dengue tropmed new sept'12
TRANSCRIPT
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Chairuddin P. Lubis, Syahril Pasaribu, Ayodhia P. Pasaribu,Inke Nadia D. Lubis
Department of Pediatrics
Faculty of Medicine, University of North Sumatera
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Prevalence of Clinical Spectrums of Dengue
Infection in Dengue Model
2
Population Infection
AsymptomaticInfection
ClinicalCases
DF
(Non-DHF)
DHF/DSS
Survive
Death
5% 76%
24% 94%
6%99.2%
0.8%
Shepard DS. Vaccine. 2004; 22: 1275-80
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3
Countries and Areas at Risk of Dengue Transmission
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4
2.5 billion in endemic countries
50 100 million dengue cases
500.000 DHF
Morbidity 1 3 weeks
20.000 deaths
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DHF INCIDENCE RATE
Dengue Bull. 2006; 30: 1-14
5
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Dengue Bull. 2006; 30: 1-14
DHF MORBIDITY & MORTALITY IN INDONESIA
FROM 1968 - 2005
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DENGUEFEVER
DENGUE
HEMORRHAGIC
FEVER
DENGUE
SHOCK
SYNDROME
DENGUE MANIFESTATIONS
WHO
DENGUE FEVER
Acute onset febrile illness that lasts 2-7
days
With 2 or more following symptoms :
- headache - ptechiea- retro-orbital pain - tourniquet test (+)
- myalgia/arthralgia
- maculopapular rash
J Pediatr. 2007; 83(2): 22-35.
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Case Definition for DHFWHO 1997
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DENGUEFEVER
DENGUE
HEMORRHAGIC
FEVER
DENGUE
SHOCK
SYNDROME
DENGUE MANIFESTATIONS
WHO
DENGUEHEMORRHAGIC
FEVER
Fever lasts 2-7 days,occasionally biphasic
Hemorrhagic tendencies
Thrombocytopenia (< 100,000 /mm3)
Evidence of plasma leakage, manifestedby : - rise in haematocrit > 20%
- drop in haematocrit following
volume replacement
- signs of plasma leakage
J Pediatr. 2007; 83(2): 22-35.
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Case Definition for DHFWHO 1997
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Dengue Hemorrhagic Fever
Grading SymptomsGrade I Hemoconcentration, fever, non specific
constitutional symptoms, only positive
tourniquet test
Grade II Spontaneous bleeding in addition to themanifestation from Grade I
Grade III Circulatory failure, rapid & weak pulse, narrow
pulse pressure, cold clammy skin, hypotension
by age, oliguria, restlessnessGrade IV Profound shock, hypotension or unrecordable
blood pressure
J Pediatr. 2007; 83(2): 22-35.
9
1997
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DENGUEFEVER
DENGUE
HEMORRHAGIC
FEVER
DENGUE
SHOCK
SYNDROME
DENGUE MANIFESTATIONS
WHO
DENGUE
SHOCK
SYNDROME
All four criteria of DHF must be present
Evidence of circulatory failure
manifested by :
- Rapid and weak pulse- Narrow pulse pressure (< 20 mmHg) or
- Hypotension for age, and
- Cold, clammy skin and restlessness J Pediatr. 2007; 83(2): 22-35.
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Case Definition for DHFWHO 1997
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The 3rd edition of the WHO
dengue guidelines
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http://whqlibdoc.who.int/publications/2009/9
789241547871_eng.pdf
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WHO 2009 Dengue Case Classification and
Levels of Severity
Dengue + Warning Signs Severe Dengue
without
with
warningsigns
1. Severe plasma leakage
2. Severe haemorrhage3. Severe organ impairment
Nathan MB. Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.
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Criteria for Dengue + Warning Signs
Probable Dengue
Live in/travel to dengue endemic
areaFever and 2 of the following
criteria :
- Nausea, vomiting
- Rash
- Aches and pain- Tourniquet test positive
- Leukopenia
- Any warning sign
Warning Signs
- Abdominal pain or tenderness
- Persistent vomiting- Clinical fluid accumulation
- Mucosal bleed
- Lethargy, restlessness
- Liver enlargement > 2 cm
- Laboratory: increase in HCTconcurrent with rapid decrease
in platelet count
Laboratory-Confirmed DengueImportant when no sign of plasma
leakage
Nathan MB. Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.
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Criteria for Severe Dengue
Severe Plasma Leakage
Leading to :
- Shock (DSS)
- Fluid accumulation with respiratory distress
Severe BleedingAs evaluated by clinician
Severe Organ Involvement
- Liver : AST or ALT > 1000
- CNS : Impaired consciousness
- Heart and other organs
Nathan MB.Dengue: guidelines for diagnosis, treatment, prevention and control. 2009. p3-21.
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Revised and expanded
edition of dengueguideline
15
This edition have been
extensively revised andexpanded by the WHO
Southeast Asian Region Office,
with the focus on
new/additional topics of current
relevance to Member States ofthe South-East Asia Region.
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2011 WHO-SEARO Dengue Case Classification
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WHO Cl ifi i f I f i d
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WHO Classification of Dengue Infections and
Grading of Severity of Dengue
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What is expanded dengue syndrome ?
Uncommon manifestation
Neurological, hepatic, renal and other isolated organ
involvement
CNS manifestations :
Convulsions, spasticity, changes in consciousness andtransient paresis
Limited evidences showed dengue viruses may cross the
blood-brain barrier and cause encephalitis
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Expanded dengue syndrome
System Unusual or atypical manifestations
Neurological Febrile seizures in young childrenEncephalopathy
Encephalitis / aseptic meningitis
Intracranial haemorrhages / thrombosis
Subdural effusions
Mononeuropathies / polyneuropathies / Guillaine-Barre
syndromeTransverse myelitis
Gastrointestinal / hepatic Hepatitis / fulminant hepatic failure
Acalculous cholecystitis
Acute pancreatitis
Hyperplasia ofPeyers patches
Acute parotitis
Renal Acute failure
Hemolytic uremic syndrome
Cardiac Conduction abnormalities
Myocarditis
Pericarditis 19
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Expanded dengue syndrome (continue..)
System Unusual or atypical manifestations
Respiratory Acute respiratory distress syndromePulmonary hemorrhage
Lymphoreticular / bone
marrow
Infection associated haemophagocytic syndrome
IAHS or Haemophagocytic lymphohisiocytosis (HLH),
idiopathic thrombocytopenic purpura (ITP)
Spontaneous splenic rupture
Lymph node infarction
Eye Macular haemorrhage
Impaired visual acuity
Optic neuritis
Others Post infectious fatigue syndrome, depression,
hallucinations, psychosis, alopecia
20
Gulati S, Maheswari A. Atypical manifestation of dengue. Trop Med Int Health.
2007; 12(9): 1087-95
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High Risk Patients
Infants, and the elderly
Obesity
Pregnant women
Peptic ulcer disease
Women who have menstruation or abnormal
vaginal bleeding
Haemolytic diseases: G6PD deficiency,
thalassemia and other hemoglobinopathies
Congenital heart disease
Chronic diseases: DM, hypertension, asthma,ischaemic heart disease, chronic renal
failure, liver cirrhosis
Patients on steroid or NSAID treatment
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1997 vs 2009 WHO Dengue Classification
1997 WHO case classification was revised because of differences in geographical areas
and age groups affected
2009 classification is more sensitive in capturing severe disease than the 1997
guidelines (92% vs 39%)
1997 classification is recommended for continuing use because the 2009 classification
creates > 2x workload to health care personnel
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Usefulness and applicability of the revised
dengue case classification by disease:multi-centre study
in 18 countries
Judit Barniol, Roger Gaczkowski, Eliana Vega Barbato, Rivaldo V da Cunha, Doris Salgado, Eric
Martnez, Carmita Soria Segarra, Ernesto B Pleites Sandoval, Ajay Mishra, Ida Safitri Laksono, Lucy
CS Lum, Jos G Martnez, Andrea Nnez, Angel Balsameda, Ivan Allende, Gladys Ramrez, Efren
Dimaano, Kay Thomacheck, Naeema A Akbar, Eng E Ooi, Elci Villegas, Tran T Hien, Jeremy Farrar,
Olaf Horstick, Axel Kroeger and Thomas Jaenisch
BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106.
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Comparison of the current (DF/DHF/DSS) and the revised classification in 1962 prospective
chart reviews (130 charts with missing information excluded)
DF/DHF/DSS Revised classification by expert reviewer
Total
classification Not Dengue Severeby expert classifia Dengue
reviewer ble WS negative WS positive
Not classifiable 23 57 159 29
268 (100%) (8.6%) (21.3%) (59.3%) (10.8%)
(13.7% of all)
DF 7 551 684 75
1317 (100%)
(0.5%) (41.8%) (51.9%) (5.7%)
(67.1% of all)
DHF 2 8 240 39
289 (100%)(grades 1 and 2) (0.7%) (2.8%) (83.0%) (13.5%)
(14.7% of all)
DSS 0 0 12 76
88 (100%)
(DHF grades 3and 4) (0%) (0%) (13.6%) (86.4%)
(4.5% of all)
Barniol J, et al. BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106.13.7% of dengue cases could not be classified by
experienced reviewers as compared to 1.6% who
could not classified with the revised classification
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Perceived advantages and disadvantages regarding the
revised dengue case classification (N=1413 comments in
1288 staff questionnaires) [1]
Advantages of the revised classification N (%)
It helps improving management and treatment 319 (22.6%)
More simple and practical 199 (14.0%)
Easier to classify according to severity 176 (12.6%)Easier to understand 71 (5.0%)
It helps improving triage and referral 45 (3.2%)
No disadvantages of the revised classification 191 (13.5%)
Other advantages 72 (5.0%)
Total of positive responses 1073(75.9%)
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Perceived advantages and disadvantages regarding the revised
dengue case classification (N=1413 comments in 1288 staff
questionnaires) [2]
Disadvantages of the revised classification N (%)
No advantages of the revised classification 25 (1.8%)
Needs more training and dissemination 67 (4.7%)
It's less specific. Needs more clinical entities and
concise protocols 54 (3.8%)Lack of manpower and resources 45 (3.2%)
Over diagnosis of dengue (saturation of hospitals) 32 (2.3%)
Warning signs: Too many, subjective, also in other
diseases 24 (1.7%)
Lack of laboratory support 10 (0.7%)Other disadvantages 83 (5.9%)
Total of negative responses 340 (24.1%)
Barniol J, et al. BMC Infectious Diseases 2011, 11:106 doi:10.1186/1471-2334-11-106.
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The Tourniquet Test
Performed by inflating a blood pressure cuff
on the upper arm to a point midway between
the systolic and diastolic pressures for 5
minutes.
Positive when > 20 ptechiae per 2.5 cm.
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Is the tourniquet test a valuable predictor of DHF?
240 children in Delhi 40% positive in DF, 62% in DHF, 64%in DSS
110 adult DHF patients in North India 39.1% positive
172 Thai children 36% DF and 52% DHF have positive test
905 Vietnamese children 548 dengue confirmed
serologically, sensitivity 41.6%, specificity 94.4%, positive
predictive value 98.3%, negative predictive value 17.3%
Halstead SB. Dengue. 2008. p171-91.
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Prevalence of signs and symptoms in infants children and adults
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Prevalence of signs and symptoms in infants, children and adults,
with significant differences in prevalence noted between children
and infants and between children and adults
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Am J Trop Med Hyg. 2005; 73(6): 1063-70.
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Global
distribution of
dengue virus
serotypes, 1970
Global
distribution of
dengue virus
serotypes, 2004
Gubler DJ. Comp Immunol
Microbiol Infect Dis. 2004.
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Clinical and laboratory findings for DHF by dengue
serotype
Southeast Asian J TropMed Public Health.
2005; 36(6): 1432-8.
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The pathogenesis of DHF/DSS is still controversial.
Two theories that have been used to explain the
pathogenesis of DHF are :
1. The virulence of infecting dengue viruses2. The antibody-dependent enhancement theory
Comp Immun Microbiol Infect Dis. 2007; 30: 329-40.
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Risk factors of severe disease
Secondary infection with a different serotype
Sequentiality of serotypes in secondary infections
Association with specific genotypes
Time interval between first and second infection Age of host
Ethnicity of host
Underlying chronic diseases
J Clin Virol. 2003; 27: 1-13.
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Homologues antibodies form
non-infectious complexes
Person who have experienced a dengue infection develop serum
antibodies that can neutralize the dengue virus of that same
(homologous) serotype
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Heterologous antibodies form
infectious complexes
In a subsequent infection with a different virus serotype, the pre
existing heterologous antibodies form complexes with the new
virus, but these heterologous antibodies do not neutralize the
new serotype
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Antibody-dependent enhancement (ADE) is the process in which
certain strains of dengue virus, complexed with these non-
neutralizing antibodies, can enter a greater proportion of the
mononuclear cells where the virus replicates unchecked, thus
increasing virus production and producing a massive infection
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Heterologous complexes enter more monocytes,
where virus replicates
The infected monocytes release vasoactive mediators, resulting in
the increased vascular permeability and hemorrhagic
manifestations that characterize dengue hemorrhagic fever or
dengue shock syndrome.
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Vascular Permeability
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Intrinsic permeability is regulated by
endothelial surface glycocalyx, and also
endothelial cells themselves.
One of the dengue nonstructural proteins,
or one of the components of the immune
response may act directly with the
glycocalyx layer to alter temporarily the
characteristics of the fiber matrix.
Transient endothelial permeability is also
caused by one or more soluble mediators
released by the endothelium or by immune
cells.
Cytokines and mediators which suggestedinduce endothelial permeability : IL-1, IL-
1, IL-2, IL-6, IL-8, TNF-, IFN-, histamine,
platelet-activating factor, vascular
endothelial growth factor (VEGF)Halstead SB. Dengue. 2008. p285-326.
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The course of dengue illness
McCall P, Lloyd L, Nathan MB.
Dengue: guidelines for diagnosis,
treatment, prevention and
control. 2009. p59-87.
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Febrile, critical and recovery phases in dengue
Febrile phase
Critical phase
Recovery phase
Dehydration, high fever may cause
neurological disturbance and febrile
seizures in young children
Shock from plasma leakage,
severe haemorrhage, organ
impairment
Hypervolemia (only if intravenous
fluid therapy has been excessive
and/or has extended into this period)
McCall P, Lloyd L, Nathan MB.Dengue: guidelines for diagnosis,
treatment, prevention and control. 2009. p3-21. 42
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Course of dengue infection and timings of
diagnosis
Lancet. 2007; 370: 1644-52.
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Laboratory Diagnosis
Early illnesstests
Virus isolation
Nucleic aciddetection
Detection of
antigens
Late illnesstests
Serologicaltests
Buchy P, Peeling R.Dengue: guidelines for diagnosis, treatment,
prevention and control. 2009. p91-107.
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i i li f i d d d
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Approximate time-line of primary and secondary dengue
virus infections and the diagnostic methods that can be used
to detect infection
Buchy P, Peeling R.Dengue:
guidelines for diagnosis,
treatment, prevention and
control. 2009. p91-107.
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Relationship between day of illness and NS1
sensitivity
Plosntds. 2009; 3(1): 360-7.
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Positive anti dengue IgM antibody results (%) in PD
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Positive anti-dengue IgM antibody results (%) in PD
and in SD patients depending on the day of serum
collection
J Clin Virol. 2004; 31: 179-84.
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IgG titers in primary vs secondary dengue fever depending
on the day of serum collection
J Clin Virol. 2004; 31: 179-84.
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Immune response to dengue infection
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Suspect of Dengue Infection
50
High fever, < 7 days
Malaise, no ARI
Emergency signs (-)Emergency signs (+)
Shock
Seizure
Encephalopathy
Bleeding
Tourniquet test
Positive Negative
Inpatient
One day observation
Observe for 24 hours
Symptoms & lab
Leucocyte 10%
Outpatient
Control until fever(-)
Advice the parent
Fever persist > 3 days
Check Hb, Ht, leucocyte
& thrombocyte
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Treatment of DHF without shock
Fluid
Drink 2 litre/day to prevent dehydration Mineral water, juice, oralit
Symptomatic
Give antipiretic if high fever or history of febrile seizure
occured. Suggestion is paracetamol. Asetosal & ibuprofenare contraindicated
Diazepam
Domperidon 1 mg/kgBB, 3 dose, 1-2 days
H2 blocker(ranitidine, cimetidine)
Antibiotic is not given
Steroid is not effective
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T t t f DHF ith t h k
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Treatment of DHF without shock
(DHF grade I and II)
52
Able to drink Unable to drinkVomit
Drink 2 L/day
Paracetamol
Anticonvulsive, if necessary
Infuse D5%:NaCl 0,9% = 3:1
Maintenance drips
Check Hb, Ht, thrombocyteevery 6-12 hours
Evaluate the symptoms & lab
Signs of shock
Diuresis
Bleeding
Hb, Ht, thrombocyte every 6-12 hours
Discharge Improve Worsen Change to
RL D5%
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Treatment of DHF grade I and II
Initial fluid 6 8 ml/kg/hour
RLD5% or RAD5%
Monitor the vital signs
Hb, Ht, thrombocyte every 6-12 hours
Improvement No ImprovementNot agitated
Strong pulse
Stable BP
Ht decrease
Diuresis 1 ml/kg/hour
Agitated
Respiratory distress
HR increase
Ht increase
Pulse pressure
< 20mmHg
Diuresis
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SHOCK O2 2-4 L/minIsotonic fluid 20 ml/kg/hour
RL/RA/NS
in 30 min
Evaluate in 30 minute, has the shock resolved?
Yes No
Adjust the fluid
Monitor
Stable
Stop the fluid not more
than 48 hours after the
shock has resolved
Continue the RL
+ Kolloid
+ Correct acidosis
Evaluate in 1 hourShock has
resolved
Not resolvedHt
Decrease Increase
Transfusion
Inotropic
Kolloid
No improvement
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Rate of infusion in DSS
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Criteria for discharging patients
Absence of fever for at least 24 hours without the use of anti fever
therapy
Return of appetite
Visible clinical improvement
Satisfactory urine output
A minimum of 2 3 days have elapsed after recovery from shock
No respiratory distress from pleural effusion and no ascites
Platelet count of more than 50.000/mm3. If not, patients can be
recommended to avoid traumatic activities for at least 1 2 weeksfor platelet count to become normal. In most uncomplicated cases,
platelet rises to normal within 3 5 days
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