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Dengue Clinical Case Management

Dengue Clinical Case Management

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Dengue Clinical Case Management

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  1. Dengue Clinical Case Management Centers for Disease Control and Prevention Division of Vector-Borne Diseases Dengue Branch CENTERS FOR DISEASE CONTROL AND PREVENTION

  2. Train-the-Trainer Initiative Staff Centers for Disease Control and Prevention Dengue Branch Eunice Soto-Gomez, Project Coordinator Kay M. Tomashek MD, MPH Christopher J. Gregory MD, MPH Rosa L. Rodríguez-Acosta, Ph.D. Janice Perez, RN D. Fermín Argüello, MD, MPH Hilda Seda, CME Coordinator Carmen Perez, Program Evaluator Puerto Rico Department of Health Helena I. Villanueva Edmarie Bonilla Members of Oficina de Preparación y Coordinación de Respuesta en Salud Pública

  3. Acknowledgements World Health Organization (WHO) and the Special Programme for Research and Training in Tropical Diseases (TDR) Clinicians of the Dengue Control Research Programme (DENCO) Dr. Lucy Lum, University of Malaysia Physicians of San Lucas Hospitals in Ponce and Guayama and Patillas CDT for help in developing this course The Pan American Health Organization (PAHO) and El Colegio de Médicos-Cirujanos de Puerto Rico for their support and funding

  4. Learning Objectives Recognize dengue, know its case definition and clinical course List diseases and conditions that are on the differential diagnosis of dengue Identify issues in each stage and how to recognize warning signs, plasma leakage and shock early Discuss how to assess a patient with dengue Demonstrate knowledge of how to treat dengue patients

  5. Overview of Lecture Dengue Virus and Human Transmission Case definition and clinical course Epidemiology Clinical and laboratory assessment Management and Treatment Case Studies

  6. Dengue Virus and Human Transmission Part I:

  7. Dengue Virus (DENV) Single stranded RNA viruses Members of Flavivirus family Tick-borne encephalitis virus Selected Flaviruses West Nile Virus Murray Valley Encephalitis Virus Japanese Encephalitis Virus St. Louis Encephalitis Virus DENV 1 DENV 3 DENV 2 DENV 4 Yellow Fever Virus

  8. Dengue Virus Four serotypes (really species): DENV-1, -2, -3, -4 All cause full spectrum of disease Infection confers lifelong serotype-specific immunity Short-term cross-immunity Can have four infections in lifetime Genetic variation within serotypes Some genetic variants thought to be more virulent Dengue virus infection can cause an acute febrile illness (called dengue) Sabin 1959. Viral and Ricketsial Infections of Man. Third Edition Philadelphia: JB Lippincott Company, 361-373.

  9. Transmission of Dengue Virus Dengue is mosquito-borne disease Aedes aegypti most common; Aedes albopictus can also sustain transmission but not found in Puerto Rico Mosquito bites human and can transmit dengue virus with as little as 102 viral particle per secretion* Mosquito remains infected for life (≥3 weeks) * Kraiselburd E et al. Trans R Soc Trop Med Hyg 1985; 79:248-51

  10. Transmission of Dengue Virus Viremia begins slightly before onset of symptoms (~24 to 48 hours) and lasts about 1 week (period of infectivity)* Most infected people remain asymptomatic** Especially those with primary infections; can be of any age. Viremia in asymptomatic blood donors can be as high as in symptomatic patients (105– 109 viral copies per mL) * Infected persons can transmit virus as early as 1 to 2 days before symptoms develop. Nishiura & Halstead, 2007. ** 53-89% of infected individuals asymptomatic in the following studies: Rodriguez L et al. Am J Trop Med Hyg 1995; 52(6):496; Endy TP et al. Am J Epid 2002; 156:40, Burke DS et al. Am J Trop Med Hyg 1988; 38:172; Tan et al. Obstet and Gyn 2008; 111(5): 1111-1117.

  11. Transmission of Dengue Virus Febrile, viremic boy with dengue virus infection Time

  12. Transmission of Dengue Virus Mosquito bites boy and gets dengue virus in blood meal Time

  13. Transmission of Dengue Virus Same, now dengue infected mosquito, bites girl and … 8 to 12 days later Extrinsic Incubation Period within the mosquito Time

  14. Transmission of Dengue Virus … gives dengue virus to her Time

  15. Transmission of Dengue Virus Girl can pass dengue virus to another mosquito if bitten while she is viremic 3 to 14 days later… Intrinsic Incubation Period within the girl Time

  16. Transmission of Dengue Virus Aedes aegypti is most efficient vector Lives around human habitation; rests in dark areas Primarily a daytime feeder; bites indoors Lays eggs in artificial, water-holding containers, and occasionally bromeliads and tree holes Prevent mosquitoes from breeding in your home and patio Get rid of containers or empty on weekly basis Fix septic tanks and seal toilets that are not used Breeding sites: plants, pools, water-filled buckets, used tires, empty oil drums, water storage containers etc.

  17. Life Cycle of Aedes aegypti Female lays on average 100-120 eggs on inside of containers (above water) five times in life time. 2 days Adult Pupa Eggs Eggs survive for up to 6 months. Eggs hatch when submerged in water, this process takes < 24 hours. Approximately 6 days Larva Note: Fecundability dependent on environmental conditions such as rain, humidity and temperature. The total time for development is dependent upon water temperature and food supply, and typically ranges from 4 to 10 days. Larvae die at temperatures below 10 degrees and above 44 degrees Celsius.

  18. Life Cycle of Aedes aegypti Female lays on average 100-120 eggs on inside of containers (above water) five times in life time. EMPTYWATER 2 days KILLADULT Adult Pupa Eggs KILL LARVA Eggs survive for up to 6 months. Eggs hatch when submerged in water, this process takes < 24 hours. Approximately 6 days Larva Note: Fecundability dependent on environmental conditions such as rain, humidity and temperature. The total time for development is dependent upon water temperature and food supply, and typically ranges from 4 to 10 days. Larvae die at temperatures below 10 degrees and above 44 degrees Celsius.

  19. Primary Prevention Measures Avoid being bitten(just after dawn until just after sunset) Use repellent containing*: DEET including: Off!, Cutter, Sawyer, and Ultrathon. Picaridin including: Cutter Advanced, Skin So Soft Bug Guard Plus Oil of lemon eucalyptus including: Repel IR3535 including: Skin so Soft Bug Guard Plus Expedition Wear long-sleeved shirt and long pants when on patio Spray permethrin or DEET repellents on clothing Use screens in house Kill adult mosquitoes and larva in your home * For more information see http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/protection-against-mosquitoes-ticks-insects-arthropods.aspx

  20. Other Routes of Transmission Evidence of transmission of dengue through receipt of donor organs or tissue1 Bone marrow transplant and renal transplant Transmission of dengue documented via receipt of bloodproducts (RBC transfusion)2,3 Seven reports of transmission after occupational exposure in a healthcare setting1 Use standard precautions 1 Wilder-Smith A, et. al. Threat of Dengue to Blood Safety in Dengue-Endemic Countries. EID 2009; 15(1):8-11. 2 Chuang et al. Review of dengue fever cases in Hong Kong during 1998 to 2005. Hong Kong Med J 2008;14:170-177. 3 Tambyah et al.Dengue hemorrhagic fever transmitted by blood transfusion. N Engl J Med 2008;359:1526-1527. 4Mohammed, H. et al. Dengue Virus in Blood Donations, Puerto Rico, 2005. Transfusion 2008; 48:1348-1354.

  21. Other Routes of Transmission DENV can be transmitted from mom to the fetus in utero or to neonate at parturition (perinatal transmission), however may be rare, only 35 cases reported in literature* Rates of perinatal transmission vary and may depend on severity of maternal dengue Reported cases were symptomatic and had symptomatic mom with dengue late in pregnancy or at delivery * Pouliot S.H., et. al. Maternal dengue and pregnancy outcomes: a systematic review. Obstetr Gynecol Survey 2010.

  22. Perinatal transmission Average time between mom and newborn onset is 7 days (range: 5-13 days) ~ similar to intrinsic incubation Most newborns cases described had fever plus thrombocytopenia and hepatomegaly. Half had hemorrhagic manifestation One quarter had pleural effusion and/or rash Clinical presentation not associated with maternal immune status or mode of delivery * Pouliot S.H., et. al. Maternal dengue and pregnancy outcomes: a systematic review. Obstetr Gynecol Survey 2010.

  23. Summary: Part I Human-mosquito-human cycle is primary mode of transmission; transmitted by infected Aedes mosquito Transmission can occur after receipt or contact with contaminated blood products or donor organs/tissues, and vertical transmission Person sick within 2 weeks of being bitten or exposure Mosquito infected for life and able to infect others in household Kill mosquitoes in house to prevent spread

  24. Case Definition Clinical Course Part II:

  25. Dengue – Clinical Spectrum 1997 WHO Case Definition Dengue virus infections Asymptomatic** Symptomatic Symptomatic DengueHemorrhagicFever (DHF) Undifferentiated Fever DengueFever No DHF - Gr I and II Dengue Shock Syndrome Bleeding bleed * Asymptomatic infections account for 50 to 83% in some studies. Rodriguez L et al. Am J Trop Med Hyg 1995; 52(6):496; Endy TP et al. Am J Epid 2002; 156:40, Burke DS et al. Am J Trop Med Hyg 1988; 38:172

  26. Dengue – Clinical Spectrum 2009 WHO Case Definition NEW FOCUS on increased vascular permeability as the most important feature that differentiates dengue from severe dengue Dengue virus infections Asymptomatic* Symptomatic Symptomatic Undifferentiated Fever Severe Dengue Infections DengueFever Warning signs No warning signs Organs severely impaired Severe plasma leakage Severe bleed * Asymptomatic infections account for 50 to 83% in some studies. Rodriguez L et al. Am J Trop Med Hyg 1995; 52(6):496; Endy TP et al. Am J Epid 2002; 156:40, Burke DS et al. Am J Trop Med Hyg 1988; 38:172

  27. 2009 New Dengue Classification Dengue case classification by severity Dengue ± warning signs Severe dengue 1. Severe plasma leakage 2. Severe hemorrhage 3. Severe organ impairment With warning signs Without Criteria for dengue ± warning signs Criteria for severe dengue 1. Severe plasma leakage leading to: • Shock (DSS) • Fluid accumulation with respiratory distress 2. Severe bleeding as evaluated by clinician 3. Severe organ involvement • Liver: AST or ALT>=1000 • CNS: Impaired consciousness • Heart and other organs • Probable dengue • Live in/travel to dengue endemic area. Fever and 2 of following criteria: • Nausea, vomiting (New) • Rash • Aches and pains (Combined) • Tourniquet test positive • Leucopenia • Any warning sign • Laboratory confirmed dengue • (important when no sign of plasma leakage) Warning signs* • Abdominal pain or tenderness • Persistent vomiting • Clinical fluid accumulation • Mucosal bleed • Lethargy; restlessness • Liver enlargement >2cm • Increase in HCT with rapid decrease in platelet count * Requiring strict observation and medical intervention WHO/TDR 2009

  28. 2009 New Dengue Classification Dengue case classification by severity Dengue ± warning signs Severe dengue 1. Severe plasma leakage 2. Severe hemorrhage 3. Severe organ impairment With warning signs Without Criteria for dengue ± warning signs Criteria for severe dengue 1. Severe plasma leakage leading to: • Shock (DSS) • Fluid accumulation with respiratory distress 2. Severe bleeding as evaluated by clinician 3. Severe organ involvement • Liver: AST or ALT>=1000 • CNS: Impaired consciousness • Heart and other organs • Probable dengue • Live in/travel to dengue endemic area. Fever and 2 of following criteria: • Nausea, vomiting (New) • Rash • Aches and pains (Combined) • Tourniquet test positive • Leucopenia • Any warning sign • Laboratory confirmed dengue • (important when no sign of plasma leakage) Warning signs* • Abdominal pain or tenderness • Persistent vomiting • Clinical fluid accumulation • Mucosal bleed • Lethargy; restlessness • Liver enlargement >2cm • Increase in HCT with rapid decrease in platelet count * Requiring strict observation and medical intervention WHO/TDR 2009

  29. 2009 New Dengue Classification Dengue case classification by severity Dengue ± warning signs Severe dengue 1. Severe plasma leakage 2. Severe hemorrhage 3. Severe organ impairment With warning signs Without Criteria for dengue ± warning signs Criteria for severe dengue 1. Severe plasma leakage leading to: • Shock (DSS) • Fluid accumulation with respiratory distress 2. Severe bleeding as evaluated by clinician 3. Severe organ involvement • Liver: AST or ALT>=1000 • CNS: Impaired consciousness • Heart and other organs • Probable dengue • Live in/travel to dengue endemic area. Fever and 2 of following criteria: • Nausea, vomiting (New) • Rash • Aches and pains (Combined) • Tourniquet test positive • Leucopenia • Any warning sign • Laboratory confirmed dengue • (important when no sign of plasma leakage) Warning signs* • Abdominal pain or tenderness • Persistent vomiting • Clinical fluid accumulation • Mucosal bleed • Lethargy; restlessness • Liver enlargement >2cm • Increase in HCT with rapid decrease in platelet count * Requiring strict observation and medical intervention WHO/TDR 2009

  30. 2009 New Dengue Classification Dengue case classification by severity Dengue ± warning signs Severe dengue 1. Severe plasma leakage 2. Severe hemorrhage 3. Severe organ impairment With warning signs Without Criteria for dengue ± warning signs Criteria for severe dengue 1. Severe plasma leakage leading to: • Shock (DSS) • Fluid accumulation with respiratory distress 2. Severe bleeding as evaluated by clinician 3. Severe organ involvement • Liver: AST or ALT>=1000 • CNS: Impaired consciousness • Heart and other organs • Probable dengue • Live in/travel to dengue endemic area. Fever and 2 of following criteria: • Nausea, vomiting (New) • Rash • Aches and pains (Combined) • Tourniquet test positive • Leucopenia • Any warning sign • Laboratory confirmed dengue • (important when no sign of plasma leakage) Warning signs* • Abdominal pain or tenderness • Persistent vomiting • Clinical fluid accumulation • Mucosal bleed • Lethargy; restlessness • Liver enlargement >2cm • Increase in HCT with rapid decrease in platelet count * Requiring strict observation and medical intervention WHO/TDR 2009

  31. Clinical Course of Dengue Dengue is a systemic and dynamic disease. After the incubation period, the illness begins abruptly and will be followed by 3 phases: Febrile phase – commences at symptom onset Critical phase – commences at time of defervescence* Recovery phase – commences when plasma leakage resolves * Defined as when body temperature drops to less than 38.0°C, and remains below this level. DENCO Slide

  32. Clinical Course of Dengue 1 to 2 days Critical Phase 3 to 5 days Mosquito bite 2 to 7 days Convalescent Phase 3 to 14 days Febrile Phase Afebrile Incubation Viremic Not viremic -2 0 2 4 6 8 10 12 Days * Typically uncomplicated DHF/DSS lasts for 10 to 12 days

  33. Febrile Phase Usually lasts 2 – 7 days Fever can be biphasic Monitoring for defervescence & warning signs are crucial to recognise progression into the critical phase Defervescence occurs on day 3 – 8 of illness Defined as when body temperature drops to less than 38.0°C & remains below this level DENCO Slide

  34. Critical Phase Onset of critical phase usually can be identified by: Defervescence Rapid decline in platelet count with rise in hematocrit Develop leukopenia ~24 hrs. before platelet drop Development of warning signs Warning Signs • Severe abdominal pain • Persistent vomiting • Clinical fluid accumulation (ascites, pleural effusion) • Mucosal bleed • Lethargy; restlessness • Liver enlargement >2cm

  35. Critical Phase • Warning signs are result of plasma leakage due to vascular permeability • Patients without plasma leakage will improve while those with significant leakage will deteriorate during this phase1 • Clinically significant plasma leakage usually lasts 24 to 48 hours from time of defervescence1,2 • Must monitor carefully for resolution of plasma leak and start of recovery phase to avoid fluid overload1 1Dengue guidelines for diagnosis, treatment, prevention and control. 3rd edition. Geneva; WHO. 2009. 2Farrar J , in Dengue :Tropical Medicine: Science and Practice (Halstead S, ed.), Imperial College Press, 2008.

  36. Recovery Phase Gradual re-absorption of extravascular fluid takes place in 48–72 hours, and diuresis ensues General well being improves, hemodynamic status stabilises, and patient may become bradycardic Laboratory HCT stabilises or may lower due to dilutional effect of reabsorbed fluid (hemodilution) WBC usually starts to rise soon after defervescence Recovery of platelet count is typically later than WBC DENCO Slide

  37. Complications During Clinical Course Shock End Organ Damage Hemorrhage Dehydration Febrile Seizures Neurologic Disease Fluid Overload Acute Pulmonary Edema Critical Phase Mosquito bite Convalescent Phase Febrile Phase Afebrile Incubation Viremic Not viremic -2 0 2 4 6 8 10 12 Days * Typically uncomplicated DHF/DSS lasts for 10 to 12 days

  38. Causes of Death in Dengue Unrecognized disease Unrecognized shock or prolonged shock Unrecognized occult hemorrhage Fluid overload Nosocomial sepsis especially in elderly

  39. Summary: Part II Most people infected with DENV are either asymptomatic or mild to moderately symptomatic Patients with severe dengue can deteriorate quickly during defervescence with rapid onset of shock due to increase in vascular permeability (critical phase) This can happen as early as 3 days after onset of symptoms Severity of plasma leak dictates level of management

  40. Epidemiology of Dengue Part III:

  41. Dengue in Puerto Rico Dengue endemic in PR with low transmission in March—June and peak transmission in August—November Dengue reportable by law to PRDH and diagnostic testing done at CDC Dengue Branch in San Juan Surveillance data used to identify where cases occurring so we can target vector control and prevention efforts Need to put your email/address on form to get results back

  42. Dengue in Puerto Rico First major epidemics reported in 1915 and 1945. However, DENV first isolated in Puerto Rico in 1963 Several large, island-wide outbreaks since then with last two large outbreaks in 1998 and 2007 involving circulation of all four serotypes This year, 16,000 suspected cases reported as of October 1st and 50% are laboratory confirmed dengue 24 laboratory confirmed deaths 22 are adults 20 to 78 years old (mean 46 yrs) 14 were females

  43. Who Gets Sick With Dengue? Age. Rates of lab-positive dengue highest in 10–19 yr-olds Infants (<1 year) and 5–9 year-old children follow Number and rates of lab-positive cases, Puerto Rico, 2010

  44. Who Gets Sick With Dengue? Sex No evidence that sex is a risk factor for infection or severe disease Race Data on race inconclusive Some suggest African ancestry may be protective against development of severe dengue while others suggest that other races protective

  45. When Do People Get Sick? Reported cases End of May or early June Week of onset date

  46. Where are the dengue cases? Rates of Laboratory-positive Dengue by Municipality, Puerto Rico, 2010 Dengue is a focal disease; rates vary by municipality. However all island has the disease.

  47. 2 to 4% of dengue cases progress to severe disease Factors have been identified that are associated with an increased risk for severe disease (i.e., DHF or DSS) Viral characteristics Inherent strain and serotype differences in pathogenicity1,2 and virulence Greatest variability in pathogenicity with DENV-2 Viral load correlates with disease severity3 Risk Factors for Severe Dengue 1 Scott Halstead (2008). Dengue. Tropical Medicine: Science and Practice. London: Imperial College Press. 2 Leitmeyer KC, Vaughn DW, Watts DM, et. al. Dengue Virus Structural Differences That Correlate with Pathogenesis. J Virol. 1999; 73(6): 4738–4747. 3 Vaughn DW, Green S, Kalayanarooj S,et. al.Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis. 2000 Jan;181(1):2-9.

  48. Risk factors for Severe Dengue Co-circulation of multiple serotypesin the same geographic region Host factors Age (infant)1 Nutritional status Obese individuals at higher risk1 Chronic disease (diabetes, asthma)2 Previous dengue infection1 Level of neutralizing antibody Timing of infection key as protective immunity wanes2 1 Scott Halstead (2008). Dengue. Tropical Medicine: Science and Practice. London: Imperial College Press. 2Figueiredo MAA, et al. (2010) Allergies and Diabetes as Risk Factors for DHF. PLoS Negl Trop Dis 4(6): e699.

  49. Risk factors for Severe Dengue Presence of non-neutralizing antibodies Non-neutralizing cross-reactive antibodies are produced in 1st dengue infection In 2nd infection, these antibodies form antibody-virus complexes that can increase viral production. Known as antibody-dependent enhancement (ADE).1,2 Associated with increased disease severity. Complicates production of vaccine for dengue. 1 Scott Halstead (2008). Dengue. Tropical Medicine: Science and Practice. London: Imperial College Press. 2 Halstead Sb, et. al. Hemorrhagic fever in Thailand; recent knowledge regarding etiology. Jpn J Med Sci Biol. 1967;20s:96-103.

  50. Infants, ADE and Severe Dengue Anti-dengue IgG antibodies passed from mother to her fetus (IgM does not cross placenta) Passively transferred maternal IgG can protect the infant Dengue in infants <4 months of age unusual As maternal IgG titer falls by ~4 to 6 months, enhancement outweighs neutralization and infant is at risk for severe disease even with primary infection. By ~1 year, no longer at increased risk. * Kliks SC, et al. Evidence that maternal dengue antibodies are important in the development of DHF in infants. Am J Trop Med Hyg 1988;38:411-19. Perret C, et al. Dengue infection during pregnancy and transplacental antibody transfer in Thai mothers. J Infect. 2005;51:287–293.Ventura AK, et al. Placental Passage of Antibodies to Dengue Virus in Persons Living in a Region of Hyperendemic Dengue Virus Infection. J Infect Dis. 1975;131:S62-68.