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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_182_библиотеки_им_акад_М_И_Перельмана.pdf
SEVERE ACUTE RESPIRATORY SYNDROME (SARS)
SARS-CoV infections exhibit findings consistent with
acute exudate diffuse alveolar damage, a pattern of
Viral Infections: Viral Infections Requiring Ancillary Tests
lung damage associated with many infectious and
noninfectious etiologies.
TERMINOLOGY
Definitions
Latin: "corona" (crown, halo), as in surface projections
on EM: Coronaviridae family
ETIOLOGY/PATHOGENESIS
Infectious Agents
Viral illness transmitted by respiratory droplets
Virus infects tracheobronchial and alveolar epithelial
cells and immune cells; binds host receptor
angiotensin-converting enzyme 2 (ACE2)
Symptoms due to direct viral cytopathic effects,
including apoptosis, hyperinduction of chemokines
and cytokines, insufficient interferon reaction, and
compromised cellular immune response
Incubation period: 2-10 days
Contagious period: Start of symptoms until 10 days
after resolution
CLINICAL ISSUES
Epidemiology
2002-2003 outbreak originating in Asia resulted in >
8,000 cases and 744 deaths in 29 countries worldwide
No cases reported since 2004
Site
Lungs
Presentation
Early symptoms of fever, headache, and myalgias
Days 2-7: Nonproductive cough and dyspnea
Day 7-10: Radiographically confirmed pneumonia
I
Laboratory Tests
CBC: Lymphopenia (70-90%)
2
This CXR shows diffuse bilateral ground-glass opacities
in a patient with SARS. Focal lower lung opacities are
the most common finding, but radiographs are normal in
20% of symptomatic patients. (From DI2: Chest.)
Serology: Enzyme immunoassay (EIA)
RT-PCR (respiratory samples, stool, plasma, serum)
Treatment
Supportive (antipyretics, oxygen, ventilation)
Isolation in negative pressure rooms
Prognosis
Overall fatality: 10% (> 50% in persons older than 60)
IMAGE FINDINGS
Radiographic Findings
Nonspecific: Normal at presentation (20%), focal
opacity in peripheral middle and lower lung zones
(40%), multifocal opacities/consolidations (27%), or
diffuse consolidation (14%)
MICROBIOLOGY
Virus Features
Enveloped, single-strand RNA virus
80-90 nm in size, helical nucleocapsid
29,727 nucleotides (13 genes; 14 proteins)
Culture
Grows in Vero-E6 cells (requires BSL-3 facility)
MICROSCOPIC PATHOLOGY
Histologic Features
Lungs
Acute exudative diffuse alveolar damage (DAD):
Edema, hyaline membranes, alveolar collapse,
desquamation of alveolar epithelial cells, and fibrous
tissue in alveolar space
After 10-14 days: Interstitial/airspace fibrosis and
pneumocyte hyperplasia
36
SEVERE ACUTE RESPIRATORY SYNDROME (SARS)
Key Facts
Etiology
Viral illness transmitted by respiratory droplets
Clinical Issues
8,000 cases and 744 deaths (2002-2003 outbreak)
Presentation: Fever, headache, and myalgias,
followed by nonproductive cough, dyspnea, and
radiographically confirmed pneumonia
Labs: Serology, RT-PCR, viral isolation
Supportive therapy: Antipyretics, oxygen, ventilation
ANCILLARY TESTS
Immunohistochemistry
Staining of alveolar epithelial cells and macrophages
using anti-SARS-associated coronavirus (SARS-CoV)
antibodies
In Situ Hybridization
Staining of pneumocytes, lymphocytes, and
macrophages
Electron Microscopy
Coronaviruses with large granular cytoplasmic
areas, nucleocapsid inclusions, and typical doublemembrane vesicles
DIFFERENTIAL DIAGNOSIS
Other Causes of Severe Respiratory Disease/
DAD
Viral pneumonia (other coronaviruses, influenza A or
B, respiratory syncytial virus, cytomegalovirus, herpes
simplex virus, Middle Eastern respiratory syndrome)
Negative SARS-CoV serology, viral proteins, or
nucleic acids &/or positive serology for other agents
Mycoplasma pneumoniae pneumonia, Mycobacterium
avium complex pneumonia, cryptococcal pneumonia,
sepsis
Positive Gram, MSS, or AFB stains
Overall fatality 10% (> 50% in persons older than 60)
Microscopic Pathology
Acute exudative DAD: Edema, hyaline membranes,
alveolar collapse, desquamation of alveolar epithelial
cells, and fibrous tissue in alveolar space
After 10-14 days: Interstitial/airspace fibrosis and
pneumocyte hyperplasia
Ancillary tests: IHC (alveolar epithelial cells and
macrophages), ISH, and EM
Noninfectious complications of transplantation,
connective tissue diseases, acute exacerbation of
idiopathic pulmonary fibrosis, drugs, radiation
therapy, acute interstitial pneumonia
Low clinical suspicion for SARS, negative SARS-CoV
serology, viral proteins or nucleic acids
Acute interstitial pneumonia
No known cause
DIAGNOSTIC CHECKLIST
CDC Guidelines
Radiologically confirmed pneumonia or acute
respiratory distress syndrome of unknown etiology
With travel to southern China, Hong Kong, Taiwan
&/or employment exposure to SARS-CoV in 10 days
before illness onset
Or unexplained cluster of cases of atypical
pneumonia without an alternative diagnosis
SELECTED REFERENCES
1. Graham RL et al: A decade after SARS: strategies for
controlling emerging coronaviruses. Nat Rev Microbiol.
11(12):836-48, 2013
2. Gu J et al: Pathology and pathogenesis of severe acute
respiratory syndrome. Am J Pathol. 170(4):1136-47, 2007
Viral Infections: Viral Infections Requiring Ancillary Tests
IMAGE GALLERY
(Left) Diffuse alveolar damage is characterized by edema, desquamation of alveolar epithelial cells, hyaline membranes, alveolar collapse, and
fibrous tissue in alveolar space. (Center) Hyaline membranes are a prominent feature of diffuse alveolar damage, seen in SARS-CoV infection.
(Right) As diffuse alveolar damage begins to organize over a period of days, the alveolar spaces are variably filled with edema, macrophages,
and fibroblasts.
I
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37
PRION DISEASES
Severe spongiform degeneration , marked neuronal
loss, and reactive gliosis are present in the cerebral
Viral Infections: Viral Infections Requiring Ancillary Tests
cortex of a patient with sporadic Creutzfeldt-Jakob disease
(sCJD).
TERMINOLOGY
Synonyms
Transmissible spongiform encephalopathy (TSE)
Definitions
Prion: Derived from term "proteinaceous infectious
particle"
Human Prion Diseases
Creutzfeldt-Jakob disease (CJD)
Variant Creutzfeldt-Jakob disease (vCJD)
Gerstmann-Straussler-Scheinker syndrome (GSS)
Fatal familial insomnia (FFI)
Kuru
Animal Prion Diseases
Bovine spongiform encephalopathy (BSE; "mad cow
disease"): Cattle
Chronic wasting disease (CWD): Deer, elk
Scrapie: Sheep
ETIOLOGY/PATHOGENESIS
Infectious Agents
Prions are infectious proteinaceous molecules devoid
of coding nucleic acids
Replication is by self-templated refolding mechanism
-helical, protease-sensitive, endogenously
expressed, "cellular" prion protein (PrP[C]) is
transformed into -sheet-rich, protease-resistant,
disease-associated "scrapie" isoform (PrP[Sc])
Initial molecule of PrP(Sc) either forms sporadically or
due to autosomal dominant mutations in PRNP gene,
or is acquired through exposure to prion-infected
tissues or improperly decontaminated instruments
I
Incubation period is years to decades
PrP(Sc) &/or soluble intermediates cause symptoms
through neuronal dysfunction and cell death
2
Immunohistochemical staining with anti-PrP antibody
(3F4) shows a fine, granular synaptic pattern ,
characteristic of sCJD MM1 and MV1. (Courtesy M.
Cohen, MD.)
CLINICAL ISSUES
Epidemiology
Overall incidence: 1 per million/year (~ 300 cases
annually in USA)
85% of cases are sporadic (sCJD); average: 60 years old
Phenotypes determined by strain (type 1, type 2)
and codon 129 genotype (MM, VV, MV)
Majority present with rapidly progressive dementia
(MM1, MV1; ~ 2/3) or ataxia (VV2, MV2; ~ 1/3)
10-15% of cases are familial (fCJD, GSS, FFI); 40-50
years old
> 20 disease-associated mutations identified (point
mutations, premature stop codons, and octapeptide
repeat insertions)
M129V polymorphism determines FFI or fCJD
phenotype, respectively, in context of D178N
mutation
< 5% of cases are infectious (kuru, vCJD) or iatrogenic
(iCJD)
Consumption of prion-infected tissues; exposure
to prion-contaminated growth hormones, corneal
transplants, dural grafts, or inadequately sterilized
surgical instruments
All cases of vCJD are codon 129MM; 20-30 years old
Site
Brain
Presentation
Rapidly progressive dementia, ataxia, myoclonus,
cortical blindness, sleep disturbances
Order of presentation and severity of symptoms vary
with specific prion disease and strain
Laboratory Tests
EEG: Periodic sharp wave complexes (PSWCs) triphasic
or sharp wave bursts every 0.52.0 seconds
CSF: 14-3-3 and tau proteins
38
PRION DISEASES
Etiology
Prions are infectious proteinaceous molecules that
replicate through self-templated refolding mechanism
(PrP[C] PrP[Sc]) and cause symptoms through
neuronal dysfunction and cell death
Clinical Issues
Incidence: ~ 1 per million/year; 85% of cases are
sporadic (sCJD), 10-15% of cases are familial (fCJD,
GSS, FFI), and < 5% of cases are infectious (kuru,
vCJD) or iatrogenic (iCJD)
Presentation: Rapidly progressive dementia, ataxia,
myoclonus, cortical blindness, sleep disturbances
(order and severity vary with specific disease and
strain)
Laboratory tests: EEG, CSF (14-3-3 and tau proteins),
MR (DWI and FLAIR)
Real-time quaking-induced conversion (RT-QuIC),
protein misfolding cyclic amplification (PMCA), and
conformation-dependent immunoassay (CDI) are
newly developed assays that directly test for PrP(Sc)
Natural History
Progressive fatal neurodegenerative illness
Treatment
No effective treatments or cures
Brain biopsy only undertaken to rule out other
potentially treatable conditions
Prognosis
Death typically within 1 year of onset of symptoms
IMAGE FINDINGS
MR
Diffusion-weighted imaging (DWI): Hyperintensity
of cerebral cortex (cortical ribboning), striatum, and
thalamus (high sensitivity and specificity for sCJD)
Fluid-attenuated inversion recovery imaging (FLAIR):
Pulvinar sign (most sensitive for vCJD)
MICROBIOLOGY
Prion Features
Aggregates of -sheet-rich isoform of PRNP gene
product PrP(Sc) arranged in amyloid fibers and plaques
Strains have identical protein sequences but differ
in affected brain areas, incubation times, and
biochemical properties
Differences in protein sequences and structures
(species barrier) determines whether prion can spread
from 1 species to another (i.e., BSE vCJD)
Culture
No role for culture
Key Facts
Brain tissue necessary for definitive diagnosis; biopsy
only to rule out potentially treatable conditions
Treatment/prognosis: No effective treatments or
cures; death typically occurs within 1 year of onset of
symptoms
Microscopic Pathology
Spongiform degeneration, marked neuronal loss,
and reactive gliosis (affected areas vary with specific
disease and strain)
IHC: Aggregates stain with anti-PrP antibody 3F4
Ancillary Tests
Western blot: Proteinase-resistant fragments
Sequencing: PRNP disease-associated mutations
MACROSCOPIC FEATURES
Brain
Can be grossly normal or exhibit atrophy of cerebral
cortex, neostriatum, and cerebellar cortex
MICROSCOPIC PATHOLOGY
Histologic Features
sCJD MM1/MV1
sCJD VV2/MV2
Kuru
vCJD
GSS
ANCILLARY TESTS
Immunohistochemistry
Monoclonal anti-PrP antibody 3F4
sCJD MM1/MV1
Viral Infections: Viral Infections Requiring Ancillary Tests
Fine, full-thickness spongiform degeneration with
astrocytosis throughout neocortex and basal ganglia,
most severe in occipital lobes; spares hippocampus
Cortical spongiform degeneration in deep laminae
(layers 5 and 6); hippocampal involvement;
corpus striatum, substantia nigra, and cerebellar
degeneration
Gross cerebellar atrophy; absence of inflammation
Intraneuronal vacuoles in medial frontal lobes,
corpora striatum, thalami, and cerebellum
Amyloid plaques with starburst morphology within
granular cell layer of cerebellum
Florid plaques consisting of kuru plaque-like stamen
surrounded by spongiform petals in cerebellar and
cerebral cortices
Severe spongiform degeneration within corpora
striatum and marked neuronal loss with gliosis in
posterior thalami
Multicentric amyloid plaques within both cerebral
and cerebellar cortices
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39
PRION DISEASES
A
Fine, granular reactivity with synaptic pattern
sCJD VV2/MV2
Kuru plaques within granule cell layer; plaque-like
reactivity in neocortex, basal ganglia, cerebellum,
and substantia nigra; perineuronal pattern in
hippocampus and cerebral cortex
Electron Microscopy
Fibrils and plaques (limited diagnostic utility)
Western Blot
Fresh brain tissue (gold standard)
Strain and familial mutation information gained from
banding pattern of proteinase K-resistant fragments
DNA Sequencing
Identifies PRNP disease-associated mutations and
M129V genotype
Viral Infections: Viral Infections Requiring Ancillary Tests
DIFFERENTIAL DIAGNOSIS
Rapidly Progressive Dementia
Autoimmune/paraneoplastic encephalitis, primary
angiitis of nervous system, and lymphomatous CNS
disease (primary and intravascular)
May present with rapidly progressive dementia,
elevated CSF 14-3-3 protein
Lacks spongiform degeneration, protein aggregates
stained by PrP IHC, or protease-resistant bands on
Western blot
Dementia With Protein Aggregates
Alzheimer disease, Parkinson disease, Huntington
disease, frontotemporal dementia, tauopathies, etc.
May present with dementia, ataxia, or sleep
disturbances
Typically longer time course (years to decades),
characteristic gross/radiologic signs of atrophy,
disease-specific protein aggregates (i.e., -amyloid,
tau, -synuclein, TDP-43)
Lacks spongiform degeneration, protein aggregates
stained by PrP IHC, or protease-resistant bands on
Western blot
ltered Mental Status With Vacuoles
Fixation artifact, cerebral edema, and status spongiosis
Vacuoles lack discrete round to oval-shaped,
punched-out appearance of spongiform
degeneration
Lacks protein aggregates stained by PrP IHC,
protease-resistant bands on Western blot
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
Freeze fresh tissue and store at -80 C for biochemical
and mutational testing for definitive diagnosis and
determination of sporadic, familial, or infectious
I
etiology
Treat formalin-fixed tissue with formic acid prior to
tissue processing and paraffin embedding
2
National Prion Disease Pathology Surveillance Center
(NPDPSC) offers most current protocols
STAGING
CDC Diagnostic Criteria for CreutzfeldtJakob Disease (2010)
sCJD
Definite: Histologically proven CJD (autopsy or
biopsy), positive IHC, Western blot confirmed
protease-resistant PrP, or presence of scrapieassociated fibrils
Probable
Rapidly progressive dementia
2 of 4 clinical features: myoclonus, visual, or
cerebellar signs, pyramidal/extrapyramidal signs,
akinetic mutism
1 positive laboratory test: EEG, 14-3-3, or MR
No alternative diagnoses from routine work-up
Possible
Progressive dementia
2 of 4 clinical features
0 positive laboratory tests: EEG, 14-3-3, or MR
Duration of illness < 2 years
No alternative diagnoses from routine work-up
iCJD
Progressive cerebellar syndrome in recipient of
human cadaveric-derived pituitary hormone or
sporadic CJD with recognized exposure risk
fCJD
Definite or probable CJD plus definite or probable
CJD in 1st-degree relative
Neuropsychiatric disorder plus disease-specific PrP
gene mutation
SELECTED REFERENCES
1. CDC’s Diagnostic Criteria for Creutzfelt-Jakob Disease
(CJD), 2010. Centers for Disease Control and Prevention
website. http://www.cdc.gov/ncidod/dvrd/cjd/
diagnostic_criteria.html. Updated August 26, 2010.
Accessed October 8, 2014
2. The National Prion Disease Pathology Surveillance Center.
http://www.cjdsurveillance.com. Accessed October 8, 2014
3. Forloni G et al: Therapy in prion diseases. Curr Top Med
Chem. 13(19):2465-76, 2013
4. Ironside JW: Variant Creutzfeldt-Jakob disease: an update.
Folia Neuropathol. 50(1):50-6, 2012
5. Puoti G et al: Sporadic human prion diseases: molecular
insights and diagnosis. Lancet Neurol. 11(7):618-28, 2012
6. Saunders SE et al: Occurrence, transmission, and zoonotic
potential of chronic wasting disease. Emerg Infect Dis.
18(3):369-76, 2012
7. Chitravas N et al: Treatable neurological disorders
misdiagnosed as Creutzfeldt-Jakob disease. Ann Neurol.
70(3):437-44, 2011
8. Mastrianni JA: The genetics of prion diseases. Genet Med.
12(4):187-95, 2010
9. Rutala WA et al: Guideline for disinfection and sterilization
of prion-contaminated medical instruments. Infect Control
Hosp Epidemiol. 31(2):107-17, 2010
10. Prusiner SB: Prions. Proc Natl Acad Sci U S A.
95(23):13363-83, 1998
40
PRION DISEASES
g
g
A
g
Gross, Radiologic, Microscopic, and Biochemical Features
Viral Infections: Viral Infections Requiring Ancillary Tests
(Left) Although no specific
ross pathological features
are associated with CJD,
eneralized cerebral atrophy
may be seen in individuals
with a prolonged clinical
course. (Right) Axial DWI
MR shows asymmetric
diffusion restriction in the
caudate nuclei and putamen.
symmetric hyperintensity
is present in the frontal
and temporal lobe cortical
ribbons , typical of sCJD.
(Courtesy N. Fischbein,
MD.)
(Left) Moderate to severe
spongiform degeneration
is present in the molecular
layer of the cerebellum,
characterized by round to
oval vacuoles with a sharply
demarcated, punched-out
appearance, typical of sCJD.
(Right) Western blot from
a patient with VV2 sCJD
shows protease K-resistant
fragments, diagnostic of
CJD (predigestion [lane
1], dilutions post digestion
[lanes 2-4], type 1 control
[lane 5], type 2 control [lane
6]). (Courtesy M. Cohen,
MD.)
(Left) Florid plaques
, severe spongiform
degeneration , marked
neuronal loss, and
liosis are characteristic
features of variant CJD
(vCJD). (Courtesy M.
Cohen, MD.) (Right)
Immunohistochemical
staining with anti-PrP
antibody (3F4) highlights
florid plaques of vCJD.
(Courtesy M. Cohen, MD.)
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EBOLA, MARBURG, AND OTHER HEMORRHAGIC FEVER VIRUS INFECTIONS
Ebola virus infection results in hepatocyte necrosis and
apoptosis with frequent oval to filamentous, eosinophilic
cytoplasmic inclusions .
Viral Infections: Viral Infections Requiring Ancillary Tests
TERMINOLOGY
Synonyms
Viral hemorrhagic fever (VHF)
Definitions
Severe febrile illness with abnormal vascular
regulation/damage
EBOLA AND MARBURG VIRUSES
Etiology/Pathogenesis
Viral infections transmitted through direct contact
with infected tissues or bodily fluids (blood, saliva,
mucus, vomit, urine, and feces)
Virus replicates in monocytes, macrophages, and
dendritic cells; disseminates to lymph nodes, liver,
spleen
Rousettus aegyptiacus (fruit bat) is reservoir for Marburg
virus; other fruit bats likely to be reservoir for Ebola
viruses
Index cases associated with animal exposure
(nonhuman primates, pigs, bats)
Asymptomatic incubation period: 2-21 days (average
8-10 days) after exposure
Infectious period: 21 days from onset of symptoms
Microbiology
Filoviridae family: Derived from "filo" (thread)
Marburg virus (MARV)
Ebola virus (EBOV)
Sudan virus (SUDV)
Ta Forest virus (TAFV)
Bundibugyo virus (BVBV)
Reston virus (RESTV): No reported disease in
humans
I
Viral features
Enveloped, single-strand RNA virus
2
This transmission electron micrograph of an Ebola
virus virion demonstrates the filamentous structure
characteristic of filoviruses. (Courtesy F. Murphy, CDC/
PHIL.)
80 nm diameter x 14,000 nm in length, with helical
nucleocapsid
19,000 nucleotide genome (7 genes)
Culture
Grows in Vero and Vero E6 cells
Requires BSL-4 facility
Presentation
Early: Fever, headache, myalgia, diarrhea, vomiting,
abdominal pain
Terminal state: Obtundation, tachypnea, anuria,
shock, lowered body temperature
Hemorrhagic manifestations in 30% of patients
Petechial rash, conjunctival bleeding, epistaxis,
melena, hematemesis
Laboratory Tests
WBC, lymphocytes, platelets; AST/ALT; PTT, TT
RT-PCR (blood)
Serology (antigen capture, IgM, IgG)
Virus isolation (blood)
Natural History
Some have transient flu-like symptoms, mild
coagulopathy, thrombocytopenia, leukocytosis, and
full recovery
Majority develop severe illness, hemorrhage, DIC,
shock, and death (~ 10 days after onset of symptoms)
Treatment
Prevention
Phase 1 vaccine trials underway using VSV and
adenovirus-vectored constructs
Avoid direct contact with blood or body fluids from
infected patients or animals
Post exposure prophylaxis
No specific therapy
Monitor for fever, other signs/symptoms for 21 days
Symptomatic
No FDA-approved viral treatments available
42
EBOLA, MARBURG, AND OTHER HEMORRHAGIC FEVER VIRUS INFECTIONS
Viral Infections: Viral Infections Requiring Ancillary Tests
Symptomatic treatment including IV fluids,
maintaining oxygen status and blood pressure, and
treating additional infections
Strict isolation and quarantine to contain outbreaks
Prognosis
Ebola: Mortality rate: 25-90%
Survivors develop antibodies that last > 10 years
May have joint or vision problems
Marburg: Mortality rate 23-90%
Macroscopic Findings
Petechiae, ecchymoses of skin, mucous membranes,
visceral organs; large effusions
Microscopic Findings
Multifocal necrosis in liver, spleen, kidneys, testes, and
ovaries with minimal inflammatory response
Liver: Hepatocyte necrosis, apoptosis, microvesicular
steatosis, Kupffer cell hyperplasia
Eosinophilic oval/filamentous cytoplasmic inclusions
(Ebola virus nucleoproteins)
Ancillary Tests
Immunohistochemistry
Anti-Ebola virus antibodies at reference laboratories
In situ hybridization
Virus RNA in macrophages and endothelial cells
Electron microscopy
Filamentous virus particles
OTHER HEMORRHAGIC FEVER VIRUSES
Etiology/Pathogenesis
Viral infections transmitted through mucous
membranes, cutaneous wounds, aerosol, or animal
bites
Viruses spread hematogenously and infect susceptible
cells (i.e., hepatocytes, Kupffer cells)
Natural reservoirs and vectors include mosquitos,
ticks, rodents, bats, and nonhuman primates
Potential for geographic spread determined by animal
reservoirs/vectors and by transmissibility between
humans
Virus Characteristics
Arenaviridae family
Derived from "arena" (sandy)
Viral features
Enveloped, single-strand RNA viruses
Spherical 110-130 nm, with helical nucleocapsid
11,000 nucleotides (4 genes)
Family members
Lassa fever virus (LASV): West Africa
Transmitted by rodents
Bunyaviridae family
Named for Bunyamwera, location of 1st virus
Viral features
Enveloped, single-strand RNA viruses
80-120 nm in size, with helical nucleocapsid
10,500-22,700 nucleotides (4-6 genes)
Family members
Crimean-Congo hemorrhagic fever virus
(CCHFV): Africa, Europe, Asia
Hantaan virus (HTNV): Asia, Europe
Puumala virus (PUUV): Europe
Rift Valley fever virus (RVFV): Africa and Arabian
Peninsula
Flaviviridae family
Derived from "flavus" (yellow)
Viral features
Enveloped, single-strand RNA viruses
Spherical, 37-50 nm in size, with icosahedral
nucleocapsid
9,600-12,300 nucleotides (1 ORF)
Family members
Dengue virus (DENV): 4 serotypes; worldwide
Yellow fever virus (YFV); Central and South
America, Africa
Transmitted by mosquitos (YFV, DENV) or ticks
(KFDV, OMFV, ALKV)
Presentation
Specific signs and symptoms vary by viral infection
Dengue fever: Fever, myalgia, severe retroorbital headache, nausea, vomiting, conjunctival
congestion, rash, lymphadenopathy, mild to severe
hemorrhages, shock
Lassa fever: Fever; malaise; weakness and headache;
hemorrhage; respiratory distress; vomiting; facial
swelling; chest, back, and abdominal pain; shock;
hearing loss; tremors; and encephalitis
Yellow fever: Fever, myalgia, nausea, vomiting,
bradycardia, conjunctival congestion, followed by
remission, then jaundice, hemorrhages, and renal
failure
Laboratory Tests
RT-PCR (blood)
Serology (IgM, IgG)
Virus isolation (blood)
Natural History
Mostly asymptomatic with only a minority
developing hemorrhagic fever, which is severe
Treatment
Primary prevention
Avoidance of mosquitos, ticks, rodents; minimize
exposed skin; use of insect repellents
Few FDA-approved vaccines available
Yellow fever vaccine (YF-Vax): 1 dose
Symptomatic
Predominantly supportive case
Ribavirin for some hemorrhagic fever viruses
Prognosis
Typically full recovery; higher rates of mortality with
some viruses and with suboptimal supportive care
Microscopic Findings
Dengue fever
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EBOLA, MARBURG, AND OTHER HEMORRHAGIC FEVER VIRUS INFECTIONS
Major Outbreaks of Ebola Virus Disease and Marburg Hemorrhagic Fever
Year Location Virus Deaths Cases Fatality (%)
1967 Germany and Yugoslavia MARV 7 31 23
1976 Zaire EBOV 280 318 88
1976 Sudan SUDV 151 284 53
1995 Zaire EBOV 280 315 81
1998-2000 Democratic Republic of Congo MARV 128 154 83
2000-2001 Uganda SUDV 224 425 53
2002-2003 Democratic Republic of Congo EBOV 128 143 89
2004-2005 Angola MARV 227 252 90
2007 Democratic Republic of Congo EBOV 187 264 71
2007-2008 Uganda BVBV 37 149 25
2012 Uganda MARV 4 15 27
2014-2015 West Africa (Sierra Leone, Liberia, Guinea
*As of February 6, 2015
Viral Infections: Viral Infections Requiring Ancillary Tests
Infection of mononuclear phagocytes and
hepatocytes; liver necrosis with minimal
inflammatory response
Gastrointestinal mucosa, skin, pulmonary alveoli,
serosal surface hemorrhages
Lassa fever
Liver and spleen: Necrosis and mononuclear
phagocytic activation with minimal immune cell
infiltrates or tissue damage
Yellow fever
Liver and kidney: Apoptosis, necrosis of
hepatocytes, Kupffer cells, and tubular epithelial
cells with minimal inflammatory response
with scattered isolated cases in Nigeria, and
Senegal)
Ancillary Tests
Immunohistochemistry
Viral-specific antibodies available commercially or at
reference laboratories
Electron microscopy
Arenaviridae: Enveloped, spherical, 110-130 nm,
helical capsid
Bunyaviridae: Enveloped, spherical, 80-120 nm,
helical capsid
Flaviviridae: Enveloped, spherical, 37-50 nm,
icosahedral capsid
KEY POINTS
EBOV 9,004* 22,525* 39
Microscopic Pathology
Hemorrhages including petechiae, ecchymoses of skin,
mucous membranes, visceral organs
Multifocal necrosis (liver, spleen, kidneys) with
minimal inflammatory response
Diagnostic Checklist
Travel and exposure history critical
DIFFERENTIAL DIAGNOSIS
Infections With "Flu-Like" Symptoms (Ebola
and Marburg Virus)
Malaria, influenza, typhoid, meningitis, dengue, Lassa
fever
Lack of exposure history or travel to endemic areas;
failure to develop rash
Identification of specific pathogen by PCR, serology,
culture, or immunohistochemistry
Systemic Infectious Disease (Other
Hemorrhagic Fever Viruses)
Typhoid fever, hepatitis, infectious mononucleosis,
leptospirosis, rickettsioses, malaria
Identification of specific pathogen by PCR, serology,
culture, or histologically
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Etiology
Viral infections frequently transmitted through direct
contact or animal vectors
Clinical Issues
Incidence: Varies widely with virus and location
Early infections present with flu-like symptoms
Hemorrhagic symptoms in minority of patients
(5-30% depending on virus)
Laboratory tests: Serology, PCR, viral culture, IHC, EM
Treatment: Avoidance of direct contact with infected
material; few vaccines or specific treatments available
SELECTED REFERENCES
1. Martines RB et al: Tissue and cellular tropism, pathology
and pathogenesis of Ebola and Marburg viruses. J Pathol.
235(2):153-74, 2015
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EBOLA, MARBURG, AND OTHER HEMORRHAGIC FEVER VIRUS INFECTIONS
Microscopic Features
Viral Infections: Viral Infections Requiring Ancillary Tests
(Left) Marburg virus infection
results in hepatocyte necrosis
and apoptosis but lacks
distinct viral inclusions.
(Right) Lassa fever virus
infection is characterized
by eosinophilic necrosis
of hepatocytes as well as
larger foci of hepatocellular
destruction.
(Left) Immunohistochemical
staining with anti-Ebola virus
antibody shows Marburg
antigens in sinusoidal
lining cells . (Right)
Immunohistochemical
staining with anti-Lassa
antibody shows Lassa
antigens in hepatocytes
and Kupffer cells .
(Left) Immunohistochemical
staining with anti-Ebola
antibody shows Ebola
antigens in hepatocytes,
sinusoids, and sinusoidal
lining cells. (Right) An
electron micrograph
demonstrates viral particles
in the cytoplasm of
infected cells.
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