Jimmy Mendigo, MD Infectious Disease Specialist DENGUE: WHO GUIDELINES FOR DIAGNOSIS AND TREATMENT Jimmy Mendigo, MD Infectious Disease Specialist Chrysanta D. Viernes, MD Internal Medicine- ITRMC

OBJECTIVES Discuss the epidemiology and burden of disease of Dengue Review the transmission Discuss the new case classification Discuss algorithms in the diagnosis and management of Dengue

EPIDEMIOLOGY most rapidly spreading mosquito-borne viral disease in the world incidence: 30-fold increase increasing geographic expansion to new countries, and from urban to rural settings 50 million dengue infections annually

EPIDEMIOLOGY

EPIDEMIOLOGY Philippines 2001-2008: 1, 020,333 cases in Cambodia, Malaysia, Philippines and Vietnam highest reported deaths in 2008 Cambodia Philippines

Burden of Disease  WHO estimates that 2.5 billion people—over 40% of the world’s population-- are at risk for dengue infection. Approximately 50-100 million infections (1 million confirmed) occur each year resulting in 500,000 hospitalizations and 20,000 deaths.

Dengue Virus Profile Genus Flavivirus Family Flaviviridae Single-stranded RNA 4 serotypes (DEN-1 to 4) 50 nm diameter with multiple copies of 3 structural proteins ( membrane bilayer and single-stranded RNA) The genome is cleaved by host and viral proteases in three structural proteins (capsid, C, prM, the precursor of membrane, M, protein and envelope, E) and seven nonstructural proteins (NS).

Vector Profile Aedes mosquitoes Tropical and subtropical species A. aegypti A. albopictus A. polynesiensis Tropical and subtropical species Urban places Immature stages are found in water-filled habitats n recent decades Aedes albopictus has spread from Asia to Africa, the Americas and Europe, notably aided by the international trade in used tyres in which eggs are deposited when they contain rainwater.

The Host Incubation period: 4-10 days Primary infection induce lifelong immunity to the infecting serotype Protection from different serotype within 2-3 months of primary infection No long-term cross-protective immunity

The Host Individual risk factors: Age, ethnicity, chronic diseases Seroepidemiological studies (Cuba and Thailand) Secondary heterotypic infection Time interval between infections Antibody-dependent enhancement of infection Antibody dependent enhancement (ADE): ADE is a phenomenon whereby sub-optimal levels of antibodies enhance viral spread rather than clearing the infection. Antibodies specific for a particular dengue serotype are produced during primary infection or acquired by infants from an immune mother. During a second infection with a distinct serotype, these antibodies bind to the new virus but are not sufficient to neutralize the particles. Cell types that naturally engulf immune complexes through “Fcg” receptors take up the bound virus. Increased viral replication and exacerbated inflammatory responses resulting from access to Fcg receptor-bearing cell types are thought to lead to severe disease. “Original antigenic sin”: Original antigenic sin was a term first coined in the 1960s to describe a phenomenon observed for influenza virus whereby the human immune system works against itself when trying to mount a response. When the body has been infected before, it can undergo a memory immune response upon seeing the agent again. In the case of original antigenic sin, the body mistakenly mounts a memory response to a similar, previously seen pathogen rather than to the current infection –- for example against the primary, rather than secondary, dengue serotype. Because the memory response is dominant, the body cannot properly fight the new infection. Original antigenic sin can impact both humoral and cellular immune responses.

Replication and Transmission Blood meal Released in circulation Viral Replication WBC and Lymphatics

Replication and Transmission Replication in the salivary gland Extrinsic Incubation 8--12 days Viral replication in midgut Female mosquito ingests infected blood

Dengue Fever Wide spectrum of clinical presentation, with unpredictable clinical evolution and outcome Three phases Febrile phase Critical phase Recovery phase Previously classified into undifferentiated fever, dengue fever and DHF Grade 1-IV

Dengue Fever Grade 1: fever, non specific constitutional symptoms; (+) TT- only hgic manifestation Grade 2: Grade 1 manifestation + spontaneous bleeding Grade 3: signs of circulatory failure (rapid weak pulse, narrow pulse pressure, hypotension, cold clammy skin) Grade 4: profound shock with undetectable pulse and BP

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.

CLINICAL MANAGEMENT

Dengue Fever Febrile Phase Critical Phase Recovery Phase

Febrile Phase Sudden onset of high-grade fever Lasts for 2-7 days facial flushing skin erythema generalized body ache myalgia and arthralgia headache sorethroat, injected pharynx, and conjunctival injection anorexia, nausea and vomiting Sudden onset of high-grade fever Lasts for 2-7 days Clinical features are indistinguishable bet wevere and non-severe dengue cases therefore monitoring for warning signs and other clinical parameters is crucial to recognizing progression to the critical phase

earliest abnormality: progressive decrease in total wbc Febrile Phase (+) TT increases the probability of dengue (+) hemorrhagic manifestations enlarged and tender liver earliest abnormality: progressive decrease in total wbc Bleeding may occur in this phase but they are not common CBC picture should alert the physician to a high probability of dengue

Critical Phase temperature drops to 37.5-38 (days 3-7) (+) increase in capillary permeability with increasing hematocrit levels significant plasma leakage lasts for 24-48 hours progressive leukopenia followed by rapid decrease in platelet precedes plasma leakage

Critical Phase if (-) increase in capillary permeability  improve if (+) increase in capillary permeability  pleural effusion and ascites degree of increase above the baseline hematocrit reflects the severity of plasma leakage

Critical Phase shock: critical volume of plasma is lost temperature may be subnormal prolonged shock  organ hypoperfusion  organ impairment, metabolic acidosis, and DIC  severe hemorrhage severe hepatitis, encephalitis or myocarditis

Recovery Phase gradual reabsorption of extravascular compartment fluid (48-72 hours) general well-being improves, appetite returns, GI symptoms abate, hemodynamic status stabilizes and diuresis ensues (+) rash: “isles of white in the sea of red”

Recovery Phase hematocrit stabilizes or may be lower due to dilutional effect of reabsorbed fluid wbc starts to rise recovery of platelet count occurs later

Approach to the Management At primary and secondary levels, health care facilities are responsible for emergency/ ambulatory triage assessment and treatment Triage is the process of rapidly screening patients soon after their arrival in the hospital or health facility in order to identify those Severe dengue With warning signs Non-urgent cases

Approach to the Management

Approach to the Management Referral centres receiving severely ill dengue patients must be able to give prompt attention to referred cases. Beds should be made available to those patients who meet the admission criteria There should be a designated area to cohort dengue patients, and a high-dependency unit for closer monitoring of those with shock. Staffed by doctors and nurses

Approach to the Management Criteria for transfer: early presentation with shock (on days 2 or 3 of illness); severe plasma leakage and/or shock; undetectable pulse and blood pressure; severe bleeding; fluid overload; organ impairment (such as hepatic damage, cardiomyopathy, encephalopathy, encephalitis and other unusual complications).

Approach to the Management Disease notification In dengue-endemic countries, cases of suspected, probable and confirmed dengue should be notified Public health measures suspected cases lives in or has travelled to a dengue-endemic area fever for three days or more low ordecreasing white cell counts thrombocytopaenia ± positive tourniquet test.

Approach to the Management Management Decisions Groups A may be sent home tolerate adequate volumes of oral fluids and pass urine at least once every 6 hours no warning signs Groups B referred for in-hospital management with warning signs, co-existing conditions, with certain social circumstances Groups C require emergency treatment and urgent referral severe dengue (in critical phase)

Group A Action Plan Encourage intake of ORS, fruit juice and other fluids Paracetamol and tepid sponge for fever Advise to come back if with no clinical improvement severe abdominal pain persistent vomiting cold and clammy extremities, lethargy or irritability or restlessness, bleeding not passing urine for more than 4–6 hours. monitor: temperature pattern, volume of fluid intake and losses, urine output, warning signs, signs of plasma leakage and bleeding, haematocrit, and white blood cell and platelet counts

Group B (with warning signs) Action Plan reference hematocrit before fluid therapy isotonic solutions 5–7 ml/kg/hour for 1–2 hours, then reduce to 3–5 ml/kg/hr for 2–4 hours, and then reduce to 2–3 ml/kg/hr or less according to the clinical response reassess: haematocrit remains the same or rises only minimally  2–3 ml/kg/hr for another 2–4 hours worsening vital signs and rising haematocrit rising  5–10 ml/kg/hour for 1–2 hours

Group B (with warning signs) Action Plan Give minimum intravenous fluid volume: maintain good perfusion and urine output of about 0.5 ml/kg/hr Intravenous fluids are usually needed for only 24–48 hours. Reduce intravenous fluids gradually when the rate of plasma leakage decreases towards the end of the critical phase. monitor: vital signs and peripheral perfusion (1–4 hourly until the patient is out of the critical phase) urine output (4–6 hourly) hematocrit (before and after fluid replacement, then 6–12 hourly) blood glucose organ functions (renal profile, liver profile, coagulation profile)

Group B (without warning signs) Action Plan Encourage oral fluids If not tolerated, start intravenous fluid therapy of 0.9% saline or Ringer’s lactate with or without dextrose at maintenance rate Patients may be able to take oral fluids after a few hours of intravenous fluid therapy. Give the minimum volume required to maintain good perfusion and urine output. Intravenous fluids are usually needed only for 24–48 hours. Close monitoring

judicious intravenous fluid resuscitation: sole intervention required Group C Action Plan admit to a hospital with access to intensive care facilities and blood transfusion plasma losses should be replaced immediately and rapidly with isotonic crystalloid solution or, in the case of hypotensive shock, colloid solutions blood transfusion: with suspected/severe bleeding judicious intravenous fluid resuscitation: sole intervention required

Goals of fluid resuscitation: Group C Action Plan Goals of fluid resuscitation: improving central and peripheral circulation (decreasing tachycardia, improving BP, warm and pink extremities, and capillary refill time <2 seconds) improving end-organ perfusion – i.e. stable conscious level (more alert or less restless), urine output ≥ 0.5 ml/kg/hour, decreasing metabolic acidosis.

Treatment of Hemorrhagic Complications Patients at risk of major bleeding are those who: prolonged/refractory shock; hypotensive shock and renal or liver failure and/or severe and persistent metabolic acidosis given non-steroidal anti-inflammatory agents pre-existing peptic ulcer disease anticoagulant therapy any form of trauma

Treatment of Hemorrhagic Complications Blood transfusion is life-saving and should be given as soon as severe bleeding is suspected or recognized Do not wait for the haematocrit to drop too low before deciding on blood transfusion Risk of fluid overload.

Treatment of Hemorrhagic Complications blood transfusion if with bleeding 5-10 ml/kg of PRBC or 10-20 ml/kg FWB repeat if with further blood loss or no rise in hematocrit after transfusion little evidence to support transfusion of platelet concentrate and FFP massive bleeding not managed by FWB/PRBC may exacerbate fluid overload

Management of Complications Fluid Overload Causes: – excessive and/or too rapid intravenous fluids; – incorrect use of hypotonic rather than isotonic crystalloid solutions; – inappropriate use of large volumes of intravenous fluids in patients with unrecognized severe bleeding; – inappropriate transfusion of FFP, platelet concentrates and cryoprecipitates; – continuation of IVF after plasma leakage has resolved – co-morbid conditions such as congenital or ischaemic heart disease, chronic lung and renal diseases

Management of Complications Clinical Features: – respiratory distress, difficulty in breathing; – rapid breathing; – chest wall in-drawing; – wheezing (rather than crepitations); – large pleural effusions; – tense ascites; Other investigations: CXR ECG ABG

Management of Complications Oxygen therapy Stop IVF When to discontinue IVF: – stable blood pressure, pulse and peripheral perfusion; – haematocrit decreases in the presence of a good pulse volume; – afebrile for more than 24–48 days (without the use of antipyretics); – resolving bowel/abdominal symptoms; – improving urine output If necessary, give oral or intravenous furosemide 0.1–0.5 mg/kg/dose once or twice daily, or continuous infusion of furosemide 0.1 mg/kg/hour.

Management of Complications If the patient has stable haemodynamic status but is still within the critical phase, reduce the intravenous fluid accordingly. Avoid diuretics during the plasma leakage phase Patients who remain in shock with low or normal haematocrit levels but show signs of fluid overload may have occult haemorrhage. Careful fresh whole blood transfusion repeated small boluses of a colloid solution

Criteria for Discharge