Dengue is a mosquito-borne infectious disease caused by small (50 nm) single-stranded RNA arboviral viruses, from the Flaviviridae family. There are four closely related, yet antigenically distinct, serotypes of dengue virus: DVN1, DNV2, DNV3, and DNV4. Infection by one serotype does not confer lasting immunity to the others.¹,²,³,⁴,⁵

The main vector for dengue infection is the female of the Aedes aegypti mosquito. They stay in or around houses where they emerge as adults and usually acquire the virus while feeding on the blood of infected individuals. The male mosquito does not transmit the disease because they feed on plant juices. Other species of mosquitoes may also transmit dengue, such as Aedes albopictus, Aedes polynesiensis, and Aedes scutellaris.¹,²,³,⁴,⁵

In the last 50 years, the world has seen an explosive outbreak of dengue, which is now considered the most important human viral mosquito-borne infection and an extremely significant global health problem. The average number of cases annually reported to the World Health Organization (WHO) jumped from 908 during 1955 to 1959 to 925,896 during 2000 to 2007. In the same time frame, the number of countries reporting dengue has been augmented from less than 10 to more than 60, and in the last 10 years the disease has spread from the rural to the urban setting.¹,²,³,⁴,⁵

Currently, more than 50 million dengue cases are estimated to occur annually. Dengue is considered endemic in more than 100 countries in all WHO regions except Europe and 2.5 billion individuals, representing two-fifths of the entire world population, are at risk of dengue. Dengue affects mainly tropical developing countries, but warmer areas of developed countries, such as the southern parts of the United States, are also affected.¹,²,³,⁴,⁵,⁶,⁷

Multiple factors have led to this increasing incidence. Growth in international business and tourism travelling; immigration flow from countries where dengue is endemic; the occurrence of climate changes, such as global warming, and increases in the intensity and duration of the rainy season, which facilitates the Aedes aegypti dispersion; the growth of uncontrolled and unplanned urbanization; and the difficulty in effectively eradicating the disease vector will likely maintain and even worsen the dengue global health problem in the future.⁵

Dengue is a flulike illness with a multifaceted clinical picture. It can be asymptomatic, or it can manifest as an undifferentiated fever without symptoms, similar to several other acute febrile diseases. It can also appear as classic dengue fever (DF), a painful but self-limited disease course, or as a life-threatening form, namely dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).¹,²,³,⁴,⁵

DF is characterized by the high and abrupt onset of fever lasting 2 to 7 days, prostration, severe headaches, retro-ocular pain, diffuse body aches, myalgia, arthralgia, mild hemorrhagic manifestations, a positive tourniquet test, facial flushing, and a diffuse cutaneous erythematous maculopapular rash. Anorexia, nausea, vomiting, biphasic fever, and liver enlargement may occur. A laboratory examination typically reveals leukopenia, and varying degrees of low platelet count. Increased liver enzymes, especially serum aspartate transaminase (AST), are frequently seen.¹,²,³,⁴,⁵,⁸,⁹

DHF and DSS are the most severe varieties of dengue disease presentations. The early manifestations of DHF and DSS are similar to DF. In fact, there is controversy if DHF and DSS are single nosologic entities or the ends of a continuum of the same illness. Children, infants, and adult patients with secondary heterotypic infections are at a higher risk of developing DHF/DSS.¹,²,³,⁴,⁵

DHF is defined as a clinical picture with a simultaneous occurrence of high fever, thrombocytopenia (≤100,000/mm³), severe hemorrhagic phenomena, and evidence of increased vascular permeability. This includes hemoconcentration (increased hematocrit), hypoalbuminemia, pleural effusion, and ascites. Depending on the amount and the rate of fluid leaving the intravascular space, the patient may develop hemodynamic instability, tachycardia, signs of poor capillary perfusion, and finally, hypotension and shock, thus characterizing DSS. If this picture is not quickly and efficiently reverted, the patient frequently experiences multiple organ failure and massive bleeding.¹,²,³,⁴,⁵ Whereas mortality rate in DF is less than 1%, it rises to approximately 12% in DHF and to up to 40% in DSS.¹⁰

The rapidly changing pattern of dengue epidemiology exposed the idea that the classification of dengue in DF, DHF, and DSS was frequently inadequate for use in the clinical setting.¹¹ Furthermore, an increased number of life-threatening cases of dengue that did not strictly adhere to DHF criteria have been observed.¹¹ Therefore, although the classification of DF, DHF, and DSS continues to be widely used, the WHO has suggested a new one, dividing the dengue spectrum into nonsevere dengue (without or with warning signs), corresponding to DF and severe dengue, that will include and expand the concept of DHF and DSS.⁵ Severe dengue was defined by the WHO as the presence of one or more of the following:

This new classification is strongly based on patient behavior during the three pathophysiologic phases of the disease. The first one is the febrile phase, when viremia occurs, and it is similar between nonsevere and severe dengue forms. It comprises the clinical and laboratory picture already described for DF. The second is the critical phase, when after 3 to 7 days of high fever, the temperature decreases or normalizes. At this point variable degrees of endothelial dysfunction causing increased capillary permeability and plasma leakage will occur. This phase lasts for 1 to 2 days and it is critical in differentiating nonsevere and severe dengue. Some patients have mild and limited increases in capillary permeability and will start to improve and recover. Others have significant and maintained plasma leakage and will progress to severe dengue. These patients usually have warning signals, such as abdominal pain or tenderness, persistent vomiting, body fluid accumulation, mucosal bleeding, lethargy, restlessness, liver enlargement, and their hematocrit increases simultaneously with a rapid platelet count decrease. The third phase, or the recovery phase, begins when the critical phase ends and it is characterized by the halting of plasma leakage and the reabsorption of fluids from the extravascular compartment. The patient’s clinical recovery is manifest and laboratory parameters go back to normal. The presence of a petechial rash, with multiple small round islands of unaffected skin (“isles of white”), and generalized pruritus are distinctive findings of this phase.⁵

The diagnosis of dengue should be suspected in individuals with a suggestive clinical picture who live or have visited an endemic area for this illness. Considering the alarming increase in the number of patients infected with dengue viruses, the occurrence of several outbreaks of the disease, the spread of the vector, and the high number of international traveling days, even medical staff working in dengue-free areas must be aware of this diagnostic possibility in febrile patients.¹²,¹³

Laboratory diagnostic methods for confirming a dengue virus infection include immunoglobulin M (IgM) and IgG antibodies, dengue antigen, virus or viral nucleic acid detection, or a combination of these procedures. After the start of the disease, the virus can be found in corporal fluids and tissues for 4 to 5 days. During the early stages of the disease, it can be isolated and its nucleic acid or antigen can be detected. At the end of the acute phase of dengue infection, when there is no more fever, serology is the method of choice for diagnosis.¹⁴

The differential diagnosis for dengue, principally in the acute febrile phase, includes other febrile viral diseases (yellow fever, Hantavirus, influenza, Chikungunya virus, O’nyong-nyong virus, acute viral hepatitis, measles, rubella, and enteroviruses), bacterial infections (leptospirosis, typhoid fever, meningococcemia, and bacterial sepsis), rickettsial diseases, malaria, autoimmune diseases, and severe acute hematologic diseases.¹,²,³,⁴,⁵,¹⁴

There is no specific treatment for dengue. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided. Early and adequate support, maintaining adequate blood pressure, and intravascular volume repletion are absolutely essential in severe dengue.¹,²,³,⁴,⁵,¹⁴

Yellow fever (YF) is a mosquito-borne infectious disease caused by the yellow fever virus, a 40-nm diameter arbovirus, which is considered the prototype for the Flavivirus genus and Flaviviridae family. The name yellow fever originated from the striking jaundice observed in the severe cases of this disease.¹⁰,⁵⁷,⁵⁸,⁵⁹,⁶⁰,⁶¹

YF originated in Africa and was spread to the American continent and to Europe through commercial routes and the slave trade. Devastating and deadly epidemics occurred throughout the 17th, 18th, and 19th century in North, South, and Central America, and European cities. The development of large-scale public health campaigns aiming at control of the mosquito vector and the development of efficacious vaccines virtually eradicated the disease in North America and Europe, and drastically decreased its incidence in Central and South America and Africa. However, because the natural epidemiology of YF in Africa and the Americas encompass a cycling of the virus between forest mosquitoes and wild nonhuman primate hosts, it is not possible to completely eradicate the disease.⁵⁹,⁶⁰

The current vectors for YF are blood-eating mosquitoes from the Culicidae family, belonging to the Haemagogus genus in the Americas and to the Aedes genus in Africa. There exist three possible cycles of YF transmission: jungle (sylvatic), intermediate, and urban transmission. In the jungle cycle, the virus is transmitted between nonhuman primates and mosquito species inhabiting the forest canopy. Occasionally, infected sylvatic mosquitos contaminate individuals working or visiting the forest. This cycle occurs in Africa and South and Central America rainforests.¹⁰,⁵⁷,⁵⁸,⁵⁹,⁶⁰,⁶¹ One important difference between the American and African cycles is that although in the American continent the infected monkeys frequently die, in Africa they usually survive without signs of infection.⁵⁸ An intermediate cycle is characterized by the YF virus (YFV) transmission to both nonhuman primates and human individuals. It occurs in the humid African savanna bordering the equatorial forests, when Aedes sp. mosquitoes indiscriminately feed on nonhuman primates and humans. The intermediate YF cycle produces small-scale outbreaks in rural villages, which are currently the most usual form of YF epidemics in Africa.¹⁰,⁵⁷,⁵⁸,⁵⁹,⁶⁰,⁶¹ The urban cycle involves the transmission of YFV from human to human by Aedes aegypti domestic mosquitoes in urban areas. It is a major cause of concern because explosive, large-scale outbreaks can occur. It is at this time present in Africa, particularly in Nigeria.¹⁰,⁵⁷,⁵⁸,⁵⁹,⁶⁰,⁶¹ It has not been described in tropical South America since 1942, in Brazil.⁵⁸

YF is nowadays endemic in tropical regions of Africa and South America and in Panama. The existing data on the YF burden are probably inexact due to the underreporting of the disease and the limitation of diagnostic capabilities in many regions where YF is endemic.⁵⁹ In South America, the rate of transmission of YF is lower than in Africa, most likely due to the launching of mass vaccination campaigns as a reaction to outbreaks of the disease.⁵⁹

YF currently affects over 200,000 individuals annually in Africa and South and Central America, with approximately 30,000 fatalities. Forty-four countries, 32 in Africa and 12 in South and Central America, are within the YF endemic zone, with almost 900 million people at risk for infection. The recent resurgence of virus circulation, urban reinfestation by the A. aegypti, and the expansion of the YF endemic zones in Africa and South America make for a dramatic potential scenario for the reemergence of explosive epidemics of urban YF.¹⁰,⁵⁸,⁵⁹,⁶⁰,⁶¹,⁶²

YF is a multisystem viral sepsis, which might be asymptomatic or have a clinical spectrum ranging from a nonspecific febrile disease to a severe and fatal hemorrhagic illness associated with shock, liver, kidney, heart, and nervous system injury. YF characteristically evolves through three phases. The first, known as the infection phase, when viremia takes place, starts 2 to 6 days after the virus inoculation and lasts for several days. The symptoms comprise an abrupt onset of high fever, chills, anorexia, nausea, vomiting, irritability, dizziness, mild hemorrhagic phenomena, malaise, tiredness, headache, generalized myalgia, lower back pain, and Faget sign, which is increasing fever with a paradoxical bradycardia. Laboratory abnormalities include low white blood cell count and increased serum transaminases. The second phase, remission, is characterized by a rapid (24 to 48 hours) reduction of fever, the abatement of other symptoms, and the viral clearance from the blood. Approximately 80% of the patients will have a benign course of the disease, recovering at this phase without the development of jaundice. The third and last phase, the intoxication phase, is distinctive as the most severe, hemorrhagic form of the disease and occurs in about 20% of the patients. The high fever returns and the patient presents with epigastralgia, vomiting, and jaundice. Multiorgan failure affecting the liver, the kidneys, and the central nervous system develops. The disease evolves with exuberant hemorrhagic diathesis, characterized by petechiae, ecchymoses, epistaxis, and hematemesis (the characteristic YF “black vomit”) due to liver failure, platelet dysfunction, and disseminated intravascular coagulation. Laboratory examination will show intense leukopenia, very high transaminases and bilirubin levels, blood coagulation disorders, increased serum creatinine, and albuminuria. At this phase, the viruses are usually missing in the blood and antibodies will appear. Later shock, confusion, seizure, and coma will develop, presaging death. The lethality rate of YF ranges from 20% to 50%. Infancy, older age, and the development of jaundice and the intoxication phase are associated with an increased severity and lethality of YFV infection.¹⁰,¹⁴,⁵⁷,⁵⁸,⁶⁰,⁶¹

YF can be distinguished from the other viral hemorrhagic viruses by the characteristic severity of liver damage and the development of jaundice. The disease can be diagnosed by serology (detection of IgM), virus isolation, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR).¹⁰,¹⁴,⁵⁷,⁵⁹,⁶⁰,⁶¹