viral haemorrhagic fevers in Nigeria

1. VIRAL HAEMORRHAGIC FEVERS IN NIGERIA
Dr. T. O. Oricha
Dept. Of Medicine
Federal Teaching Hosptal, Gombe

2. Outline
•Introduction
•Epidemiology
•Pathogenesis
•Clinical features
•Differential diagnosis
•Diagnosis
•Management and Treatment
•Prevention
•Ebola virus disease
•Conclusion
•References

3. Introduction
•Viral haemorrhagic fever (VHF) is a term first coined by Russian physicians in the 1940s
•Syndrome of:
Fever
Constellation of initially nonspecific signs and symptoms
Propensity for bleeding and shock
•Caused by more than 30 RNA viruses

4. Introduction
•Pathogenic hallmarks:
Microvascular instability with capillary leak
Impaired haemostasis
•High case fatality rates
•Correct diagnosis depends on demonstration of the infecting virus or one of its products in acute serum samples
•Barrier nursing
•Avoidance of parenteral exposure

5. Introduction
•4 taxonomic families:
Filoviridae: Marburg, Ebola
Arenaviridae: Junin, Machupo, Guanarito, Sabia, Chapare, Lassa, Lujo
Bunyaviridae: Rift Valley fever, Crimean- Congo, Hantaan, Seoul, Puumala and others, Sin Nombre, Black Creek Canal, Bayou, Andes and others
Flaviviridae: Yellow fever, Dengue, KyasanurForest disease, Omsk HF, Alkhurma

6. Introduction
•VHFs in Nigeria:
Yellow fever (YF)
Lassa fever (LF)
Dengue HF (DHF)
Ebola HF (EHF) / Ebola virus disease (EVD)
Marburg HF (MHF)
Crimean-Congo HF (CCHF)
Rift valley fever (RVF)

7. Introduction
•Common characteristics of HF viruses.
Enveloped viruses with a ssRNAgenome
Cytoplasmic replication
Pantropic targeting prim dendritic and monocyte/macrophage cells
Sporadic outbreaks
Both genders and all age groups affected

8. Introduction
Generally asymptomatic or flu-like symptoms
Severe cases associated with high levels of virus in blood
Rodents/insects are natural reservoirs/vectors
Continuously emerging or re-emerging
Geographically restricted by presence of natural host

9. Epidemiology

10. Epidemiology
•Map showing cases/distribution of YF

11. Epidemiology

12. Epidemiology
•LF: map of Nigeria 2012 and 2013 outbreaks

13. Epidemiology
•Reported outbreaks of LF, 16th March, 2012

14. Epidemiology
•Geographic distribution of EHF outbreaks and fruit bats of Pteropodidaefamily

15. Epidemiology
•Geographic distribution of MHF outbreaks and fruit bats of Pteropodidaefamily

16. Epidemiology

17. Epidemiology
•Geographic distribution of CCHF

18. Epidemiology
•Geographic distribution of RVF outbreaks

19. Epidemiology
•Tomori et al; 1988
•Serosurvey for abs to viral agents with hemorrhagic febrile infections
•1,677 human sera from different parts of Nigeria
•357 (21.3%) +ve for Lassa
•42 (2.5%) +ve for Rift valley
•30 (1.8%) +ve for Ebola
•29(1.7%) +ve for Marburg
•Abs to Lassa and RVF viruses were found in all locations in Nigeria
•EV and MV abs found mainly in northern savanna zones

20. Epidemiology
•Olaleyeet al; 1996
•3,121 human sera from 6 ecological zones tested for presence of abs to RVF virus, 1985-1989
•461 sera (14.8%) showed haemagglutination-inhibiting ab
•390 of 461 reactive sera (84.6%) revealed neutralizing ab
•Of 461 sera tested for IgM, 107 gave +veresults (23.2%)
•Higher exposure among livestock workers/wild-life rangers
•Longitudinal study of 164 febrile pxs: infection rate 6.7%.

21. Epidemiology
•25 countries at risk of YF in Africa
•Nigeria among 18 affected
•West Africa worst hit; 13 of 14 countries
•Increased cases in West Africa linked to high non-immunized subjects.
•Bt1984-1994, multifocal epidemics in Nigeria, 23,958 cases and 6,350 deaths.
•Cases reported 2000-2004 was 42
•As of 8 Feb. 2013, 38 suspected cases in 10 states

22. Epidemiology
•cases of YF reported in Nigeria, 1950-2004

23. Epidemiology
•Carey et al; Aug 1964 to Dec 1968
•32 strains of dengue virus were recovered from febrile patients seen at UCH, Ibadan.
•18 strains identified as dengue type 1
•14 as dengue type 2.
•1 April 2014, FMOH reported case of death from DHF: 15-year old lady at IrruaTeaching Hospital, Edo state.

24. Epidemiology
•Idris A. N. et al; 2013
•Sero-prevalence of DENV-3 among 256 patients with febrile illnesses in UMTH
•26 (10.1%) had neutralizing antibodies to DENV-3
•Titresbt1:10 and 1:320

25. Epidemiology
Umoh et al; 1983
•Sera from 1164 cattles in north; 25.7% had pptg abs against CHF-C virus
David-West TS et al; 1974
•A survey for neutralizing abs to Congo virus.
•Total sample population of 250: 141 males and 109 females
•9 males and 15 females had +ve ab levels

26. Epidemiology
•These viruses are zoonotic, maintained in nature in mammals
•Exception of dengue virus, as humans are considered to be reservoir
•Endemic area restricted by the distribution of natural reservoir and/or arthropod vector
•Reservoir/vector to human
•Human to human

27. Epidemiology
•Transmission to Humans
Inoculation into mucus membranes or broken skin of body fluids/feces
Mosquitoes or ticks
Aerosol transmission
Sexual transmission
•Large outbreaks almost always result of amplification in healthcare settings
•Risk of transmission during incubation period or from asymptomatic persons is negligible

28. Epidemiology
•Overview of the ecology and epidemiology of these viruses
Disease
Reservoir/Vector
Distribution
Clinical
cases/year
YF
Monkey/mosquito (Aedes
aegypti, other Aedesspp.)
Sub-Saharan Africa, South America
5,000-200,000
LF
Rodent (multimammaterat or MastomysNatalensis)
West Africa
30,000-50,000
EHF
Fruit bat (Egyptian fruit bat or Rousettusaegyptiacus); non-human primates
West, Central, East Africa
5-500
MHF
Fruit bat (Egyptian fruit bat or Rousettus
Aegyptiacus); non-human primates
West, Central, East Africa
5-300

29. Epidemiology
•Overview of the ecology and epidemiology of these viruses
Disease
Reservoir/Vector
Distribution
Clinical
cases/year
DHF
Human/mosquito (Aedesaegyptiand albopictus)
Tropics and subtropics
100,000- 200,000
CCHF
Wild and domestic vertebrates /tick (primarily Hyalomma
Species)
Africa, Balkans, South Russia, Middle East, West China etc
~500
RVF
Domestic livestock/ mosquitoes (Aedesand
Others)
Sub-Saharan Africa,
Madagascar, Saudi Arabia, Yemen
100-100 000

30. Epidemiology
•Overview of the ecology and epidemiology of these viruses
Disease
Disease-to- infection
Ratio
Case fatality
Human-to- Human
Transmissibility
Risk factors for transmission
YF
1 : 2–20
20-50%
No
Not vaccinated. Sporadic cases in jungle, outbreaks in semi-humid savannah
LF
1 : 5–10
10-25%
Moderate
Contact with rodents and their excreta
EHF
1 : 1
25-90%
High
Contact with caves or diseased primates
MHF
1 : 1
25-90%
High
Contact with caves or diseased monkeys

31. Epidemiology
•Overview of the ecology and epidemiology of these viruses
Disease
Disease-to- infection
Ratio
Case fatality
Human-to- Human
Transmissibility
Risk factors for transmission
DHF
1 : 10–100
Untreated:
10-15%
Treated:< 1
None
Crowded population; bad water, sewage waste systems
CCHF
1 : 1–2
15-30%
High
Contact with blood of diseased animals (ruminants)
RVF
1 : 100
10–50%
None
Epizootics of ruminants. Contact with animal blood

32. Pathogenesis
•Viral properties
Virus
Virus family
Physical Type of
Nucleic Acid
Virus
Particle Size
(nm)
Size of
Nucleic Acid
in Virion
(kb/kbp)
Gene products
YF
Flaviviridae
ss +vesense RNA
40-60
spheroidal
10.9
3 structural proteins: capsid, premembrane, and envelope
7 non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5
LF
Arenaviridae
ss bi- segmented ambisenseRNA
110-130
round, oval, or pleomorphic
10-19
Large segment: Zn- binding protein, RNA polymerase
Small segment: nucleoprotein, surfaceGP precursor

33. Pathogenesis
•Viral properties
E
Filoviridae
ss –vesense RNA
800-1100
Cylindrical or
tubular
18-19
Nucleoprotein, polymerase
Cofactor, matrix protein, sGP, Δ-peptide, GP1,2, transcription activator, secondary matrix protein, RNA-dependent
RNA polymerase
M
Filoviridae
ss –vesense RNA
800-1100
Cylindrical or
tubular
18-19
Nucleoprotein, polymerase
Cofactor, matrix protein, GP1,2, transcription activator, secondary matrix protein, RNA- dependent
RNA polymerase

34. Pathogenesis
•Viral properties
D
Flaviviridae
ss +vesense RNA
40-65
spherical
11
3 structural proteins
7 non-structural proteins
CCHF
Bunyaviridae
ss –vesense, ambisensetriple segmentdRNA
80–120
spherical or pleomorphic
L(11- 14.4)
M(4.4– 6.3)
S(1.7–2.1)
L segment: RNA polymerase
M segment: envelope proteins (Gc, Gn)
S segment: nucleocapsid protein
RVF
Bunyaviridae
ss –vesense, ambisensetriple segmentdRNA
90-110
spherical or pleomorphic
L(6.6)
M(3.9)
S(1.7)
L segment: RNA polymerase
M segment: 2 SPs (Gc, Gn), 2 NSPs (78 kDaand 14 kDaNSmprotein)
S segment: structural nucleoprotein, small NSP

35. Pathogenesis
Infection
Dendritic cells/Macrophages
Draining lymph nodes (Replication)
Tissue invasion
Bloodstream (Dissemination)
Inflammatory cells
Vasoactive mediators (TNF-α, NO, MCP-1)
Recovery
Capillary endothelial cell permeabilty
Plasma leakage/haemorrhage/shock
Recovery
Death
Tissue damage (liver, kidney)
Viraemia
Secondary viraemia

36. Pathogenesis

37. Pathogenesis

38. Pathogenesis
•Mechanism of endothelial dysfunction

39. Pathogenesis
•Summary of pathogenesis of VHFs

40. Pathogenesis
•Major pathogenic mechanisms
Depletion of hepatic coagulation factors
Cytokine storm (TNF-α, IL-10, IL-1Ra, TRAIL, etc)
Increased vascular permeability
Complement activation, and DIC
Impaired innate immune response from non-lytic viral replication
Thrombocytopenia & Inhibition of Platelet Fn.

41. Pathogenesis
•Pathogenic mechanisms proposed for VHFs
Virus
Leukopenia/
Immunesuppression
Thrombocytopenia
Platelet altered function
Reduced
coagnfactors
DIC
Endothelial dyfn
YF
+
+
?
+
+
+
LF
+
+/N
+
-
-
+
EHF
+
+
+
+
+
+
MHF
+
+
+
+
+
+
DHF
+
+
+
+
+
+
CCHF
+
+
?
+
+
+
RVF
+
+
?
+
+
+

42. Pathogenesis
•Pathobiological and Clinical Aspects of VHFs
VHF
I.P (days)
Onset
Bleeding
Rash
Jaundice
Heart
Lung
Kidney
CNS
Eye
YF
3-6
Abrupt
+++
0
+++
++
+
++
++
0
LF
5-16
Gradual
+
+
0
++
+
0
+
0
EHF
2-21
Abrupt
++
+++
+
++
+
+
+
+
MHF
2-21
Abrupt
++
+++
+
++
+
+
+
+
DHF
3-15
Abrupt
++
+++
+
++
+
0
+
0
CCHF
3-12
Abrupt
+++
0
++
+
+
0
+
0
RVF
2-5
Abrupt
++
+
++
+
0
+
++
+

43. Pathogenesis
•Natural history

44. Clinical features
•Spectrum from mild or asymptomatic infection to severe vascular permeability with shock, multi-organ system failure and death
•Clinical presentation may differ for each viral HF as it progresses
•Distinct phases of disease and recovery
•Biphasic illnesses with quiescent period of days (YF and DHF)

45. Clinical features
Incubation period days to weeks
Fever and
Constitutional symptoms:
•General malaise
•Anorexia
•Headache
•Myalgia
•Arthralgia
•Sore throat
•Chest or retrosternal pain and lumbosacral pain

46. Clinical features
GIT features: Nausea/Vomiting, Abdominal pain/tenderness, Diarrhoea(may become bloody in later stages), Constipation
Conjunctival injection/haemorrhage
Skin rash: Morbilliform, Maculopapular, Petechial, Ecchymotic
Orthostatic hypotension
Neck pain/stiffness, retro-rbitalpain/photophobia (RVF)

47. Clinical features
End of first week (vascular instability)
Facial flushing
Oedema
Bleeding
Haematemesis, melena/haematochezia, metrorrhagia, petechiae, purpura, epistaxis, bleeding from gums, venepuncturesites
Internal bleeding from GIT
Haemoptysisand haematuriaare infrequent
Hypotension/shock
Proteinuria

48. Clinical features
CNS manifestations (end-stage disease)
•Disorientation
•Tremor
•Gait anomalies
•Convulsions
•Hiccups
Renal failure (end-stage disease)
Spontaneous abortion/vaginal bleeding, maternal/fetal mortality ~100% in 3rd trimester

49. Clinical features
•Persistent myalgia
•Arthralgia
•Anorexia
•Weight loss
•Alopecia
•Orchitis
•Irritability
•Memory changes
No permanent sequelaein most cases
Depression
Post-traumatic stress
Social stigmatization
Convalescence (up to a year)

50. Differential diagnosis
•Initial misdiagnosis of more familiar syndromes is common
•Malaria and bacterial septicaemia, most common
•Possibility of co-infection should be considered

51. Differential diagnosis
•Features making VHF less likely:
oHaemorrhage in the first few days of illness
oConjunctival injection/sub-conjunctival haemorrhageaccompanied by itching
oJaundice on presentation (except YF)
oProminent pulmonary symptoms
oResponse to antibiotics

52. Differential diagnosis
Viruses:
•Inluenza
•Viral hepatitis (hp.A, B, E, EBV and CMV)
•Herpes simplex or varicella-zoster (fulminant)
•HIV/AIDS
•Measles
•Rubella
•Haemorrhagic or flat smallpox
•Alphavirusinfection (chikungunya, o’nyong- nyong)

53. Differential diagnosis
Bacteria:
•Typhoid fever
•Bacillary dysentery
•Meningococcaemia
•Staphylococcaemia
•Septic abortion
•Septicaemicplague
•Streptococcal pharyngitis
•PTB (advanced)
•Acute abd. emergencies
•Tularaemia
•Pyelonephritis
•Post-infectious GN
•Anthrax (inhalation or GI)
•Relapsing fever
•Leptospirosis
•Rickettsia
•Q fever
•Ehrlichiosis

54. Differential diagnosis
Parasites:
•Malaria
•Amoebiasis
•Giardiasis
•African tripanosomiasis(acute stages)
Non-infectious
•Heat stroke
•ITP/TTP
•Acute glaucoma
•Haem. malignancies
•Drug sensitivity/overdose
•Chemical poisoning
•Haematoxicsnake bite envenomation

55. Diagnosis
Clinical Diagnosis
Laboratory Diagnosis
Case Definition

56. Diagnosis
Clinical Diagnosis
History of illness
Detailed epidemiological history
Physical examination
Preliminary basic laboratory results

57. Diagnosis
Clinical Diagnosis
Clinically compatible syndrome
Fulfills any epidemiologic linkage criteria
•High index of suspicion for persons in high-risk occupations: abattoir workers, veterinarians, farm workers/hunters/taxidermists.
•Acts of bioterrorism must be considered
•Alternative diagnoses should always be aggressively sought

58. Diagnosis
•Wbc& diff; ESR
•Hb/Hct
•Platelet count
•BUN/creatinine
•AST, ALT, lactate
•Blood gas
•Coagnstudies (PT/PTT, fibrinogen, FDP, D-dimer)
•Urinalysis
•Blood culture
•Stool culture
•Thick/thin blood smears
•Rapid testfor malaria
•Assay for Salmonella
•Indicated Clinical Laboratory Tests

59. Diagnosis
Laboratory Diagnosis
•VHF still suspected after initial work-up/lab tests
•Specialized laboratory testing
ELISA
RT-PCR
Cell culture
IFA
Immunohistochemicalstaining of formalin-fixed tissue: skin, liver, spleen (Post-mortem diagnosis)

60. Diagnosis
Laboratory Diagnosis
•No test can reliably diagnose VHF before onset of illness
•Test of contacts/asymptomatic persons not recommended
Acute febrile stage
•Identify virus/virus antigen/nucleic acid
•Prognostic value
•Samples: serum, throat washings, urine, CSF, breast milk
ELISA antigen tests
RT-PCR
Multiplex PCR assays
Cell culture (high containment facility; 2–10 days)

61. Diagnosis
oFalse negative
Limitations: of the various lab assays
Inhibitory substances in the blood
•Repeat in 1-2 days and, if necessary, again in convalescence, if high clinical suspicion
•Discard diagnosis if virus, antigen or nucleic acid cannot be detected during first 7 days of illness and IgMis negative
oFalse-positive

62. Diagnosis
Laboratory Diagnosis
Sub-acute and convalescent stages
•IgMantibody (sub-acute stage)
•IgG antibody (convalescent stage)
•ELISA or IFA
•Antibody seroconversion(4-fold increase in titre) retrospectively diagnose acute disease

63. Diagnosis
Case Definition
2011Case Definition
Clinical Criteria
Laboratory Criteria
Epidemiologic Linkage

64. Diagnosis
Fever >40°C
One or more of:
Severe headache
Muscle pain
Erythematous maculopapularrash on trunk with fine desquamation after 3-4 days
Vomiting
Diarrhea
Pharyngitis (LF)
Abdominal pain
Bleeding unrelated to injury
Retrosternal chest pain (LF)
Proteinuria (LF)
Thrombocytopenia
Clinical Criteria
•Illness with ACUTE ONSET with:

65. Diagnosis
Laboratory Criteria
•One or more of:
Detection of VHF viral antigens in blood by ELISA antigen detection
VHF viral isolation in cell culture of blood/tissues
Detection of VHF-specific genetic sequence by RT-PCRfrom blood or tissues
Detection of VHF viral antigens in tissues by immunohistochemistry

66. Diagnosis
Epidemiologic Linkage
•One or more of the following exposures within 3wks:
Contact with blood/body fluids of VHF px
Residence in/travel to VHF endemic area
Work in lab that handles VHF specimens
Work in lab that handles bats, rodents, primates from endemic areas
Exposure to semen of confirmed acute/convalescent case of VHF in 10wks of the person's symptom onset

67. Diagnosis
oCase Classification
•Suspected
Clinical criteria
Epidemiologic linkage criteria.
•Confirmed
Clinical criteria
Laboratory criteria.

68. Management and Treatment
•Routine universal precautions
•Consultation with infectious disease specialists or clinicians with experience when diagnosis is suspected
•When to ‘sound the alarm’ of VHF is case-by- case decision
•All cases of confirmed VHF should be reported to
oGovernment health authorities
oWHO

69. Management and Treatment
•In Nigeria
Access to basic lab tests for broad range of dx in diff. dx of VHF is limited
Empiric treatment to cover usual range of infectious agents
Admission to isolation ward based on nonspecific clinical/epidemiological features
On-site specialized diagnostics advocated

70. Management and Treatment
General supportive measures
Antiviral drugs
Antibody therapy
Immune modulators
Coagulation modulators
Management of convalescence

71. Management and Treatment
General supportive measures
Fluid Management
•Aggressive fluid replacement
Crystalloids (Ringers lactate or normal saline)
Vasopressors (dopamine or norepinephrine) to maintain CVP bt8-12 mmHg or MAP >65 mmHg in adults
Dobutamine
Peritoneal/haemo-dialysis (renal syndrome)

72. Management and Treatment
Blood Products and Management of DIC
Packed rbcto maintain Hct> 30%
Platelet concentrate (1-2 U/10 kg) if platelet count <50,000/μL (<20 000/μL without bleeding)
FFP(15-20 mL/kg) if bleeding is present & fibrinogen levels <100mg/dL
Fibrinogen concentrates (total dose 2-3g) or cryoprecipitates(1U/10 kg)
VitKif underlying malnutrition or liver dx

73. Management and Treatment
Antibiotics and/or antiparasitics
Pain control and ulcer prophylaxis
Management of seizures
Nutrition
Management of pregnant patients
Uterine evacuation (extreme caution)
Lab parameters should be monitored closely

74. Management and Treatment
Antiviral drugs
Ribavirin
•Guanosineanalogue
•Lethal mutagenesis
Efficacious in treatment of LF
Used for CCHF
•Not efficacious for EHF/MHF

75. Management and Treatment
•Ribavirin Therapy
Indication
Route
Dose
Interval
Treatment
IV
IV
IV
30mg/kg (max.2g)
15mg/kg (max.1g)
7.5mg/kg (max.500mg)
Loading dose, followed by:
Every 6hrs for 4days, followed by:
Every 8hrs for 6days
Prophylaxis
PO
PO
35mg/kg (max.2.5g)
15mg/kg (max.1g)
Loading dose, followed by:
Every 8hrs for 10days

76. Management and Treatment
Ribavirin
•Side-effect: haemolyticanaemia
•Contraindications (relative)
oSevere anaemiaor haemoglobinopathy
oCAD
oRenal insufficiency
odecompensated liver disease
obreast-feeding
oKnown hypersensitivity
oPregnancy
Other antiviral drugs (Experimental therapies)

77. Management and Treatment
Antibody Therapy
•Severe/refractory cases when ribavirin is not an option
Immune Modulators
•Corticosteroids if adrenal insufficiency
Coagulation Modulators (experimental)

78. Management and Treatment
Abstinence/condom use for 3 months
Separate toilet facilities
Regular hand-washing
Avoid breast-feeding
Warm packs
Acetaminophen/NSAID
Cosmetics; hair-growth stimulants
Anxiolytics/antidepressants
Nutritional supplements
Psychological counselling
Management of Convalescence

79. Prevention
Patient isolation
Personal Protective Equipment (PPE)
Nursing precautions
Contact tracing
Post-exposure prophylaxis
Environmental shedding and disinfection
Vaccines
Reservoir/vector control

80. Ebola virus disease
•First appeared in 1976in 2 villages in Central Africa, the 2nd near Ebola river
•Index case 2yr-old boy Emile died on 6 Dec.2013, Guinea.
•WHO reported outbreak: 25, March 2014
•Countries affected: Nigeria, Senegal, Guinea, Liberia, Sierra Leone, US, Spain.
•By 14th October, 2014:
9,216 suspected cases; 4,555 deaths
4,995 cases; 2,729 deaths lab confirmed
•Average case fatality rate: 50%

81. Ebola virus disease
Country reports fall into 2 categories:
Widespread and intense transmission (Guinea, Liberia, and Sierra Leone)
Initial case/cases, or localized transmission (Nigeria, Senegal, Spain, USA)
•On August 8, WHO Director-General declared this outbreak a Public Health Emergency of International Concern

82. Ebola virus disease
•20 July, 2014 first case in Nigeria Patrick Sawyer (from Liberia); died, July 25.
•Cases in Nigeria
•Case fatality rate: 40%
•891contacts have now completed 21-day follow-up (362 in Lagos, 529 in PortHarcourt)
CASE DEFINITION
CASES
DEATHS
Confirmed
19
7
Probable
1
1
Suspected
0
0
All
20
8

83. Ebola virus disease
5 species:
•Zaire ebolavirus(1976) -in present outbreak
•Sudan ebolavirus(1976)
•Côte d'Ivoire ebolavirus(1994; also known as Tai Forest ebolavirus)
•Reston ebolavirus(1994)
•Bundibugyoebolavirus(2007)

84. Ebola virus disease
•Life cycle of theEbolavirus

85. Ebola virus disease
Viral Proteins
Nucleoprotein (NP)
Polymerase cofactor (VP35)
Matrix protein (VP40)
soluble GP (sGP), GP1,2
Transcription activator (VP30)
Secondary matrix protein (VP24)
RNA-dependent RNA polymerase (L)

86. Ebola virus disease
•Entry via: conjunctiva and oropharynx, or injured skin, eating of freshly killed bats
•Extensive replication in lymph nodes, spleen, liver
GP1,2-mediated entry mechanisms:
Endocytosis
Macropinocytosis
sGP:
Anti-inflammatory
Endothelial barrier protector function
Induces cytopathiceffects

87. Ebola virus disease
GP1,2 and VP40
Activate endothelial cells to express ICAM-1, VCAM- 1, and E-selectin
Induce macrophages to secrete TNF-α, IL-6, IL-8, GPO-α
VP35 and VP24 inhibit IFN activity
•EV inhibits dendritic cell maturation/cytokine production, with reduced T cell proliferation
•Decreased CD4/CD8 T lymphocytes by apoptosis mediated by Fas/FasL

88. Ebola virus disease
•Multifocal necrosis occurs most severely in liver, spleen, kidneys, testes, and ovaries
•Survivors develop IgG mainly against NP early, and VP40
•Thereafter cytotoxic T cells are activated
•Terminally ill patients never develop IgG and only 1/3 mount weak IgMresponse

89. Ebola virus disease
•Replication cycle of EV

90. Ebola virus disease
•Clinical features
•Incubation period: 5 days (2-21 days)
Early features
Sudden onset fever, headache, myalgia, sore throat, extreme fatigue
Conjunctivitis
Relative bradycardia
Nausea/vomiting, abdominal pain and watery diarrhea
Perifollicular, non-itching, maculopapularrash (5th day)

91. Ebola virus disease
Haemorrhagic manifestations (5-7th day), in ˂50%:
Epistaxis/gum-bleeding
Haematemesis/melaena
Petechiae/ecchymoses
Haemorrhagesfrom needle sticks
Visceral haemorrhagic effusions
Dehydration, prostration; ghost-like facial expression
Hepatosplenomegaly, oedema, orchitis, scrotal/labial reddening, myocarditis and pancreatitis

92. Ebola virus disease
Poor prognosis is marked by:
Haemorrhagic signs
Oliguria/anuria; shock
Tachypnoea
Neurological symptoms: confusion or coma
Death due to shock occurs 6-9 days after onset
Abortion is a common consequence
Recovery may last for wks: weakness, arthralgia, uveitis, orchitis, hearing loss

93. Ebola virus disease
•Oral bleeding
•Rectal bleeding

94. Ebola virus disease
Other Lab. findings
•Low wbc
•Low platelet count
•Prolonged PT/aPTT
•Low fibrinonogen
•High FDP
•High liver enzymes
•Renal failure
Diagnosis
•RT-PCR assay
•Antibody-capture ELISA
•Antigen-capture detection tests
•Serum neutralization test
•Electron microscopy
•Cell culture.
•No test can detect infection in incubation period

95. Ebola virus disease
•Case classification criteria
CLASSIFICATION
CRITERIA
Suspected
Sudden onset of high fever and contact; or
Sudden onset of high fever and at least 3 of: headache, vomiting, anorexia, diarrhoea, lethargy, abdominal pain, muscle/joint aches, difficulty swallowing, breathing difficulty, or hiccup; or
Any person with unexplained bleeding; or
Sudden, unexplained death
Probable
Suspected case or death from suspected EVD with epidemiological link to confirmed case but no lab confirmation
Confirmed
Probable or suspected case with lab confirmation
Non-case
Suspected or probable case with a -velab result

96. Ebola virus disease
Management
•Isolation
•No specific antiviral therapy
•Supportive care
Rehydration with oral or intravenous fluids
Treatment of specific symptoms
•Activated protein C (experimental)
•rNAPc2 (completed phase 1 trial)

97. Ebola virus disease
oPEP and vaccine (undergoing trials)
Vesicular stomatitis virus vectored vaccine
DNA plasmid vaccine
•Proper case management
•Surveillance
•Contact tracing
•Good laboratory service
•Safe burials
•Social mobilisation
Prevention and control

98. Ebola virus disease
Focus of risk reduction measures
Reducing risk of wildlife-to-human transmission
Reducing risk of human-to-human transmission
Outbreak containment measures
Controlling infection in health-care settings
WHO response
Nigeria response

99. Conclusion
•VHFs are emerging infectious dxscaused by ssRNAviruses belonging to 4 families
•7 have been shown to be present in Nigeria either by case identification or serological evidence
•They cause uniformly severe infections with high fatality rates to mostly asymptomatic infections
•Hallmark is vascular instability
•Important to spot due to public health implications
•Minimizing contact is essential
•Nigeria successfully contained EVD
•Efforts must continue to prevent re-emergence in the country and to contain the disease in worst hit areas

100. THANK YOU FOR LISTENING

101. References
•David Mabeyet al, Principles of Medicine in Africa, 4th Edition; 2013; Ch.34
•Jeremy Farrar et al; Manson’s Tropical Diseases, 23rd Edition; 2014; Ch.16
•http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious- diseases-related-to-travel/viral-hemorrhagic-fevers
•https://www.gov.uk/lassa-fever-origins-reservoirs-transmission-and- guidelines; Lassa fever: map of Nigeria 2012 and 2013 outbreaks
•WHO. International Travel and Health: Situation as on 1 January 2010. Geneva: WHO; 2010; Appendix 1a: Yellow Fever countries at risk, 2008
•http://www.flutrackers.com/forum/showthread.php?t=181234; reported outbreaks of Lassa fever as of 16th March, 2012
•http://www.cdc.gov/vhf/lassa/resources/distribution-map.html
•http://www.health.gov.ng/index.php/news-media/9- uncategorised/162-health-minister-debunks-outbreak-of-ebola-virus- in-nigeria-says-is-dengue-fever

102. References
•Daily Trust (Abuja) 2 APRIL 2014Nigeria: Govt-We Have Case of Dengue Fever, Not Ebola Virus
•Umoh et al; Prevalence of antibodies to Crimean haemorrhagicfever- Congo virus in cattle in northern Nigeria; Int. J. Zoonoses. 1983, Dec; 10(2):151-4
•Tomori O et al; The American journal of tropical medicine and hygiene;1988 Mar; 38(2): 407-10. Viral hemorrhagic fever antibodies in Nigerian populations. OLALEYE et al; Rev. sci. tech. Off. int. Epiz., 1996,Sept. 15(3),923-935; Rift Valley fever in Nigeria: infections in humans
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•Overview of the epidemiological situation of yellow fever in Africa; The yellow fever situation in Africa and South America in 2004, Weekly Epidemiological Record. Vol. 80, 29, 2005 249–256; http://www.who.int/wer
•Epidemiological data 2000-2004; http://www.who.int/csr/disease/yellowfev/surveillance/en/#figures

103. References
•http://www.thetraveldoctor.com/nigeria-medical-alert; CASES OF YELLOW FEVER IN NIGERIA, Mar 01, 2013
•D. E. Carey et al; DENGUE VIRUSES FROM FEBRILE PATIENTS IN NIGERIA, 1964-68; The Lancet, Volume 297, Issue 7690, Pages 105 - 106, 16 January 197
•David-West TS et al, (1974); Seroepidemiologyof Congo virus (related to the virus of Crimean haemorrhagicfever) in Nigeria. Bull WHO 51: 543- 546
•Idris A. N. et al; Sero-prevalence of dengue type-3 Virus among patients with febrile illnesses attending a tertiary hospital in Maiduguri, Nigeria; International Journal of Medicine and Medical Sciences; Vol. 5(12), pp. 560-563, December 2013
•http://ci.vbi.vt.edu/pathinfo/pathogens/Rift_Valley_Fever_virus.html
•http://vhfc.org/lassa_fever/virology
•Pathogenesis of the Viral Hemorrhagic Fevers, Annual Review of Pathology: Mechanisms of Disease; 2013; Vol. 8: 411-440
•https://microbewiki.kenyon.edu/index.php/Infection Mechanism of Genus Ebolavirus

104. References
•www.medscape.com/Clinical Aspects of Marburg Hemorrhagic Fever; Pathology & Pathophysiology; fig.3: Marburg hemorrhagic fever pathogenesis model
•http://wwwn.cdc.gov/ National Notifiable Diseases Surveillance System (NNDSS); 2011 Case Definition
•http://en.wikipedia.org/wiki/File:EbolaCycle.png
•http://virologytidbits.blogspot.com/2014/03/Molecular aspects of Ebola and other Filoviruses
•WHO: EBOLA RESPONSE ROADMAP UPDATE; 17, October, 2014
•http://www.who.int/mediacentre/factsheets/fs103/en/Ebola virus disease; September, 2013
•http://wwwnc.cdc.gov/travel/notices/watch/ebola-nigeria
•http://en.wikipedia.org/wiki/Ebola virus epidemic in West Africa