Canada Communicable Disease Report

Statement on Dengue

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

Dengue is caused by a group of four antigenically distinct flavivirus serotypes (DEN-1, 2, 3 and 4), which are transmitted by Aedes mosquitoes. It occurs through much of the tropics (e.g. the Caribbean, the Americas, Asia, the South Pacific and Africa) and is the most common arboviral disease worldwide. Approximately 50-100 million cases occur annually, including up to 500,000 cases of dengue hemorrhagic fever (DHF) and 24,000 deaths^(1-6) .

Dengue is regularly diagnosed in travellers^(5,7-12) and may be expected to occur about as often or even more often than malaria in persons returning from South and Central America, the Caribbean and Asia^(11,12) . A growing body of literature is available on the specific risk of dengue exposure among travellers: seroprevalence has ranged from a few percent to up to 45%^(7-12) among ill travellers returning from areas of endemicity; a seroepidemiologic study of a unit of US soldiers deployed to Somalia suggested that 7.7% had been infected with dengue⁽¹³⁾ ; a small study of Israeli travellers returning from tropical areas indicated 3.8% had recently been exposed to dengue⁽¹⁾ , and another suggested a dengue attack rate of 3.4/1,000 in persons visiting Southeast Asia⁽⁷⁾ ; and two retrospective studies of German expatriates and longterm travellers who stayed in areas of risk found dengue seroprevalence rates of 4.3% and 7.4%^(15,16) . Interestingly, there is some evidence that dengue is no more prevalent among travellers visiting friends and relatives than among vacation travellers⁽¹⁷⁾ , although severe disease might be^(18,19) .

There is no specific treatment⁽⁵⁾ for or vaccine against dengue, though certain personal protective measures have been associated with reduced risk of disease and/or infection^(13,20-23) .

Epidemiology

Dengue is a disease with a modern history. It is thought that extant lineages diverged as recently as 500-1,000 years ago and that the current genetic variability of human-adapted serotypes reflects very recent change, i.e. over the last several centuries^(24-28) . Factors posited as contributing to the rapid emergence and spread of dengue include increased urbanization and adaptation of mosquito vectors to this environment, human population growth (especially in urban areas), globalization of transportation networks, and insufficient public health infrastructure, including vector control programs^(2,3,29) .

Dengue is primarily a threat in urban and peri-urban areas where the virus is maintained in an endemic/epidemic cycle that involves human hosts and Aedes (principally Ae. aegypti) mosquitoes^(1,2,30,31) . Dengue virus (DEV) also circulates in a sylvatic cycle in Africa and Asia. The zoonotic pattern of transmission is thought to represent the ancestral form, with human-adapted serotypes likely arising independently from the sylvatic cycles⁽²⁵⁾ . Although humans may occasionally be infected through the sylvatic cycle, they are tangential hosts, and maintenance in the zoonotic cycle involves vertical transmission in Aedes mosquitoes and periodic amplification in non-human primates^(1,25,30,32) .

The main vector of endemic/epidemic dengue, Aedes aegypti, has a cosmopolitan distribution in the tropics and subtropics⁽³³⁾ . The habits of this species are somewhat variable. Where dengue presents a substantial threat, Ae. aegypti tends to take most of its meals from humans; feeds frequently, often from multiple hosts; bites throughout the day, inside and outside, with activity often being highest in the morning and late afternoon; and larvae develop in relatively clean standing water found in the peri-domestic habitat, for example, in flower pots, tires, cisterns or other artificial containers.

The incubation period of DEV in humans is 3 to 14 days (typically 5 to 7 days), and infected humans may remain viremic for up to 12 days (typically 4 to 5 days), during which time they can infect susceptible female mosquitoes that feed upon them⁽³⁰⁾ . Development of the virus in the mosquito, i.e. the extrinsic incubation period (EIP), depends on several factors, including viral genotype, size of the inoculum and temperature(^6,34) . An EIP of 10 or more days is typical^(35,36) .

When the appropriate conditions are in place, epidemic dengue activity can be explosive with infection rates sometimes exceeding 50% and multiple serotypes in circulation⁽²²⁾ . Infection with a given serotype is thought to provide long-lasting immunity against the same serotype and may provide short-term (i.e. several months) heterotypic protection against other serotypes. However, beyond the short term, infection with one serotype might predispose towards more severe disease when subsequent infection is with a different serotype^(4-6,30) .

Clinical

The spectrum of illness associated with DEV infection is highly variable, ranging from non-apparent infection through clinical presentations that comprise non-specific febrile illness, classic dengue fever (DF), dengue hemorrhagic fever (DHF), DHF with dengue shock syndrome (DSS), and other unusual syndromes, such as encephalopathy and fulminant liver failure^(30,37,38) . For severe disease (DHF/DSS) the case fatality rate can be as high 15% but can be reduced to below 1% with appropriate medical intervention⁽³⁰⁾ . Factors implicated as affecting disease severity include the strain and serotype of the infecting virus, previous infection with a different serotype, time interval between and sequentiality of serotypes causing primary and subsequent infections, age and host genotype^(2,37,39-42) . However, regardless of risk factors that might be present, the likelihood that infection will lead to a given outcome varies inversely with the severity of disease, i.e. asymptomatic, non-specific febrile illness and classic DF are generally more likely outcomes than DHF and DSS^(29,43-47) .

Though previous exposure to dengue is a risk factor for DHF, it is not sufficient to predict it. Indeed, travellers with such history are still thought to be at relatively low risk of severe disease. Hence, there is no reason to routinely discourage travel to endemic areas for persons with a known history of dengue infection, nor is screening for previous exposure generally indicated. However, travellers with a known history of infection should be informed of the risk posed by a previous infection and advised that appropriate precautions should be taken (see Prevention). In some circumstances, for example based on an individuals' risk tolerance and/or epidemic transmission conditions at the destination environment, deferral of travel might be warranted.

The classic approach to dengue disease classification has been to differentiate between DF and DHF. The first is a non-specific febrile illness with classical signs and symptoms, such as sudden onset of high fever, severe headache, incapacitating myalgias and arthralgias, nausea, vomiting and rash^(5,30) accompanied by occasional bleeding manifestations; the hallmark of DHF, on the other hand, is increased vascular permeability and consequent capillary leakage⁽⁴⁸⁾ , which may ultimately progress to DSS. Case definitions for DF and DHF, as well as severity grades for DHF, have been developed by the World Health Organization (WHO)⁽⁴⁹⁾ and are summarized in the figure 1⁽⁵⁰⁾. While the WHO case definitions represent the current standard, there is increasing recognition that dengue-associated conditions present as a complex of clinical symptoms, and divisions between the various case definitions are often blurred^(15,51-55).

Figure 1.* The range of dengue disease ⁽⁵⁰⁾

The range of dengue disease

The case definitions of dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) are indivated as provided by the WHO. For a diagnosis of DHF Grade I, each of the four criteria listed in part b of the figure must be met. There is a contention from some clinicians that this requirement results in an under-reporting of severe dengue diseases as a patient with only two or three severe conditions would be classified as having DF. A generalized time course of the events associated with DF, DHF and DSS is indicated in part d of the figure. The incubation period before the development of signs of infection generally ranges from 4 to 7 days. Hypovolemic shock can develop during the late stage of disease and usually lasts 1 to 2 days.

a- Dengue fever (DF)

Febrile illness with 2 or more of the following; headache, retro-orbital pain, myalgia, arthralgia, rash, leukopenia, haemorrhagic manifestations and virus recovery, serological response or temporal occurrence with other cases.

 

c- Dengue shock syndrome (DSS)

Rapid/weak pulse and narrow pulse pressure; or manifestations of hypotension, cold, clammy skin and restlessness.

 

* Reprinted by permission from Macmillian Publishers Ltd: Nature Review Microbiology, Whitehead SS, Blaney JE, Durbin AP et al. Prospects for a dengue virus vaccine. 2007; 5:518-28

Physicians should consider dengue in the differential diagnosis of all patients who have fever and a history of travel to a risk area within 2 weeks of onset of symptoms⁽⁵⁶⁾ . When desired, confirmation of the dengue diagnosis through serologic, molecular or other testing procedures such as antigen detection is possible. It is important in this regard that the diagnostic procedure employed should take account of the stage of disease, specifically that detection of antibodies might not be possible during the febrile period (especially the early stages), whereas detection of viral RNA, virion or dengue proteins may be difficult during defervescence⁽⁵⁵⁾ . In addition to poor sensitivity during the febrile period, interpretation of serologic results can be complicated by cross-reactivity with other flaviviruses or related vaccines and/or previous exposure to dengue^(37,55-59) . Ideally, serologic testing should include examination of acute- and convalescent-phase serum samples collected 0-5 days and 6-30 days from fever onset, respectively^(5,15,56) .

There is no specific therapy for dengue^(5,60) , although the WHO has set out guidelines for management of the severe disease, i.e. DHF and DSS⁽⁴⁹⁾ . Critical in this regard is early and effective plasma replacement, though debate exists as to the specific approach to be used for severe disease^{(5,30,49,55,60)} , e.g. use of colloid or crystalloid solutions in patients with worsening shock.

Vaccines

Substantial effort has been devoted to the development of dengue vaccines, and progress has been made in recent years^(50,61) . However, considerable research and development remains to be done, and licensure of a vaccine is not imminent^(50,61,62) .

Prevention

Because there is no specific therapy for dengue, prevention of exposure to potentially infected mosquitoes is critical. There are experimental data to indicate an association between use of treated bed nets and window screening and a reduced risk of infection with dengue^(19-23) . Further, many entomological studies demonstrate that topical repellents, especially N,N diethyl-methyltoluamide (DEET)^(63-67) , prevent the bites of dengue vectors and hence are reasonably expected to reduce the risk of dengue. Therefore, for all travellers to areas of dengue risk, personal protective measures are recommended (evidence basis AII). This includes use of topical repellents that contain DEET, insecticide-treated clothing and insecticide-treated bed nets. For further information on personal protective measures, see the CATMAT Statement on Personal Protective Measures to Prevent Arthropod Bites⁽⁶⁸⁾ .

Dengue and Canadian travellers

There are no current data that specifically address risk of exposure to dengue for Canadian travellers, though it is likely similar to levels experienced by travellers more generally. As regards case reports, from1974 to 1996 the Zoonotic Diseases Division within Health Canada (now part of the Public Health Agency of Canada) recognized 158 confirmed and 373 suspected cases of flavivirus infection, primarily dengue, in travellers. More recently, the number of dengue infections recognized by the National Microbiology Laboratory in Canadian travellers has ranged from 50-100 infections annually (H Artsob. Unpublished data). This estimate data does not include results from Ontario, as these samples are tested by the Ontario Public Health Laboratory.

When assessing dengue it must be remembered that risk is not static but, rather, varies spatially and temporally. Where possible, advice should be based on the most up-todate risk information available. Credible organizations that provide information that might be of use include:

1. The Public Health Agency of Canada: http://www.phac-aspc.gc.ca/tmp-pmv/pub-eng.php
2. The United States Centers for Disease Control and Prevention: http://www.cdc.gov/ncidod/dvbid/dengue
3. The World Health Organization: http://www.who.int/topics/dengue/en/
4. The Pan American Health Organization (for dengue in the Americas): http://www.paho.org/english/ad/dpc/cd/ Dengue.htm
5. The Program for Monitoring Emerging Diseases (ProMED): http://www.promedmail.org/
6. The World Health Organization: http://www.who.int/topics/dengue/en/

Recommendations

Table 1 presents evidence-based medicine categories for the strength and quality of the evidence for each of the recommendations that follow.

Table 1: Strength and quality of evidence summary sheet*

Categories for the strength of each recommendation
CATEGORY	DEFINITION
A	Good evidence to support a recommendation for use.
B	Moderate evidence to support a recommendation for use.
C	Poor evidence to support a recommendation for or against use.
D	Moderate evidence to support a recommendation against use.
E	Good evidence to support a recommendation against use.
Categories for the strength of each recommendation
GRADE	DEFINITION
I	Evidence from at least one properly randomized, controlled trial.
II	Evidence from at least one well designed clinical trial without randomization, from cohort or case-controlled analytic studies, preferably from more than one centre, from multiple time series, or from dramatic results in uncontrolled experiments.
III	Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.
* From: Macpherson DW. Evidence-based medicine. CCDR 1994;20:145-47. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/94pdf/cdr2017.pdf

 

Recommendations	EBM rating
Personal protective measures should be used to reduce exposure to the bites of dengue vectors.	A II
There is no reason to routinely discourage travel to endemic areas for persons with a known history of dengue infection, nor is screening for previous exposure generally indicated.	B III

 

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* Members: Dr. P.J. Plourde (Chair); Dr. C. Beallor; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean
Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. P. Teitelbaum; Dr. Anita Pozgay
Ex-Officio Representatives: Dr. M. Tepper; Dr. J. Given; Dr. R. Weinman; Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. N. Marano; Dr. P. Arguin; Dr. P. Charlebois; Dr. A. Duggan;
Member Emeritus: Dr. C.W.L. Jeanes.

† This statement was prepared by S. Schofield, PhD, an entomologist consultant for CATMAT. This statement was approved by CATMAT.

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^† Members:Dr. P.J. Plourde (Chair); Dr. C. Beallor; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean

Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. P. Teitelbaum; Dr. Anita Pozgay

Ex-Officio Representatives: Dr. M. Tepper; Dr. J. Given; Dr. R. Weinman; Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. N. Marano; Dr. P. Arguin; Dr. P. Charlebois; Dr. A. Duggan;

Member Emeritus: Dr. C.W.L. Jeanes.
^† This statement was prepared by S. Schofield, PhD, an entomologist consultant for CATMAT. This statement was approved by CATMAT.

 

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