DENGUE MODULE

Dr. Clio Jis Francis

IMPORTANCE

• The incidence of Dengue increased 30-fold over the last 50 years
• Up to 50-100 million infections are now estimated to occur annually in over 100 endemic countries.
• Recent estimates indicate 390 million dengue infections per year, and 96 million (67–136 million) manifest clinically (with variable severity of disease). ¹ 
• Another study estimates that 3.9 billion people in 128 countries are at risk of dengue virus infection. ²
• Before 1970, only 9 countries had experienced severe dengue epidemics.
• The disease is now endemic in more than 100 countries in the WHO regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific.

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DENGUE GLOBAL SPREAD 1942-2013

Messina, Trends Microbiol 2014;22(3):138

IMPORTANCE

• In 2015, 2.35 million cases of dengue were reported in the Americas alone, of which 10,200 cases were diagnosed as severe dengue resulting in 1,181 deaths.
• In 2015 Delhi, India recorded its worst outbreak since 2006 with over 15,000 cases ³
• Recently, dengue became regarded as the most prevalent and rapidly spreading mosquito-born viral disease affecting humans ⁴

HISTORY

• First case of presumed dengue fever reported in a Chinese medical encyclopedia from the Jin Dynasty (265 –420 AD) referred to "water poison" associated with flying insects. ⁵
• Primary vector, Aedes aegypti, spread out of Africa in the 15th to 19th centuries associated with increased globalization associated with the slave trade. ⁵
• By 1906 transmission by the Aedes mosquitoes confirmed. ⁶
• In 1907 dengue second disease (after yellow fever) attributed to a virus. ⁶

HISTORY

• Origins of the Spanish word dengue uncertain, but possibly derived from dinga in the Swahili phrase Ka-dinga pepo, which describes the disease as caused by an evil spirit. ⁷
• Slaves in the West Indies, who contracted dengue, described as having the posture and gait of a dandy; thus the disease was known as "dandy fever". ⁷
• Term "break-bone fever" first applied by physician, United States Founding Father Benjamin Rush, in 1789 report of the 1780 Philadelphia epidemic. In the report he used the more formal term "bilious remitting fever". ⁷

HISTORY

• Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". ⁷
• First known epidemic of dengue hemorrhagic fever (DHF) occurred in Manila, Philippines between 1953 to 1954 ⁸
• In India, dengue was first isolated in Calcutta in 1943 ⁸
• Over the last 70 years international travel and urbanization contributed to dengue spread ⁹

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DENGUE IN INDIA

• All states & Union Territories (except Lakshadweep) reported Dengue in 2017
• In 2017 a dengue fever outbreak affected at least 9,271 people in Delhi. Most cases of dengue in Delhi are generally observed during the monsoon season which runs from July to September. ¹⁰
• Incidence
• 2010: 28,292 cases
• 2012: 50,222 cases
• 2013: 75,808 cases
• Case Fatality Rate:
• 1996: 3.3%
• 2013: 0.3%

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VIROLOGY OF DENGUE

• Dengue is mosquito-borne viral infection
• Genus : Flavivirus
• Single stranded RNA
• 4 dengue virus serotypes ¹¹: DEN-1

DEN-2

DEN-3

DEN-4

• Genome:

3 structural Protein genes

• M protein
• E protein
• C protein

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7 non-structural (NS) proteins

_NS1

• NS2A, NS2B
• NS3
• NS4A, NS4B
• NS5

• Infection with one serotype thought to produce lifelong immunity to that type, but only short-term protection against the other three ⁸.
• Risk of severe disease from secondary infection increases if previously exposed to serotype DEN-1 then contract serotype DEN-2 or DEN-3, or if previously exposed to DEN-3 then acquire DEN-2 ¹²

VIROLOGY AND DISEASE

LIFE CYCLE AND TRANSMISSION

• A. aegypti (lifespan: 30 days)
• A. albopictus (tiger mosquito) (lifespan: 8 weeks)

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Vectors causing dengue

Credit: East county Magazine

Human

Human

Credit: Sanofi

DENGUE LIFE CYCLE

Courtesy CDC

www.cdc.gov -entomologyecology

MOSQUITO BEHAVIOR

• A. aegypti: survives best at Temp: 16-30 ◦C, Humidity: 60-80%, Altitude : up to 1000 feet above sea level ¹³
• Adult mosquitoes rest indoors, are unobtrusive, and prefer to feed on humans during daylight hours. ¹³
• Two peaks of biting activity, early morning for 2 to 3 hours after daybreak and in the afternoon for several hours before dark. Mosquitoes will feed all day indoors and on overcast days.
• Female mosquitoes are very nervous feeders, disrupting the feeding process at the slightest movement, only to return to the same or a different person to continue feeding moments later.
• A. aegypti females often feed on several persons during a single blood meal and, if infective, may transmit dengue virus to multiple persons in a short time
• Life span 30 days

MOSQUITO BEHAVIOR

• A. Albopictus native to tropical and subtropical regions with warm and humid climate, active all year long; however, adapting successfully to cooler, temperate regions, where they hibernate over winter. ¹³
• Life span up to 8 weeks

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Various breeding sites for mosquitoes

Credit: daily news

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Credit: Royalty-free stock photo ID: 723755887

CLINICAL MANIFESTATIONS

Overview:

• Dengue fever severe, flu-like illness that affects infants, young children and adults, but seldom causes death. ¹⁴
• Dengue should be suspected when a high fever (40 C/104 F) accompanied by two of the following symptoms: severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands or rash. ¹⁴
• Symptoms usually last for 2–7 days, after an incubation period of 4–10 days after the bite from an infected mosquito. ³

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CLINICAL MANIFESTATIONS

Credit: Alison Days

In essence, Dengue virus infection causes: high fever, severe headache, eye +

bone, joint, muscle pain + low white and platelet count (especially women)

DENGUE COURSE

Majority of DEN1 first cases mild, but later type can lead to more severe disease!

�CLINICAL SUMMARY: DENGUE FEVER�

• An acute febrile illness of 2-7 days duration with two or more of the following manifestations ¹⁵
• Headache
• Retro-orbital pain
• Myalgia
• Arthralgia
• Rash
• Hemorrhagic manifestations

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WATCH OUT!

• Severe dengue is a potentially deadly complication due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding, or organ impairment. ¹⁴
• Warning signs occur 3–7 days after the first symptoms in conjunction with a decrease in temperature (below 38 C/100 F)
• Warning Signs include: severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums, fatigue, restlessness and blood in vomit. ¹⁴
• Next 24–48 hours of the critical stage can be lethal; proper intensive medical care is needed to avoid complications and risk of death. ¹⁴

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�DENGUE HEMORRHAGIC FEVER�

A case with clinical criteria of dengue fever, PLUS ¹⁵

• Hemorrhagic tendencies evidenced by one or more of the following
• Positive tourniquet test
• Petechiae, ecchymoses or purpura
• Bleeding from mucosa, gastrointestinal tract, injection sites or other sites
• Thrombocytopenia (<100,000 cells per cumm)
• Evidence of plasma leakage due to increased vascular permeability, manifested by one or more of the following:
• Rise in average hematocrit for age and sex > 20%
• More than 20% drop in hematocrit following volume replacement treatment compared to baseline
• Signs of plasma leakage (pleural effusion, ascites, peripheral edema)

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SIGNS AND SYMPTOMS OF DENGUE HEMORRHAGIC FEVER

RASH/PETECHIAE

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BLEEDING

Credit: mrdenguepatrolsmkpengalat.blogspot.com

�DENGUE SHOCK SYNDROME�

• All the above criteria for DHF with evidence of circulatory failure manifested by ¹⁵ :
• Rapid and weak pulse
• Narrow pulse pressure (mmHg)

or

• Hypotension for age
• Cold and clammy skin
• Restlessness
• Cognitive impairment

RISK GROUP

Age, Immunocompromised, comorbidity

DEADLY COURSE FEATURES

Critical Phase: can start 3-4 days after typical onset

• Leakage of plasma from the blood vessels, results in fluid accumulation in the chest and abdominal cavity, depletion of fluid from the circulation, and decreased blood supply to vital organs. ¹⁶
• Organ dysfunction and severe bleeding may be observed ¹⁶.
• Shock (dengue shock syndrome) and hemorrhage (dengue hemorrhagic fever) occur in less than 5% of all cases of dengue ¹⁶

RECOVERY COURSE

Recovery phase:

• Resorption of the leaked fluid into the bloodstream occurs ¹⁶
• Lasts two to three days ¹⁷
• Improvement can be accompanied with severe itching and a slow heart rate ¹⁷
• Rash may occur with either a maculopapular or a vasculitic appearance, followed by peeling of the skin ¹⁷
• Fluid overload state may occur and if it affects the brain it may cause a reduced level of consciousness or seizures ¹⁷
•  Feeling of fatigue may last for weeks in adults ¹⁷

ATYPICAL MANIFESTATIONS

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• CNS: Encephalopathy, encephalitis, febrile seizures, I/C bleed
• GI: Acute Hepatitis / fulminant hepatic failure, cholecystitis, cholangitis acute pancreatitis
• Renal: Acute renal failure, hemolytic uremic syndrome, acute tubular necrosis
• Cardiac: Cardiac arrhythmia, cardiomyopathy, myocarditis, pericardial effusion
• Respiratory: Pulmonary edema, ARDS, pulmonary hemorrhage. pleural effusion
• Eye: Conjunctival bleed, macular hemorrhage, visual impairment, optic neuritis

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DIAGNOSIS: SUSPECTED DENGUE

• Nucleic acid amplification tests preferred method of laboratory diagnosis ¹⁸
• Performed on serum specimens collected 7 days or less after symptom onset
• Confirmation from a single acute-phase serum specimen obtained early in illness (≤7 days after fever onset)
• Detecting viral genomic sequences with RT-PCR
• Or dengue nonstructural protein 1 (NS1) antigen by immunoassay

DIAGNOSIS

• Difficult since similar to malaria, leptospirosis and thyphoid fever
• Lab tests definitive but often come back too late to guide treatment decisions
• Detecting viral antigen ¹⁹
• Detecting specific antibodies in the patient’s serum ¹²
• Acute-phase blood after onset and convalescent-phase sample taken 2 to 3 weeks later ¹²

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MANAGEMENT

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• Symptomatic and supportive ¹⁴
• Bed rest in acute phase
• Iced drinks with glucose/electrolytes
• Cold/tepid sponging to keep temperature below 38.5 C
• Paracetamol antipyretics : lower the body temperature
• Aspirin/NSAIDS : Ibuprofen, etc. avoided- cause gastritis, vomiting, acidosis, platelet dysfunction and severe bleeding
• Paracetamol is preferable in doses:
• 1-2 years: 60 -120 mg/dose
• 3-6 years: 120 mg/dose
• 7-12 years: 240 mg/dose
• Adult : 500 mg/dose
• If no liver disease then up to six 500 mg daily in divided doses

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Credit: drbarak.com

Credit: Bristol Laboratories

Tepid Sponging

Credit: Aina Jeffery

ORS

Credit: Flickr

• Without warning signs
• Fluids: ORS & Fruit juices together with breast feeding or formula feeding ,
• Antipyretics & tepid sponging
• Rush to hospital if warning signs develop
• With warning signs
• I/V Fluids ( In children with shock due to dengue a rapid dose of 20 mL/kg is reasonable. The rate of fluid administration is then titrated to a urinary output of 0.5–1 mL/kg/h, stable vital signs and normalization of hematocrit ²⁰
• Antipyretics
• Platelet transfusion if <20,000

HEMORRHAGIC OR SHOCK THREAT

Prevention

PREVENTION

PREVENTION BEST PRACTICES

• Main method to control or prevent the transmission of dengue virus is to combat vector mosquitoes: ²¹
• Prevent mosquitoes access to egg-laying habitats by environmental management and modification;
• Dispose of solid waste properly and remove artificial man-made habitats
• Cover, empty and clean domestic water storage containers on a weekly basis
• Apply appropriate insecticides to water storage outdoor containers

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PREVENTION BEST PRACTICES

• Main method to control or prevent the transmission of dengue virus is to combat vector mosquitoes: ²¹
• Use of personal household protection such as window screens, long-sleeved clothes, insecticide treated materials, coils and vaporizers
• Improve community participation and mobilization for sustained vector control
• Apply insecticides as space spraying during outbreaks as one of the emergency vector-control measures
• Active surveillance of vectors to determine effectiveness of control interventions

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Credit: Surete

IMPLEMENTATION EXAMPLE

Identify Larvae and Clearing out ²²

• Methods available :
• Fumigation
• Bleach
• Larvae eating fish (GAMBUSIA)
• Kerosene and burn

Credit: Pramod Carpenter 

GAMBUSIA FISH

STATUS OF DENGUE THERAPY

• No dengue-specific therapeutic interventions available
• Safe and effective vaccines would best control the disease and possibly reduce deadly outcomes
• Dengvaxia (CYD-TDV a live attenuated recombinant tetravalent vaccine)
• Sanofi Pasteur first used in Mexico in 2015
• Licensed in several endemic countries
• Guidelines to improve effectiveness and decrease severe dengue syndromes

STATUS OF DENGUE VACCINE

• Dengvaxia (CYD-TDV) – live, attenuated recombinant, tetravalent vaccine
• WHO recommends giving only to 9 to 45 years old with laboratory confirmed previous dengue virus infection. ^23,24
• 3-dose series on a 0/6/12 month schedule.
• Vaccine efficacy 76% in seropositive and 38.8% in seronegative participants. ²⁴

VACCINE ELIGIBILITY

• DO NOT vaccinate a person without laboratory evidence of previous dengue virus infection

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VACCINE ELIGIBILITY

• Children and adults 9–45 years old ²³
• Laboratory confirmation of previous dengue virus infection
• Living in dengue-endemic areas are eligible for the Dengvaxia dengue vaccine.

VACCINE EFFICACY AND SAFETY

• Vaccine efficacy with laboratory evidence of previous dengue virus infection
• Vaccine safety: Most frequent side effect - headache, injection site pain, malaise and myalgia

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WHO RESPONSE AND IMPLEMENTATION EMPHASIS

WHO responds to dengue in the following ways: ²⁷

• Prevent mosquito access to egg-laying habitats
• Properly dispose of solid waste and remove man-made habitats
• Weekly empty, clean and cover domestic water storage containers
• Apply optimal insecticides to outdoor water storage containers
• Use household protection like screens, long-sleeved clothes, insecticide treated materials, coils and vaporizers.
• Improve community participation and response in sustained vector control
• Apply insecticides via space spraying during outbreaks as an emergency vector-control method.
• Monitor and survey vectors to assess control effectiveness

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ANTI - DENGUE DAY

• International Anti-Dengue Day observed every year on 15 June
• Idea was first agreed upon in 2010
• First event held in Jakarta, Indonesia in 2011
• Further events were held in 2012 in Yangon, Myanmar and in 2013 in Vietnam
• Goals:
• Increase public awareness
• Mobilize resources for prevention and control
• Demonstrate Asian region's commitment to tackling the disease

JOIN THE MOVEMENT

ZERO IN ON ZERO^TM BEST PRACTICES FOR PREVENTING AND MANAGING DENGUE FEVER

TAKE HOME POINTS

• Best way to address dengue disease and complications is prevention.
• Early symptoms are classic but beware of hemorrhagic progression with high mortality risk if symptoms do not subside as fever drops.
• Critically important to map outbreaks and clinical disease patterns since serotypes matter and prevention of mosquito and viral delivery with human to mosquito vector propagates disease and rate.
• Vaccines, when coupled with dengue prior infection status, will better eradicate dengue.

REFERENCES

1. Bhatt, S., et al., The global distribution and burden of dengue. Nature, 2013. 496(7446): p. 504-7.

2. Messina, J.P., et al., Global spread of dengue virus types: mapping the 70 year history. Trends Microbiol, 2014. 22(3): p. 138-46.

3. Comprehensive guidelines for prevention and control of dengue and dengue haemorrhagic fever. 2011, World Health Organization Regional Office for South-East Asia: New Delhi, India.

4. Guzman, M.G. and E. Harris, Dengue. Lancet, 2015. 385(9966): p. 453-65.

5. Gubler, D.J., Dengue and dengue hemorrhagic fever. Clin Microbiol Rev, 1998. 11(3): p. 480-96.

6. Henchal, E.A. and J.R. Putnak, The dengue viruses. Clin Microbiol Rev, 1990. 3(4): p. 376-96.

7. Halstead, S.B., ed. Dengue Tropical Medicine: Science adn Practice. 2008, Imperial College Press: River Edge, N.J. 1-10.

8. WHO. Dengue guidelines for diagnosis, treatment, prevention and control. 2009 February 1, 2023; Available from: http://wwwnc.cdc.gov.

9. Campeau, L., et al., Containment measures for emerging and re-emerging vector-borne and other infectious diseases of poverty in urban settings: a scoping review. Infect Dis Poverty, 2018. 7(1): p. 95.

10. DENGUE: Latest News, Videos and Photos of DENGUE, in The Times of India. 2018. p. http://timesofindia.com/topic/DENGUE.

11. Parida, M., et al., Rapid detection and differentiation of dengue virus serotypes by a real-time reverse transcription-loop-mediated isothermal amplification assay. J Clin Microbiol, 2005. 43(6): p. 2895-903.

12. Guzman, M.G. and G. Kouri, Advances in dengue diagnosis. Clin Diagn Lab Immunol, 1996. 3(6): p. 621-7.

13. Scott, T.W., et al., A fitness advantage for Aedes aegypti and the viruses it transmits when females feed only on human blood. Am J Trop Med Hyg, 1997. 57(2): p. 235-9.

14. Dengue Bulletin, W.H. Organization, Editor. 2016.

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REFERENCES

15. Wiener, C., Brown, C., Hemnes, A., and Harrison, T., Harrison’s Principles of Internal Medicine. 18 ed. 2012, New York: McGraw-Hill Medical.

16. Gould, E.A. and T. Solomon, Pathogenic flaviviruses. Lancet, 2008. 371(9611): p. 500-9.

17. Simmons, C.P., et al., Dengue. N Engl J Med, 2012. 366(15): p. 1423-32.

18. Sharp, T.M., et al., Dengue and Zika Virus Diagnostic Testing for Patients with a Clinically Compatible Illness and Risk for Infection with Both Viruses. MMWR Recomm Rep, 2019. 68(1): p. 1-10.

19. Johnson, B.W., B.J. Russell, and R.S. Lanciotti, Serotype-specific detection of dengue viruses in a fourplex real-time reverse transcriptase PCR assay. J Clin Microbiol, 2005. 43(10): p. 4977-83.

20. Ranjit, S. and N. Kissoon, Dengue hemorrhagic fever and shock syndromes. Pediatr Crit Care Med, 2011. 12(1): p. 90-100.

21. CDC. Dengue. 2023; December 16, 2021:[Available from: http://www.cdc.gov/Dengue/.

22. Park, K., Park’s Textbook of Preventive and Social Medicine. 23 ed. 2015.

23. Halstead, S.B., Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine. Hum Vaccin Immunother, 2018. 14(9): p. 2158-2162.

24. Revised SAGE Recommendations Dengue Vaccines. 2018; Available from: http://who.int/immunization/diseases/dengue/revised_SAGE_recommendations_dengue_vaccines_apr2018/en//

25. Hadinegoro, S.R., et al., Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med, 2015. 373(13): p. 1195-206.

26. Sridhar, S., et al., Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. N Engl J Med, 2018. 379(4): p. 327-340.

27. 2018 02 August, 2018]; Available from: http://www.who.int/tdr/publications/documents/dengue-swg.pdf.

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