1. 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

2. 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

3. 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

4. EPIDEMIOLOGY

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

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

7. 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).

8. 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.

9. 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

10. 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.

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

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

13. 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

14. 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

15. 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.

16. CLINICAL
MANAGEMENT

17. Dengue Fever
Febrile Phase
Critical Phase
Recovery Phase

18. 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

19. 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

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

21. 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

22. 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

23. 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”

24. 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

26. 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

27. Approach to the Management

28. 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

29. 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).

30. 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.

31. 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)

32. 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

33. 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

34. 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)

35. 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

36. 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

37. 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.

41. 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

42. 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.

43. Treatment of Hemorrhagic Complications
blood transfusion if with bleeding
5-10 ml/kg of PRBC or 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

44. 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

45. 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

46. 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.

47. 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

48. Criteria for Discharge