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The Aedes trio in the Americas — dengue, chikungunya and Zika

Important mosquito-borne viruses that are transmitted between humans via vector mosquitoes have a way of appearing or reappearing in the United States and in the Americas. Dengue is a classic example. Ships brought mosquitoes (Aedes aegypti) and viremic individuals to ports in the U.S. more than 300 years ago. Benjamin Rush, MD, a signatory to the Declaration of Independence, described a major dengue outbreak in Philadelphia in 1780. Cases continued to occur in the eastern U.S. port cities and Gulf Coast states for more than 150 years with a dramatic outbreak in New Orleans involving an estimated 40,000 people in 1873. Outbreaks finally ended in the country for a time in 1945. However, the mosquito vector did not disappear in Texas and the Gulf Coast states, and an additional dengue virus vector, the Asian tiger mosquito, Aedes albopictus, was introduced into the U.S. in the 1980s and spread.

Thomas Yuill

Efforts to eradicate A. aegypti in the Americas began in the 1940s with support of the Rockefeller Foundation and approval of the Pan American Health Organization (PAHO), and subsequently were intensified. By 1962, this vector had been eliminated in 18 continental countries and several Caribbean islands. Dengue cases in these countries essentially disappeared with just a single case reported in these areas in 1955. However, A. aegypti was not eradicated in the U.S., Cuba, Venezuela and several Caribbean countries. Dengue outbreaks subsequently occurred in Jamaica, Puerto Rico, Haiti, the Lesser Antilles and Venezuela. Political and economic support of the A. aegypti eradication program deteriorated in the 1960s, and soon this vector was again widely spread in the Americas, and with it, the four dengue viruses. In 2002, there was a total of over 1 million dengue cases in the Americas. And now dengue is again a current concern in the U.S. with sporadic local transmission in recent years by A. aegypti in Florida and Texas and by A. albopictus on Long Island, New York. Although dengue viruses have not become endemic in the U.S., they show no sign of disappearing in the tropical and subtropical areas of the Americas where A. aegypti is abundant.

Donald Kaye

Chikungunya virus (CHIKV) is another visitor that has possibly returned after an apparent absence of nearly 200 years. A viral exanthema with clinical characteristics very similar to CHIKV disease appeared in the Caribbean islands in 1827, apparently from Zanzibar, spreading into North and South America. It has been speculated that it was in fact CHIKV disease. Obviously, no laboratory tests were available at that time to confirm a CHIKV etiology of the outbreak. If the outbreak was due to CHIKV, it subsequently disappeared, only to re-emerge in the Caribbean Island of Saint Martin in November 2013. Since then, it has been spreading throughout the Caribbean, and on to Central, South and North America. PAHO reported the cumulative chikungunya case numbers for 2013-2014, involving 43 countries — including 11 cases in Florida — as 24,682 confirmed cases and 1,118,763 suspected cases with 192 deaths. As of Aug. 7, PAHO has reported 15,515 confirmed locally acquired cases and 475,602 suspected cases with 61 deaths in 38 countries in the Americas so far in 2015. This is doubtless an underestimate, since many infected individuals do not seek medical attention and are not counted.

Chikungunya infections are socially and financially disruptive. The infection causes arthralgia, sometimes severe and incapacitating, that may persist for weeks or months causing time lost from work and school. Case fatality rates are low, and deaths usually occur in the elderly or individuals with comorbidities. Medical facilities have been overloaded in some areas experiencing severe outbreaks. There have been outbreaks in popular tourist destinations, which have discouraged people from traveling to those places. In a few cases, cruise ships have avoided some of these outbreak localities. There is no indication that chikungunya virus is going away anytime soon in the Americas.

Is there a risk for greater CHIKV spread in the U.S.? The mosquito vector involved in the Americas is A. aegypti. In addition to persistent populations of this mosquito in the southeastern U.S., in the past 2 years, this mosquito has been detected in small numbers in several places in California. However, no local transmission of CHIKV has occurred, nor does that seem very likely, even though 32 imported chikungunya cases have been diagnosed in California this year. Similarly, CHIKV infections have been laboratory confirmed in other states where A. aegypti are found, but only 11 Florida cases were locally acquired. The rest were imported from areas outside the U.S. where the virus was being transmitted. Vector mosquito populations do not appear sufficiently abundant to support long-term ongoing transmission in the U.S. Although A. albopictus is more widely spread in the central and Eastern states than A. aegypti, this species does not appear likely to spark a CHIKV outbreak. A. albopictus was the vector responsible for the large CHIKV outbreak in Reunion Island in 2010. However, the CHIKV there had a mutation at residue 226 of the membrane fusion glycoprotein E1 (E1-A226V) that facilitated vector transmission efficiency for A. albopictus but not A. aegypti. The American CHIKV isolates are an Asian subtype that do not have this mutation, so the lack of transmission efficiency limits the role of this mosquito in ongoing transmission, at least for the present time.

And now, we have a new mosquito-borne virus in the Americas: Zika virus. This virus is originally from Africa, where it was isolated from a rhesus monkey in the Zika Forest of Uganda in 1947. Sporadic human cases of fever with rash occurred in Africa until 2007, when outbreaks occurred on Yap Island, Micronesia, and then in French Polynesia. The appearance of Zika virus for the first time in the Americas occurred in Brazil early this year. It is speculated that a viremic individual arrived in the country to attend the FIFA World Cup football (soccer) games the previous summer, resulting in undetected, low-level transmission afterward. Early this year, patients presenting with dengue-like symptoms appeared in public health facilities in Natal, Rio Grande do Norte state. The symptoms included arthralgia, edema of extremities, mild fever, maculopapular rash that was frequently pruritic, headaches, retro-orbital pain, nonpurulent conjunctivitis, vertigo, myalgia and digestive disorders. Dengue and chikungunya virus infections were ruled out by initial laboratory tests. In March, blood samples were tested in the Molecular Virology Laboratory of the Carlos Chagas Institute, Oswaldo Cruz Institute, in the state of Paraná, Brazil. The 364 bp amplicons encompassing the envelope protein coding region had a high degree of identity to that of the Asian lineage of Zika virus. The virus has already begun to spread rapidly in Brazil, with cases reported in Bahia, Maranhão, Pernambuco, Rio Grande do Norte, Paraíba, Sergipe, Rio de Janeiro, São Paulo, Roraima, Alagoas, Pará, Ceará, Piauí and Paraná states. PAHO has advised countries with established populations of A. aegypti to be on alert for Zika fever cases. There are no epidemiological barriers to halt its spread throughout the Americas where dengue virus also occurs. There are large populations of susceptible people and abundant vector mosquitoes that can facilitate spread of the virus. Should Zika virus continue to spread in the Americas, which seems very likely, viremic individuals will arrive in the U.S. with the risk of sporadic initiation of ongoing transmission, which has been the case with dengue and chikungunya viruses in recent years.

Differential diagnosis among dengue, chikungunya and Zika viruses will be challenging for clinicians. Symptoms are similar enough to be confusing in the absence of laboratory confirmation. This has been a particular challenge in Brazil, where tens of thousands of Zika virus and chikungunya virus infections and hundreds of thousands of dengue cases have been reported recently. Reference laboratories are not equipped (nor financed) to test the enormous volume of samples that large outbreaks can generate. Low-cost, sensitive and specific tests are needed to permit decentralization of laboratory testing to local health care units. Surveillance efforts also will be stressed to the limit.

Effective control of these virus infections is not possible now. There are no commercially available vaccines, although several dengue vaccines are undergoing clinical trials. Community-level vector mosquito control has been difficult and insufficient to prevent or halt outbreaks. Some interesting vector control efforts through release of genetically modified A. aegypti are underway, and look promising.

In the Americas we now have six mosquito-borne viruses circulating — four dengue virus types (1-4), plus chikungunya and Zika viruses. Every day, thousands of passengers get on long-distance commercial aircraft. A few of them will be viremic when they disembark. What mosquito-borne viruses will they bring to the Americas? Will we be ready?

Disclosure: Kaye and Yuill report no relevant financial disclosures.

Important mosquito-borne viruses that are transmitted between humans via vector mosquitoes have a way of appearing or reappearing in the United States and in the Americas. Dengue is a classic example. Ships brought mosquitoes (Aedes aegypti) and viremic individuals to ports in the U.S. more than 300 years ago. Benjamin Rush, MD, a signatory to the Declaration of Independence, described a major dengue outbreak in Philadelphia in 1780. Cases continued to occur in the eastern U.S. port cities and Gulf Coast states for more than 150 years with a dramatic outbreak in New Orleans involving an estimated 40,000 people in 1873. Outbreaks finally ended in the country for a time in 1945. However, the mosquito vector did not disappear in Texas and the Gulf Coast states, and an additional dengue virus vector, the Asian tiger mosquito, Aedes albopictus, was introduced into the U.S. in the 1980s and spread.

Thomas Yuill

Efforts to eradicate A. aegypti in the Americas began in the 1940s with support of the Rockefeller Foundation and approval of the Pan American Health Organization (PAHO), and subsequently were intensified. By 1962, this vector had been eliminated in 18 continental countries and several Caribbean islands. Dengue cases in these countries essentially disappeared with just a single case reported in these areas in 1955. However, A. aegypti was not eradicated in the U.S., Cuba, Venezuela and several Caribbean countries. Dengue outbreaks subsequently occurred in Jamaica, Puerto Rico, Haiti, the Lesser Antilles and Venezuela. Political and economic support of the A. aegypti eradication program deteriorated in the 1960s, and soon this vector was again widely spread in the Americas, and with it, the four dengue viruses. In 2002, there was a total of over 1 million dengue cases in the Americas. And now dengue is again a current concern in the U.S. with sporadic local transmission in recent years by A. aegypti in Florida and Texas and by A. albopictus on Long Island, New York. Although dengue viruses have not become endemic in the U.S., they show no sign of disappearing in the tropical and subtropical areas of the Americas where A. aegypti is abundant.

Donald Kaye

Chikungunya virus (CHIKV) is another visitor that has possibly returned after an apparent absence of nearly 200 years. A viral exanthema with clinical characteristics very similar to CHIKV disease appeared in the Caribbean islands in 1827, apparently from Zanzibar, spreading into North and South America. It has been speculated that it was in fact CHIKV disease. Obviously, no laboratory tests were available at that time to confirm a CHIKV etiology of the outbreak. If the outbreak was due to CHIKV, it subsequently disappeared, only to re-emerge in the Caribbean Island of Saint Martin in November 2013. Since then, it has been spreading throughout the Caribbean, and on to Central, South and North America. PAHO reported the cumulative chikungunya case numbers for 2013-2014, involving 43 countries — including 11 cases in Florida — as 24,682 confirmed cases and 1,118,763 suspected cases with 192 deaths. As of Aug. 7, PAHO has reported 15,515 confirmed locally acquired cases and 475,602 suspected cases with 61 deaths in 38 countries in the Americas so far in 2015. This is doubtless an underestimate, since many infected individuals do not seek medical attention and are not counted.

Chikungunya infections are socially and financially disruptive. The infection causes arthralgia, sometimes severe and incapacitating, that may persist for weeks or months causing time lost from work and school. Case fatality rates are low, and deaths usually occur in the elderly or individuals with comorbidities. Medical facilities have been overloaded in some areas experiencing severe outbreaks. There have been outbreaks in popular tourist destinations, which have discouraged people from traveling to those places. In a few cases, cruise ships have avoided some of these outbreak localities. There is no indication that chikungunya virus is going away anytime soon in the Americas.

Is there a risk for greater CHIKV spread in the U.S.? The mosquito vector involved in the Americas is A. aegypti. In addition to persistent populations of this mosquito in the southeastern U.S., in the past 2 years, this mosquito has been detected in small numbers in several places in California. However, no local transmission of CHIKV has occurred, nor does that seem very likely, even though 32 imported chikungunya cases have been diagnosed in California this year. Similarly, CHIKV infections have been laboratory confirmed in other states where A. aegypti are found, but only 11 Florida cases were locally acquired. The rest were imported from areas outside the U.S. where the virus was being transmitted. Vector mosquito populations do not appear sufficiently abundant to support long-term ongoing transmission in the U.S. Although A. albopictus is more widely spread in the central and Eastern states than A. aegypti, this species does not appear likely to spark a CHIKV outbreak. A. albopictus was the vector responsible for the large CHIKV outbreak in Reunion Island in 2010. However, the CHIKV there had a mutation at residue 226 of the membrane fusion glycoprotein E1 (E1-A226V) that facilitated vector transmission efficiency for A. albopictus but not A. aegypti. The American CHIKV isolates are an Asian subtype that do not have this mutation, so the lack of transmission efficiency limits the role of this mosquito in ongoing transmission, at least for the present time.

And now, we have a new mosquito-borne virus in the Americas: Zika virus. This virus is originally from Africa, where it was isolated from a rhesus monkey in the Zika Forest of Uganda in 1947. Sporadic human cases of fever with rash occurred in Africa until 2007, when outbreaks occurred on Yap Island, Micronesia, and then in French Polynesia. The appearance of Zika virus for the first time in the Americas occurred in Brazil early this year. It is speculated that a viremic individual arrived in the country to attend the FIFA World Cup football (soccer) games the previous summer, resulting in undetected, low-level transmission afterward. Early this year, patients presenting with dengue-like symptoms appeared in public health facilities in Natal, Rio Grande do Norte state. The symptoms included arthralgia, edema of extremities, mild fever, maculopapular rash that was frequently pruritic, headaches, retro-orbital pain, nonpurulent conjunctivitis, vertigo, myalgia and digestive disorders. Dengue and chikungunya virus infections were ruled out by initial laboratory tests. In March, blood samples were tested in the Molecular Virology Laboratory of the Carlos Chagas Institute, Oswaldo Cruz Institute, in the state of Paraná, Brazil. The 364 bp amplicons encompassing the envelope protein coding region had a high degree of identity to that of the Asian lineage of Zika virus. The virus has already begun to spread rapidly in Brazil, with cases reported in Bahia, Maranhão, Pernambuco, Rio Grande do Norte, Paraíba, Sergipe, Rio de Janeiro, São Paulo, Roraima, Alagoas, Pará, Ceará, Piauí and Paraná states. PAHO has advised countries with established populations of A. aegypti to be on alert for Zika fever cases. There are no epidemiological barriers to halt its spread throughout the Americas where dengue virus also occurs. There are large populations of susceptible people and abundant vector mosquitoes that can facilitate spread of the virus. Should Zika virus continue to spread in the Americas, which seems very likely, viremic individuals will arrive in the U.S. with the risk of sporadic initiation of ongoing transmission, which has been the case with dengue and chikungunya viruses in recent years.

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Differential diagnosis among dengue, chikungunya and Zika viruses will be challenging for clinicians. Symptoms are similar enough to be confusing in the absence of laboratory confirmation. This has been a particular challenge in Brazil, where tens of thousands of Zika virus and chikungunya virus infections and hundreds of thousands of dengue cases have been reported recently. Reference laboratories are not equipped (nor financed) to test the enormous volume of samples that large outbreaks can generate. Low-cost, sensitive and specific tests are needed to permit decentralization of laboratory testing to local health care units. Surveillance efforts also will be stressed to the limit.

Effective control of these virus infections is not possible now. There are no commercially available vaccines, although several dengue vaccines are undergoing clinical trials. Community-level vector mosquito control has been difficult and insufficient to prevent or halt outbreaks. Some interesting vector control efforts through release of genetically modified A. aegypti are underway, and look promising.

In the Americas we now have six mosquito-borne viruses circulating — four dengue virus types (1-4), plus chikungunya and Zika viruses. Every day, thousands of passengers get on long-distance commercial aircraft. A few of them will be viremic when they disembark. What mosquito-borne viruses will they bring to the Americas? Will we be ready?

Disclosure: Kaye and Yuill report no relevant financial disclosures.