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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_182_библиотеки_им_акад_М_И_Перельмана.pdf
RABIES VIRUS INFECTION
Hippocampal pyramidal neurons from a raccoon
contain Negri bodies , pathognomonic cytoplasmic
eosinophilic inclusions characteristic (but not required for
Viral Infections: Morphological Diagnosis of Viral Infections
diagnosis) of rabies encephalitis.
TERMINOLOGY
Definitions
Latin: "Rabies" (rage, madness)
Greek: "Lyssavirus" (Lyssa, goddess of madness, rage,
and frenzy)
Greek "rhabdos" ("rod," for Rhabdoviridae family)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Zoonotic infection transmitted by bites from infected
animals (dogs > bats > other mammals)
Virus replicates in muscle, spreads from peripheral
nerves to CNS by retrograde axonal transport, then to
salivary glands and other organs
Incubation period 1-3 months (longer incubation with
more distal sites of infection)
Can be as short as 1 week and as long as 1 year
CLINICAL ISSUES
Epidemiology
55,000 deaths per year (primarily Asia and Africa)
Most common in children under age 15
Site
Skin, muscle, central nervous system
Presentation
Initial symptoms of fever and pain and paraesthesia at
wound site
Early onset of autonomic dysfunction (often
overlooked)
Excess salivation may be evident but other signs
I
may be subtle
1
Rabies virus particles have a bullet-shaped
morphology seen on thin-section electron microscopy.
(Courtesy G. Nielsen, MD.)
Furious rabies (70%): Hyperactivity, excited behavior,
hydrophobia, and aerophobia with progression to
death by cardiorespiratory arrest (days)
Paralytic rabies (30%): Gradual muscle paralysis
starting at wound site, coma development, and
eventual death (more prolonged time course)
Laboratory Tests
Direct fluorescent antibody (dFA) test (brain tissue)
RT-PCR (saliva, skin biopsy)
Antibodies (serum, CSF)
Animal testing (in known exposure) is performed by
public health services
Natural History
Progressive fatal inflammation of brain & spinal cord
Treatment
Primary prevention
Human diploid cell vaccine (HDCV) or purified
chick embryo cell vaccine (PCECV) on days 0, 7, and
21 or 28
Rapid fluorescent focus inhibition test (RFFIT)
determines rabies virus neutralizing antibody level
in serum
Postexposure prophylaxis
Local treatment of wound (i.e., soap and water,
detergent, or povidone iodine)
Nonimmunized
HDCV or PCECV on days 0, 3, 7, and 14
Human rabies immune globulin (HRIG)
Immunized
HDCV or PCECV on days 0 and 3
Presentation with symptoms
Palliative therapy
Aggressive therapy with rare survival (i.e., rabies
vaccine, HRIG, ribavirin, IFN-, and ketamine)
Prognosis
Typically fatal once symptoms develop
50
RABIES VIRUS INFECTION
Etiology
Zoonotic infection transmitted by animal bites
Virus replicates in muscle, spreads from peripheral
nerves to CNS (1-3 month incubation)
Clinical Issues
55,000 deaths per year worldwide
Presents with fever, pain and paraesthesia at wound
site; furious (70%) and paralytic (30%) rabies
Diagnosis: Direct fluorescent antibody (dFA) test
Key Facts
Prevention: Rabies vaccine; monitor titre with RFFIT
Prophylaxis: Wound treatment, vaccine, Ig
Microscopic Pathology
Leptomeningeal and perivascular lymphocytic
inflammatory infiltrate, Babs nodules
Negri bodies (not required for diagnosis)
Ancillary Tests
Anti-rabies virus abs (IHC); bullet-shaped virions (EM)
Viral Infections: Morphological Diagnosis of Viral Infections
MICROBIOLOGY
Virus Features
Enveloped, single-strand, RNA virus
Bullet shape 180 nm x 75 nm, helical nucleocapsid
11,600-12,000 nucleotide genome (5 genes)
Culture
Virus detectable by immunofluorescence in mouse
neuroblastoma cells (MNA) or baby hamster kidney
(BHK) cells 5 hours to 5 days post inoculation
MICROSCOPIC PATHOLOGY
Histologic Features
Leptomeningeal and perivascular lymphocytic
inflammatory infiltrate (often mild)
Neuronophagia and glial nodules (Babs nodules)
Cytologic Features
Negri bodies: Eosinophilic cytoplasmic inclusions
(2-10 m) in neurons (not required for diagnosis)
Magenta with Mann, Giemsa, and Sellers stains with
basophilic interior granules
ANCILLARY TESTS
Immunohistochemistry
Anti-rabies virus antibodies (nucleocapsid)
Electron Microscopy
Bullet-shaped virions; Negri bodies with budding virus
DIFFERENTIAL DIAGNOSIS
Other Infectious Causes of Encephalitis
Arboviruses, measles virus, Nipah virus
cytoplasmic, Negri body-like inclusions (measles/
Nipah)
Lack of detection of rabies viral antigen by
immunofluorescent staining or nucleic acids
Prolonged clinical stability or improvement
Guillain-Barr Syndrome
Lack of detection of viral antigen or nucleic acids
Sensory involvement, lack of fever, absence of
encephalitic signs
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
History of exposure to potentially infected animals or
travel to endemic areas
Immunization history and antibody levels
SELECTED REFERENCES
1. Lichtenberg, F: Pathology of Infectious Diseases. New York:
Raven Press, 1991
IMAGE GALLERY
(Left) A cytoplasmic Negri body is present in a cerebellar Purkinje cell from a lethal human case of rabies. (Courtesy F. von Lichtenberg
Collection of ID Pathology, BWH.) (Center) A silver stain highlights dying neurons
Collection of ID Pathology, BWH.) (Right) A microglial reaction to nerve cell necrosis
Lichtenberg Collection of ID Pathology, BWH.)
in lethal rabies encephalitis. (Courtesy F. von Lichtenberg
is present in rabies encephalitis. (Courtesy F. von
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RESPIRATORY SYNCYTIAL VIRUS INFECTION
Giant syncytial cells are seen in RSV pneumonia .
The alveolar lumina are filled with cellular debris .
(Courtesy Franz von Lichtenberg Collection of Infectious
Viral Infections: Morphological Diagnosis of Viral Infections
Disease Pathology, BWH.)
TERMINOLOGY
Abbreviations
Respiratory syncytial virus (RSV)
Definitions
"Syn" from Latin meaning "together"
"Cyt" from Latin "cyto" meaning "cell"
Syncytium: Multinucleated cell lacking dividing cell
membranes
Member of Paramyxoviridae family, subfamily
Pneumoviridae
ETIOLOGY/PATHOGENESIS
Infectious Agents
Most common cause of bronchiolitis in infants < 1
year old
Most common in fall, winter, and spring in temperate
climates, but can vary annually
Initial infection
Respiratory epithelium is infected through
inhalation of infectious droplets or via direct contact
with ocular mucosa
CLINICAL ISSUES
Epidemiology
Affects 70% of infants by age 1 and 100% of infants by
age 2 years
25-40% of exposed infants will have symptoms
of bronchiolitis or pneumonia; 0.5-2% will need
hospitalization
200,000 deaths per year, mainly in infants in
developing countries
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Site
Upper and lower respiratory tract
1
RSV pneumonia is seen in an infant. Note the giant
syncytial cell characteristic of the disease . (Courtesy
Franz von Lichtenberg Collection of Infectious Disease
Pathology, BWH.)
Severity of disease is thought to be mediated by
strength of host immune response to virus
Presentation
Initial presentation: Rhinitis, fever, cough
May progress to bronchiolitis (wheeze and decreased
oral intake) or pneumonia
Respiratory symptoms last 4-6 days
Host can continue shedding viral particles for 1-3
weeks
Immunosuppressed patients may present with severe
respiratory symptoms without prodrome
Laboratory Tests
ELISA of nasopharyngeal aspirates
Treatment
No effective vaccine
Supportive treatment for mild cases
Oxygenation and hydration for more severe cases
corticosteroids and epinephrine nebulizers
RSV immunoglobulin for severe cases
Prophylaxis with pavilizumab
Monoclonal antibody targeting RSV protein F, for
selected cases such as premature neonates, infants
with congenital heart disease, and infants with
impaired lung function
Prognosis
Complications: Respiratory failure, encephalopathy (in
2% of hospitalized patients), seizures
Studies suggest that repeated infection in infancy may
increase risk of subsequent asthma development
High-Risk Groups
Premature infants, especially in 1st year of life
Children with chronic lung disease such as
bronchopulmonary dysplasia in first 2 years of life
Children with congenital heart disease
Immunodeficient patients (children > adults)
52
RESPIRATORY SYNCYTIAL VIRUS INFECTION
Etiology
Most common cause of bronchiolitis in infants < 1
year old
Clinical Issues
Affects 70% of infants by age 1 and 100% of infants
by age 2 years
Complications: Respiratory failure, encephalopathy
(in 2% of hospitalized patients), seizures
Key Facts
Microscopic Pathology
Giant syncytial cells can be seen in lining of bronchi,
bronchioles, and alveoli
Airway epithelium, lumen, and smooth muscle
inflammatory infiltrate
Hyperplastic lymphoid follicles
Patchy epithelial lining sloughing
Viral cytopathic effect leading to syncytia formation
Viral Infections: Morphological Diagnosis of Viral Infections
IMAGE FINDINGS
Radiographic Findings
Hyperinflation and diffuse interstitial markings
MICROBIOLOGY
Viral Features
RNA virus
Enveloped, negative sense, single stranded
15.2 kb genome encoding 11 proteins
Subgroups A and B have been identified, although
their significance is unclear
MICROSCOPIC PATHOLOGY
Histologic Features
Giant syncytial cells can be seen in lining of bronchi,
bronchioles, and alveoli
Airway epithelium, lumen, and smooth muscle
inflammatory infiltrate
Patchy epithelial lining sloughing
Hyperplastic lymphoid follicles
Airway obstruction due to inflammatory debris, fibrin,
and edema
Cytologic Features
Viral cytopathic effect leading to syncytia formation
ANCILLARY TESTS
Molecular Diagnostics
RT-PCR
DIFFERENTIAL DIAGNOSIS
Infectious
Parainfluenza, adenovirus, influenza, measles
Consider age of patient and temporal association
Detection of pathogens using serology, PCR, or
immunofluorescence
Noninfectious
Asthma
Detached epithelium, eosinophilic plugging, smooth
muscle hyperplasia, marked inflammatory infiltrate
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
High index of suspicion in cases involving a premature
patient during RSV outbreak seasons
SELECTED REFERENCES
1. Johnson JE et al: The histopathology of fatal untreated
human respiratory syncytial virus infection. Mod Pathol.
20(1):108-19, 2007
IMAGE GALLERY
(Left) Syncytial giant cells are seen in RSV infection . The surrounding lung tissue displays interstitial pneumonitis. (From DP: Nonneoplastic
Pediatrics.) (Center) RSV infection results in the formation of multinucleated cells
DP: Nonneoplastic Pediatrics.) (Right) Multinucleated giant cells
characteristic of pulmonary RSV infection. (From DP: Nonneoplastic Pediatrics.)
, proteinaceous material, and degenerative debris in the alveoli are all
and eosinophilic cytoplasmic inclusions . (From
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SECTION 2
Viral Infections
Requiring Ancillary Tests
RNA Viruses
Arbovirus Infections I-2-2
Enterovirus Infection I-2-6
Hepatitis A and E Virus Infections I-2-8
Hepatitis C Virus Infection I-2-12
Human T-Lymphotropic Virus Type I Infection I-2-16
I-2-18
I-2-22
Lymphocytic Choriomeningitis Virus Infection I-2-26
Mumps Virus Infection I-2-28
Poliovirus Infection I-2-30
Rotavirus Infection I-2-32
Rubella I-2-34
Severe Acute Respiratory Syndrome (SARS) I-2-36
Prion Diseases I-2-38
I-2-42
ARBOVIRUS INFECTIONS
Severe destruction of neurons, microglial nodules, and
neuronophagia are present in the hippocampus in a
case of Japanese encephalitis.
Viral Infections: Viral Infections Requiring Ancillary Tests
TERMINOLOGY
Definitions
Arbovirus: Derived from "arthropod-borne virus"
ETIOLOGY/PATHOGENESIS
Infectious Disease
Viral infections transmitted by arthropod vectors such
as mosquitos and ticks
> 250 arboviruses; at least 80 cause human disease
(e.g., hemorrhagic fever, encephalitis)
Symptomatic disease
Reservoir include birds and mammals
Majority not transmissible by humans due to low
viremia (exceptions: Dengue fever, yellow fever,
chikungunya disease)
Onset 3-15 days after bite from infected mosquito or
tick
Symptomatic disease
New, nonimmune hosts encounters virus
Direct viral or host immune response leads to
damage
VIRUSES
Bunyaviridae Family
Named for Bunyamwera, village where virus 1st
detected
Viral features
Enveloped, single-strand RNA viruses
80-120 nm in size, with helical nucleocapsid
10,500-22,700 nucleotides
Family members
Bunyamwera virus (BUNV): Africa
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2
California encephalitis virus (CEV): North America
Crimean-Congo hemorrhagic fever virus (CCHFV):
Africa, Asia, Europe
A predominantly lymphocytic inflammatory infiltrate ,
typical for arboviral encephalitides, is present in the
meninges in a case of Japanese encephalitis.
Heartland virus (HRTV): 10 cases in USA
(2009-2014)
La Crosse encephalitis virus (LACV): 80-100
neuroinvasive disease cases per year in USA
Rift Valley fever virus (RVFV): Africa and Middle East
Sandfly fever Naples virus (SFNV): Europe and Asia
Sandfly fever Sicilian virus (SFSV): Europe and Asia
Severe fever with thrombocytopenia syndrome
(SFTS) virus (SFTSV): Asia
Toscana virus (TOSV): Mediterranean
Flaviviridae Family
Derived from "flavus" (yellow)
Viral features
Enveloped, single-strand RNA viruses
37-50 nm in size, with icosahedral nucleocapsid
9,600-12,300 nucleotides
Family members
Dengue virus (DENV); 4 serotypes; > 100 million
cases worldwide annually
Japanese encephalitis virus (JEV): 35,000-50,000
cases with 15,000 deaths annually in Asia
Kyasanur forest disease virus (KFDV): India
Murray Valley encephalitis virus (MVEV): Australia,
New Guinea
Omsk hemorrhagic fever virus (OHFV): Russia
Powassan virus (POWV): 47 cases reported in USA
(2001-2012)
St. Louis encephalitis virus (SLEV): 100
neuroinvasive disease cases per year (range: 2-1,967)
in USA (1964-2010)
Tick-borne encephalitis virus (TBEV): Europe, Russia
West Nile virus (WNV): 1,164 neuroinvasive disease
cases per year (range: 19-2,946) in USA (1999-2013);
~ 100 deaths annually
Yellow fever virus (YFV): Central and South
America, Africa
Reoviridae Family
Derived from "respiratory enteric orphan viruses"
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ARBOVIRUS INFECTIONS
Viral features
Nonenveloped, double-strand RNA viruses
60-70 nm in size, with icosahedral nucleocapsid
18,200-30,500 nucleotides
Family members
Banna virus (BAV): Asia
Colorado tick fever virus (CTFV): ~ 100 cases per
year in USA
Togaviridae Family
Derived from "toga" (garment covering), describing
viral envelope
Viral features
Enveloped, single-strand RNA viruses
60-65 nm in size, with icosahedral capsid
10,000-12,000 nucleotides
Family members
Barmah Forest virus (BFV): Australia
Chikungunya virus (CHIKV): Worldwide; 1st locally
transmitted case in North America in 2013
Eastern equine encephalitis virus (EEEV): 6 cases per
year in USA
Mayaro virus (MAYV): South America
Ross River virus (RRV): Australia and Pacific islands
Semliki Forest virus (SFV): Africa
Sindbis virus (SINV): Africa, Middle East, Australia
Venezuelan equine encephalitis virus (VEEV): South
and North America
Western equine encephalitis virus (WEEV): 639 cases
in USA since 1964
Site
Frequently brain
Liver (YF)
Mononuclear cells (DENV)
Presentation
Most infections are asymptomatic
Mild cases with slight fever, headache, and body aches
Severe infections with rapid onset, headache, high
fever, disorientation, tremors, convulsions, paralysis,
coma, or death
Distinguishing features
Lymphadenopathy, rash: DENV, WNV
Arthralgia, rash: CHIKV, MAYV, RRV, BFV, SINV
Hemorrhagic signs: YFV, DENV, KFDV, OHFV, CHFV,
SFTSV
Fever and CNS involvement: EEEV, WEEV, WNV,
SLEV, VEEV, LACV, JEV, POWV, MVEV, KFDV, TBEV
Laboratory Tests
EEG: Abnormalities (60-90% of cases)
CSF: Pleocytosis
CBC: Thrombocytopenia (DENV, SFTSV, HRTV)
Virus-specific IgM, IgG and neutralizing antibodies
(serum, CSF)
RT-PCR (serum, CSF)
Virus culture
Natural History
Typically self-limited
Viral Infections: Viral Infections Requiring Ancillary Tests
VECTORS
Mosquitos
Aedes: Derived from "unpleasant"
Distinctive black and white markings on body/legs
> 700 species including Aedes aegypti, Aedes
albopictus, Aedes vexans, Aedes triseriatus
Transmit: DENV, YFV, WNV, CHIKV, EEEV
Culex: Latin term for "midge" or "gnat"
Drab monocolor mosquitos
> 1,200 species including Culex tritaeniorhynchus,
Culex quinquefasciatus, Culex pipiens
Transmit: WNV, JEV, SLEV, WEEV
Coquillettidia
Large yellowish mosquitos
57 species including Coquillettidia perturbans
Transmit: WNV, EEEV
Ticks
Ixodes
Hard-bodied ticks
243 species including Ixodes scapularis, Ixodes ricinus,
Ixodes persulcatus
Transmit: TBEV and Powassan
CLINICAL ISSUES
Epidemiology
More common in warmer months when mosquitoes
and ticks are active
Treatment
Primary prevention
Avoidance of mosquitos and ticks; minimization of
exposed skin; use of insect repellents
Vaccines
JEV: Inactivated Vero cell culture-derived Japanese
encephalitis vaccine (IXIARO): 2 doses (28 days
apart)
YFV: 17D yellow fever vaccine (YF-Vax): 1 dose
Other vaccines (i.e., DENV, WNV) are in
development
Presentation with symptoms
Predominantly supportive care
Ribavirin for some hemorrhagic fever viruses (RVFV,
CHFV)
Prognosis
Full recovery in most cases; permanent neurological
symptoms and fatality in up to 20-30% of severe cases
IMAGING FINDINGS
MR
Brain: T2 FLAIR hyperintensity
MACROSCOPIC FINDINGS
Brain (Autopsy)
Features range from near-normal to severe edema,
hyperemia, and herniation
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3
ARBOVIRUS INFECTIONS
No purulent material in meninges
MICROSCOPIC FINDINGS
Histologic Features
Brain
Predominantly lymphocytic meningeal and
perivascular inflammatory infiltrates
Microglial nodules: Clusters of activated microglial
cells
Neuronophagia: Dying neuron within microglial
nodule
Affects gray matter more than white matter
Liver (DENV, YF)
Hepatic necrosis (without viral cytopathic effect)
Cytologic Features
No characteristic nuclear inclusions
Viral Infections: Viral Infections Requiring Ancillary Tests
ANCILLARY TESTS
Immunohistochemistry
CD68 highlights microglial clusters
Virus-specific antibodies may be available
commercially or at reference laboratories
In Situ Hybridization
Viral specific probes may be available commercially or
at reference laboratories
Next Generation Sequencing
Identifies novel viruses from nonhuman sequences
Electron Microscopy
Bunyaviridae: Pleomorphic, spheroidal, enveloped,
80-120 nm, distinct surface projections
Flaviviridae: Uniform, spheroidal, enveloped 40-60
nm, with small surface projections
Reoviridae: Wheel-shaped, nonenveloped, 60-70 nm
Togaviridae: Slightly pleomorphic, spherical,
enveloped, 70 nm, distinct surface projections
Neutrophilic or eosinophilic predominant
infiltrates; granulomatous inflammation
Autoimmune &/or immune-mediated encephalitides
Gliomas
Infiltrating edge may appear modestly hypercellular,
with elongated tumor cell nuclei appearing microglialcell like; prominent perivascular lymphocytic cuffing
can be present
Overall hypercellularity, absence of microglial clusters,
and cytologic atypia and hyperchromasia of tumor
nuclei
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
Travel, immunization, and exposure history essential
Serology, RT-PCR, IHC, or ISH may be necessary to
identify specific viral infection
Many infections must be reported to state health
departments
Biopsy of brain tissue for viral infections is
uncommon unless glioma is in differential diagnosis
KEY POINTS
Etiology
Viral infections transmitted by arthropod vectors such
as mosquitos and ticks
Clinical Issues
Incidence: Varies widely with virus and location
Most infections are asymptomatic or are associated
with slight fever, headache, and body aches
Severe infections present with rapid onset, headache,
high fever, and can progress to paralysis, coma, or
death
Laboratory tests: Serology, RT-PCR, viral culture
Treatment: Avoidance of mosquito and tick bites;
vaccination (Japanese encephalitis, yellow fever);
supportive therapy
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DIFFERENTIAL DIAGNOSIS
Other Viral Causes of Encephalitis
Herpes simplex virus 1, herpes simplex virus
2, varicella-zoster virus, Epstein-Barr virus,
cytomegalovirus, rabies virus, measles virus, JC
polyomavirus, adenovirus
Characteristic nuclear inclusions or detection of
virus by IHC with commercially available antibodies
Nonviral Causes of Encephalitis
Neisseria meningitidis, Borrelia spp., Treponema pallidum,
Leptospira spp., Mycoplasma spp., Rickettsia rickettsii,
Mycobacterium tuberculosis, Candida spp., Mucor spp.,
Cryptococcus neoformans, Toxoplasma gondii, Naegleria
fowleri, etc.
Organisms observed on H&E, Gram, AFB, MSS, or
PAS-D stains
Microscopic Pathology
Predominantly lymphocytic meningeal and
perivascular inflammatory infiltrates
Microglial nodules and neuronophagia
Identify specific virus by RT-PCR, IHC, ISH, viral
culture, or serology
SELECTED REFERENCES
1. Centers for Disease Control and Prevention. Arbovirus
Catalog. https://www.cdc.gov/arbocat/. Accessed
November 11, 2014
2. Chan BK et al: Deep sequencing to identify the causes of
viral encephalitis. PLoS One. 9(4):e93993, 2014
3. Lani R et al: Tick-borne viruses: a review from the
perspective of therapeutic approaches. Ticks Tick Borne
Dis. 5(5):457-65, 2014
4. Lichtenberg, F: Pathology of Infectious Diseases. New York:
Raven Press, 1991
ARBOVIRUS INFECTIONS
A
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Radiologic and Microscopic Features
Viral Infections: Viral Infections Requiring Ancillary Tests
(Left) Aedes aegypti is a
vector for several disease
causing viruses including
dengue, chikungunya, and
yellow fever. (Courtesy
R. Pollock, PhD.) (Right)
xial FLAIR MR in a
atient with West Nile
virus meningoencephalitis
shows bilaterally symmetric
high signal intensity in the
thalami . There is subtle
hyperintensity in the basal
anglia and right internal
capsule . (From DI2:
Brain.)
(Left) A predominantly
lymphocytic perivascular
infiltrate is present in
this case of Eastern equine
encephalitis. (Courtesy F.
von Lichtenberg Collection
of ID Pathology, BWH.)
(Right) Neuronal necrosis
is a prominent feature of
Eastern equine encephalitis.
(Courtesy F. von Lichtenberg
Collection of ID Pathology,
BWH.)
(Left) Diffuse inflammation
and beginning gliosis is
resent in a long-lasting
case of Eastern equine
encephalitis. (Courtesy F.
von Lichtenberg Collection
of ID Pathology, BWH.)
(Right) A neutrophil
invades a dead pyramidal
neuron in a case of Eastern
equine encephalitis.
(Courtesy F. von Lichtenberg
Collection of ID Pathology,
BWH.)
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