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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
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
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
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
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
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)
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
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
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
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
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
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)
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
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
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
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
•Oyewale Tomori; Rift valley fever virus infection in man in Nigeria; Journal of Medical Virology; Volume 5, Issue 4, pages 343–350, 1980
•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