- Email: [email protected]
Travelling arboviruses: A historical perspective
Journal Pre-proof Travelling arboviruses: A historical perspective Scott B. Halstead PII:
S1477-8939(19)30155-3
DOI:
https://doi.org/10.1016/j.tmaid.2019.101471
Reference:
TMAID 101471
To appear in:
Travel Medicine and Infectious Disease
Received Date: 1 August 2019 Accepted Date: 26 August 2019
Please cite this article as: Halstead SB, Travelling arboviruses: A historical perspective, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/j.tmaid.2019.101471. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Travelling Arboviruses: A Historical Perspective Scott B. Halstead
Corresponding Author: Scott B. Halstead, M.D. Emeritus Professor Uniformed Services University of the Health Sciences Bethesda, Maryland
Address: 5824 Edson Lane, N. Bethesda, MD 20852 Tel: 301-984-8704 Email: [email protected]
1
Abstract: Chikungunya, dengue, yellow fever and Zika viruses share many attributes. All are complex and widespread zoonoses of subhuman primates that have made successful transitions to the urban Aedes aegypti transmission cycle. More important, they have an established record of traveling, having moved from their place of origin hundreds of years ago, sometimes repeatedly. Understanding their epidemiology requires a knowledge of past behaviors including unexplained restraints to their travel. This is a review of mechanisms that may contribute to invasiveness and pathogenicity of these important human pathogens.
Imported viral diseases have experienced a recent global upsurge. In 2016 – 2017, Brazil had its largest outbreak of jungle yellow fever in history with cases occurring in unvaccinated travelers.1 Just previously, the Western hemisphere suffered pandemics of imported chikungunya in 2013 - 2015, and Zika in 2015 - 17. 2,3 In 2007, chikungunya virus generated the fastest moving and largest mosquito-borne viral pandemic in history starting with a sharp outbreak on the coastal East African island of Reunion, then crossing the Indian Ocean to Asia. In 2013, chikungunya virus arrived in the Western Hemisphere, traveling from Asia and across the Pacific Ocean. Zika virus traveled the same route, silently at first throughout Asia and then, causing overt disease, completed its circuit across the Pacific. 3 As befits travelling viruses, chikungunya and Zika have found their way back to the homes of travelers resident in Australia, Europe and the United States. Meanwhile, steadily in the background is the global pandemic of dengue. Are these recent scourges related in some way or just unwelcome coincidences? They are indeed related. Firstly, each of these viruses is a traveler. Secondly, all evolved and circulate in huge subhuman primate zoonoses, three of them plus dengue 2 in Africa and dengue 1 – 4 in Asia. 4Thirdly, to infect humans successfully, each of these viruses evolved to exploit a unique urban transmission system – the bite of a virus-infected Aedes aegypti aegypti, a water-container breeding, anthropophilic mosquito that evolved in Africa from a still existing species, Aedes aegypti formosus, a treehole breeding zoophilic mosquito.5 In Africa, Aedes aegypti formosus, 2
with its broad feeding preference, is a bridge vector between the West African yellow fever zoonosis and the urban transmission cycle. It may as well bridge the movement of other African zoonotic viruses to humans. Yellow fever virus and the urban transmission system was exported from Africa to the American tropics during the 16th century slave trade. 6Aedes aegypti didn’t stop there. Soon, the mosquito was shipped to the Gulf and East Coasts of colonial North America then back across the Atlantic to Europe, the Mediterranean Basin and then on to all of Asia. 5 Once a mechanism for transmission to humans was in place these seven viruses began to travel.7 Yellow fever virus, once well established in the Caribbean, Central and South America, promptly followed the same route as Aedes aegypti, outbreaks occurring as early as 1737 in coastal Virginia, a major outbreak in Philadelphia with 5000 deaths in the summer of 1793, and during the next few years repeated outbreaks in New York City and north to Boston. 8 Yellow fever also traveled to Europe, with 20 outbreaks identified in English, French and Spanish ports beginning with an attack in Gibralter in 1800.9 All of these outbreaks occurred during the period of global cooling called “the little ice age.” Fortunately, for the world, yellow fever virus never exited Africa going east. However, chikungunya virus did. An emergence event was directly observed on Zanzibar in 1871 by an astute 19th century observer who watched as chikungunya crossed the Indian Ocean to seed outbreaks in India that traveled widely in SE Asia. 10 He also identified chikungunya as the cause of an epidemic febrile exanthema with arthritis occurring among natives and colonists of all ages in Batavia (Jakarta), Indonesia in 1779.11 He further noted that chikungunya virus left East Africa at 30 – 50 year intervals.12 Indeed, in 1828, the virus for the first time traveled around the Horn of Africa across the Atlantic Ocean to produce a large outbreak of “dengue” in the Caribbean and in North and South America.2,12 A recent
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example of emergence from Africa was the virologically documented massive epidemic of chikungunya in India in 1963.13 The epidemic, first recognized in Calcutta and transmitted by Aedes aegypti, swept down the East Coast of India and was accompanied by severe disease with deaths in infants, faithfully anticipating the clinical features of the Reunion outbreak. 14-16 Each of these virologically documented pandemics closely resemble the epidemiological and clinical features described by Dr. Christie in Zanzibar a century and a half ago. All exhibited virgin soil epidemiological attributes with high attack rates of a short febrile disease with a debilitating post illness arthritis more severe in adults than children occurring in persons of differing ethnicities and ages. Long before the emergence of the East, Central, South Africa mutation (ECSA) chikungunya virus exhibited profound epidemiological competence for transmission in urban areas. An epidemiologically more important introduction of chikungunya into Asia occurred silently, possibly early in the 20th century. Careful work in the 1960s established chikungunya to be endemic in Burma, Thailand, Cambodia and Vietnam but not in the Philippines, Malaysia, Singapore or Indonesia.17 Clinical features and epidemiology of chikungunya were fully studied in Thai children where the virus produced 20-30% of milder cases of Thai hemorrhagic fever.18,19 The virus was highly endemic throughout all of Thailand, achieving a 80% seroprevalence rate in adults in Bangkok with antibody prevalence rates dropping near the Malaysia border.20,21 It is notable that chikungunya virus caused mild febrile disease in children but, adults being highly immune, infrequently presented with the arthritis syndrome. A remarkable event occurred in the late 1970s. Without specific intervention, chikungunya virus transmission completely stopped in Bangkok.22 At the same time chikungunya became established in the Philippines and in Indonesia, where it grumbles persistently to this day.
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From the standpoint of distance traveled and staying power, dengue 1 – 4 viruses are in a class by themselves. There is evidence that all four dengue viruses circulate in stable subhuman primate zoonoses on the Southeast Asian mainland.4 Serological studies have shown DENV zoonoses exist throughout tropical Asia including the Philippines and the Indonesian archipelago.23 When Aedes aegypti became widely disseminated in colonial urban areas of Asia 200-300 years ago, each of the four viruses accomplished the transition to the urban transmission cycle. During the late 18th and through the 19th centuries there were many published accounts of classical dengue-like disease in European settlers in many countries of Asia.24 Indeed, the intensity of dengue virus transmission among settlers on the east coast of Australia was such that outbreaks of severe and fatal dengue (secondary dengue infections) were reported in the late 19th and early 20th centuries.25,26 Remarkably, dengue 2 may have established urban transmission in the Americas before it emerged in Asia. DENV 2 was the first dengue virus to be isolated in America. 27 Well described outbreaks of dengue-like disease were reported frequently from coastal southern American cities beginning nearly two hundred years ago. One such outbreak in Philadelphia in 1780 was described by Benjamin Rush. A clinical feature uniquely associated with dengue virus infection was the occurrence of post-illness depression.28 A compelling case can be made that this DENV 2 may have been exported from Africa long ago, perhaps as a human pathogenic strain of the long-established African DENV 2 subhuman primate zoonosis.29,30 Sailing ships effectively supported virus travel. Today, jet airplanes move viruses farther and faster than ever before. What is the traveler to do? First, the good news. When Zika arrived in the Western Hemisphere, it was widely predicted that dengue antibodies might modify the course of a Zika virus infection or vice versa. Neither of these predictions have come true. 31 An entirely
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unsuspected outcome has been that Zika behaves like a highly effective dengue vaccine. The 2015-16 Zika epidemic was followed by a reduction in clinical dengue cases throughout Latin America from 2,413,693 in 2015 to approximately 500,000 in both 2017 and 2018 or a 77% reduction in dengue cases (PAHO data). Similar outcomes were reported from surveillance studies in Salvador, Brazil.32,33 It is suspected that Zika infection may protect an epidemiologically and clinically important group, the monotypic dengue-immunes that are responsible for secondary DENV clinical disease.34 Further good news, chikungunya and Zika virus transmission is declining in the Americas. These latter two viruses are single species and until now, as far as we know, are maintained in a transmission system that requires infected humans. As such, each are candidates for eradication via herd immunity. It should be recalled that chikungunya virus was widely seeded throughout tropical America in 1827-8 but then disappeared.2 Chikungunya transmission spontaneously ceased in Bangkok. This suggests that chikungunya endemicity requires very high populations of Aedes aegypti. All over Asia, steady increase in modal ages of dengue patients is evidence that modern societies, fortunately, do not sustain high densities of Aedes aegypti.35 However, pockets of high density vector mosquito populations maintain chikungunya endemically at modest levels in Indonesia and the Philippines. Chikungunya and Zika viruses are enzootic and endemic across much of sub-Saharan Africa conveying continuous but limited risk to travelers. Chikungunya cases are much better documented and studied than Zika virus, with sporadic outbreaks being reported from West, Central, North and East Africa. A recent metaanalysis documented a modest prevalence of chikungunya IgM antibodies, virus or viral RNA or IgG antibodies evenly distributed throughout all sectors of sub-Saharan African human
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populations except South Africa.36 Whether human cases occur in Africa only as a result of urban cycle transmission or occasionally from the chikungunya zoonosis is not known. The future of Zika virus in the American tropics is a mystery. In South and Southeast Asia, Zika virus must have been imported at some period in the past from Africa and then established as a zoonosis. 37,38 The components and extent of this zoonosis are unknown. Sporadic Zika febrile cases in humans have been reported from Asia. 39 Will Zika virus establish a zoonosis in the American tropics? If this happens, the epidemiology of this virus in South America may be rewritten. Concerning yellow fever, the ferocity of the 2016-2018 sylvatic outbreak has greatly subsided. Fortunately, to prevent yellow fever there is an excellent, safe, long-lasting, widely available vaccine, Stamaril. Deciding whether a traveler to a country with YF enzootic activity based upon a specific in-country travel destination is ill-advised. The recent experience shows that all travelers to tropical South America should receive yellow fever vaccine. Next, there is not such good news. There are four viruses that circulate in every tropical and subtropical country causing millions of infections and hospitalizations year after year. Indeed, the incidence of dengue cases in travelers now exceeds that of infectious disease due to other specific etiologies. What is the advice to the traveler? The comments here are directed to those who provide medical counseling to residents of high income countries of Europe, the Americas, Australasia, India and China who plan to visit countries with a high incidence of human infections caused by dengue viruses. The vast majority of travelers will be dengue naïve and at risk to their first dengue infection. In addition to a disease, infection by a single DENV has three outcomes: 1) durable protection against reinfection with the same dengue serotype, 2) short term protection against infection or disease with a different dengue serotype and 3) an
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immune response that leads to severe disease with a heterotypic DENV infection.18,40,41 There is a severe disease unique variant occurring during first dengue infections of infants circulating passively acquired multitypic dengue antibodies from their dengue-immune mothers. 42 In young children, first dengue infections often produce a quite trivial clinical responses, a fairly severe one in adults and, rather capriciously, a fatal outcome in the elderly with chronic disease. To understand why this occurs, a comment on the pathogenesis dengue infections in partially dengue-immune hosts is required. Humans circulating antibodies from a single dengue infection or antibodies passively transferred from dengue-immune mothers are at risk to a unique immune complex driven phenomenon that accelerates intracellular production of virus and may lead to disease of increased severity, antibody dependent enhancement (ADE). Enhanced infection occurs regularly when IgG DENV antibodies at non-neutralizing concentrations attach to DENVs forming immune complexes that infect Fc-receptor bearing cells.43,44 Infection via Fc-receptors suppresses innate cell defenses and increases intracellular infection by a mechanism labeled “intrinsic ADE – iADE.” 45,46 This differs from extrinsic ADE (eADE) – a cell surface phenomenon involving better attachment of immune complexes to Fc receptors than that achieved by dengue virus to viral receptors. eADE contributes a 3-fold while iADE a 100-fold increase in virus production.47 Individuals with enhanced dengue infection may experience a sudden and profound capillary leak late in the febrile period. This is the remediable dengue vascular permeability syndrome (DVPS) - fever, thrombocytopenia, abnormal hemostasis, elevated liver enzyme levels, hypoalbuminemia, complement activation and vascular permeability. At first, it was thought that DENVs infected target cells - monocytes, macrophages and dendritic cells – when
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attacked by the immune elimination response released capillary damaging pro-inflammatory and anti-inflammatory factors.48 The “cytokine storm.” 49 Based upon recent research the cytokine storm hypothesis has been replaced by evidence that DENV non-structural protein 1 (NS1) is itself directly pathogenic. NS1 is produced during cellular infections with each of the four dengue viruses.50 Instead of remaining cell-bound, dengue NS1 circulates in great quantities in acute phase blood. 51 Concentrations of NS1 in early acute phase serum correlate directly with ensuing disease severity during secondary DENV infections. 52 NS1 interacts with toll-like receptor 4 (TLR 4) on the surface of monocytes, macrophages and endothelial cells to release of a range of cytokines and chemokines. In vitro, NS1 resulted in the disruption of the integrity of endothelial cell monolayers. In vivo, DENV 2 NS1 circulating in sub-lethally DENV 2-infected C57BL/6 mice produced lethal vascular permeability.53 DENV NS1 was shown to directly alter the barrier function of
pulmonary endothelial cell monolayers through disruption of the endothelial glycocalyx-like layer (EGL) by triggering the activation of endothelial sialidases, cathepsin L, and heparanase, enzymes responsible for degrading sialic acid and heparan sulfate proteoglycans.54 Vaccination of mice with DENV 2 NS1 protected them against endothelial leakage and death from lethal DENV 2 challenge. Mice immunized with all four DENV NS1 proteins were completely protected against homologous DENV challenges. In conclusion, dengue NS1 toxicosis controlled by ADE contributes to endothelial damage, complement activation, liver damage and hemostatic abnormalities.55
During their first dengue infection adults frequently express a similar complaint “That is the worst disease I have ever had.” Dengue usually starts abruptly with fever, chills, retro-orbital headache, followed by inappetance, altered taste, nausea, vomiting, prostration and myalgia. During the course of infection, individuals often sense that they are getting worse. They worry about their prognosis. A remarkable feature of dengue, not well researched, is the post-illness depression. 56,57 The long convalescence and the delays experienced in reassigning dengue 9
survivors back to active duty during WW II was the motivation behind a still active program of US military medical research on dengue. What is the future for these travelling arboviruses? For dengue, a tetravalent live attenuated vaccine has completed phase 3 testing and has been licensed in the European Union and the United States for use only by individuals older than 9 years who have previously had at least one prior dengue infection. In susceptibles, this vaccine, Dengvaxia, has been shown to provide limited protection leaving non-protective antibodies capable of enhancing breakthrough dengue disease to a more severe outcome compared with susceptible controls.58 Protection and safety issues and recommendations for use of dengue vaccine in travelers are described in greater detail elsewhere.59,60 Because a test that specifically and sensitively identifies past dengue infection has not been designated, Dengvaxia is not recommended for dengue-immune travelers. What does the future hold for chikungunya and Zika viruses outside Africa? Both evolved initially in complex subhuman primate zoonoses. Having achieved this status, can they adapt to new faunas? Yellow fever virus accomplished this feat in the Americas several centuries ago. As time goes on, it appears that sylvatic yellow fever virus is sealed within its complex zoonosis. American sylvatic yellow fever virus has not emerged into the urban transmission cycle since urban yellow fever transmission was interrupted nearly 100 years ago. This suggests that American sylvatic yellow fever virus is quite different from West African sylvatic yellow fever virus where more than one emergence event from sylvatic to the urban cycle may have occurred. The competence of Aedes aegypti in the Americas to transmit sylvatic yellow fever viruses should attract much more vigorous research attention than at present.1,61 The issue of vector competence may lie at the heart of the other great yellow fever mystery. Why has
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yellow fever virus not invaded Asia? It is true that expatriate cases of acute yellow fever acquired in Africa have been hospitalized in China, events that did not result in further transmission.62 If chikungunya and Zika crossed the Indian Ocean easily, why not yellow fever? The answer must be linked to the historical fact that yellow fever never reached the East Coast of Africa.63 Like in America there may be a biological barrier, in virus and/or mosquito, that prevents yellow fever virus maintained in the Central African zoonotic cycle from successful transmission by Aedes aegypti aegypti. It is important that we know more about the biology of Central African yellow fever viruses. The future of travelling arboviruses may still hold many surprises. RESEARCH NOTE: The literature searches for this review derive largely from PubMed and supplemented by personal global field research activities in arbovirology beginning in 1957. The search for historical outbreaks of yellow fever was facilitated by consulting Google. WORDS: 2837
1. Possas C, Lourenco-de-Oliveira R, Tauil PL, et al. Yellow fever outbreak in Brazil: the puzzle of rapid viral spread and challenges for immunisation. Mem Inst Oswaldo Cruz 2018; 113(10): e180278. 2. Halstead SB. Reappearance of chikungunya, formerly called dengue, in the Americas. Emerg Infect Dis 2015; 21(4): 557-61. 3. Musso D, Gubler DJ. Zika Virus. Clin Microbiol Rev 2016; 29(3): 487-524. 4. Vasilakis N, Weaver SC. The history and evolution of human dengue emergence. Adv Virus Res 2008; 72: 1-76. 5. Powell JR, Gloria-Soria A, Kotsakiozi P. Recent History of Aedes aegypti: Vector Genomics and Epidemiology Records. Bioscience 2018; 68(11): 854-60. 6. Bryant JE, Holmes EC, Barrett AD. Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas. PLoS Pathog 2007; 3(5): e75. 7. Kraemer MUG, Reiner RC, Jr., Brady OJ, et al. Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus. Nature microbiology 2019; 4(5): 854-63. 8. Eckert J. In the days of the epidemic: the 1793 yellow fever outbreak in Philadelphia as seen by physicians. Transactions & studies of the College of Physicians of Philadelphia 1993; 15(5): 31-8. 9. Morillon M, Mafart B, Matton T. Yellow fever in Europe in 19th Century. in Ecological Aspects of Past Settlement in Europe. In: Bennike P, Bodzsar EB, Suzanne C, eds. European Anthropological Association, Biennal Yearbook Budapest: Eötvös University Press,; 2002 p 211-22.
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10. Christie J. Remarks on "kidinga Pepo"' a peculiar form of exantematous disease. Epidemic in Zanzibar, East Coast of Africa, from July 1870 till January 1871. BMJ 1872; 1: 577-79. 11. Bylon D. Korte aatekening, wegens eene algemeene ziekte, doorgans genaamd de knokkelkoorts. Verhandelungen van het Bataviaasch Genootschop der Konsten in Wetenschappen 1780; 2: 1730. 12. Christie J. On epidemics of dengue fever: their diffusion and etiology. Glasgow Med J 1881; 3: 161-76. 13. Carey DE, Myers RM, de Ranitz CM, Jadhav M. The 1964 Chikungunya Epidemic at Vellore, South India, including observations on Concurrent Dengue. TransRSocTropMedHyg 1969; 63(4): 434-45. 14. Anderson CR, Singh KRP, Sarkar JK. Isolation of chikungunya virus from Aedes aegypti fed on naturally infected humans in Calcutta. Curr Sci 1965; 334: 579-80. 15. Sarkar JK, Chatterjee SN, Chakravarty SK, Mitra AC. Virological studies in nine fatal cases of fever with haemorrhagic manifestation in Calcutta. Ind Jour Pathol Bacteriol 1966; 9(2): 123-7. 16. Rao TR. Recent epidemics caused by Chikungunya virus in India, 1963-65. Science & Culture 1966; 32: 215-20. 17. Halstead SB. Mosquito-borne haemorrhagic fevers of South and South-East Asia. BullWorld Health Organ 1966; 35: 3-15. 18. Nimmannitya S, Halstead SB, Cohen S, Margiotta MR. Dengue and chikungunya virus infection in man in Thailand, 1962-1964. I. Observations on hospitalized patients with hemorrhagic fever. AmJTropMedHyg 1969; 18(6): 954-71. 19. Halstead SB, Nimmannitya S, Margiotta MR. Dengue and Chikungunya virus infection in man in Thailand, 1962-1964 : II. Observations on Disease in Outpatients. AmJTropMedHyg 1969; 18(6): 972-83. 20. Halstead SB, Scanlon J, Umpaivit P, Udomsakdi S. Dengue and chikungunya virus infection in man in Thailand, 1962-1964 : IV. Epidemiologic studies in the Bangkok metropolitan area. AmJTropMedHyg 1969; 18(6): 997-1021. 21. Halstead SB, Udomsakdi S, Scanlon J, Rohitayodhin S. Dengue and chikungunya virus infection in man in Thailand, 1962-1964: V. Epidemiologic observations outside Bangkok. AmJTropMedHyg 1969; 18(6): 1022-33. 22. Nisalak A, Thaikruea I, Teeraratkul A, Endy TP, Innis BL, Vaughn DW. Chikungunya in Thailand: A reemerging disease? International Conference on Emerging Infectious Diseases; 1998 8-11 March; Altanta, GA; 1998. 23. Althouse BM, Durbin AP, Hanley KA, Halstead SB, Weaver SC, Cummings DA. Viral kinetics of primary dengue virus infection in non-human primates: a systematic review and individual pooled analysis. Virology 2014; 452-453: 237-46. 24. Siler JF, Hall MW, Hitchens AP. Dengue: Its history, epidemiology, mechanism of transmission, etiology, clinical manifestations, immunity, and prevention. The Philippine Journal of Science 1926; 29: 1304. 25. Hare FE. The 1897 epidemic of dengue in North Queensland. The Australasian Medical Gazette 1898; 21 March: 98-107. 26. Halstead SB. Dengue and hemorrhagic fevers of Southeast Asia. Yale JBiolMed 1965; 37: 434-54. 27. Anderson CR, Downs WG. Isolation of dengue virus from a human being in Trinidad. Science 1956; 124: 224-5. 28. Rush B. An account of the bilious remitting fever, as it appeared in Philadelphia, in the summer and autumn of the year 1780. Medical Inquiries and Observations. 1 ed. Philadelphia: Prichard and Hall; 1789: 89-100. 29. Vasilakis N, Tesh RB, Weaver SC. Sylvatic dengue virus type 2 activity in humans, Nigeria, 1966. Emerg Infect Dis 2008; 14(3): 502-4.
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30. Vasilakis N, Cardosa J, Hanley KA, Holmes EC, Weaver SC. Fever from the forest: prospects for the continued emergence of sylvatic dengue virus and its impact on public health. Nat Rev Microbiol 2011; 9(7): 532-41. 31. Gordon A, Gresh L, Ojeda S, et al. Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua. PLoS Med 2019; 16(1): e1002726. 32. Ribeiro GS, Kikuti M, Tauro LB, et al. Does immunity after Zika virus infection cross-protect against dengue? The Lancet Global health 2018; 6(2): e140-e1. 33. Perez F, Llau A, Gutierrez G, et al. The decline of dengue in the Americas in 2017: discussion of multiple hypotheses. Trop Med Int Health 2019. 34. Ribeiro GS, Kikuti M, Tauro LB, et al. Can Zika virus antibodies cross-protect against dengue virus? - Authors' reply. The Lancet Global health 2018; 6(5): e495. 35. Cummings DA, Iamsirithaworn S, Lessler JT, et al. The impact of the demographic transition on dengue in Thailand: insights from a statistical analysis and mathematical modeling. PLoS Med 2009; 6(9): e1000139. 36. Simo FBN, Bigna JJ, Well EA, et al. Chikungunya virus infection prevalence in Africa: a contemporaneous systematic review and meta-analysis. Public health 2019; 166: 79-88. 37. Marchette NJ, Garcia R, Rudnick A. Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia. Am J Trop Med Hyg 1969; 18(3): 411-5. 38. Weaver SC, Costa F, Garcia-Blanco MA, et al. Zika virus: History, emergence, biology, and prospects for control. Antiviral Res 2016; 130: 69-80. 39. Wikan N, Smith DR. Zika virus from a Southeast Asian perspective. Asian Pac J Trop Med 2017; 10(1): 1-5. 40. Sabin AB. Research on dengue during World War II. AmJTropMedHyg 1952; 1: 30-50. 41. Grange L, Simon-Loriere E, Sakuntabhai A, Gresh L, Paul R, Harris E. Epidemiological risk factors associated with high global frequency of inapparent dengue virus infections. Front Immunol 2014; 5: 280. 42. Halstead SB, Lan NT, Myint TT, et al. Infant dengue hemorrhagic fever: Research opportunities ignored. Emerg Infect Dis 2002; 12: 1474-9. 43. Halstead SB, Chow J, Marchette NJ. Immunologic enhancement of dengue virus replication. Nature New Biology 1973; 243(122): 24-6. 44. Halstead SB, O'Rourke EJ. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. JExpMed 1977; 146: 201-17. 45. Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 2010; 10(10): 712-22. 46. Ubol S, Halstead SB. How Innate Immune Mechanisms Contribute to Antibody-Enhanced Viral Infections. Clin Vaccine Immunol 2010; 17(12): 1829-35. 47. Boonnak K, Dambach KM, Donofrio GC, Marovich MA. Cell Type Specificity and Host Genetic Polymorphisms Influence Antibody Dependent Enhancement of Dengue Virus Infection. J Virol 2011; 85(4): 1671-83. 48. Rothman AL. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 2011; 11(8): 532-43. 49. Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. Microvascular and endothelial function for risk prediction in dengue: an observational study. Lancet 2015; 385 Suppl 1: S102. 50. Puerta-Guardo H, Glasner DR, Espinosa DA, et al. Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism. Cell reports 2019; 26(6): 1598-613.e8.
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51. Young PR, Hilditch PA, Bletchly C, Halloran W. An antigen capture enzyme-linked immunosorbent assay reveals high levels of the dengue virus protein NS1 in the sera of infected patients. J Clin Microbiol 2000; 38(3): 1053-7. 52. Libraty DH, Young PR, Pickering D, et al. High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 2002; 186: 1165-8. 53. Glasner DR, Ratnasiri K, Puerta-Guardo H, Espinosa DA, Beatty PR, Harris E. Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components. PLoS Pathog 2017; 13(11): e1006673. 54. Puerta-Guardo H, Glasner DR, Harris E. Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability. PLoS Pathog 2016; 12(7): e1005738. 55. Glasner DR, Puerta-Guardo H, Beatty PR, Harris E. The Good, the Bad, and the Shocking: The Multiple Roles of Dengue Virus Nonstructural Protein 1 in Protection and Pathogenesis. Annual review of virology 2018; 5(1): 227-53. 56. Martelli CM, Nascimento NE, Suaya JA, et al. Quality of life among adults with confirmed dengue in Brazil. Am J Trop Med Hyg 2011; 85(4): 732-8. 57. Sabin AB. Dengue. In: Rivers TM, ed. Viral and Rickettsial Infections of Man, 2nd Edition. Philadelphia: J.B. Lippincott Company; 1952: 556-68. 58. Sridhar S, Luedtke A, Langevin E, et al. Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. N Engl J Med 2018; 379(4): 327-40. 59. Wilder-Smith A, Hombach J, Ferguson N, et al. Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine. Lancet Infect Dis 2019; 19(1): e31-e8. 60. Halstead SB. Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine. Hum Vaccin Immunother 2018; 14(9): 2158-62. 61. Moreira-Soto A, Torres MC, Lima de Mendonca MC, et al. Evidence for multiple sylvatic transmission cycles during the 2016-2017 yellow fever virus outbreak, Brazil. Clin Microbiol Infect 2018; 24(9): 1019.e1-.e4. 62. Chen J, Lu H. Yellow fever in China is still an imported disease. Biosci Trends 2016; 10(2): 158-62. 63. Ellis BR, Barrett AD. The enigma of yellow fever in East Africa. Rev Med Virol 2008; 18(5): 331-46.
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S1477-8939(19)30155-3
DOI:
https://doi.org/10.1016/j.tmaid.2019.101471
Reference:
TMAID 101471
To appear in:
Travel Medicine and Infectious Disease
Received Date: 1 August 2019 Accepted Date: 26 August 2019
Please cite this article as: Halstead SB, Travelling arboviruses: A historical perspective, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/j.tmaid.2019.101471. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Travelling Arboviruses: A Historical Perspective Scott B. Halstead
Corresponding Author: Scott B. Halstead, M.D. Emeritus Professor Uniformed Services University of the Health Sciences Bethesda, Maryland
Address: 5824 Edson Lane, N. Bethesda, MD 20852 Tel: 301-984-8704 Email: [email protected]
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Abstract: Chikungunya, dengue, yellow fever and Zika viruses share many attributes. All are complex and widespread zoonoses of subhuman primates that have made successful transitions to the urban Aedes aegypti transmission cycle. More important, they have an established record of traveling, having moved from their place of origin hundreds of years ago, sometimes repeatedly. Understanding their epidemiology requires a knowledge of past behaviors including unexplained restraints to their travel. This is a review of mechanisms that may contribute to invasiveness and pathogenicity of these important human pathogens.
Imported viral diseases have experienced a recent global upsurge. In 2016 – 2017, Brazil had its largest outbreak of jungle yellow fever in history with cases occurring in unvaccinated travelers.1 Just previously, the Western hemisphere suffered pandemics of imported chikungunya in 2013 - 2015, and Zika in 2015 - 17. 2,3 In 2007, chikungunya virus generated the fastest moving and largest mosquito-borne viral pandemic in history starting with a sharp outbreak on the coastal East African island of Reunion, then crossing the Indian Ocean to Asia. In 2013, chikungunya virus arrived in the Western Hemisphere, traveling from Asia and across the Pacific Ocean. Zika virus traveled the same route, silently at first throughout Asia and then, causing overt disease, completed its circuit across the Pacific. 3 As befits travelling viruses, chikungunya and Zika have found their way back to the homes of travelers resident in Australia, Europe and the United States. Meanwhile, steadily in the background is the global pandemic of dengue. Are these recent scourges related in some way or just unwelcome coincidences? They are indeed related. Firstly, each of these viruses is a traveler. Secondly, all evolved and circulate in huge subhuman primate zoonoses, three of them plus dengue 2 in Africa and dengue 1 – 4 in Asia. 4Thirdly, to infect humans successfully, each of these viruses evolved to exploit a unique urban transmission system – the bite of a virus-infected Aedes aegypti aegypti, a water-container breeding, anthropophilic mosquito that evolved in Africa from a still existing species, Aedes aegypti formosus, a treehole breeding zoophilic mosquito.5 In Africa, Aedes aegypti formosus, 2
with its broad feeding preference, is a bridge vector between the West African yellow fever zoonosis and the urban transmission cycle. It may as well bridge the movement of other African zoonotic viruses to humans. Yellow fever virus and the urban transmission system was exported from Africa to the American tropics during the 16th century slave trade. 6Aedes aegypti didn’t stop there. Soon, the mosquito was shipped to the Gulf and East Coasts of colonial North America then back across the Atlantic to Europe, the Mediterranean Basin and then on to all of Asia. 5 Once a mechanism for transmission to humans was in place these seven viruses began to travel.7 Yellow fever virus, once well established in the Caribbean, Central and South America, promptly followed the same route as Aedes aegypti, outbreaks occurring as early as 1737 in coastal Virginia, a major outbreak in Philadelphia with 5000 deaths in the summer of 1793, and during the next few years repeated outbreaks in New York City and north to Boston. 8 Yellow fever also traveled to Europe, with 20 outbreaks identified in English, French and Spanish ports beginning with an attack in Gibralter in 1800.9 All of these outbreaks occurred during the period of global cooling called “the little ice age.” Fortunately, for the world, yellow fever virus never exited Africa going east. However, chikungunya virus did. An emergence event was directly observed on Zanzibar in 1871 by an astute 19th century observer who watched as chikungunya crossed the Indian Ocean to seed outbreaks in India that traveled widely in SE Asia. 10 He also identified chikungunya as the cause of an epidemic febrile exanthema with arthritis occurring among natives and colonists of all ages in Batavia (Jakarta), Indonesia in 1779.11 He further noted that chikungunya virus left East Africa at 30 – 50 year intervals.12 Indeed, in 1828, the virus for the first time traveled around the Horn of Africa across the Atlantic Ocean to produce a large outbreak of “dengue” in the Caribbean and in North and South America.2,12 A recent
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example of emergence from Africa was the virologically documented massive epidemic of chikungunya in India in 1963.13 The epidemic, first recognized in Calcutta and transmitted by Aedes aegypti, swept down the East Coast of India and was accompanied by severe disease with deaths in infants, faithfully anticipating the clinical features of the Reunion outbreak. 14-16 Each of these virologically documented pandemics closely resemble the epidemiological and clinical features described by Dr. Christie in Zanzibar a century and a half ago. All exhibited virgin soil epidemiological attributes with high attack rates of a short febrile disease with a debilitating post illness arthritis more severe in adults than children occurring in persons of differing ethnicities and ages. Long before the emergence of the East, Central, South Africa mutation (ECSA) chikungunya virus exhibited profound epidemiological competence for transmission in urban areas. An epidemiologically more important introduction of chikungunya into Asia occurred silently, possibly early in the 20th century. Careful work in the 1960s established chikungunya to be endemic in Burma, Thailand, Cambodia and Vietnam but not in the Philippines, Malaysia, Singapore or Indonesia.17 Clinical features and epidemiology of chikungunya were fully studied in Thai children where the virus produced 20-30% of milder cases of Thai hemorrhagic fever.18,19 The virus was highly endemic throughout all of Thailand, achieving a 80% seroprevalence rate in adults in Bangkok with antibody prevalence rates dropping near the Malaysia border.20,21 It is notable that chikungunya virus caused mild febrile disease in children but, adults being highly immune, infrequently presented with the arthritis syndrome. A remarkable event occurred in the late 1970s. Without specific intervention, chikungunya virus transmission completely stopped in Bangkok.22 At the same time chikungunya became established in the Philippines and in Indonesia, where it grumbles persistently to this day.
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From the standpoint of distance traveled and staying power, dengue 1 – 4 viruses are in a class by themselves. There is evidence that all four dengue viruses circulate in stable subhuman primate zoonoses on the Southeast Asian mainland.4 Serological studies have shown DENV zoonoses exist throughout tropical Asia including the Philippines and the Indonesian archipelago.23 When Aedes aegypti became widely disseminated in colonial urban areas of Asia 200-300 years ago, each of the four viruses accomplished the transition to the urban transmission cycle. During the late 18th and through the 19th centuries there were many published accounts of classical dengue-like disease in European settlers in many countries of Asia.24 Indeed, the intensity of dengue virus transmission among settlers on the east coast of Australia was such that outbreaks of severe and fatal dengue (secondary dengue infections) were reported in the late 19th and early 20th centuries.25,26 Remarkably, dengue 2 may have established urban transmission in the Americas before it emerged in Asia. DENV 2 was the first dengue virus to be isolated in America. 27 Well described outbreaks of dengue-like disease were reported frequently from coastal southern American cities beginning nearly two hundred years ago. One such outbreak in Philadelphia in 1780 was described by Benjamin Rush. A clinical feature uniquely associated with dengue virus infection was the occurrence of post-illness depression.28 A compelling case can be made that this DENV 2 may have been exported from Africa long ago, perhaps as a human pathogenic strain of the long-established African DENV 2 subhuman primate zoonosis.29,30 Sailing ships effectively supported virus travel. Today, jet airplanes move viruses farther and faster than ever before. What is the traveler to do? First, the good news. When Zika arrived in the Western Hemisphere, it was widely predicted that dengue antibodies might modify the course of a Zika virus infection or vice versa. Neither of these predictions have come true. 31 An entirely
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unsuspected outcome has been that Zika behaves like a highly effective dengue vaccine. The 2015-16 Zika epidemic was followed by a reduction in clinical dengue cases throughout Latin America from 2,413,693 in 2015 to approximately 500,000 in both 2017 and 2018 or a 77% reduction in dengue cases (PAHO data). Similar outcomes were reported from surveillance studies in Salvador, Brazil.32,33 It is suspected that Zika infection may protect an epidemiologically and clinically important group, the monotypic dengue-immunes that are responsible for secondary DENV clinical disease.34 Further good news, chikungunya and Zika virus transmission is declining in the Americas. These latter two viruses are single species and until now, as far as we know, are maintained in a transmission system that requires infected humans. As such, each are candidates for eradication via herd immunity. It should be recalled that chikungunya virus was widely seeded throughout tropical America in 1827-8 but then disappeared.2 Chikungunya transmission spontaneously ceased in Bangkok. This suggests that chikungunya endemicity requires very high populations of Aedes aegypti. All over Asia, steady increase in modal ages of dengue patients is evidence that modern societies, fortunately, do not sustain high densities of Aedes aegypti.35 However, pockets of high density vector mosquito populations maintain chikungunya endemically at modest levels in Indonesia and the Philippines. Chikungunya and Zika viruses are enzootic and endemic across much of sub-Saharan Africa conveying continuous but limited risk to travelers. Chikungunya cases are much better documented and studied than Zika virus, with sporadic outbreaks being reported from West, Central, North and East Africa. A recent metaanalysis documented a modest prevalence of chikungunya IgM antibodies, virus or viral RNA or IgG antibodies evenly distributed throughout all sectors of sub-Saharan African human
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populations except South Africa.36 Whether human cases occur in Africa only as a result of urban cycle transmission or occasionally from the chikungunya zoonosis is not known. The future of Zika virus in the American tropics is a mystery. In South and Southeast Asia, Zika virus must have been imported at some period in the past from Africa and then established as a zoonosis. 37,38 The components and extent of this zoonosis are unknown. Sporadic Zika febrile cases in humans have been reported from Asia. 39 Will Zika virus establish a zoonosis in the American tropics? If this happens, the epidemiology of this virus in South America may be rewritten. Concerning yellow fever, the ferocity of the 2016-2018 sylvatic outbreak has greatly subsided. Fortunately, to prevent yellow fever there is an excellent, safe, long-lasting, widely available vaccine, Stamaril. Deciding whether a traveler to a country with YF enzootic activity based upon a specific in-country travel destination is ill-advised. The recent experience shows that all travelers to tropical South America should receive yellow fever vaccine. Next, there is not such good news. There are four viruses that circulate in every tropical and subtropical country causing millions of infections and hospitalizations year after year. Indeed, the incidence of dengue cases in travelers now exceeds that of infectious disease due to other specific etiologies. What is the advice to the traveler? The comments here are directed to those who provide medical counseling to residents of high income countries of Europe, the Americas, Australasia, India and China who plan to visit countries with a high incidence of human infections caused by dengue viruses. The vast majority of travelers will be dengue naïve and at risk to their first dengue infection. In addition to a disease, infection by a single DENV has three outcomes: 1) durable protection against reinfection with the same dengue serotype, 2) short term protection against infection or disease with a different dengue serotype and 3) an
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immune response that leads to severe disease with a heterotypic DENV infection.18,40,41 There is a severe disease unique variant occurring during first dengue infections of infants circulating passively acquired multitypic dengue antibodies from their dengue-immune mothers. 42 In young children, first dengue infections often produce a quite trivial clinical responses, a fairly severe one in adults and, rather capriciously, a fatal outcome in the elderly with chronic disease. To understand why this occurs, a comment on the pathogenesis dengue infections in partially dengue-immune hosts is required. Humans circulating antibodies from a single dengue infection or antibodies passively transferred from dengue-immune mothers are at risk to a unique immune complex driven phenomenon that accelerates intracellular production of virus and may lead to disease of increased severity, antibody dependent enhancement (ADE). Enhanced infection occurs regularly when IgG DENV antibodies at non-neutralizing concentrations attach to DENVs forming immune complexes that infect Fc-receptor bearing cells.43,44 Infection via Fc-receptors suppresses innate cell defenses and increases intracellular infection by a mechanism labeled “intrinsic ADE – iADE.” 45,46 This differs from extrinsic ADE (eADE) – a cell surface phenomenon involving better attachment of immune complexes to Fc receptors than that achieved by dengue virus to viral receptors. eADE contributes a 3-fold while iADE a 100-fold increase in virus production.47 Individuals with enhanced dengue infection may experience a sudden and profound capillary leak late in the febrile period. This is the remediable dengue vascular permeability syndrome (DVPS) - fever, thrombocytopenia, abnormal hemostasis, elevated liver enzyme levels, hypoalbuminemia, complement activation and vascular permeability. At first, it was thought that DENVs infected target cells - monocytes, macrophages and dendritic cells – when
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attacked by the immune elimination response released capillary damaging pro-inflammatory and anti-inflammatory factors.48 The “cytokine storm.” 49 Based upon recent research the cytokine storm hypothesis has been replaced by evidence that DENV non-structural protein 1 (NS1) is itself directly pathogenic. NS1 is produced during cellular infections with each of the four dengue viruses.50 Instead of remaining cell-bound, dengue NS1 circulates in great quantities in acute phase blood. 51 Concentrations of NS1 in early acute phase serum correlate directly with ensuing disease severity during secondary DENV infections. 52 NS1 interacts with toll-like receptor 4 (TLR 4) on the surface of monocytes, macrophages and endothelial cells to release of a range of cytokines and chemokines. In vitro, NS1 resulted in the disruption of the integrity of endothelial cell monolayers. In vivo, DENV 2 NS1 circulating in sub-lethally DENV 2-infected C57BL/6 mice produced lethal vascular permeability.53 DENV NS1 was shown to directly alter the barrier function of
pulmonary endothelial cell monolayers through disruption of the endothelial glycocalyx-like layer (EGL) by triggering the activation of endothelial sialidases, cathepsin L, and heparanase, enzymes responsible for degrading sialic acid and heparan sulfate proteoglycans.54 Vaccination of mice with DENV 2 NS1 protected them against endothelial leakage and death from lethal DENV 2 challenge. Mice immunized with all four DENV NS1 proteins were completely protected against homologous DENV challenges. In conclusion, dengue NS1 toxicosis controlled by ADE contributes to endothelial damage, complement activation, liver damage and hemostatic abnormalities.55
During their first dengue infection adults frequently express a similar complaint “That is the worst disease I have ever had.” Dengue usually starts abruptly with fever, chills, retro-orbital headache, followed by inappetance, altered taste, nausea, vomiting, prostration and myalgia. During the course of infection, individuals often sense that they are getting worse. They worry about their prognosis. A remarkable feature of dengue, not well researched, is the post-illness depression. 56,57 The long convalescence and the delays experienced in reassigning dengue 9
survivors back to active duty during WW II was the motivation behind a still active program of US military medical research on dengue. What is the future for these travelling arboviruses? For dengue, a tetravalent live attenuated vaccine has completed phase 3 testing and has been licensed in the European Union and the United States for use only by individuals older than 9 years who have previously had at least one prior dengue infection. In susceptibles, this vaccine, Dengvaxia, has been shown to provide limited protection leaving non-protective antibodies capable of enhancing breakthrough dengue disease to a more severe outcome compared with susceptible controls.58 Protection and safety issues and recommendations for use of dengue vaccine in travelers are described in greater detail elsewhere.59,60 Because a test that specifically and sensitively identifies past dengue infection has not been designated, Dengvaxia is not recommended for dengue-immune travelers. What does the future hold for chikungunya and Zika viruses outside Africa? Both evolved initially in complex subhuman primate zoonoses. Having achieved this status, can they adapt to new faunas? Yellow fever virus accomplished this feat in the Americas several centuries ago. As time goes on, it appears that sylvatic yellow fever virus is sealed within its complex zoonosis. American sylvatic yellow fever virus has not emerged into the urban transmission cycle since urban yellow fever transmission was interrupted nearly 100 years ago. This suggests that American sylvatic yellow fever virus is quite different from West African sylvatic yellow fever virus where more than one emergence event from sylvatic to the urban cycle may have occurred. The competence of Aedes aegypti in the Americas to transmit sylvatic yellow fever viruses should attract much more vigorous research attention than at present.1,61 The issue of vector competence may lie at the heart of the other great yellow fever mystery. Why has
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yellow fever virus not invaded Asia? It is true that expatriate cases of acute yellow fever acquired in Africa have been hospitalized in China, events that did not result in further transmission.62 If chikungunya and Zika crossed the Indian Ocean easily, why not yellow fever? The answer must be linked to the historical fact that yellow fever never reached the East Coast of Africa.63 Like in America there may be a biological barrier, in virus and/or mosquito, that prevents yellow fever virus maintained in the Central African zoonotic cycle from successful transmission by Aedes aegypti aegypti. It is important that we know more about the biology of Central African yellow fever viruses. The future of travelling arboviruses may still hold many surprises. RESEARCH NOTE: The literature searches for this review derive largely from PubMed and supplemented by personal global field research activities in arbovirology beginning in 1957. The search for historical outbreaks of yellow fever was facilitated by consulting Google. WORDS: 2837
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30. Vasilakis N, Cardosa J, Hanley KA, Holmes EC, Weaver SC. Fever from the forest: prospects for the continued emergence of sylvatic dengue virus and its impact on public health. Nat Rev Microbiol 2011; 9(7): 532-41. 31. Gordon A, Gresh L, Ojeda S, et al. Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua. PLoS Med 2019; 16(1): e1002726. 32. Ribeiro GS, Kikuti M, Tauro LB, et al. Does immunity after Zika virus infection cross-protect against dengue? The Lancet Global health 2018; 6(2): e140-e1. 33. Perez F, Llau A, Gutierrez G, et al. The decline of dengue in the Americas in 2017: discussion of multiple hypotheses. Trop Med Int Health 2019. 34. Ribeiro GS, Kikuti M, Tauro LB, et al. Can Zika virus antibodies cross-protect against dengue virus? - Authors' reply. The Lancet Global health 2018; 6(5): e495. 35. Cummings DA, Iamsirithaworn S, Lessler JT, et al. The impact of the demographic transition on dengue in Thailand: insights from a statistical analysis and mathematical modeling. PLoS Med 2009; 6(9): e1000139. 36. Simo FBN, Bigna JJ, Well EA, et al. Chikungunya virus infection prevalence in Africa: a contemporaneous systematic review and meta-analysis. Public health 2019; 166: 79-88. 37. Marchette NJ, Garcia R, Rudnick A. Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia. Am J Trop Med Hyg 1969; 18(3): 411-5. 38. Weaver SC, Costa F, Garcia-Blanco MA, et al. Zika virus: History, emergence, biology, and prospects for control. Antiviral Res 2016; 130: 69-80. 39. Wikan N, Smith DR. Zika virus from a Southeast Asian perspective. Asian Pac J Trop Med 2017; 10(1): 1-5. 40. Sabin AB. Research on dengue during World War II. AmJTropMedHyg 1952; 1: 30-50. 41. Grange L, Simon-Loriere E, Sakuntabhai A, Gresh L, Paul R, Harris E. Epidemiological risk factors associated with high global frequency of inapparent dengue virus infections. Front Immunol 2014; 5: 280. 42. Halstead SB, Lan NT, Myint TT, et al. Infant dengue hemorrhagic fever: Research opportunities ignored. Emerg Infect Dis 2002; 12: 1474-9. 43. Halstead SB, Chow J, Marchette NJ. Immunologic enhancement of dengue virus replication. Nature New Biology 1973; 243(122): 24-6. 44. Halstead SB, O'Rourke EJ. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. JExpMed 1977; 146: 201-17. 45. Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 2010; 10(10): 712-22. 46. Ubol S, Halstead SB. How Innate Immune Mechanisms Contribute to Antibody-Enhanced Viral Infections. Clin Vaccine Immunol 2010; 17(12): 1829-35. 47. Boonnak K, Dambach KM, Donofrio GC, Marovich MA. Cell Type Specificity and Host Genetic Polymorphisms Influence Antibody Dependent Enhancement of Dengue Virus Infection. J Virol 2011; 85(4): 1671-83. 48. Rothman AL. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 2011; 11(8): 532-43. 49. Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. Microvascular and endothelial function for risk prediction in dengue: an observational study. Lancet 2015; 385 Suppl 1: S102. 50. Puerta-Guardo H, Glasner DR, Espinosa DA, et al. Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism. Cell reports 2019; 26(6): 1598-613.e8.
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