrit or shock cases in CHIKV infection as compared to dengue cases with high hematocrit in 40–69% of cases and shock in 10–39% of cases when comparing the clinical data and laboratory features within dengue infections and chikungunya [21]. The arthralgias were more frequent in CHIKV in 70–100% of cases as compared to at least 10% of dengue cases. The Zika infections may present Oedema in limbs as compared to dengue and chikungunya which is low or nil. The presence of this type of differences does not exclude atypical complications and presentations of the disease, thus the laboratory diagnosis plays a crucial role [22].

DENV, ZIKV and CHIKV are transmitted by *Aedes aegypti* vector. Therefore, the areas where the disease is spread may be the same leading potentially to

co-infections. Co-infection cases within different dengue serotypes have been reported in various countries like Peru where isolation of DENV-1 and DENV-3 in the department of Madre de Dios was reported [23]. Although this type of findings, the connection between dengue co-infections and severity of the infection needs to be further examined. Reports of DENV and CHIKV co-infections have been exhibited since 1964 in Asia, Africa, the Caribbean, North America, South America. Dengue and malaria co-infections have been reported in various countries such as India, Pakistan, Indonesia, Japan, Malaysia, Brazil and many others; and even co-infections among dengue, malaria and chikungunya have been reported in South Africa and Asia. A systematic review to determine global prevalence and distribution of malaria, dengue and chikungunya coinfections reported evidence of coinfections within these agents in 42 countries. The most prevalent confection was malaria/dengue followed by dengue/chikungunya, Malaria/Chikungunya and Malaria/Dengue/Chikungunya [24]. Clinical presentations between dengue and malaria are alike so it can sometimes cause a co-infection misdiagnosis. Anemia is a major symptom of infections caused by malaria which are not presented in dengue cases but it is often in this type of co-infections. On the other hand, lowering of platelets and hemoglobin content, reduced aspartate aminotransferase levels and elevated alanine aminotransferase levels are also observed [25].

In 1970, dengue disease was classified as non-classical dengue fever, classical dengue fever, dengue hemorrhagic fever and dengue shock syndrome. Sometime after this, various studies reported lack of correlation between classification and disease severity [26]. This classification showed a high specificity in the identification of hemorrhagic dengue; however, its sensitivity was low when detecting severe dengue cases requiring medical care and/or hospitalization. Thus, the WHO proposed a new classification according to the level of clinical severity by dividing dengue disease in two categories, severe dengue and non-severe dengue in 2008 [1]. This classification makes possible to establish the management and improve notifications for a better epidemiological surveillance so that warning signs and early warning of severe cases requiring hospitalization are proposed [1]. Regarding a study conducted to compare both classifications, it was found that the sensitivity of the new classification to detect severe cases was 65%, and the old classification was 30%. The new classification had 72% of sensitivity to detect patients needing advanced medical services and the old classification only had 32%. Further studies alike indicate that the WHO classification in 2009 has brought benefits in epidemiology and clinical use, some others have proposed to include other variables on severe dengue categories in order to increase sensitivity in a case detection that may require advanced medical care [27].

### **5. Dengue vectors and mechanisms of infection**

Dengue virus is mainly transmitted by *Aedes aegypti* and *Aedes albopictus* mosquitoes*. Aedes aegypti* is a tropical mosquito regarded as the most important disease transmission vector in urban areas, there are also other vector viruses like ZIKV and CHIKV. Dengue outbreaks have also been attributed to *Aedes albopictus*, *Aedes polynesiensis* and various species of complex *Aedes scutellaris* [1]. *Aedes aegypti* is a species with a strong predilection for human blood adapted to urban zones, especially in human dwellings; it is an efficient vector due to certain features like the egg-laying in a wide range of containers, the egg resistance to drying and the capacity of the female mosquito to bite in multiple occasions until they meet their need of blood. *Aedes albopictus* has adapted to temperate and tropical climates and it is a zoophilic and anthrophilic species and as well as *Aedes aegypti,* they both feed

**23**

*Lessons Learned and Recent Advances in Dengue Research*

during the day [1]. Some laboratory studies have reported that *Aedes albopictus* can become infected and transmit other 22 arboviruses such as CHIKV, Eastern equine encephalitis virus (EEEV), Ross river virus (RRV), Western equine Encephalitis (WEE), YFV among others [28]. The vertical virus transmission (transovarial or transovum) of an infected female mosquito to its eggs and subsequent progeny provides a mechanism as the arbovirus may be maintained in nature during climate conditions such as cold periods in temperate and hot regions, and dry in tropical areas or during the lack of susceptible vertebrate host. Many flaviviruses like YFV, Japanese encephalitis virus (JEV), SLEV, WNV can be transmitted in a vertical manner in its natural vectors [29]. Such natural transmission for DENV has already been approved by *Aedes aegypti* and *Aedes albopictus*; however, it occurs in a smaller proportion in *Aedes aegypti*. Moreover, its potential for transmission and maintenance of disease in nature has not been established yet. The preference of *Aedes aegypti* for little organic matter in water or clean water when it comes to lay eggs provides information about the possible places that these mosquito larvae may be found. However, some studies reported that septic tanks have been identified as places where a high *Aedes aegypti* replication can occur [30]. A study in Brazil assessed rudimentary cesspits as possible *Aedes aegypti* breeding sites identifying immature and adult forms of *Aedes aegypti* in cesspits. The average number of insects found was similar to the one reported in common breeding habitats which confirmed the new place of breeding of this vector [30]. Thus, the identification of new *Aedes aegypti* breeding sites indicates a change in habits or an adaptation of the mosquito in its environment that also need to be considered in vector control strategies of *Aedes aegypti.* Climatic factors play a significant role in its biological cycle and displacement of dengue vector. In a study about the effect of temperature on mosquitoes, it was found that mosquitoes maintained at 20°C were less sensitive to the infection and died in less time which lessened the likelihood of midgut infection without affecting the extrinsic incubation period of DENV as compared to a

*DOI: http://dx.doi.org/10.5772/intechopen.92076*

constant 10°C temperature range [31].

**6. Dengue virus jungle cycle and reverse zoonosis**

DENV can circulate in jungle cycles where virus can remain in place using *nonhuman primates* (NHP) as reservoirs or viruses transmitted in an urban cycle can infect non-human primates ('spillback' or 'reverse zoonosis') [12]. The urban and jungle cycles are shown to exist in Asia and Africa, in countries such as Malaysia, Senegal, the Philippines where DENV would be identified by a virus isolation from species such as *Presbytis obscura*, *Erythrocebus patas,* and *Macaca fascicularis* respectively [32]. Studies conducted in South East Asia reported antibodies in nonhuman primates in Indonesia, the Philippines, Cambodia, Vietnam and Malaysia. DENV viral isolation or identification by RT-PCR in NHP has not been reported in Americas but wild caught patas monkeys (*Erythrocebus patas*) and rhesus macaques (*Macaca mulatta*) showing antibodies against DENV by PRNT were reported in a study carried out between 2010 and 2012 in Puerto Rico [32]. As no evidences of DENV jungle cycle in America were shown, it is believed that these results may represent a spillback infection and non-human primates would get the infection of urban cycles presented in the population. In Argentina 2020, antibodies against DENV-1 y DENV-3 in howler monkeys (*Alouatta caraya*) were found; and in Brazil between 2006 and 2014, low antibodies against DENV in free-living golden headed lion tamarins (*Leontopithecus chrysomelas*) were found [32]. These cases were also assumed to result from spillback infection. A study in Thailand in 2008–2009 identified 6 DENV positive-dogs by RT-PCR and/or viral isolation in urban areas,

#### *Lessons Learned and Recent Advances in Dengue Research DOI: http://dx.doi.org/10.5772/intechopen.92076*

*Dengue Fever in a One Health Perspective*

require advanced medical care [27].

**5. Dengue vectors and mechanisms of infection**

Dengue virus is mainly transmitted by *Aedes aegypti* and *Aedes albopictus* mosquitoes*. Aedes aegypti* is a tropical mosquito regarded as the most important disease transmission vector in urban areas, there are also other vector viruses like ZIKV and CHIKV. Dengue outbreaks have also been attributed to *Aedes albopictus*, *Aedes polynesiensis* and various species of complex *Aedes scutellaris* [1]. *Aedes aegypti* is a species with a strong predilection for human blood adapted to urban zones, especially in human dwellings; it is an efficient vector due to certain features like the egg-laying in a wide range of containers, the egg resistance to drying and the capacity of the female mosquito to bite in multiple occasions until they meet their need of blood. *Aedes albopictus* has adapted to temperate and tropical climates and it is a zoophilic and anthrophilic species and as well as *Aedes aegypti,* they both feed

co-infections. Co-infection cases within different dengue serotypes have been reported in various countries like Peru where isolation of DENV-1 and DENV-3 in the department of Madre de Dios was reported [23]. Although this type of findings, the connection between dengue co-infections and severity of the infection needs to be further examined. Reports of DENV and CHIKV co-infections have been exhibited since 1964 in Asia, Africa, the Caribbean, North America, South America. Dengue and malaria co-infections have been reported in various countries such as India, Pakistan, Indonesia, Japan, Malaysia, Brazil and many others; and even co-infections among dengue, malaria and chikungunya have been reported in South Africa and Asia. A systematic review to determine global prevalence and distribution of malaria, dengue and chikungunya coinfections reported evidence of coinfections within these agents in 42 countries. The most prevalent confection was malaria/dengue followed by dengue/chikungunya, Malaria/Chikungunya and Malaria/Dengue/Chikungunya [24]. Clinical presentations between dengue and malaria are alike so it can sometimes cause a co-infection misdiagnosis. Anemia is a major symptom of infections caused by malaria which are not presented in dengue cases but it is often in this type of co-infections. On the other hand, lowering of platelets and hemoglobin content, reduced aspartate aminotransferase levels and

elevated alanine aminotransferase levels are also observed [25].

In 1970, dengue disease was classified as non-classical dengue fever, classical dengue fever, dengue hemorrhagic fever and dengue shock syndrome. Sometime after this, various studies reported lack of correlation between classification and disease severity [26]. This classification showed a high specificity in the identification of hemorrhagic dengue; however, its sensitivity was low when detecting severe dengue cases requiring medical care and/or hospitalization. Thus, the WHO proposed a new classification according to the level of clinical severity by dividing dengue disease in two categories, severe dengue and non-severe dengue in 2008 [1]. This classification makes possible to establish the management and improve notifications for a better epidemiological surveillance so that warning signs and early warning of severe cases requiring hospitalization are proposed [1]. Regarding a study conducted to compare both classifications, it was found that the sensitivity of the new classification to detect severe cases was 65%, and the old classification was 30%. The new classification had 72% of sensitivity to detect patients needing advanced medical services and the old classification only had 32%. Further studies alike indicate that the WHO classification in 2009 has brought benefits in epidemiology and clinical use, some others have proposed to include other variables on severe dengue categories in order to increase sensitivity in a case detection that may

**22**

during the day [1]. Some laboratory studies have reported that *Aedes albopictus* can become infected and transmit other 22 arboviruses such as CHIKV, Eastern equine encephalitis virus (EEEV), Ross river virus (RRV), Western equine Encephalitis (WEE), YFV among others [28]. The vertical virus transmission (transovarial or transovum) of an infected female mosquito to its eggs and subsequent progeny provides a mechanism as the arbovirus may be maintained in nature during climate conditions such as cold periods in temperate and hot regions, and dry in tropical areas or during the lack of susceptible vertebrate host. Many flaviviruses like YFV, Japanese encephalitis virus (JEV), SLEV, WNV can be transmitted in a vertical manner in its natural vectors [29]. Such natural transmission for DENV has already been approved by *Aedes aegypti* and *Aedes albopictus*; however, it occurs in a smaller proportion in *Aedes aegypti*. Moreover, its potential for transmission and maintenance of disease in nature has not been established yet. The preference of *Aedes aegypti* for little organic matter in water or clean water when it comes to lay eggs provides information about the possible places that these mosquito larvae may be found. However, some studies reported that septic tanks have been identified as places where a high *Aedes aegypti* replication can occur [30]. A study in Brazil assessed rudimentary cesspits as possible *Aedes aegypti* breeding sites identifying immature and adult forms of *Aedes aegypti* in cesspits. The average number of insects found was similar to the one reported in common breeding habitats which confirmed the new place of breeding of this vector [30]. Thus, the identification of new *Aedes aegypti* breeding sites indicates a change in habits or an adaptation of the mosquito in its environment that also need to be considered in vector control strategies of *Aedes aegypti.* Climatic factors play a significant role in its biological cycle and displacement of dengue vector. In a study about the effect of temperature on mosquitoes, it was found that mosquitoes maintained at 20°C were less sensitive to the infection and died in less time which lessened the likelihood of midgut infection without affecting the extrinsic incubation period of DENV as compared to a constant 10°C temperature range [31].
