Viral Hemorrhagic Fever

Slide 1 · Viral hemorrhagic fever

Vascular injury, hemorrhage, immune evasion and organ pathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Classify the principal viral groups and modes of exposure.

Explain endothelial, cytokine-mediated and hemostatic injury.

Relate Ebola immune evasion to multiorgan morphology.

Differentiate the mechanism of severe dengue from filoviral disease.

Slide 3 · A multisystem syndrome, not one virus

Vascular damage is the unifying lesion.

The clinical syndrome may culminate in widespread hemorrhage and shock.

Different viral groups can produce overlapping manifestations.

Etiology and severity vary across infections.

Slide 4 · Clinical disease spans a broad severity range

Mild acute illness

Fever, myalgia, rash

Hematologic abnormalities

Deterioration and shock

Potential clinical spectrum—not an inevitable sequence for every patient

Slide 5 · Hemorrhage is not required at presentation

Early / mild spectrum

Fever and headache

Myalgia and rash

Neutropenia and thrombocytopenia

Severe spectrum

Hemorrhagic manifestations

Hemodynamic deterioration

Shock and multiorgan injury

Slide 6 · The implicated viruses are enveloped RNA viruses

Four groups are highlighted by Robbins.

Arenaviridae

Filoviridae

Bunyavirales

Flaviviridae

Slide 7 · Four viral groups: An etiologic orientation

Group named by Robbins

Anchor example or context

Teaching distinction

Arenaviridae

Lassa virus

Contact-associated spread may occur

Filoviridae

Ebola, Marburg

Prominent outbreaks and immune evasion

Bunyavirales

Crimean–Congo fever

Hemorrhagic phenotype can be prominent

Flaviviridae

Dengue

Severe disease includes plasma leakage

Slide 8 · Reservoir and vector ecology shape incidence

Animal / insect host

Geographic ecological range

Human exposure

Incidental human infection

Geographic risk follows the distribution of relevant hosts or vectors

Slide 9 · Humans are usually incidental hosts

Natural cycle

Virus circulates through animal or insect hosts.

Host distribution constrains potential exposure.

Human infection

Exposure to an infected host or vector.

Clinical disease may emerge after spillover.

Slide 10 · Rodents and bats are named animal exposures

Rodents and bats as typical infected animal hosts.

Animal exposure represents one pathway to human infection.

The importance of a given host depends on the particular virus.

Slide 11 · Mosquitoes and ticks are vector exposures

Mosquito-associated exposure

Infection through an infected mosquito vector

Dengue: Aedes mosquitoes

Tick-associated exposure

Infection through an infected tick vector

Not all hemorrhagic fever viruses share this route

Slide 12 · One label encompasses distinct exposure routes

Human viral hemorrhagic fever

Animal encounter

Rodents or bats

Vector encounter

Mosquitoes or ticks

Person-to-person contact

Selected viruses

Slide 13 · Selected viruses spread between people

Lassa virus

Crimean–Congo hemorrhagic fever virus

Ebola virus

Marburg virus

Slide 14 · Transmission can occur through contact

Symptomatic individual or cadaver

Contact with infectious material

Exposed individual

Potential secondary infection

Person-to-person spread is documented for selected viruses only

Slide 15 · Exposure history is mechanistically informative

Ecology-linked infection

Animal or arthropod exposure

Risk reflects host range

Humans often incidental

Contact-linked infection

Symptomatic cases / cadavers

Secondary spread possible

Outbreak amplification possible

Slide 16 · The same syndrome can arise by different mechanisms

Do not equate hemorrhage with a unique pathogen.

Virologic etiology must be distinguished from the clinical syndrome.

Exposure context helps organize the differential.

Overlapping manifestations do not prove identical tissue injury.

Slide 17 · Vascular injury is a central pathologic event

Viral infection

Blood-vessel injury / dysfunction

Hemorrhage and tissue hypoperfusion

Organ dysfunction and shock

Conceptual causal chain; Relative contributions vary by virus

Slide 18 · One pathway: Direct endothelial injury

Endothelial infection

Cell injury

Vascular dysfunction

Hemorrhagic manifestations

Direct injury is one mechanism discussed by Robbins

Slide 19 · A second pathway: Infected immune cells

Macrophage / dendritic-cell infection

Inflammatory cytokine production

Vascular injury and systemic effects

Severe clinical disease

Immune-cell-mediated injury is an alternative, not an exclusive route

Slide 20 · Direct and cytokine-mediated pathways converge

Direct route

Endothelial infection

Direct cell injury

Vascular damage

Indirect route

Macrophage or dendritic-cell infection

Inflammatory cytokines

Vascular damage

Slide 21 · Vascular injury links mechanism to phenotype

Vascular dysfunction

Hemorrhage

Petechiae / bleeding

Circulatory compromise

Shock

Tissue effects

Necrosis

Slide 22 · Immune-mediated tissue damage is a general principle

A host immune response may contribute to pathology as it attempts to control infection.

Cytokine-mediated inflammation is one mechanism of systemic injury.

In hemorrhagic fevers, infected macrophages and dendritic cells can participate in vascular damage.

Slide 23 · Clinical severity differs among infections

Common features

Vascular abnormalities

Hematologic derangements

Potential shock

Virus-specific variation

Dominant mechanism of injury

Prominence of hemorrhage

Extent and distribution of necrosis

Slide 24 · Ebola: Immune evasion promotes high viral burden

Filoviral evasion of innate immunity

Weakening of type I interferon action

Rapid viral replication

High levels of virus

VP24 and VP35 as mechanistic examples

Slide 25 · Type I interferon is the targeted antiviral axis

Viral proteins VP24 and VP35 interfere with type I IFN defenses.

Interferon-dependent responses are part of antiviral host defense.

Ebola inhibits steps in signaling and virus sensing.

The outcome favors ongoing viral replication.

Slide 26 · VP24 interferes with STAT1 nuclear translocation

Type I IFN response

STAT1-dependent signaling

VP24 blocks STAT1 nuclear entry

Impaired downstream antiviral response

Functional mechanism reported for Ebola VP24

Slide 27 · STAT1 localization matters to signaling

Intact response: Conceptual

STAT1 reaches the nucleus

Interferon-responsive gene expression can proceed

VP24 interference

STAT1 nuclear translocation is inhibited

Interferon-responsive signaling is blunted

Slide 28 · VP35 conceals double-stranded viral RNA

Viral double-stranded RNA

VP35 binds viral RNA

Reduced access to RIG-I sensing

Impaired innate detection

Cytoplasmic viral RNA recognition is impeded

Slide 29 · RIG-I is an RNA-sensing receptor

RIG-I helps detect viral RNA in the cytoplasm.

RIG-I as a detector bypassed by VP35.

Binding of viral RNA by VP35 prevents recognition.

Impaired sensing favors immune evasion.

Slide 30 · VP35 also inhibits interferon signaling

VP35: Sensing level

Binds double-stranded viral RNA

Prevents cytoplasmic RIG-I detection

VP35: Response level

Inhibits type I IFN signaling

Adds a second level of immune evasion

Slide 31 · VP24 and VP35 act at distinct checkpoints

Viral protein

Target or process

Functional consequence

VP24

STAT1 nuclear translocation

Blunted IFN-driven response

VP35

Double-stranded viral RNA

Reduced RIG-I detection

VP35

Type I IFN signaling

Additional signaling inhibition

Slide 32 · Combined immune evasion explains replication

Host viral sensing / response

VP35 + VP24 interfere

Antiviral control weakened

Rapid viral replication

Mechanistic interpretation drawn description

Slide 33 · Virulence is not synonymous with one lesion

Ebola combines immune evasion with disseminated viral replication.

Vascular damage can reflect infected cells and host-derived cytokines.

Clinical deterioration results from multiple converging pathologic effects.

Slide 34 · Early symptoms reflect a nonspecific viral illness

Fever and headache

Myalgia and rash

Neutropenia and thrombocytopenia

Slide 35 · Neutropenia is part of the described spectrum

A low neutrophil count may accompany early illness.

The finding is not specific for a hemorrhagic-fever pathogen.

Interpret it alongside exposure, symptoms and other cytopenias.

Its presence alone does not establish severe disease.

Slide 36 · Thrombocytopenia links clinical and bleeding biology

Reduction in platelets

Impaired primary hemostasis

Increased propensity for bleeding

Petechiae may appear

One contributor—not a sufficient explanation for all hemorrhage

Slide 37 · Deterioration may be abrupt

Initially apparent

Febrile illness

Myalgia, rash

Hematologic abnormalities

Potential subsequent deterioration

Sudden hemodynamic decline

Shock

Organ damage

Slide 38 · Shock reflects major circulatory compromise

Hemorrhagic fever can progress to shock.

Shock as a severe syndrome outcome.

Vascular damage and systemic injury are proximal pathologic themes.

Bleeding alone does not account for every hemodynamic effect.

Slide 39 · Hemorrhage has four interacting contributors

Hemorrhagic phenotype

Platelets

Low count or dysfunction

Vessels

Endothelial injury

Coagulation

Cytokine-associated DIC

Liver

Reduced clotting factors

Slide 40 · A low platelet count is only one mechanism

Quantitative defect

Thrombocytopenia

Fewer available platelets

Functional defect

Platelet dysfunction

Ineffective hemostatic activity

Slide 41 · Endothelial injury adds a vascular component

Infection / cytokine injury

Endothelial damage

Loss of vascular integrity

Bleeding / tissue injury

Injury can coexist with platelet and coagulation abnormalities

Slide 42 · Cytokine-induced DIC can amplify bleeding

Systemic inflammatory signaling

Coagulation activation

Microvascular thrombosis and consumption

Hemorrhage + ischemic injury

DIC is a systemic thrombohemorrhagic complication

Slide 43 · DIC combines thrombosis and consumption

Microvascular thrombosis

Small-vessel thrombi

Reduced tissue perfusion

Organ injury

Consumptive coagulopathy

Platelets and factors depleted

Secondary fibrinolysis

Bleeding tendency

Slide 44 · Hepatic necrosis can worsen coagulopathy

Injury of hepatocytes

Loss of hepatic synthetic capacity

Deficiency of clotting factors

Hemorrhagic tendency

Hepatic injury as a source of factor deficiency

Slide 45 · Bleeding is therefore multifactorial

Pathologic driver

Immediate consequence

Clinical correlate

Thrombocytopenia / dysfunction

Impaired platelet hemostasis

Petechiae / bleeding

Endothelial injury

Vascular damage

Hemorrhages

Cytokine-induced DIC

Factor / platelet consumption

Thrombohemorrhagic state

Hepatic injury

Factor deficiency

Coagulopathy

Slide 46 · Petechiae are a recognizable manifestation

Petechiae may reflect several concurrent lesions.

Platelet depletion or dysfunction

Endothelial injury

Coagulopathy associated with DIC or hepatic damage

Slide 47 · Extent of bleeding varies by infection

Prominent hemorrhage

Can be conspicuous in Crimean–Congo fever

Part of the pathologic phenotype

Severity interpretation

Visible hemorrhage may not be life-threatening

Overall risk also reflects shock and organ dysfunction

Slide 48 · Tissue necrosis can follow vascular injury

Vascular lesion / hemorrhage

Local circulatory failure

Tissue damage

Necrosis

Necrosis ranges from focal to massive across infections

Slide 49 · Necrotic extent and inflammation can diverge

Extent of necrosis

Mild and focal

Or extensive / massive

Inflammatory reaction

Often unexpectedly minimal

Do not equate scant inflammation with minor injury

Slide 50 · The pathology can be severe but paucicellular

Marked tissue damage may occur with little inflammation.

Necrosis is sometimes widespread.

The accompanying inflammatory infiltrate is often scant.

This dissociation is emphasized in Ebola virus infection.

Slide 51 · Ebola demonstrates multiorgan viral replication

Ebola infection

Liver

Hepatocellular necrosis

Spleen

Lymphocyte apoptosis

Other organs

Hemorrhage / replication

Slide 52 · Liver morphology: Hepatocellular necrosis

Liver injury

Viral replication in the organ

Hepatocellular necrosis

Histologic reaction

Relatively scant inflammation

Hepatic injury may aggravate coagulopathy

Slide 53 · Spleen morphology: Lymphocyte apoptosis

Ebola infection of splenic tissue

Lymphocyte apoptosis

Loss of splenic lymphocytes

Immune-tissue injury

Pathologic association in Ebola infection; Not a quantitative cell-count model

Slide 54 · Splenic viral replication involves several cells

Cell population

Source-described finding

Dendritic cells

Viral replication

Fibroblasts

Viral replication

Monocytes

Viral replication

Lymphocytes

Apoptosis

Slide 55 · Liver and spleen show different dominant lesions

Liver

Hepatocyte necrosis

Scant inflammation

Coagulation-factor deficiency may follow

Spleen

Lymphocyte apoptosis

Virus in dendritic cells, fibroblasts and monocytes

Immune-system injury

Slide 56 · Microscopy helps explain systemic consequences

Hepatocyte damage

Clotting-factor deficit

Hemorrhagic tendency

Potential hemodynamic effects

Morphology-to-physiology inference, paired with documented hepatic injury

Slide 57 · Ebola caused a major West African outbreak

2014–2016: Sierra Leone, Liberia and Guinea.

This as a major Ebola outbreak.

Human-to-human transmission drove rapid spread.

Historical outbreak context—not a present-day surveillance update.

Slide 58 · The 2014–2016 outbreak burden was substantial

Robbins-reported historical metric

Value

Cases reported to WHO

More than 28,000

Deaths reported to WHO

More than 11,000

Slide 59 · Ebola transmission can amplify an outbreak

Infected symptomatic person

Contact with infectious secretions

Secondary human infection

Further transmission

Explosive outbreak spread to person-to-person exposure

Slide 60 · Further Ebola outbreaks occurred in DRC

Several outbreaks in the Democratic Republic of Congo since 2017.

The outbreak pattern underscores the relevance of person-to-person contact.

This is historical source context; No current outbreak claim is implied.

Slide 61 · Ebola mortality varies across outbreaks

Approximately 40% mortality during a 2019 outbreak.

This figure is specific to the cited historical outbreak.

It should not be generalized to every filovirus or setting.

Mortality is distinct from the frequency or volume of hemorrhage.

Slide 62 · Ebola vaccines were used in outbreak control

Effective Ebola vaccines had been developed by the time covered.

The text notes deployment during outbreaks in Guinea and the Democratic Republic of Congo.

The source does not supply a current vaccination schedule or product-specific policy.

Slide 63 · Case application: Ebola pathology

A fatal febrile illness has hemorrhage, hepatocyte necrosis with little inflammation, and splenic lymphocyte apoptosis.

Which viral syndrome and two key tissue processes are most strongly suggested?

Interpretation: Ebola-associated hemorrhagic fever; Hepatocellular necrosis and splenic lymphocyte apoptosis.

Slide 64 · Dengue broadens the hemorrhagic-fever spectrum

Severe dengue can cause hemorrhage, plasma leakage and organ failure.

Dengue is an Aedes-transmitted flavivirus.

Clinical illness ranges from fever to severe disease.

The severe phenotype is not mechanistically identical to Ebola.

Slide 65 · Dengue transmission is mosquito-associated

Aedes mosquito

Dengue virus transmission

Human infection

Variable clinical severity

Robbins additionally notes less common prenatal/perinatal and transfusion routes

Slide 66 · Most dengue illness is not severe dengue

Common dengue illness

Fever and headache

Macular rash

Severe myalgia (“breakbone fever”)

Severe dengue

Bleeding / hepatitis

Plasma leakage and shock

Organ failure / respiratory distress

Slide 67 · Severe dengue involves vascular leakage

Dengue immune-pathogenic effects

Plasma leakage

Reduced effective circulatory volume

Shock / respiratory distress

Severe dengue mechanism

Slide 68 · Severe dengue has identifiable organ lesions

Organ or compartment

Reported pathologic consequence

Circulation

Plasma leakage / shock

Liver

Hepatitis or liver failure

Lung

Diffuse alveolar damage with hyaline membranes

Multiple organs

Widespread hemorrhages / dysfunction

Slide 69 · Four dengue serotypes complicate immunity

Infection with one serotype

Protection against that same serotype

Weak cross-reactive antibodies

Potential risk during a different-serotype infection

Cross-reactive response is not reliably protective

Slide 70 · Antibody-dependent enhancement is a proposed mechanism

Prior dengue infection / maternal antibodies

Cross-reactive weak antibodies

Fc receptor–mediated macrophage uptake

Increased viral infectivity

Antibody-dependent enhancement (ADE) as a contributing model

Slide 71 · Severe dengue is linked to heterotypic immunity

Prior same-serotype infection

Protective serotype-specific immunity

Not the classic ADE scenario

Different-serotype exposure

Weak cross-reactive antibodies

Can promote Fc-receptor uptake

Higher risk of severe dengue

Slide 72 · Maternal antibodies support the ADE model

Severe dengue also occurs in infants with maternal dengue antibodies.

This clinical observation is consistent with antibody-dependent enhancement.

The model remains a partial explanation of heterogeneous dengue severity.

Slide 73 · Dengue and Ebola differ in emphasis

Dimension

Ebola

Severe dengue

Agent group

Filoviridae

Flaviviridae

Highlighted immune mechanism

VP24 / VP35 interferon evasion

Cross-reactive antibody enhancement

Highlighted organ injury

Liver necrosis; splenic apoptosis

Hepatitis; alveolar damage

Relevant transmission

Human contact possible

Aedes mosquito vector

Slide 74 · Case application: Severe dengue

A patient with previous dengue infection develops fever, vascular leakage and shock after infection by a different dengue serotype.

What antibody-mediated mechanism is proposed to contribute to this severity?

Interpretation: Weak cross-reactive antibodies can facilitate Fc receptor–mediated uptake by macrophages (ADE).

Slide 75 · Mechanism-to-morphology review

Initiating mechanism

Pathologic effect

Clinical implication

Endothelial / cytokine injury

Vascular damage

Hemorrhage, shock

DIC / factor depletion

Hemostatic failure

Bleeding tendency

Ebola hepatocyte infection

Necrosis with scant inflammation

Organ injury / factor deficiency

Heterotypic dengue immunity

Enhanced macrophage uptake (proposed)

Risk of severe dengue

Slide 76 · Three distinctions to retain

A shared hemorrhagic phenotype does not imply a shared route of transmission.

Visible bleeding is only one consequence of vascular and systemic injury.

Ebola interferon evasion and dengue ADE describe different immune-pathogenic mechanisms.

Slide 77 · Source references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 8: Infectious Diseases, pp. 318–320.

Robbins, Cotran & Kumar. Chapter 8: Mechanisms of Viral Injury, p. 308.

Robbins, Cotran & Kumar. Chapter 4: Disseminated Intravascular Coagulation, p. 114; Chapter 14: Red Blood Cell and Bleeding Disorders, p. 608.