dengue - duo · 2017-12-07 · dengue occurrence, causes, pathogenesis, diagnosis, prognosis,...
TRANSCRIPT
Dengue Occurrence, causes, pathogenesis, diagnosis, prognosis, treatment,
and prevention, with a special focus on Myanmar and Norway
Written by: Medical student Mari K. Guldahl
Supervisor: Professor Espen Bjertness, Department of Community Medicine and Global Health, University of Oslo
Resource group: Dr. Kay Khine Mauk, University of Medicine and Professor Thein Thein Htay, University of Public Health, Myanmar
Project thesis, faculty of medicine
UNIVERSITY OF OSLO.
27.01.2017
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Abstract Dengue is a viral disease occurring in more than 100 endemic countries in Asia, the Americas and Africa. The number of clinical cases are estimated to be between 58 and 96 million every year. Myanmar is an example of a country that is suffering from a high dengue burden. Norway on the other hand, has very few cases of infected returning travelers. Increasing urbanization, travel and climate change are facilitating the spread and increasing incidence of the disease. The virus consists of four distinct serotypes, dengue virus 1-4, and is carried by the Aedes mosquito. Infection creates immunity against that particular serotype, but not against the others. Secondary infections with another serotype have the potential to cause more severe disease. Humans are infected by a bite from an infected mosquito and the infection can go unnoticed or manifest clinically. Symptomatic disease can be classified in two different ways. The first divides dengue into non-severe dengue, non-severe dengue with waring signs and severe dengue. The other uses the terms dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Common symptoms of the disease are fever, headache, myalgia and arthralgia, rashes, retro-orbital pain and nausea. The disease may progress to become more severe with plasma leakage, fluid accumulation, depletion of intracellular volume, bleeding and shock, and the common signs are abdominal pain, bleeding, vomiting and hepatomegaly. In cases of severe disease, observation and prompt treatment with i.v. fluids are important to prevent or treat hypovolemic shock. There is no antiviral treatment available for dengue. Prevention has mainly been through vector control, but the recent licensing of a new vaccine is an important addition to the battle against dengue.
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Table of contents
Introduction 4
Methods 4
Occurence 5Global burden 5
Distribution 6
Dengue in Myanmar 8
Dengue in Norway 10
Causes 10
Vector 10
Virus 12
Pathogenesis and pathophysiology 13Antibody-dependent enhancement (ADE) 14
Diagnosis 14Classification 14
Symptoms and signs 17
Diagnostic tests 19
Prognosis 20
Treatment 21
Prevention 23Vector control and surveillance 23
Vaccine 25
Discussion 27
Conclusion 28
Acknowledgments 28
References 29
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Introduction Dengue is the worlds most rapidly spreading mosquito-borne viral disease(1). WHO estimates about 50-100 million new infections occur every year in more than 100 endemic countries(2). Both global incidence and number of countries affected by the disease are increasing(1). In this thesis I will describe occurrence, causes, pathogenesis, diagnosis, treatment and prevention of dengue, with main focus on occurrence and clinical diagnosis. Further more, I will describe trends in occurrence of dengue in a country with endemic areas (Myanmar) and in a country where cases occur only due to travel to endemic countries (Norway). Finally, I want to explore possible reasons for the dramatic increase in occurrence in these countries and in the world in general. I chose Norway because that is my homeland. I focused on Myanmar because little information is available on dengue fever in Myanmar compared to neighboring countries, and it is a country which has a development cooperation with Norway. This thesis shed light on a globally important, but often neglected disease.
Methods Searches were done in different databases, McMaster Plus, PubMed and Cochrane library, with the keywords «Dengue», «Dengue fever» and «Dengue Myanmar», in addition to keywords such as epidemiology, treatment, prognosis, diagnosis and prevention. I also used MeSH terms and clinical queries in my searches on PubMed. From these searches I also looked at similar articles fields and hand picked from reference lists. For data on possible vaccines and antiviral therapies I searched for clinical trials in addition to the information I found in different articles. I started working with review articles about dengue, and from there I did more specialized searches, for example «Dengue vector», «Aedes aegypti dengue», «Aedes albopictus dengue», «Dengue vaccine» and «Dengue climate». After working through the hits, information was also gathered through handpicked references from different papers. I addition to searches for articles I also searched within the WHO homepage to find information on occurrence and guidelines. For occurrence of dengue in Norway I used the MSIS database(3) and resources from the website for the Norwegian Institute of Public Health(4). Data from Myanmar was collected from different articles about dengue in Myanmar, from surveillance data from WHO(5-7) and from information on the website for the Ministry of Health and Sports in Myanmar(8). I also requested and was provided with resources from the Ministry of Health in Myanmar. My supervisor, Prof. Espen Bjertness, also provided me with several useful articles in addition to access to an electronic library of articles related to health in Myanmar.
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Occurence Global burden The dengue virus causes more human cases every year than any other arbovirus(9). The exact number and full global burden of dengue fever is uncertain. Cases of dengue fever is often underreported and many cases are misclassified(10). Changes in case definitions, health care availability, diagnostic capabilities and subclinical cases all influence the number of cases reported. There may also be variations in time and geographic regions(11). Based on WHO, there were 2.2 million reported dengue cases in 2010 and 3.2 million in 2015(10). In contrast to these numbers, WHO estimates that up to 50-100 million infections occur annually. This constitutes a 30-fold increase in incidence in the last 50 years(1, 2). However estimates of dengue burden varies greatly in different studies, mainly due to passive and poor surveillance, cases not being reported, lack of available simple diagnostic tests and analysis that should be comparable give inconsistent results. Cyclical epidemics giving yearly epidemiological fluctuations of dengue also makes estimations difficult(12, 13). A study from 2013 estimated 390 million dengue infections per year, of which 96 million manifests clinically(14). This leaves 294 inapparent cases, which means that there are insufficient symptoms to be detected or no symptoms at all. Even though they do not contribute directly to the disease burden, these cases can still transmit the disease and contribute to continued circulation of the virus(15). Another study, based on analysis of the Global burden of disease study in 2013, found an incidence of 58.4 million symptomatic cases in 2013. Even though this number is significantly lower, it still shows more than a doubling of apparent cases every decade since 1990(16). The increase in dengue incidence is caused by increased incidence in countries where dengue is already present, spread of the disease to new geographical areas and the change from mainly being a paediatric disease to increasingly affecting older age groups(16-19). The fact that dengue is becoming more common in working adults, means that the burden on society might also be increasing. With a longer course of illness and a higher number of hospitalized patients compared with other febrile illnesses, the impact on society might already be higher for dengue than for many other similar diseases(20, 21). The increased incidence of dengue might also cause an increase in the number of secondary cases. Antibodies from past infections is though to be the cause of more severe disease, and an increase in secondary infections might lead to a higher number of severe cases of dengue, adding to the already high burden of the disease(22).
Historically, dengue was nearly eradicated in America in the 1970s by a program targeting A. aegypti to control yellow fever. This led to dengue mostly being confined to South-East Asia during this time period. However, with the termination of the program in the 1970s, the mosquito re-invaded the area and dengue has spread(23, 24).
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On the basis of 58.4 million global cases, the total annual cost of dengue illness was estimated to be 8.9 billion US$, or $1.56 per capita(25). In South-East Asia, a study showed an annual economic burden of US$ 950 million in just 12 countries, or $1,65 per capita(26). The same study also showed the disease burden as the annual number of disability-adjusted life years (DALYs), which was 214 000 DALYs for the 12 countries studied or 372 DALYs per million inhabitants. This is higher than that of several other common conditions in the area, including hepatitis B, upper respiratory infections, otitis media and Japanese encephalitis. It was ranked just under malaria in this study. Stanaway and colleagues found that dengue was responsible for 1.14 million DALYs globally in 2013(16).
Dengue is considered as a neglected tropical disease (NTD) both by the WHO, CDC and the scientific journal PLOS Neglected Tropical Diseases. Their definitions on NTDs are not quite the same, but are similar in that they include diseases that mostly affect areas and populations that suffers from poverty, it is mostly infectious diseases and they constitute a significant burden(27-29). Horstick and colleagues raised the question if dengue should still be considered as a NTD. They found that dengue differs form other NTDs by affecting both poor and rich populations, it is not a «hidden» chronic disease like most other NTDs, and it receives more attention and funding. They also found that dengue shares characteristics with other NTDs in that it is a disease with high morbidity and low mortality that affects tropical and subtropical countries with limited resources. It is most common in densely populated urban areas that often have limited access to preventive measures and high quality medical care, and poorer populations tend to be more affected. Dengue lacks effective interventions and are in need of further funding for research and development, like most other NTDs. This in particularly made them conclude than dengue should still be considered as a NTD(30). Even though the impact of dengue has reached a similar level as some of the most visible infectious diseases, dengue receives less attention and funding, and is considered as unimportant in comparison(24). Thus the term neglected disease seems fitting.
Distribution It has been estimated that 2.5 billion people are at risk for dengue fever, mainly in tropical and subtropical countries. The disease is endemic in more than 100 countries, which means that it occurs every year(31, 32). A study of dengue occurrence identified 128 countries where dengue were present. This produced an estimated population at risk of 3.97 billion people(33). Other studies sets the number of endemic countries as high as 141(25). In addition to endemic transmission there are dengue epidemics or dengue outbreaks, when a vast number of the population get infected in a short period of time. During a dengue outbreak there are more cases of dengue disease than expected in a given time period or area(31, 34). Factors that contribute to epidemics in a given area are the capacity for vector control, changes in serotypes and immunity in the population(34). During epidemics, infection rates are often 40%
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to 50% among people not previously exposed to the virus, but can reach as high as 80% to 90%(32). Due to poor surveillance, planning and implementation of emergency response plans, the impact of dengue epidemics is often amplified, causing reduced quality of medical care, increased mortality, chaos and confusion(24).
South-East Asia and the Western Pacific Region bears nearly 75% of the global dengue disease burden(1). From the estimation of 96 million annual infections, Asia bore 70% of this burden, the Americas 14% and Africa 16%(14). Stanaway and colleagues estimated that of 58.4 million cases, there were nearly 46 million cases in South Asia, East Asia and South-East Asia combined. I comparison it estimated 5.8 million cases in Latin America and 5.6 million cases in Sub-Saharan Africa(16). In Asia, the disease has affected most countries, and dengue haemorrhagic fever (DHF) is a leading cause of hospitalization and death among children. It has also become one of the leading heath problems in the Americas the last 30 years, with incidence dramatically increasing in South America and the Caribbean(24, 35). Previously, dengue was not considered as a major problem in Africa, but is now estimated to have a burden of disease equivalent to the Americas(14, 24). Here most countries also lack national dengue surveillance, and reporting is not mandatory(30), making underreporting more probable than in other regions. Cases of the disease is also found increasingly in Australia. Travel, migration and established populations of Aedes vectors are now creating opportunities for outbreaks in North America and Europe(35).
The dengue virus has been spread around the world, mainly by human transport(9). Transmission of dengue to new areas can happen by movement of viremic travelers to areas where the vectors are already present, but transmission can also occur by transportation of the vector by ship or aircrafts(36, 37). Changes in human dynamics has facilitated the spread of dengue. For example by increasing movement of people, and by rapid urbanization and population growth leading to the creation of more breeding sites within crowded communities(9, 38, 39). Factors in the climate are also associated with the risk of dengue transmission and outbreaks, and thereby has a great influence on incidence. Temperature, precipitation and humidity have a significant association with cases of dengue fever (DF). Temperature and precipitation affects incidence through direct effects on dengue transmission rates. I addition precipitation also has indirect effect through mosquito population dynamics(34, 40). A study on the effects of weather and climate change on dengue in Mexico estimated that dengue incidence will increase with 40% by 2080 without the implementation of adaption strategies. The increase would be greatest in already endemic areas with a potential higher portion of severe dengue cases(41). It seems highly likely that the prospected climate change will have an impact on the epidemiology, but human behavior is currently seen as most influential on the distribution of the disease(42).
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Dengue in Myanmar Myanmar is located in a tropical zone and has a climate with relatively high temperatures and humidity. These conditions are optimal for the dengue vector A. aegypti(43). The first case of DHF was recorded in 1969 and the first outbreak of dengue was recorded in 1970. By 1991, dengue had spread to twelve of fourteen Sates/Divisions. Dengue is now endemic in Myanmar, occurring in a cyclical pattern of endemo-epidemicity(44-46). Already before the first recorded case, Myanmar undertook anticipatory measures in 1964. These included a surveillance program, establishment of a national committee on DHF and an Aedes control unit. The disease was made notifiable in 1966 and serological surveys carried out in 1968 showed that there was already a high prevalence of dengue antibodies among the population(44, 45).
From 1991 to 2001 Myanmar had a yearly average of 6207 cases of dengue, with 138 deaths. Children were the worst affected. There were variations among different states/divisions, with the highest number of cases and deaths in Yangon. The highest number of cases was registered in the monsoon period, which is from the second week of May to the second week of October. From 1991 to 2001, no case-free month was registered, showing that DF and DHF occurs all year around, in particular in the Yangon region. It is important to know that these numbers were only hospital cases(43, 47). Dengue started as an urban disease in Myanmar, but more cases has been reported in rural areas since 1998, and by 2011 the distribution of dengue cases was equal in urban and rural areas(7, 48). All four serotypes of the virus has been recorded in the country(49, 50). The incidence of DF and DHF is increasing. The case fatality rate (CFR) of DF and DHF combined has shown a downward trend, but it was higher than the rate in Thailand in 2001. CFR had decreased from 4% to 1% in 2012(7, 47). Morbidity has been increasing over the last four decades(48). A report on hospitalization rates in 2013 shows that DHF was the 6th leading cause of hospitalization and morbidity, accounting for 4,8% of all inpatients and 2,8% of total morbidity. The highest number of hospitalized cases was recorded in the Yangon Region followed by Mandalay Region, Ayeyawady Region, Mon State and Bago Region. The only areas where dengue was not among the top 15 cases of morbidity was in North and South Shan State, Chin State and Kachin State (figure 1). This report clearly show the burden that dengue constitutes in Myanmar(51, 52).
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Disclaimer: The names shown and the boundaries used on this map do not imply official endorsement or acceptance by the United Nations.
Data Sources :
Base Map - MIMU
Boundaries - WFP/MIMU
Place names - Ministry of Home Affairs
(GAD) translated by MIMU
Map ID: MIMU1052v02Creation Date: 8 July 2015.A4Projection/Datum: Geographic/WGS84
Email : [email protected]
Map of the Republic of the Union of Myanmar
Myanmar Information Management Unit
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Myanmar has a dengue action plan that can be instituted to prevent outbreaks through active surveillance and vector control(48). Prevention and control measures in the country includes surveillance, spraying and fogging of insecticide, the use of larvicides and health education through mass media making the population aware of precautions to prevent dengue(44, 53). The Department of Health, through the vector-borne disease program, is responsible for these preventive measures(54). Below is a graph showing cases and deaths of dengue from 2003 to 2012 in Myanmar based on reported cases to the WHO(6).
There seems to be a sudden increase in deaths in 2010. Additionally, numbers from DengueNet, WHO’s central data management system for surveillance on DF, shows 158 deaths in 2005(5) even though the graph has no deaths registered. This begs the question of how reliable these numbers are, and shows the difficulties in finding correct surveillance data on dengue in Myanmar. The DengueNet web site only provided numbers from 2005(5).
Stanaway and colleagues made country-level estimates for dengue in their analysis from the Global Burden of Disease (GBD) study 2013. Here they estimated 582 600 cases of dengue in Myanmar in 2013, including 167.9 deaths. They also calculated a burden of 16 630 DALYs in 2013(16). This may indicate that dengue fever is grossly underreported in Myanmar, as it also seems to be globally, or that GBD overestimates. Even if this is just an estimate, it is clear that the burden of dengue fever in Myanmar is high, in particular in Yangon.
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Figure 2: Reported cases and deaths of dengue in Myanmar from 2003 to 2012(6).
Dengue in Norway Dengue fever has been nominative notifiable in Norway since July 2012. Two cases of DHF has been reported in Norway, in 1996 and 2008. Both of these were primary infections(55). All dengue fever cases that has been reported in Norway, originated abroad with the patient being infected while traveling (Table 1). Most cases originate from Asia, with the highest number of cases from Thailand(55, 56). Since dengue only occurs in patients returning from travels abroad, Norwegians traveling to areas where dengue is endemic is advised to be vigilant about avoiding mosquito bites. Advice to travelers include proper clothing covering arms and legs, mosquito repellant, impregnated mosquito nets around beds and strollers, closing doors and windows before turning on the light, and staying above the second floor, preferably in air-conditioned rooms. Previously infected individuals should be particularly vigilant because of the increased risk of DHF, but they are not advised against traveling to endemic areas(55, 57).
Norway in general has a cool climate, not suitable for the dengue vector. However, the mosquito, Aedes albopictus, is currently spreading in Europe. With estimated climate change, the mosquito can establish itself in costal areas in the southern parts of Norway and thereby potentially bringing dengue fever to the country(58).
Causes Dengue is an arthropod-borne viral illness, caused by the dengue virus. There are four serotypes, DENV 1-4, which are transmitted by Aedes mosquitoes(39).
Vector Aedes aegypti and Aedes albopictus are the most important vectors, with transmission to humans primarily by A. aegypti. A. aegypti can be found all over the world and has colonized most tropical countries(59, 60). A. aegypti is most common in urban areas, while A. albopictus is found in suburban and rural areas(61). A. albopictus is considered a less efficient dengue vector, even though it has a greater competence for the virus than A. aegypti. A. albopictus is currently only a minor contributor in dengue transmission compared to A. aegypti(9, 62, 63).
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Table 1: Number of cases diagnosed per year, distributed by place of infection(56).
Date: 02.01.2017 (dd.mm.yyyy) Disease: Dengue feverData updated: 02.01.2017
Place of infection 2012 2013 2014 2015 2016Norway - - - - -
Unknown - - - - -Abroad 30 57 73 98 59
Total 30 57 73 98 59
However, changes in the distribution of A. albopictus is making this vector more important as a cause for dengue. Their eggs are more resistant to cold and drought, which allows the mosquito to survive in areas with a different climate(64). It is now present in several countries in the Northern Hemisphere, and can potentially cause future epidemics(65). In addition to the transmission of dengue fever, the Aedes mosquitoes are vectors for Chikungunya fever, Rift Valley fever, Yellow fever and Zika virus(66-68).
Dengue viruses are transmitted by female Aedes mosquitoes, as the female is the only one that seeks bloody meals(35, 69). They prefer to feed on humans and lay their eggs in artificial containers in domestic areas, like spiritual worship bowls, metal or cement tanks and flower vases. This makes transmission more common in highly populated, urban areas, especially in areas without reliable water systems, where water needs to be collected and stored(37, 54). Bites from the female A. aegypti mosquito most often occurs around sunrise and sunset, for 2-3 hours after daybreak and for 3-4 hours before nightfall. The mosquito breeds outdoors, but prefers to take shelter and often feed indoors(35, 70). A. aegypti is considered as a particularly efficient epidemic vector because it often feeds on several individuals during a gonotrophic cycle(37, 69). In a study including three mosquito populations, A. aegypti proved to be the most aggressive biter(71).
There is a strong connection between the incidence of dengue and the density of Aedes mosquitoes(40). The population of A. aegypti has been shown to increase during rainy periods, and with the increase in population, follows an increase in the incidence of dengue. Rainfall produces ideal conditions for reproduction and is favorable for mosquito population dynamics by creating available larval habitats(72, 73). A study by Oo and colleagues found an increase in breeding sites with the addition of secondary sites like discarded tires during monsoon season. The same study also showed an increase in larvae, shortening of the larval stage and an increased pupation rate during the rainy season(61), facilitating an increase in mosquito population. With evaporation of water in containers, competition between the mosquitoes increase and potential egg laying may be deterred(11). This might suggest that temperatures that are to high might decrease the abundance of the vector, but it has also been shown that low temperatures limits the mosquito’s laying off eggs and thereby decreasing the number of vectors(73). All of this shows that climate has an important role in the spread of dengue, but
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Image 1: Aedes aegypti (65) (left)
Image 2: Aedes albopictus (66) (right)
these variables alone cannot account the distribution of A. aegypti around the world. Changes such as urbanization, development of infrastructure like modern transportation, population growth, socioeconomic factors and control efforts have been observed to follow similar patterns as the distribution of the vector, which shows that human behavior and the domestic environment have an important effect on the distribution of A. aegypti and the epidemiology of dengue(24, 42, 64).
Virus The four serotypes of the dengue virus, DENV 1, 2, 3 and 4 belong to the genus Flavivirus, family Flavaviridae(35). Being an arthropod-borne virus, the dengue virus is a RNA virus with high mutation rates. Mutation rates, in addition to large virus populations and small genome sizes, results in high levels of genetic variation that can have made it possible for the dengue virus to infect different host environments(9). Viruses are maintained in mosquito-human-mosquito cycle(70). The virus enters an adult female mosquito by biting an infected human. The virus then replicates in the mosquito and after replication, the infected mosquito can transmit the virus to another human(74). The mosquito will in all likelihood remain infectious for the rest of its life. Other ways of transmission, such as transfusion, transplant and transplacental transmission are rare(35). In addition to these human cycles of the virus, there are sylvatic cycles of the dengue virus. This means transmission to non-human primate hosts. The virus does not seem to cause disease in these hosts(9, 75). To spread effectively, the virus needs to be in contact with non-immune hosts(69). Increased transmission is achieved when the vector inhabits new areas or a new serotype is introduced(23).
The transmission of the virus can avoid detection due to inapparent/subclinical and asymptomatic infections. Transmission to mosquitoes then occurs before the onset of symptoms or in cases where no symptoms or illness arises. This means that inapparent infection could be the factor that supports the circulation of dengue viruses in between epidemics. These were the results of the study by Duong and colleagues. They also found that asymptomatic and pre-symptomatic individuals actually were more infectious than symptomatic people with a higher viral load in infected mosquitoes, thus increasing the probability of mosquito infection(15).
Since the virus is carried by mosquito vectors, the ecology of the virus is closely tied to the ecology of the vectors. But the virus itself is also affected by their surroundings, for instance an increase in temperature is associated with faster replication and shorter incubation period, thereby facilitating virus transmission(11). It is clear that climate change will affect the
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epidemiology and evolution of the virus, but there is need for further research to fully understand how this will alter the global burden of dengue(9).
Multiple virus serotypes often cocirculate in the same city, called hyperendemicity. Epidemics with more than one serotype are also becoming more frequent(60, 70). This may increase the rate of genetic change in the viruses, thereby increasing the risk of new strains with higher virulence or greater epidemic potential(24, 70). The possible discovery of a new serotype of the dengue virus, DENV 5, can lead to even bigger challenges(75, 76). Infection with one serotype of the dengue virus protects against infection by the same serotype. It does not protect against infection with another serotype, thereby allowing multiple sequential infections as there are no long-lasting cross-protective immunity. On the contrary, subsequent infection by a different serotype can cause antibody-dependent enhancement (ADE) and more severe disease(9, 37, 38, 63). This means that in areas with hyperendemicity, the risk of severe disease is higher(60). Several studies where serological testing were included found no association between serotype and the severity of disease(50, 77), but other studies has found that certain serotypes causes a higher percentage of severe disease. Which serotype differed between geographical areas and between primary and secondary infection(78).
Pathogenesis and pathophysiology The clinical outcome of dengue infection is dependent on several factors both within the patient, the vector and in the virus itself. Examples are genetic factors within the host that affect susceptibility and severity, immune response in the host and viral factors like virulence(77, 79-81). The knowledge of the pathophysiology of dengue disease is limited(80). When the virus is transmitted to a human host from a mosquito bite, the virus spreads to several tissues including lymphoid tissues. Replication of the virus within the host then causes a viremia with a peak around the onset of fever. The main targets for the virus are dendritic cells, monocytes and macrophages. There is also evidence of infection of endothelial cells and hepatocytes with possible spread to other organs(80-82). The understanding of dengue’s pathophysiology has changed. Earlier the haemorrhagic manifestations were highlighted, as seen in the term dengue haemorrhagic fever (DHF). It is now known that plasma leakage is the important factor in the development of more severe disease(19, 69). The main pathological mechanism in severe disease is dengue vascular permeability syndrome (DVPS)(79). This involves increased capillary permeability, leading to vascular leakage with fluid accumulation, depletion of intravascular volume and shock(83). There can also be leakage of electrolytes, protein and blood cells. Ultimately all of this can lead to tissue hypoxia with metabolic acidosis and hyponatremia(79). Normally, the vascular leakage happens before any severe hemorrhage(18). Dengue infection usually leads to some degree of coagulopathy that can be enhanced by hypotension and hypoxia(84). Hemorrhage
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then occurs due to a degree of disseminated intravascular coagulation (DIC), liver damage and thrombocytopenia. The exact mechanism behind the increased permeability and altered hemostasis is not well known(79). Suggestions for the pathogenesis behind increased severity in secondary infections are antibody-dependent enhancement, cytokine storm and cross-reactive T-cells(82). Dengue nonstructural protein 1 (NS1) also has a role in the pathogenesis(85). Halstead has suggested that NS1, as a toxin, can cause DVSP with activation of complement, thrombocytopenia, altered hemostasis and vascular damage(79, 86).
Antibody-dependent enhancement (ADE) Antibodies are important for the resolution of the infection and immunity against new infection, but they can also be a risk factor for severe disease(81). ADE happens when IgG antibody immune complexes contributes to worsening of an infectious disease. Infection with a dengue virus causes an immune response and it is this response that later can cause ADE when the patient is infected a second time with another serotype(79). The fact that there is a higher percentage of severe cases in secondary infections compared to primary infections strengthens the theory of ADE in dengue(78). The innate immune response is suppressed by the immune complex resulting in increased intracellular virus production and infection, with production of cytokines and chemokines and increased concentrations of NS1. The result is enhanced disease(79, 85) The pathogenic mechanism of ADE could explain all the aspects of DVPS. How often DVPS occurs and how severe the disease becomes is dependent upon the sequence of infection in regard to serotype and the time between primary and secondary infection, with increased interval causing increased severity(79). The problem with this theory is that severe disease also occurs with primary infection(50, 87). A possible explanation is passively acquired antibodies witch can happen through transmission of maternal antibodies to infants(79, 87). This phenomenon has been reported in several studies. It does however, not account for the cases of severe disease in patients with primary infection older then 1 year where maternal antibodies are no longer present(87).
Diagnosis Classification A classification system for dengue is important to guide clinicians to correctly diagnose and identify patients at risk for severe dengue disease and prompt correct treatment. It is also important in dengue research and in regard to collecting reliable data on the disease to estimate the burden and thereby need for further interventions. Preferably the classification system should be simple, standardized and reproducible. Is should be applicable to the majority of cases without any need for modification or interpretation(77, 88).
The WHO’s classification from 1997 divided dengue disease into undifferentiated fever, dengue fever (DF), dengue haemorrhagic fever (DHF) and DHF with hypovolemic shock,
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dengue shock syndrome (DSS). They graded DHF severity into four grades, I and II were considered as DHF, III and IV as DSS. Thrombocytopenia with concurrent haemoconcentration differentiates DHF from DF(89). However, these guidelines have never been formally validated and questions were asked if the classification was really helpful. Some of the problems found with the classification were that there is to much overlap between DF, DHF and DSS, tests required for classification are not always helpful or available, especially in countries with limited resources, and the focus on DHF can give a false picture of the global disease burden when other endpoints of dengue is ignored. The requirements of DHF are not always fulfilled and does not include unusual manifestations, causing under-diagnosis of severe disease and underestimates of the number of cases. At the same time, two of the four criteria for DHF were found to be almost as common in patients with DF. The emphasis on haemorrhage in DHF is also misleading, when the most important factor is plasma leakage and not bleeding(17, 77, 88, 90). Santamaria and colleagues found that several countries in Latin America and Asia adapted the classification to such a degree that epidemiological data were no longer comparable, making research and vaccine trials difficult(18). In spite of critics and the suggestion of a new classification system by the WHO in 2009, the terms DH, DHF and DSS are still frequently used(1). That is why I still want to mention these definitions in this paper. No concrete case definition is given for DF and laboratory conformation is recommended, but acute febrile illness with two or more additional manifestations like headache, retro-orbital pain, myalgia, arthralgia, rash, haemorrhagic manifestations, leukopenia and supportive serology or an incident at the same location and time as other confirmed dengue fever cases, makes dengue fever probable. Laboratory confirmation can be made after one of the following criteria; dengue virus isolation, a fourfold or greater change in IgG or IgM antibody to dengue virus antigens, detection of dengue virus antigen or detection of dengue virus genome by PCR. The definition of DHF demands the presence of fever or history of acute fever, haemorrhagic tendencies (positive tourniquet test, petechiae, ecchymoses or purpura, bleeding from the mucosa, GI-tract, injection sites or other lesions, hematemesis or melena), thrombocytopenia and evidence of plasma leakage due to increased vascular permeability (rise in haematocrit equal/greater than 20% above average, drop in haematocrit following volume replacement treatment equal/greater than 20% of baseline or signs of plasma leakage like pleural effusion, ascites and hypoproteinaemia). For the definition of DSS, all the four criteria for DHF must be present in addition to signs of circulatory failure with rapid and weak pulse and narrow pulse pressure, or hypotension and cold, clammy skin and restlessness(89).
As many found it difficult to apply the old criteria in clinical practice and changes in the epidemiology have caused changes in clinical manifestations, WHO reconsidered their classification(1, 17, 91). They suggested classifying dengue into non-severe dengue and severe
�15
dengue, with non-servere dengue divided into patients with and without warning signs. The classification is showed in the figure below(1). The revised classification has been shown to identify more cases, it was more sensitive for recognition of severe disease and easier to use in clinical practice. It reduces the requirement of laboratory testing and it is perceived as better in regard to triage and management. Some issues have also been registered, for example unnecessary hospital admissions due to the use of warning signs in endemic countries and the need for further training and information(19). Even though the new classification has been well received, it has yet to be implemented in several countries and many other guidelines exist. There is inconsistent application of the guidelines and geographical variations in clinical presentation still causes adaption of the guideline to local circumstances, thereby maintaining the problem of gathering comparable data(19, 91).
Dengue disease can also have unusual manifestations in different organ systems, sometimes called expanded dengue syndrome (EDS). Atypical manifestations can be convulsions, encephalopathy, intracerebral heamorrhage, nerve palsy, spasticity, changes in consciousness, myocarditis, haemothorax, acalculous cholecystitis, jaundice, pancreatitis, and thyroiditis(32, 92-94).
�16
Chapter 1: Epidemiology, burden of disease and transmission
11
CH
APTER 1
severe dengue cases which did not fulfi l the strict criteria of DHF, led to the request for the classifi cation to be reconsidered. Currently the classifi cation into DF/DHF/DSS continues to be widely used. (29) A WHO/TDR-supported prospective clinical multicentre study across dengue-endemic regions was set up to collect evidence about criteria for classifying dengue into levels of severity. The study fi ndings confi rmed that, by using a set of clinical and/or laboratory parameters, one sees a clear-cut difference between patients with severe dengue and those with non-severe dengue. However, for practical reasons it was desirable to split the large group of patients with non-severe dengue into two subgroups -- patients with warning signs and those without them. Criteria for diagnosing dengue (with or without warning signs) and severe dengue are presented in Figure 1.4. It must be kept in mind that even dengue patients without warning signs may develop severe dengue.
Expert consensus groups in Latin America (Havana, Cuba, 2007), South-East Asia (Kuala Lumpur, Malaysia, 2007), and at WHO headquarters in Geneva, Switzerland in 2008 agreed that:
“dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome”;
the classifi cation into levels of severity has a high potential for being of practical use in the clinicians’ decision as to where and how intensively the patient should be observed and treated (i.e. triage, which is particularly useful in outbreaks), in more consistent reporting in the national and international surveillance system, and as an end-point measure in dengue vaccine and drug trials.
Figure 1.4 Suggested dengue case classifi cation and levels of severity
Probable denguelive in /travel to dengue endemic area. Fever and 2 of the following criteria:
Laboratory-confi rmed dengue(important when no sign of plasma leakage)
Warning signs*
concurrent with rapid decrease in platelet count
*(requiring strict observation and medical intervention)
Severe plasma leakageleading to:
distress
Severe bleedingas evaluated by clinician
Severe organ involvement
CRITERIA FOR DENGUE ± WARNING SIGNS CRITERIA FOR SEVERE DENGUE
DENGUE ± WARNING SIGNS SEVERE DENGUE
1. Severe plasma leakage2. Severe haemorrhage3.Severe organ impairmentwithout
with warning signs
Figure 3: WHO’s suggested dengue case classification and levels of severity(1).
Symptoms and signs After infection with the dengue virus, there is an incubation period of 3-7 days before symptoms arise. The disease then goes through three phases; a febrile phase, a critical phase and a recovery phase(1, 38). The low availability of laboratory tests to confirm dengue in many countries(95), makes clinical features important in diagnosis of dengue. In fact, clinical diagnosis is most often what determines if the patient should be hospitalized and treatment is started before other test results are available(41, 74). Dengue disease can range from a mild to severe and possibly fatal illness with a broad spectrum of clinical presentations, making a clinical diagnosis difficult(60, 85). Many of the common signs and symptoms of dengue disease are listed in the two WHO classifications as described above and listed in figure 3(1, 89). Clinical features are most common in the first 72 hours of illness(21). In addition to fever, the most common clinical features of dengue are headache, myalgia, arthralgia, retro-orbital pain, rash, drowsiness and nausea with loss of appetite and sometimes vomiting. Other common, but less frequent symptoms are abdominal pain and bleeding (petechia, ecchymoses, gingival bleeding, epistaxis, hematemesis, melena etc)(20, 21, 94-97). Symptoms and signs varies with age. Children often have less symptoms than adults. For example they often lack symptoms from the musculoskeletal system that are common in adults, and infections in adults are more often accompanied by a tendency for bleeding(77, 84, 85). But with increasing age in adults, symptoms and signs again become less frequent, and a clinical diagnoses more difficult(21).
With dengue disease, there is often an acute onset of fever and malaise(84). The fever usually subsides within a few days(69). It is during the febrile phase that the most common symptoms listed above occurs, and it usually lasts for 2-7 days. It is usually not possible to distinguish between severe and non-severe dengue during this phase(1, 23, 38, 81). The critical phase, or the phase of defervescence, is where increased vascular permeability is usually recognized. This period usually last around 24-48 hours and is where the separation between severe and non-severe dengue becomes apparent(1, 81, 84). Continuos surveillance is important during this stage(80), as progress from mild and vague symptoms to irreversible shock can happen within a few hours(24). Abdominal pain, cold extremeties, sweating, paleness, changes in respiration, irritability, pericardial or pleural effusion, ascites, reduction of blood pressure, rapid or weak pulse, narrowing of pulse pressure, decreased platelet count and increasing hematocrit are sign suggestive of capillary leakage and should be a warning of possible deterioration and need for treatment(38, 79, 95). The recovery phase is characterized by the reversal of vascular permeability after 48-72 hours and improvement of the patient’s condition. During this phase, a maculopapular rash or peeling on the extremities can often emerge. Even though most cases are short and mild, many
�17
experience fatigue, lethargy and even depression for some time after recovery. This is most common in adults(38, 69, 98). Additional testing can be useful to make a diagnosis. In both of the guidelines created by the WHO, the tourniquets test is important in the diagnosis of dengue(1, 89). However, several studies show that this test is often not performed by the clinician(19, 90). Patients with dengue have been shown to have lower leukocyte levels than other febrile illnesses(20, 96, 97). Low and colleagues suggest the use of leukopenia as a sign of dengue in older adults, as it becomes more profound with increasing age when compared with differential diagnoses for dengue(21). Thrombocytopenia is also a common feature of dengue that might be able to distinguish dengue from other diseases(20, 60, 96, 97), though also common to some degree in other febrile illnesses(77). Thrombocytopenia usually becomes more evident later in the disease(21). Hematocrit has been shown to be significantly higher in dengue cases compared to controls. It is considered as a good measure of capillary leak in some studies(77). Other studies have shown no difference between dengue and non-dengue disease(20, 96), implying that it is not useful in making a diagnosis. It is however, recommended as a measure to predict severe disease(1, 77). The problem is that baseline for a given patient is not always known and fluid therapy may hide changes(83), making measurements unreliable. Radiological measures of fluid accumulation can be a good additional measure to indicate plasma leakage and severe disease(83). Unfortunately, this is not available in many medical facilities in the tropics(77).
There are many other diagnoses that have to be considered when a patient presents with fever. Due to the similar features for dengue and many other febrile illnesses, many patients are admitted for observation with possible dengue. To avoid overwhelming of health care capacity, it is important to consider other possible diagnosis(81). The differential diagnoses for dengue varies with the different stages of disease and with the local environment. During the febrile stage, other arboviral diseases like chikungunya is a possibility in addition to measles, rubella, enterovirus, adenovirus and influenza. Other diseases than can be considered are typhoid, malaria, leptospirosis, viral hepatitis, HIV seroconversion illness, SARS, rickettsial diseases and Epstein-Barr virus(EBV). Bacterial sepsis and meningococcaemia should be considered, especially in patients with shock. Acute abdominal conditions can be a differential diagnosis during the critical phase. Hantavirus and Yellow fever could be considered both in the febrile and critical phase(32, 38, 69, 99). Clinical findings are often of little help in deciding if the illness is really dengue or some of these other diseases, especially in the febrile phase(69).
�18
Figure 4:The course of dengue illness (1).
25
Chapter 2: Clinical management and delivery of clinical services
CH
APTER 2
CHAPTER 2. CLINICAL MANAGEMENT AND DELIVERY OF CLINICAL SERVICES
2.1 OVERVIEW
Dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum that includes both severe and non-severe clinical manifestations (1). After the incubation period, the illness begins abruptly and is followed by the three phases -- febrile, critical and recovery (Figure 2.1).
For a disease that is complex in its manifestations, management is relatively simple, inexpensive and very effective in saving lives so long as correct and timely interventions are instituted. The key is early recognition and understanding of the clinical problems during the different phases of the disease, leading to a rational approach to case management and a good clinical outcome. An overview of good and bad clinical practices is given in Textbox A.
Activities (triage and management decisions) at the primary and secondary care levels (where patients are fi rst seen and evaluated) are critical in determining the clinical outcome of dengue. A well-managed front-line response not only reduces the number of unnecessary hospital admissions but also saves the lives of dengue patients. Early notifi cation of dengue cases seen in primary and secondary care is crucial for identifying outbreaks and initiating an early response (Chapter 5). Differential diagnosis needs to be considered (Textbox B).
Figure 2.1 The course of dengue illness*
Days of illness
Temperature
Potential clinical issues
Laboratory changes
Serology and virology
Dehydration Shock Reabsorption bleeding fl uid overload
1 2 3 4 5 6 7 8 9 10
Organ impairment
Hematocrit
Platelet
ViraemiaIgM/IgG
Febrile Critical Recovery phasesCourse of dengue illness:
40°
* Source: adapted from Yip (2) by chapter authors.
Dengue fever can be ruled out if a patient is presenting with fever lasting over 2 weeks, or there has been more than 2 weeks since the person has been in an area with known dengue transmission(23).
Diagnostic tests Due to the wide range of clinical signs and symptoms, laboratory confirmation is often crucial to make the diagnosis of dengue infection(85). A purely clinical evaluation can lead to a misdiagnosis(95). A study in five countries in South-East Asia showed that a clinical diagnosis had a positive predictive value(PPV) of 85,2%, but a sensitivity of only 28,8% when using virological confirmation as a gold standard(41). Using solely the clinical presentation can cause dengue cases to be missed and thereby contribute to the underreporting of the disease. A laboratory diagnosis of dengue can be made in different ways. The method used depends on what test is available at a given health facility, and at what time in the disease the patient seeks medical attention. Existing methods are serology, antigen detection of NS1 and detection dengue virus by isolation or genome detection with PCR(95, 100, 101). There are many different methods and available assays within these groups. I will not go into specifics on these, but rather give an overview on the basic concepts. At the first stage of the disease with fever, NS1 antigens and viremia are present. After the fever subsides the viremia ends and antibodies can be detected for a few weeks. This means that in the first few days of infection, diagnosis can be made by the detection of virus or NS1 and by serology after the end of the febrile period(84). The use of only one of these tests might cause cases to be missed as their sensitivity varies throughout the course of the disease(22, 102). The detection of virus can be made by virus isolation or detection of viral RNA. Virus isolation provides a specific result(85), but samples must be taken during viremia and it requires incubation making it time consuming. It is rarely used in clinical practice(23, 100, 102). Tests using nucleic amplification, like PCR, can be used for both diagnosis and for serotyping(85, 97). It shows high sensitivity(103), especially in the first days of illness (up to a 100%). Later sensitivity gradually decreases(102). Unfortunately, PCR requires equipment and facilities that are not available in many endemic areas(100). NS1 tests can be easy, fast and inexpensive(104). It has been shown that NS1 circulates for longer than viral RNA. It is present and detectable both before and after defervescence in primary infections, making it a better marker than PCR and IgM(102, 105). Compared to the two other tests, NS1 also show better overall sensitivity and performance in some studies(101, 102). Other studies have shown similar results for PCR and NS1(103), while some favors PCR over NS1 detection(97). Sensitivity of NS1 tests varies between serotypes and is decreased in secondary infections. However sensitivity increases in more severe cases(104, 105). Serological testing involves testing of IgM and IgG. Infection creates an IgM response, in addition high levels of IgG occurs during secondary infections. Serological testing for IgM is
�19
the most common method because it is easy, fast, inexpensive and requires no additional equipment(85, 102). Although a convenient test, very low sensitivity in the first 4 days and an overall lower sensitivity than PCR and NS1, makes the test best served as a complement to either one of the other tests(97, 102). IgM also has a poor sensitivity in secondary infections(102). An IgM:IgG ratio can be used to determine if it is a primary or secondary infection(85). IgG can also be detected where there has been past infection(85). Unfortunately many of the studies on diagnostic tests includes small groups and have varied results. It seems that none of the tests above are perfect for the diagnosis of dengue. Combination of at least two tests is recommended to make a reliable diagnosis, but this often leads the diagnosis taking to long. The use of more than one test can also decrease specificity leading to an increased rate of false positive tests with an increased burden on the health care system(97).
Prognosis Reliable prognostic factors for dengue are lacking(20). Due to non-specific clinical presentation, predicting the progression from mild to severe disease, and thereby estimating the prognosis of dengue disease, remains challenging. Lack of knowledge about pathogenesis and pathophysiology also makes it hard to find potential prognostic markers(80). Getting an early prognosis could help the clinician with triage and decision making, and thereby reducing morbidity and mortality(106). Many studies have failed to conclude on symptoms or signs that are associated with severe disease. A meta-analysis by Zhang and colleagues found five symptoms/signs that could possibly predict the development of severe disease. These were bleeding, hepatomegaly, vomiting/nausea, abdominal pain and skin rash, with hematemesis, melena and hepatomegaly showing the strongest association. Headache seemed to have a protective effect(107). The same associations where found in a meta-analysis by Huy and colleagues in addition to an association with neurological symptoms(108). Other measurements that have been shown to be associated with more severe disease or poorer outcome are increased CRP(109), abnormal liver enzyme levels(108, 110), viremia lasting after defervescence(110), thrombocytopenia and prolonged PT and APTT(108). The number of tissues infected with the virus also correlates with disease severity(79). The detection of plasma leakage in dengue cases indicates an increased risk for the patient and should lead to close observation and attention to prevent development of shock(88, 108). When the disease has developed in to the stage of vascular leakage, the prognosis rests on the abilities of the treating medical team(13, 98). Due to this, prognosis will be affected by the availability and quality of health services which varies with geography and socioeconomic factors(88). Vascular leakage can have different manifestations. Of these, clinically detectable fluid accumulation, like ascites or pleural effusion, are associated with more severe disease(83).
�20
Secondary infection is also a prognostic factor as these patients are more likely to develop severe disease. Concurrent infection with more than one serotype has also been shown to produce more severe cases(78, 111). As the time between primary and secondary infection increases, the risk also increases(79). Other factors shown to be associated with poorer outcome are young age, female sex, underweight/malnutrition, place of residence and later presentation to hospital(77, 80, 83, 108, 110, 112). Many other markers are being studied for their possible predictive value, examples are NS1 because of the association between sensitivity and severe disease(104), microparticles generated from erythrocytes and thrombocytes during dengue infection(113), gene expression in patients(114), and cytokines and chemokines like IL-10 and IFNɣ(106).
Treatment Improved clinical management has reduced CFR from 20% to less than 0,5% in some endemic countries(81). Correct management is important, but the fact remains that treatment of dengue is only supportive(85). There is no available antiviral therapy(13, 80). The goal of clinical intervention in dengue cases is to prevent vascular leakage, shock and organ failure. Fluids and close observation are currently the only way to do that(115). In mild cases, oral fluids and paracetamol are sufficient and patients can stay home(38, 85, 99). Paracetamol is used with caution in regard to liver function(85). Patients needs to be advised of warning signs that should prompt contact with the hospital(38, 99). Many places also have arrangements where patients come to a clinic everyday for evaluation(38). Hospital admission for observation and administration of intravenous fluids are necessary in more severe cases with signs plasma leakage and shock. Fluids need to administered carefully in correct doses to avoid fluid overload(38, 85, 99). According to guidelines by the WHO, fluid loss should be replaced with an isotonic crystalloid solution. Fluid resuscitation with higher volumes of crystalloids without glucose is necessary when the patient is in shock. In severe hypovolemic shock, or when the patient already has received a bolus of crystalloids, a colloid solution is recommended(99). After several studies on the subject however, the optimal choice of fluids is still debatable(115). With increasing severity, vasopressors, inotropic therapies, corrections of imbalance in electrolytes and glucose, and blood transfusions might be necessary. Complications in other organs also needs treatment, like oxygen therapy for respiratory distress or renal-replacement therapy for impairment of the kidneys( 38, 99, 115). The risk of complications increases with fluid treatment beyond 48 hours(99). Among these complications are respiratory distress. Fluid accumulation due to vascular leakage can cause respiratory distress by itself when it occurs in the pleural cavity or causes pulmonary oedema. Fluid therapy, particularly with large volumes and longer duration of IV fluids, increases the risk for this symptom. The treatment worsens the fluid overload if not done properly. This especially applies to older patients or patients with comorbidities(83).
�21
�22
Figure 5: Dengue case management algorithm (1).
PRESUM
PTIV
E D
IAG
NO
SIS
Live
in/
trave
l to
deng
ue e
ndem
ic a
rea.
Fe
ver an
d tw
o of
the
follo
win
g cr
iteria
:
WARN
ING
SIG
NS
*
with
rap
id d
ecre
ase
in p
late
let c
ount
*(re
quiri
ng s
trict
obs
erva
tion
and
med
ical
inte
rven
tion)
DEN
GUE W
ITHO
UT W
ARN
ING
SIG
NS
ASSESSMENT
Labo
rato
ry c
onfir
med
den
gue
(impo
rtant
whe
n no
sig
n of
pla
sma
leak
age)
CLASSIFICATION MANAGEMENT
NEG
ATIV
E
DEN
GUE W
ITH W
ARN
ING
SIG
NS
Gro
up A
(May
be
sent
hom
e)
Gro
up c
rite
ria
Patie
nts
who
do
not h
ave
war
ning
sig
ns
AN
D
who
are
abl
e:
flu
ids
6 h
ours
Labo
rato
ry te
sts
Trea
tmen
tA
dvic
e fo
r:
day
in a
dults
and
acc
ordi
ngly
in
child
ren.
Patie
nts
with
sta
ble
HC
T ca
n be
sen
t hom
e.
Mon
itori
ngD
aily
rev
iew
for di
seas
e pr
ogre
ssio
n:
Adv
ice
for im
med
iate
ret
urn
to h
ospi
tal i
f de
velo
pmen
t of a
ny w
arni
ng s
igns
, an
d
ho
me
care
car
d fo
r den
gue)
.
Gro
up c
rite
ria
Patie
nts
with
any
of t
he fo
llow
ing
feat
ures
:
pr
egna
ncy,
infa
ncy,
old
age
, di
abet
es
m
ellit
us,
rena
l fai
lure
al
one,
livi
ng fa
r fro
m h
ospi
tal
Labo
rato
ry te
sts
Trea
tmen
t
to
lera
ted,
sta
rt in
trave
nous
flui
d
ther
apy
0,9
% s
alin
e or
Rin
ger’s
Lac
tate
at m
aint
enan
ce rat
e.
Mon
itori
ngM
onito
r:
co
unts.
Gro
up C
(Req
uire
em
erge
ncy
treat
men
t)
Gro
up c
rite
ria
Patie
nts
with
any
of t
he fo
llow
ing
feat
ures
:
Labo
rato
ry te
sts
Trea
tmen
t of c
ompe
nsat
ed s
hock
Star
t IV
fluid
res
usci
tatio
n w
ith is
oton
ic c
rysta
lloid
sol
utio
ns a
t 5–1
0 m
l/kg
/hr
ove
r 1
hou
r. Re
asse
ss p
atie
nts’
con
ditio
n.
If pa
tient
impr
oves
:fo
r 2
–4 h
ours
,
th
en to
2-3
ml/
kg/
hr fo
r 2
–4 h
ours
and
then
red
uced
furth
er d
epen
ding
on
haem
odyn
amic
sta
tus;
If pa
tient
is s
till u
nsta
ble:
if H
CT
incr
ease
s
if H
CT
decr
ease
s, th
is in
dica
tes
blee
ding
and
nee
d to
cro
ss-m
atch
and
tran
sfus
e bl
ood
as s
oon
as p
ossibl
e.
Trea
tmen
t of h
ypot
ensi
ve s
hock
Initi
ate
IV fl
uid
resu
scita
tion
with
cry
stallo
id o
r co
lloid
sol
utio
n at
20
ml/
kg a
s a
bolu
s fo
r 1
5 m
inut
es.
If pa
tient
impr
oves
:
If pa
tient
is s
till u
nsta
ble:
if H
CT
was
low
(<40%
in c
hild
ren
and
adul
t fem
ales
, <45%
in a
dult
mal
es) t
his
indi
cate
s bl
eedi
ng,
th
e ne
ed to
cro
ss-m
atch
and
tran
sfus
e (see
abo
ve);
if H
CT
was
hig
h co
mpa
red
to b
asel
ine
valu
e, c
hang
e to
IV c
ollo
ids
at 1
0–2
0 m
l/kg
as
a se
cond
bol
us o
ver 3
0 m
inut
es to
1 h
our;
re
asse
ss a
fter se
cond
bol
us.
If pa
tient
is im
prov
ing
redu
ce th
e ra
te to
7–1
0m
l/kg
/hr
for 1
–2 h
ours
, th
en b
ack
to IV
cys
tallo
ids
and
redu
ce rat
es a
s ab
ove;
if pa
tient
’s co
nditi
on is
stil
l uns
tabl
e, rep
eat H
CT
afte
r se
cond
bol
us.
If H
CT
decr
ease
s, th
is in
dica
tes
blee
ding
(see
abo
ve);
if H
CT
incr
ease
s
th
en red
uce
to 7
–10
ml/
kg/
h 1
–2 h
ours
, th
en c
hang
e ba
ck to
cry
stallo
id s
olut
ion
and
redu
ce rat
e as
abo
ve.
Trea
tmen
t of h
aem
orrh
agic
com
plic
atio
nsG
ive
5–1
0 m
l/kg
of f
resh
pac
ked
red
cells
or 1
0–2
0 m
l/kg
of f
resh
who
le b
lood
.
Gro
up B
(Ref
erre
d fo
r in
-hos
pita
l car
e)
OR:
Exi
sting
war
ning
sig
ns
La
bora
tory
test
s
Trea
tmen
tO
btai
n re
fere
nce
HC
T be
fore
flui
d th
erap
y.G
ive
isot
onic
sol
utio
ns s
uch
as 0
.9 %
sal
ine,
Ri
nger
’s La
ctat
e. S
tart
with
5–7
ml/
kg/
hr fo
r 1
–2 h
ours
, th
en re
duce
to 3
–5 m
l/kg
/hr
for
2–4
hr,
and
then
redu
ce to
2–3
ml/
kg/
hr
or le
ss a
ccor
ding
to c
linic
al re
spon
se.
Reas
sess
clin
ical
sta
tus
and
repe
at H
CT:
hr
for an
othe
r 2
–4 h
ours
;
m
l/kg
/hr
for 1
–2 h
ours
.Re
asse
ss c
linic
al s
tatu
s, r
epea
t HC
T an
d re
view
flui
d in
fusi
on r
ates
acc
ordi
ngly
:
th
e ra
te o
f pla
sma
leak
age
decr
ease
s
to
war
ds th
e en
d of
the
criti
cal p
hase
.
This
is in
dica
ted
by:
in
take
in
a s
tabl
e pa
tient
.
Mon
itori
ngM
onito
r:
ho
urly
unt
il pa
tient
is o
ut o
f crit
ical
pha
se
th
en 6
–12
hou
rly)
profi
le, co
agul
atio
n pr
ofile
, as
indi
cate
d).
PO
SIT
IVE
DEN
GUE C
ASE M
AN
AG
EM
EN
T
Co-
exis
ting
cond
ition
sSo
cial
cir
cum
stan
ces
NEG
ATIV
E
WARN
ING
SIG
NS
*
w
ith rap
id d
ecre
ase
in p
late
let c
ount
*(re
quiri
ng s
trict
obs
erva
tion
and
med
ical
inte
rven
tion)
PO
SIT
IVE
SEVERE D
EN
GUE
Gro
up C
(Req
uire
em
erge
ncy
treat
men
t)
Gro
up c
rite
ria
Patie
nts
with
any
of t
he fo
llow
ing
feat
ures
:
Labo
rato
ry te
sts
Trea
tmen
t of c
ompe
nsat
ed s
hock
Star
t IV
fl uid
res
usci
tatio
n w
ith is
oton
ic c
rystal
loid
sol
utio
ns a
t 5–1
0 m
l/kg
/hr
ove
r 1 h
our.
Reas
sess
pat
ient
s’ c
ondi
tion.
If pa
tient
impr
oves
:fo
r 2–4
hou
rs,
th
en to
2-3
ml/
kg/
hr fo
r 2–4
hou
rs a
nd th
en red
uced
furth
er d
epen
ding
on
haem
odyn
amic
sta
tus;
If pa
tient
is s
till u
nsta
ble:
if H
CT
incr
ease
s
if H
CT
decr
ease
s, th
is in
dica
tes
blee
ding
and
nee
d to
cro
ss-m
atch
and
tran
sfus
e bl
ood
as s
oon
as p
ossibl
e.
Trea
tmen
t of h
ypot
ensi
ve s
hock
Initi
ate
IV fl
uid
resu
scita
tion
with
cry
stal
loid
or co
lloid
sol
utio
n at
20 m
l/kg
as
a bo
lus
for 15 m
inut
es.
If pa
tient
impr
oves
:
If pa
tient
is s
till u
nsta
ble:
if H
CT
was
low
(<4
0%
in c
hild
ren
and
adul
t fem
ales
, <
45
% in
adu
lt m
ales
) thi
s in
dica
tes
blee
ding
,
the
need
to c
ross
-mat
ch a
nd tr
ansfus
e (see
abo
ve);
if H
CT
was
hig
h co
mpa
red
to b
asel
ine
valu
e, c
hang
e to
IV c
ollo
ids
at 1
0–2
0 m
l/kg
as
a se
cond
bol
us o
ver 30 m
inut
es to
1 h
our;
re
asse
ss a
fter se
cond
bol
us.
If pa
tient
is im
prov
ing
redu
ce th
e ra
te to
7–1
0m
l/kg
/hr
for 1–2
hou
rs, th
en b
ack
to IV
cys
tallo
ids
and
redu
ce rat
es a
s ab
ove;
if pa
tient
’s co
nditi
on is
stil
l uns
tabl
e, rep
eat H
CT
afte
r se
cond
bol
us.
If H
CT
decr
ease
s, th
is in
dica
tes
blee
ding
(see
abo
ve);
if H
CT
incr
ease
s
then
red
uce
to 7
–10 m
l/kg
/h
1–2
hou
rs, th
en c
hang
e ba
ck to
cry
stal
loid
sol
utio
n an
d re
duce
rat
e as
abo
ve.
Trea
tmen
t of h
aem
orrh
agic
com
plic
atio
nsG
ive
5–1
0 m
l/kg
of f
resh
pac
ked
red
cells
or 10–2
0 m
l/kg
of f
resh
who
le b
lood
.
Gro
up B
(Ref
erre
d fo
r in
-hos
pita
l car
e)
OR:
Exi
stin
g w
arni
ng s
igns
Labo
rato
ry te
sts
Trea
tmen
tO
btai
n re
fere
nce
HC
T be
fore
fl ui
d th
erap
y.G
ive
isot
onic
sol
utio
ns s
uch
as 0
.9 %
sal
ine,
Ri
nger
’s La
ctat
e. S
tart
with
5–7
ml/
kg/
hr fo
r 1
–2 h
ours
, th
en re
duce
to 3
–5 m
l/kg
/hr
for
2–4
hr,
and
then
redu
ce to
2–3
ml/
kg/
hr
or le
ss a
ccor
ding
to c
linic
al re
spon
se.
Reas
sess
clin
ical
sta
tus
and
repe
at H
CT:
hr
for an
othe
r 2–4
hou
rs;
m
l/kg
/hr
for 1–2
hou
rs.
Reas
sess
clin
ical
sta
tus,
rep
eat H
CT
and
revi
ew fl
uid
infu
sion
rat
es a
ccor
ding
ly:
th
e ra
te o
f pla
sma
leak
age
decr
ease
s
to
war
ds th
e en
d of
the
criti
cal p
hase
.
This
is in
dica
ted
by:
in
take
in
a s
tabl
e pa
tient
.
Mon
itori
ngM
onito
r:
ho
urly
unt
il pa
tient
is o
ut o
f crit
ical
pha
se
th
en 6
–12 h
ourly
)
pr
ofi le
, co
agul
atio
n pr
ofi le
, as
indi
cate
d).
Day
s of
illn
ess
Tem
pera
ture
Pote
ntia
l clin
ical
issu
es
Labo
rato
ry c
hang
es
Sero
logy
and
vir
olog
y
Deh
ydra
tion
S
hock
Re
abso
rptio
n bl
eedi
ng F
luid
ove
rloa
d
1 2
3
4
5
6
7
8
9
1
0
Org
an im
pair
men
t
Hem
atoc
rit
Plat
elet
Vir
aem
iaIg
M/I
gG
Febr
ile C
ritic
al R
ecov
ery
phas
esC
ours
e of
den
gue
illne
ss:
40°
DEN
GUE C
ASE M
AN
AG
EM
EN
T
If an effective antiviral therapy was discovered, it could decrease morbidity and mortality together with the burden on health care facilities and possibly reduce transmission of the virus(81). Strategies for antiviral therapies are inhibiting viral or host targets. Considering viral targets, possibilities are viral-entry inhibitors and enzyme/protein inhibitors. The host targets can be the host’s immune response, or other factors leading to patient’s symptoms, and factors within the host necessary for the life cycle and replication of the virus(115, 116). There are registered clinical trials on the use of Balapiravir, Ceglosivir, Chloroquine, Modipafant, Corticosteroids and Lovastatin for the treatment of dengue, most of them are completed and some are still ongoing or starting(117-121). All of these aims to inhibit factors within the host, except for Balapiravir who targets a dengue virus protein(115, 116). In addition, there are development of experimental drugs that have yet to progress to clinical trials(122). But even with a working antiviral drug, the short time of viremia and difficulties with efficient diagnosis and accurate prognostic factors could limit its usefulness(115).
Prevention The global strategy for prevention and control of dengue involves five elements: vector control, active disease surveillance, emergency preparedness, capacity building and training, and vector control research(85).
Vector control and surveillance As there are no treatment or widely available vaccine against dengue virus, the only way of fighting the disease is by controlling the vector(123). Vector control is attempted by chemical, biological and community interventions(124). There has been increasing focus on the community aspect of dengue prevention and control in the last decades(125). Examples of community interventions are environmental control and education(126). An important factor in environmental control is reducing the number of breeding sites. The breeding sites for A. aegypti are mainly artificial domestic containers. Since these are created by people, it should be possible control or prevent them(61). This is attempted by removing containers that fill up with water, covering, emptying and cleaning water-storage containers and waste clean-up. To achieve this, the inhabitants, leaders in the community, local health services, vector control personnel and the government needs to cooperate. Campaigns to increase knowledge and mobilize the members of the community are often necessary(61, 124, 125). House screening is another community environmental intervention, which has been shown to significantly reduce dengue incidence(127). Environmental measures not only includes individual houses, but also need to be implemented in public places. Development of appropriate infrastructure with water systems and waste management are also important aspects(85). Intervention programs based on education can include distribution on educational material, meetings, lectures, visits and training by public health personnel and the use of mass media(123, 125). The inclusion of education in a
�23
community intervention has been shown to be effective, but mostly in a limited timeframe as peoples efforts might decline over time(123). In a systematic review by Heintze and colleagues they found that community-based control reduced larval indices. The effect on dengue transmission and incidence was more uncertain and long term sustainability was not assessed, making the lasting effect questionable(125). Inclusion of people in the community in vector control is though to be more sustainable than a purely vertical approach(54). Community efforts like clean-up campaigns are probably the most common intervention, but since they are rarely the only intervention in place, their contribution to vector and disease reduction is unknown(127). Even though the effect of education and other community interventions is uncertain, it is still perceived as important and such interventions should be maintained(128). Chemical interventions include the use of insecticides, larvicides and insect repellant. These interventions are often very effective short-term. Insecticides are employed by spraying, fogging or in insecticide-treated materials like mosquito-nets, curtains or clothing(61, 124, 127). Chemicals are also used in lethal ovitraps(129), though traps without insecticides are also used(130). Spraying and fogging with insecticides like pyrethroids are often carried out as a response to outbreaks(131, 132), but there is not enough evidence supporting the effectiveness of such measures(127). The use of space-spraying of insecticides only effects adult mosquitoes, giving a short-term effect on mosquito population. Evidence for the effect on disease transmission is inconclusive(131). Larvicides, like temephos, are widely used for vector control by adding to breeding sites(133). Recently, A. aegypti has started to develop a resistance to conventional insecticides(80, 134) and larvicides(133, 134), thereby reducing their effect. Insect repellants can help in avoiding exposure to the vector for single individuals. A review by Patel and colleagues concluded that DEET in 20% concentrations or more, protected against A. aegypti and A. albopictus. DEET is safe to use and should be the first choice(71). This kind of personal protection is recommended for travelers(55), but for people living en endemic areas, such measures are often to comprehensive and costly(132). In general it is important that chemical interventions does not lead to a reduction of community efforts due to a false sense of security(128). Biological interventions can be introduction of copepods, larvivorous fish, turtles and other predatory organisms(61, 124). They exert their effect by preying on or competing with immature forms of the mosquito(127). It has been shown to be both effective and sustainable in some studies(124), while others have concluded that the evidence for this is lacking(127, 135, 136). A meta-review concluded that biological methods gives better and more sustainable result than chemical control when it comes to vector reduction(128). It also has the benefit of avoiding toxicity and resistance which can be a problem with chemical agents(135). A downside with biological measures is high costs and difficult logistics. You need appropriate facilities and competence to initiate and you often have to reintroduce the organisms after some time, making it harder to maintain(85, 135).
�24
The evidence of the effects of dengue control programs are scarce and it is difficult to make any conclusions on which of them actually works(124, 127, 128). Poor surveillance of dengue, variations in entomological measurements, the use of vector indices instead of dengue incidence, weaknesses in study design and the fact that more than one intervention is often implemented at the same time, make interpretation of study results difficult(123, 124, 126, 127). There is need for further research with blinded RCTs that has longer follow-up periods and uses disease related outcomes instead of vector presence(128). Present strategies has not been successful enough in controlling the vector and there is need for new approaches(39, 137). Genetically engineered mosquitoes, mosquitoes infected with microbes like Wolbachia and new insecticides are being developed and tested as new methods of vector control(137).
Surveillance is important, not only for assessment of burden and spread, but also for planning and evaluation of vector control programs and early detection of epidemics. It should include surveillance of detected cases, vectors and risk factors for epidemics(2). A review on dengue surveillance systems by Runge-Ranzinger and colleagues found that passive surveillance is the most common, using trends in the population to detect an increase in reported cases and thereby alerting of an epidemic. Underreporting, slow reporting and absence of a defined threshold for outbreak response are known problems. Other systems recored that had potential for detecting an outbreak were shifts in serotypes and syndromic surveillance of fever, absence from school, clinical syndromic case definitions and internet searches(138). A study in Hanoi showing that rainfall always peaked 2-3 months before peaks in DF cases, suggested the use of metrological data such as rainfall can be used to assess the risk and predict outbreaks of dengue(34). Appropriate response to epidemics can reduce dengue cases, but control measures need to initiated early in an outbreak(137). To launch an outbreak response, you need a plan which should include strategies to deal with the increased pressure on health services and efforts for vector control. In this setting, space-spraying of insecticides if the recommended intervention for vector control(2).
Vaccine The presence of four different serotypes and a poor understanding of pathogenesis and immune response to dengue infection make the development of a vaccine very challenging. In addition, it is difficult to find an appropriate animal model for research because dengue mostly affect humans and not animals(139). Possible approaches to a dengue vaccine are live attenuated viruses, inactivated viruses, subunit vaccines, DNA vaccines, virus like particles, vectored vaccines, and chimeric live
�25
viruses(63, 80).There are several candidates undergoing clinical trials(140), and one vaccine was licensed in 2015(141).
The CYD-TDV vaccine, Dengvaxia, became the first licensed vaccine against dengue in December 2015 when it was approved in Mexico(141). In October 2016, Sanofi Pasteur announced that the vaccine was approved in 11 countries(142). It is a recombinant, live, attenuated, tetravalent vaccine made of chimeric yellow fever and dengue virus (CYD)(63). Two phase III trials for CYD-TDV, given in 3 doses, reported efficacies of 56,5% and 60,8%. Best efficacy was recorded for serotypes 3 and 4. The efficacy for serotype 2 was not significant (35%) in one of the trials. The efficacy was also better in seropositive patients than in seronegative. The vaccine gave a reduction in hospitalization and severe cases. No repetitive adverse effects were detected, but safety follow-up is still ongoing. Both studies concluded that the vaccine is safe and efficacious(143, 144). However, in an evaluation of the long-term safety of the vaccine there were an increased risk for hospitalizations due to confirmed dengue in vaccinated younger children, particularly children between 2 and 5 years old(145). An analysis by Ferguson and colleagues indicated an increase in hospitalization in vaccinated seronegative individuals. In seropositive individuals, the risk was reduced. They also predicted that even in areas with high transmission, reduction in dengue incidence will be moderate(146). Other evaluations have shown that vaccination of both seropositive and seronegative patients could give an increase in hospitalizations of unvaccinated children. Serological screening and vaccination of only seropositive patients decreased hospitalizations(147). This shows that even though the vaccine is an important advance in the prevention of dengue, with the potential to reduce overall incidence and hospitalizations(145, 148), there is still need for further research and surveillance on its effects. The development of additional candidates should continue(139). WHO’s position is that countries with a high dengue burden should consider introduction of the vaccine, but only in a population with a high seroprevalence, preferably over 70%. This is because of the lower efficacy and higher risk of severe dengue with vaccination of seronegative patients. Age groups for vaccination are determined by the epidemiology in each country, but children younger than 9 years should not be vaccinated due to increased risk of severe disease in younger children. 3 doses with 6 months intervals is recommended administration. The introduction of the vaccine should not lead to a reduction of other control measures(82).
Of other vaccine candidates, two are currently undergoing phase 3 trials(149, 150). Like CYD-TDV, both of these are tetravalent live attenuated vaccines(63). I addition to this, four other vaccines are under development in phase 1 and 2 trials(151).
�26
Discussion Dengue is a viral disease which poses a substantial global burden. Although the quality of data on the occurrence of dengue is weak, parts of the increased incidence could be due to increased reporting. However, based on the literature it is likely that there has been a real increase in incidence the last decades. The estimated number of annual cases is between 58 and 96 million clinical cases. With the addition of inapparent infections, the estimation becomes a total of 390 million infections annually(14, 16). Clearly this neglected tropical disease deserves the attention of the international community(30). It affects many countries in Asia, South America and Africa(14), and spread to North America and Europe can be imminent(35). Dengue spreads by introduction of the vector, Aedes mosquitoes, to new areas, but spread is also facilitated by movement of infected humans. Increase in travel and trading can cause the spread of both the virus and the vector(37). Together with climate change that can cause an increase in temperatures, there is a possibility that dengue can occur in Norway in the future, and not only in individuals returning from travel which is the only source of the disease today(55). Population growth and urbanization together with an optimal climate are factors that in all likelihood have led to increasing incidence and spread of dengue in Myanmar. With the highest number of cases in Yangon, the most highly populated region, it seems that the disease has a potential to grow with increasing travel, urbanization and population growth in other areas(39, 152). Climate change will also be an important factor in the feature. Higher temperatures can increase incidence in some areas, but result in a reduction in others as both the vector and the virus can be hampered by temperatures that are to high. Climate change will most likely also lead to more frequent periods with extreme precipitation and damaging cyclones that increase the risk of dengue transmission. On the other hand, heat waves and drying trends may occur which inhibits dengue transmission(11, 40, 153). Myanmar is not among the countries who has licensed the new vaccine(142), but this might happen in the feature with the possibility of decreasing incidence and the burden dengue constitutes in the country. The diagnosis of dengue can be difficult. Many places rely on a clinical diagnosis(95), where the clinical picture varies from a mild febrile illness to severe disease with vascular leakage and shock(38). A laboratory diagnosis can be made by detection of viral RNA, antigens or antibodies, but none of the tests are guaranteed to confirm the diagnosis at all stages of disease. As a consequence, the use of either NS1 antigens or PCR detection of RNA, together with antibodies are favorable(97, 102), for example by a 3 in 1 test that can detect NS1, IgM and IgG simultaneously(63). Treatment is limited to symptomatic and supportive therapy as no antiviral therapy currently exist. Fluids are the cornerstone in treatment of dengue, particularly in more severe disease.
�27
Research on finding alternative treatment options are ongoing and imminent to reduce the burden of the disease(115). The fact that incidence is still increasing suggests that todays control measures are insufficient. Among the different methods for vector control, evidence on the effect of each and every one is lacking. Further research using reliable methods are necessary so that countries can make better informed decisions on how to prevent the disease(127). A vaccine has recently been licensed in several countries(142). Hopefully this will contribute to reduce the incidence of dengue. Unfortunately, the vaccine is not recommended in areas with low seroprevalence or for children under 9 years old(82), leaving many potential patients unprotected. In addition the efficacy is not good for all serotypes(144) and some predict that the reduction in incidence will only be moderate(146). Time will tell how much of an impact the vaccine will have. Until then continued surveillance and further research is important.
Conclusion Dengue is a disease with a very high global burden that seems to be increasing. Even though the disease has such a great impact, our knowledge about it is limited. There is urgent need for further research on epidemiology to ascertain the true impact of the disease and reasons for its rapid spread in the last decades. Research should also be focused on the pathogenesis and pathophysiology to get a better understanding of the disease and a foundation for the development of tools in diagnosis, prognosis, treatment and prevention. Lastly the world needs to prepare for the possible impacts further increase in travel, population growth and climate change will have on the disease and how to adapt to these changes.
Acknowledgments I would like to thank my supervisor Espen Bjertness for all his help with my thesis. I would also like to thank Dr. Kay Khine Mauk from the University of Medicine and Professor Thein Thein Htay from University of Public Health in Myanmar for all their help in providing information on dengue in Myanmar, and Senior Librarian Marte Ødegaard, Medical Library, University of Oslo, for providing assistance in search and search strategies for publications from Myanmar.
�28
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