This document provides an overview of viral hemorrhagic fever (VHF) and focuses on yellow fever. It classifies VHFs and describes their pathogenesis. Yellow fever is caused by a flavivirus transmitted by mosquitoes. It presents with fever, bleeding, liver and kidney damage. Diagnosis involves blood tests showing low platelets and clotting factors. Treatment focuses on supportive care; vaccines can prevent yellow fever.

1. MOHAMMED LUKMAN ABOLAJI
Department of Family Medicine,
Aminu Kano Teaching Hospital, Kano.
VIRAL HEAMORRAGIC FEVER

2. SYNOPSIS
 Over view of viral hemorrhagic fever
 Classification
 Pathogenesis
 Complications
 Yellow Fever
 Epidemiology
 Virology
 Transmission
 Pathophysiology
 Clinical Presentation
 Work Up Treatment
 Complication Prognosis

3. SYNOPSIS
Lassa Fever
 Epidemiology
 Pathophysiology
 Clinical Spectrum
 Case Definition
 Work Up
 Management
 Complications
 References

4. INTRODUCTION
 Viral hemorrhagic fevers (VHFs) are a group of
febrile illnesses caused by RNA viruses from
several viral families.
 These highly infectious viruses lead to a
potentially lethal disease syndrome characterized
by
o Fever, malaise, vomiting
o Mucosal and gastrointestinal (GI) bleeding

5. VHF
VHFs are of particular public health importance
because they:
 Spread within a hospital setting
 Have a high case-fatality rate
 Are difficult to recognize and detect rapidly
 Have no effective treatment
 Have a potential usage for bioterrorism
 Drain the healthcare system following an
outbreak

6. Virus Family Disease (Virus)
Natural
Distribution
Usual Source of Human
Infection
Incubation (Days)
Arenaviridae
Arenavirus Lassa fever Africa Rodent 5-16
Argentine HF (Junin) South America Rodent 7-14
Bolivian HF (Machupo) South America Rodent 9-15
Brazilian HF (Sabia) South America Rodent 7-14
Venezuelan HF (Guanarito) South America Rodent 7-14
Bunyaviridae
Phlebovirus Rift Valley fever Africa Mosquito 2-5
Nairovirus Crimean-Congo HF
Europe, Asia,
Africa
Tick 3-12
Hantavirus
Hemorrhagic fever with renal
syndrome, Hantavirus pulmonary
syndrome
Asia, Europe,
worldwide
Rodent 9-35
Filoviridae
Filovirus Marburg and Ebola Africa Fruit bat 2-216
Flaviviridae
Flavivirus Yellow fever
Tropical Africa,
South America
Mosquito 3-6
Dengue HF
Asia, Americas,
Africa
Mosquito 5-7

7. Pathogenesis
 The primary defect in patients with viral
hemorrhagic fever (VHF) is that of increased
vascular permeability.
 Hemorrhagic fever viruses have an affinity for the
vascular system, leading initially to signs such as
flushing, conjunctival injection, and petechial
hemorrhages, usually associated with fever and
myalgias.
 Later, frank mucous membrane hemorrhage may
occur, with accompanying hypotension, shock,
and circulatory collapse.
 The relative severity of the clinical presentation
may vary depending on the virus in question,
amount, and route of exposure.

9. VHF
 Hemorrhagic complications are multifactorial and
are related to hepatic damage, consumptive
coagulopathy and primary marrow injury to
megakaryocytes.
 Multisystem organ failure affecting the
hematopoietic, neurologic, and pulmonary
systems often accompanies the vascular
involvement.
 Case-fatality rates of patients with VHF vary from
less than 10% to 90%.
 Complications from VHF infection include
retinitis, orchitis, hepatitis, transverse myelitis,
and uveitis

10. YELLOW FEVER
 Yellow fever is the prototype of the Flavivirus genus of
the family Flaviviridae.
 Yellow fever circulates zoonotically as 5 genotypes:
 type IA in West and Central Africa,
 type IB in South America,
 type II in West Africa,
 type III in East Central Africa
 type IV in East Africa.
Types IA and IB virus are capable of urban
transmission between human beings by Aedes
aegypti.

11. YELLOW FEVER
 Yellow fever is transmitted by tree-hole breeding
mosquitoes (Haemagogus and Aedes species) during
the tropical wet season and early dry season.
 Large vaccination campaigns and A aegypti control
programs have decreased the incidence of yellow
fever worldwide.
 Nonetheless, yellow fever has reemerged across
Africa and South America, despite the availability of
an effective live-attenuated 17D vaccine.
 The populations at highest risk for the illness are
those in countries that lack the funding and
infrastructure to support a widespread vaccination
program.
 Flaviviruses, including those that cause yellow fever,
also have a potential use as biologic weapons. [9]

12. YELLOW FEVER

13. EPIDEMIOLOGY
 An estimated 200,000 cases of yellow fever occur
annually, with 30,000 deaths per year.
 Accurate incidence reporting is limited by the
occurrence of asymptomatic disease, underreporting
of the disease, and lack of diagnostic capabilities in
endemic areas.
 90% of reported cases occur in Africa, where Aaegypti
is rampant.
 Transmission occurs in largely unvaccinated
populations of sub-Saharan Africa.
 The countries at greatest risk lie within a band from
15° north to 10° south of the equator. [This region
includes 32 countries in sub-Saharan Africa.

14. EPIDEMIOLOGY

15. VIROLOGY
 Yellow fever virus is a positive-sense, single-
stranded, ribonucleic acid (RNA) ̶ enveloped
flavivirus with a diameter of about 50-60 nm.
 The virus is transmitted via the saliva of an
infected mosquito.
 Local replication of the virus takes place in the
skin and regional lymph nodes.
 Viremia and dissemination follows.

16. TRANSMISSION

17. PATHOPHYSIOLOGY
 The virus gains entrance through receptor-
mediated endocytosis. RNA synthesis occurs in
the cytoplasm and protein synthesis takes place
in the endoplasmic reticulum.
 Virions are released through the cell membrane.
 The infection quickly disseminates to the kidneys,
lymph nodes, spleen, and bone marrow.
 Renal failure occurs as renal tubules undergo
fatty change and eosinophilic degeneration, likely
due to direct viral effect, hypotension, and hepatic
involvement.

18. PATHOPHYSIOLOGY
 The liver is the most important organ affected in
yellow fever. The disease was labeled "yellow"
based on the profound jaundice observed in
affected individuals.
 Hepatocellular damage is characterized by
lobular steatosis, necrosis, and apoptosis with
subsequent formation of Councilman bodies
(degenerative eosinophilic hepatocytes).
]

19. PATHOPHYSIOLOGY
 The kidneys also undergo significant pathologic
changes. Albuminuria and renal insufficiency evolve
secondary to the prerenal component of yellow fever;
consequently, acute tubular necrosis develops in
advanced disease.
 Hemorrhage and erosion of the gastric mucosa lead
to hematemesis, popularly known as black vomit.
 Fatty infiltration of the myocardium, including the
conduction system, can lead to myocarditis and
arrhythmias.

20. PATHOPHYSIOLOGY
 Central nervous system (CNS) findings can be
attributed to cerebral edema and hemorrhages
compounded on metabolic disturbances.
 The bleeding diathesis of this disease is
secondary to reduced hepatic synthesis of
clotting factors, thrombocytopenia, and platelet
dysfunction.
 The terminal event of shock can be attributed to
a combination of direct parenchymal damage and
a systemic inflammatory response.

21. PATHOPHYSIOLOGY
 Finally, circulatory shock develops secondary to
cytokine storm, with evidence of increased levels
of
 interleukin (IL)-6,
 IL-1 receptor antagonist,
 interferon-inducible protein-10, and
 tumor necrosis factor (TNF)–alpha.
• Viral antigens are found diffusely in kidneys,
myocardium, and hepatocytes.
• In individuals who survive yellow fever, the
recovery is complete, with no residual fibrosis.

22. CLINICAL PRESENTATION
After an incubation period of 3-6 days,
 most individuals with yellow fever have a mild, self-
limiting illness consisting of fever, headache, myalgia,
and malaise.
 More serious illness develops in 15% of cases and
presents with the abrupt onset of general malaise,
fever, chills, headache, lower back pain, nausea, and
dizziness. .
 This stage is marked by vomiting, abdominal pain,
renal failure, and hemorrhage.
 Physical findings include pulse-fever dissociation
(Faget sign), conjunctival injection, and facial flushing
 Petechiae, ecchymoses, epistaxis, and bleeding from
gums and venipuncture sites can progress to melena,
hematemesis, and metrorrhagia.

23. CLINICAL PRESENTATION
 Other physical findings, such as scleral icterus,
jaundice, epigastric tenderness, and hepatomegaly,
develop as disease progresses.
 Disseminated intravascular coagulation (DIC),
induced by liver dysfunction, leads to consumption of
platelets and clotting factors.
 Ischemia primarily affects the kidneys and central
nervous system leading to altered mental status
and/or signs of volume overload (jugular venous
distension, presence of rales, and S3 gallop, or
edema
 In late stages of disease, shock and multiorgan
dysfunction syndrome (MODS) dominate the clinical
picture..
 Tachypnea and hypoxia with impending respiratory
failure may develop as a consequence of sepsis and
acute respiratory distress syndrome (ARDS).

24. WORK UP
 Full blood count
 Leukopenia with relative neutropenia
 Thrombocytopenia as part of a consumptive
coagulopathy
 Initial hemoconcentration
 Subsequent hemorrhage and hemodilution resulting
in decreasing complete blood cell counts
 Coagulation studies
 Reduced fibrinogen and clotting factors II, V, VII, VIII,
IX, and X and the presence of fibrin split products
indicates DIC
 Decreased synthesis of clotting factors may result in
an elevated prothrombin time
 Prolonged clotting times may be found

25. WORK UP
 Chemistries
 Elevated ALT ,AST
 Elevated creatinine
 Hypoglycemia secondary to hepatic dysfunction
 Metabolic acidosis
 Urinalysis
 Elevated urinary protein levels
 Elevated urobilinogen levels

26. WORK UP
 CXR - pulmonary edema, secondary bacterial pulmonary
infections,
 CT intracranial hemorrhage .
 ECG -prolongation of PR and QT intervals. Arrhythmias
are commonly due to myocarditis. ST-T wave
abnormalities.
 Electrolyte abnormalities

27. WORK UP
 Rapid detection methods
 Detection of yellow fever antigen using monoclonal
enzyme immunoassay in serum specimens
 Detection of viral genome sequences in tissue or in
blood or other body fluid using PCR assay
 Serologic testing methods
 ELISA. Confirmation is difficult because of cross-
reactivity with other viruses, particularly in Africa,
where multiple flaviviruses exist]
 Immunoglobulin M (IgM) antibody-capture enzyme-
linked immunosorbent assay (MAC-ELISA) is used to
detect the specific IgM for yellow fever; a single
positive serum titer is diagnostic.

28. MANAGEMENT
 No specific treatment exists for yellow fever;
however, supportive care is critical
 vasoactive medications,
 fluid resuscitation,
 ventilator management, and
 treatment of DIC, hemorrhage, secondary
infections, and renal and hepatic dysfunction.
 Patient should be isolated with mosquito netting
in areas with potential vector mosquitoes.

29. COMPLICATIONS
 Liver failure
 Renal failure
 Pulmonary edema
 Myocarditis
 Secondary bacterial infections
 Hemorrhage or disseminated intravascular
coagulation
 Encephalitis (rare)
 Shock or death
 Secondary bacterial infections are frequent
complications in patients who survive the critical
period of illness.

30. PROGNOSIS
 Yellow fever ranges in severity from a self-limited
infection to life-threatening hemorrhagic fever.
 About 15-25% of affected individuals develop a more
severe phase of disease that involves fever, jaundice,
and liver and renal failure.
 Case-fatality rates in South America are reportedly
higher than in West Africa.
 Mortality is a function of patient susceptibility and of
the virulence of the infecting strain.
 The mortality risk in patients who present in the toxic
stage of yellow fever is up to 50%.
 Infancy and age older than 50 years is associated
with increased severity of illness and lethality.

31. VACCINATION
 Prevention remains the cornerstone to minimizing the
risk of yellow fever.
 Single dose of the live attenuated virus (17D) vaccine
 lifelong immunity in 95% of patients
 A booster dose recommended for the following high-
risk populations after 10 years.
 Poor financing remains a problem and a major reason
for low vaccination rates among residents of endemic
areas

32. LASSA FEVER
 Lassa fever first appeared in Lassa, Nigeria, in 1969.
It has been found in all countries of West Africa and is
a significant public health problem in endemic areas.
 In populations studied, Lassa fever accounts for 5-
14% of hospitalized febrile illnesses.
 Its natural reservoir is a small rodent of the genus
Mastomys known as “multimammate rat” whose
virus-containing excreta is the source of transmission.

33. EPIDEMIOLOGY

34. LASSA FEVER
 Lassa virus has an unusual potential for human-to-
human spread and has
 resulted in many small epidemics in Nigeria, Sierra
Leone, and Liberia.
 Medical workers in Africa and the United States have
also contracted the
 disease.
 Patients with acute Lassa fever have been
transported by international
 aircraft, necessitating extensive surveillance among
passengers and crews.

35. LASSA FEVER VIRUS

36. LASSA FEVER
 Environmental conditions in Nigeria support the
natural reservoirs of Lassa fever virus and cases
of person to person transmission is presently
been reported.

37. PATHOPHYSIOLOGY
• Vascular damage
 Disorders of coagulation
 Immunological impairment
 End organ damage

38. CLINICAL SPECTRUM
 A spectrum from asymptomatic (80%) to severe
disease, characterized by loss of plasma from small
vessels (capillaryleakage) and bleeding.
 Liver involvement is common, including jaundice.
 Clinically, these infections can be confused with other
causes of febrile illness and a high index of suspicion
is needful.

39. PRESENTATION
 • Incubation Period Lassa Fever 10 (3 – 21)
days
 Common symptoms:
 Fever, malaise, fatigue and body aches.
 Nausea; vomiting; diarrhoea; headache
 Diarrhoea; productive cough; proteinuria; low BP
anaemia.
 Facial edema; convulsions; mucosal bleeding
(mouth, nose, eyes);
 Internal bleeding; confusion; disorientation; coma
and death.

40. CASE DEFINITION
 Fever >380C for < 3weeks AND
 Absence of signs of local inflammation (ie. the
sickness is systemic) AND
 Absence of a clinical response after 48hr of anti-
malaria treatment &/OR a broad spectrum
antibiotic AND
 Two major or one major and two minor signs:

41. CASE DEFINITION CRITERIA
 MAJOR SIGNS
 Bleeding
 Swollen neck or face
 Conjunctivitis or
subconjunctival
 Haemorrhage Spontaneous
abortion
 Petechial or haemorrhagic
rash
 New onset tinnitus or altered
hearing
 Persistent hypotension
 Raised transaminases esp.
AST>ALT
 Known exposure to a Lassa
fever case
 MINOR SIGNS
 Headache
 Sore throat
 Vomiting
 Diffuse abdominal pain/
tenderness
 Chest/ retrosternal pain
 Cough
 Diarrhea
 Generalized myalgia or
arthralgia
 Profuse weakness
 Proteinuria
 Leucopenia < 4000/L

42. WORK UP
 • FBC:-mild Leucopaenia and Lymphopaenia / Mild
thrombocytopaenia
 Urinalysis: Proteinuria
 Serum: High BUN
 High liver transaminases (AST>150 U/L)
 Definitive Tests:
 IgM ELISA, IgG ** (** occurs late)
 Lassa Virus Antigen
 RT-PCR (3rd day)
 Viral culture (7- 10 days)
 Post mortem – Immunohistochemistry on tissue
specimens

43. MANAGEMENT
 Isolation and Infection control – barrier nursing
 • Ribavirin : shown to reduce mortality 5-10
fold if given intravenously within 6 days of the
clinical illness.
 Loading dose: IV 30mg/kg (max. 2g), followed by
15mg/kg 6hrly for 4days (max. 1g), then 7.5mg/kg
(max. 500mg) 8 hrly for 6 days
 Dilute Ribavirin in 150mls of 0.9%NS and infuse
slowly.
 no convincing evidence that oral rivabirin delays
or prevents Lassa fever

44. MANAGEMENT

45. COMPLICATIONS
 Deafness (1/3 of cases), permanent
 Spontaneous abortion
 Hypovolemic shock
 Respiratory distress resulting from airway
obstruction, pleural effusion, or congestive heart
failure may occur.
 10–20% of patients experience late neurologic
involvement characterized by intention tremor of the
tongue and associated speech abnormalities. In
severe cases, there may be intention tremors of the
extremities, seizures, and delirium. The CSF is
normal.
 Anuria
 Death

46. REFRENCES
 Cleri DJ, Ricketti AJ, Porwancher RB, Ramos-
Bonner LS, Vernaleo JR. Viral hemorrhagic
fevers: current status of endemic disease and
strategies for control. Infect Dis Clin North Am.
2006 Jun. 20(2):359-93.
 Quaresma JA, Pagliari C, Medeiros DB, Duarte
MI, Vasconcelos PF. Immunity and immune
response, pathology and pathologic changes:
progress and challenges in the immunopathology
of yellow fever. Rev Med Virol. 2013 Sep.
23(5):305-18.
 Barnett ED, Wilder-Smith A, Wilson ME. Yellow
fever vaccines and international travelers. Expert
Rev Vaccines. 2008 Jul. 7(5):579-87.

47. REFRENCES
 LASSA FEVER OUTBREAK IN NIGERIA Daily
Situation Report No. 11: 19 January, 2016 Nigeria
Centre for Disease
Control(NCDC).http://reliefweb.int/sites/reliefweb.i
nt/files/resources/Lassa11.pdf
 Centers for Disease Control. Lassa Fever. Fact
sheet.
http://www.cdc.gov/vhf/lassa/pdf/factsheet.pdf

48. THANK YOU FOR YOUR
ATTENSION