GEN PATHOLOGY 2018 2 ND BI
VIRAL INFECTIONS MEASLES (rubeola) virus
ACUTE (TRANSIENT) INFECTIONS
Measles,
Mumps
Poliovirus
West nile virus
Viral hemorrhagic fever: enveloped RNA viruses – Arenaviridae,
Filoviridae, Bunyaviridae, Flaviviridae
 These viruses are structurally heterogenous
 Differing degrees of genetic diversity – a variable that has
impact of the host to re-infection by viruses of the same
type.
o e.g. mumps virus – has only one genetic
subtype and infects people only once
o influenza – repeatedly infects people because of
new genetic variants arise periodically in nature.
MASONG|1
 affects multiple organs and causes a wide range of
disease, from mild, self-limited infections to severe
systemic manifestations
 is a leading cause of vaccine preventable death and ilnes
worldwide
 mostly affects children in developing countries: about 10 to
1000 times more likely to die
 epidemics of measles occur among unvaccinated individuals
PATHOGENESIS
 measles virus is a single-stranded RNA virus of the
paramyxovirus family:
o mumps
o respiratory syncytial virus
o parainfluenza virus (a cause of croup)
o human metapneumovirus
 Transmitted by respiratory droplets
 Three (3) cell-surface receptors have been identified for the
virus:
o CD46 (a complement -regulatory protein that
inactivates C3 convertases)
o Signaling lymphocytic activation molecule (SLAM,
a molecule in T -cell activation)
o Nectin 4 (adherens junction protein)
 CD46 – expressed on all nucleated cells
 SLAM – expressed on cells of the immune system
 Nectin 4 – expressed on epithelial cells
 All of these receptors bind the viral hemagglutinin
protein
1)
The virus initially multiplies within the respiratory tract and
then spreads to local lymphoid tissues
2) Replication of the virus in lymphatic tissue is followed by
viremia and systemic dissemination to many tissues,
including the :
o conjunctiva,
o skin,
o respiratory tract,
o urinary tract,
o small blood vessels,
o lymphatic system,
o CNS.
 Most children develop T-cell–mediated immunity to
measles virus that helps control the viral infection and
produces the measles rash.
 Hence, the rash is less frequent in people with
deficiencies in cell-mediated immunity.
 in malnourished children with poor medical care,
measles virus may cause:
o croup,
o pneumonia,
o diarrhea and protein-losing enteropathy,
o keratitis leading to scarring and blindness,
o encephalitis,
o hemorrhagic rashes (“black measles”)
 Antibody-mediated immunity to measles virus protects
against reinfection
MORPHOLOGY
 The blotchy, reddish brown rash of measles virus
infection on the face, trunk, and proximal
extremities is produced by dilated skin vessels,
edema, and a mononuclear perivascular
infiltrates
GEN PATHOLOGY 2018 2 ND BI
 Koplik spots – pathognomonic,
 Ulcerated mucosal lesions in the oral
cavity near the opening of the
Stensen ducts
 are marked by necrosis, neutrophilic
exudate, and neovascularization
 Warthin-Finkeldey cells – pathognomonic
 randomly distributed multinucleate giant
cells, in lymphoid organs that have marked
follicular hyperplasia and large germinal
centers
 have eosinophilic nuclear and cytoplasmic
inclusion bodies
 pathognomonics are also found in the lung and sputum
MUMPS
 usually associated w ith pain and swelling of the salivary
glands
 is a member of the paramyxovirus family
PATHOGENESIS
 has two (2) types of surface glycoproteins:
 one with hemagglutinin and neuraminidase activities
 the other with cell fusion and cytolytic activities
1) Enter the upper respiratory tract through inhalation of
respiratory droplets
2) Spread to draining lymph nodes where they replicate in
lymphocytes (preferentially in activated T cells)
3) Then spread through the blood to the salivary and other
glands
 Mumps virus infects salivary gland ductal epithelial
cells, resulting in desquamation of involved cells,
edema, and inflammation that leads to the classic
salivary gland pain and swelling
Aseptic meningitis - most common extrasalivary gland
complication of mumps infection, occurring in up to 15% of
cases
MORPHOLOGY
 Mumps parotitis is bilateral in 70% of cases
o affected glands are enlarged, have a
doughy consistency, and are moist,
glistening, and reddish-brown on
cross-section
o On microscope, the gland interstitium is
edematous and diffusely infiltrated by
macrophages, lymphocytes, and plasma
cells, which compress acini and ducts
 mumps orchitis
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o testicular swelling may be marked,
caused by edema, mononuclear cell
infiltration, and focal hemorrhages
o Because the testis is tightly contained
within the tunica albuginea,
parenchymal swelling may compromise the
blood supply and cause areas of
infarction
 Infection and damage of acinar cells in the
pancreas may release digestive enyzmes, causing
parenchymal and fat necrosis and neutrophil-rich
inflammation
 Mumps encephalitis
o causes perivenous demyelination and
perivascular mononuclear cuffing.
POLIOVIRUS INFECTION
 causes an acute systemic viral infection, leading to a wide
range of manifestations, from mild, self-limited infections to
paralysis of limb muscles and respiratory muscles
 Poliovirus is a spherical, unencapsulated RNA virus of
the enterovirus genus
 Only infects humans
 Other enteroviruses cause:
o childhood diarrhea as well as rashes
(coxsackievirus A),
o conjunctivitis (enterovirus 70),
o viral meningitis (coxsackieviruses and
echovirus),
o myopericarditis (coxsackievirus B)
 There are three (3) serotypes of poliovirus
 each of which is included in the Salk formalin-fixed
(killed) vaccine and the Sabin oral, attenuated
(live) vaccine
 transmitted by: fecal-oral route
PATHOGENESIS
1) virus infects human cells by binding to CD155, an
epithelial adhesion molecule
2) virus is ingested and replicates in the mucosa of the
pharynx and gut, including tonsils and Peyer patches in the
ileum
3) Poliovirus then spreads through lymphatics to lymph nodes
and eventually the blood, producing transient viremia and
fever
 in about 1 of 100 infected persons poliovirus invades the
CNS and replicates in motor neurons of the spinal cord
(spinal poliomyelitis) or brain stem (bulbar
poliomyelitis)
WEST NILE VIRUS
 an acute systemic viral infection that causes a mild, self-
limited infection or neuroinvasive disease associated
with long-term neurologic sequelae
 is an arthropod-borne virus (arbovirus) of the
flavivirus group, which also includes viruses that cause
dengue fever and yellow fever
 is transmitted by mosquitoes to birds and to mammals
 BIRDS are major reservoir
 HUMANS are incidental hosts
 Most affected patients acquire the infection from a
mosquito bite; less commonly, human-to-human
transmission occurs by blood transfusion, organ
transplantation, breast-feeding, or transplacental
spread
GEN PATHOLOGY 2018 2 ND BI MASONG|3
PATHOGENESIS o cytokine-induced disseminated intravascular
1) After inoculation by a mosquito, West Nile virus replicates coagulation
in skin dendritic cells, which then migrate to lymph o deficiency of clotting factors because of
nodes hepatic injury
2) Here, the virus replicates further, enters the bloodstream,
and, in some individuals, crosses the blood-brain barrier LATENT INFECTIONS (HERPESVIRUS INFECTIONS )
3) In the CNS, the virus infects neurons
 chemokine receptor CCR5 contributes to resistance  Latency is defined as the persistence of viral genomes in
to neuroinvasive infection, cells that do not produce infectious virus
 hence mutations in both copies of the CCR5 gene that  Herpesvirus – most frequently establish latent infections
lead to loss of function are associated with an o are large encapsulated viruses with double-
increased rate of symptomatic infection stranded DNA genomes that encode
 Recall that in HIV infection the role of this receptor is the approximately 70 proteins
opposite —CCR5 loss-of- function is protective because  There are eight types of human herpesviruses,
HIV uses the receptor to infect host T cells belonging to three subgroups that are defined by the
 Symptoms: type of cell most frequently infected and the site of latency:
o fever, 1) α-group viruses, including:
o headache  HSV-1,
o myalgia  HSV-2,
o fatigue  VZV,
o anorexia  infect epithelial cells and produce
o nausea latent infection in neurons
o maculopapular rash 2) lymphotropic β-group viruses, including:
 CNS complications:  CMV,
o Meningitis  human herpesvirus-6 (which causes
o Encephalitis exanthem subitum, also known as
o meningoencephalitis roseola infantum and sixth disease,
 also recently found complications: a benign rash of infants),
o Perivascular and leptomeningeal chronic  human herpesvirus-7 (a virus
inflammation without a known disease
o microglial nodules association), which infect and
o neuronophagia predominantly involving the produce latent infection in a variety
temporal lobes and brain stem of cell types
 in risk are: immunosuppressed persons and older adults 3) the γ-group viruses EBV and KSHV/HHV-8,
 diagnosis: serology, viral culture and PCR-based tests  the cause of Kaposi sarcoma,
which produce latent infection
VIRAL HEMORRHAGIC FEVER mainly in lymphoid cells
 HERPESVIRUS SIMIAE (monkey B virus) is an Old World
 is a severe life-threatening multisystem syndrome in which monkey virus that resembles HSV -1 and can cause fatal
there is vascular dysregulation and damage, leading to neurologic disease in animal handlers.
shock
 caused by: enveloped RNA viruses belonging to four
different genera: HERPES SIMPLEX VIRUSES
o Arenaviridae,
o Filoviridae,  HSV-1 and HSV-2 differ serologically but are closely
o Bunyaviridae, related genetically and cause a similar set of primary and
o Flaviviridae recurrent infection
 can produce a spectrum of illnesses, ranging from a mild PATHOGENESIS
acute disease characterized by fever, headache, 1) Both viruses replicate in the skin and the mucous
myalgia, rash, neutropenia, and thrombocytopenia membranes at the site of entry of the virus (usually
 to severe, life-threatening disease in which there is oropharynx or genitals), where they produce infectious
sudden hemodynamic deterioration and shock virions and cause vesicular lesions of the epidermis.
 definitive hosts: animals or insects 2) The viruses spread to sensory neurons that innervate
 incidental host: humans these primary sites of replication
PATHOGENESIS 3) Viral nucleocapsids are transported along axons to the
1) blood vessels damage may be caused by: neuronal cell bodies, where the viruses establish latent
o direct infection of and damage to infection
endothelial cells
o infection of macrophages and dendritic cells  During latency the viral DNA remains within t he nucleus
leading to production of inflammatory of the neuron, and only latency-associated viral RNA
cytokines transcripts (LATs) are synthesized
 NO viral proteins appear produced during latency
2) There may be hemorrhagic manifestations, including:  LATs may contribute to latency by:
o petechiae, caused by a combination of o conferring resistance to apoptosis,
thrombocytopenia or o silencing lytic gene expression through
o platelet dysfunction, heterochromatin formation,
o endothelial injury
GEN PATHOLOGY 2018 2 ND BI
o serving as precursors for microRNAs that
downregulate expression of critical HSV lytic genes
 HSVs can evade antiviral CTLs by inhibiting the MHC
class I recognition pathway, and elude humoral
immune defenses by producing receptors for the Fc
domain of immunoglobulin and inhibitors of
complement
 in addition to causing cutaneous lesions, HSV-1 is the
major infectious cause of cornel blindness
o corneal epithelial disease – due to direct viral
damage
o corneal stromal disease – appears to be
immune-mediated
 HSV-1 is also the major cause of fatal sporadic
encephalitis:
 Infection spread to the brain and involves the temporal
lobes and orbital gyri of the frontal lobes
MORPHOLOGY
 HSV-infected cells contain large, pink to purple
intranuclear inclusions (Cowdry type A) that
consist of viral replication proteins and virions
at various stage of assembly that push the host
cell chromatin out to the edges of the nucleus
 HSV-1 and HSV-2 cause lesions ranging from self-
limited cold sores and gingivostomatitis to
life-threatening disseminated visceral infections
and encephalitis
 Fever blisters or cold sores favor the facial skin
around mucosal orifices (lips, nose), where their
distribution is frequently bilateral and independent
of skin dermatomes
 intraepithelial vesicles aka blisters
 GINGIVOSTOMATITIS, which is usually
encountered in children,
o is caused by HSV-1
o is a vesicular eruption extending from the
tongue to the retropharynx and causing
cervical lymphadenopathy.
o Swollen, erythematous HSV lesions of the
fingers or palm (herpetic whitlow) occur
in infants
 GENITAL HERPES is often caused by HSV-2 than
by HSV-1
o is characterized by vesicles on the genital
mucous membranes as well as on the
external genitalia that are rapidly
converted into superficial ulcerations,
rimmed by an inflammatory infiltrate
 Two forms of corneal lesions are caused by HSV:
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1) HERPES EPITHELIAL KERATITIS shows typical
virus-induced cytolysis of the superficial
epithelium
2) HERPES STROMAL KERATITIS is characterized
by infiltrates of mononuclear cells around
keratinocytes and endothelial cells, leading to
neovascularization, scarring, opacification of the
cornea, and eventual blindness
 HERPES SIMPLEX ENCEPHALITIS
 Herpes esophagitis is frequently complicated by
superinfection with bacteria or fungi
 Herpes bronchopneumonia, sometimes stemming
from intubation of a patient with active oral
lesions, is often necrotizing
 herpes hepatitis may cause liver failure
VARICELLA-ZOSTER VIRUS (VZV)
Acute infection with VZV causes chickenpox and
reactivation of latent VZV causes shingles (also called
herpes zoster)
 Like HS, VZV infects mucous membranes, skin, and
neurons and causes a self-limited primary infection in
immunocompetent individuals
 Like HSV, VZV evades immune responses and establishes a
latent infection in sensory ganglia
 In contrast to HSV, VZV is transmitted in epidemic fashion
by respiratory aerosols, disseminates hematogenously, and
causes widespread vesicular skin lesions
 Localized recurrence of VZV is most frequent and painful in
dermatomes innervated by the trigeminal ganglia, where
the virus is most likely to be latent .
MORPHOLOGY
 chickenpox rash occurs approximately 2 weeks
after respiratory infection
o Lesions appear in multiple waves
centrifugally from the torso to the head
and extremities
o Each lesion progresses rapidly from a
macule to a vesicle, which resembles a
dewdrop on a rose petal
o After a few days most chickenpox vesicles
rupture, crust over, and heal by
regeneration, leaving no scars
 Shingles occurs when VZV that has long
remained latent in the dorsal root ganglia after
a previous chickenpox infection is reactivated and
infects sensory nerves that carry it to one or more
dermatomes
o There, the virus infects keratinocytes and
causes vesicular lesions, which, unlike
chickenpox, are often associated with
intense itching, burning, or sharp pain
because of concomitant radiculoneuritis
o This pain is especially severe when the
trigeminal nerves are involved; rarely, the
geniculate nucleus is involved, causing
facial paralysis (RAMSAY HUNT
SYNDROME).
o The sensory ganglia contain a dense,
predominantly mononuclear infiltrate,
with herpetic intranuclear inclusions within
neurons and their supporting cells
GEN PATHOLOGY 2018 2 ND BI
CYTOMEGALOVIRUS
 a β-group herpesvirus, can produce a variety of disease
manifestations, depending on the age of the host, and,
more importantly, on the host’s immune status
 CMV latently infects monocytes and their bone marrow
progenitors and can be reactivated when cellular
immunity is depressed
 CMV causes an asymptomatic or mononucleosis-like
infection in healthy individuals but devastating systemic
infections in neonates and in immunocompromised people
 CMV-infected cells exhibit gigantism of both the entire cell
and its nucleus, which typically contains a large inclusion
surrounded by a clear halo (“owl’s eye”).
Transmission of CMV
 Transplacental transmission, from a newly acquired or
primary infection in a mother who does not have protective
antibodies (congenital CMV).
 Neonatal transmission, through cervical or vaginal
secretions at birth, or later through breast milk from a
mother who has active infection (perinatal CMV).
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 Transmission through saliva during preschool years,
especially in day care centers. Toddlers so infected readily
transmit the virus to their parents.
 Transmission by the genital route is the dominant
mode after about 15 years of age. Spread may also occur
via respiratory secretions and the fecal-oral route.
 Iatrogenic transmission, at any age through organ
transplants or blood transfusions
 CMV can infect dendritic cells and impair antigen
processing and the ability of dendritic cells to stimulate T
lymphocytes
 CMV can evade immune defenses by downmodulating MHC
class I and II molecules and by producing homologues of
TNF receptor, IL-10, and MHC class I molecules
 CMV can evade NK cells by:
 producing ligands that block activating receptors
and class I–like proteins that engage inhibitory
receptors
MORPHOLOGY
 Infected cells are strikingly enlarged, often to a
diameter of 40 µm, and show cellular and
nuclear pleomorphism.
 Prominent intranuclear basophilic inclusions
spanning half the nuclear diameter are usually
set off from the nuclear membrane by a clear
halo
In the infected organs:
o In the glandular organs, the parenchymal
epithelial cells are infected; i
o n the brain, the neurons;
o in the lungs, the alveolar macrophages and
epithelial and endothelial cells;
o in the kidneys, the tubular epithelial and
glomerular endothelial cells
CONGENITAL INFECTIONS of CMV
 infection acquired in utero
 sometimes when the virus is acquired from a mother with
primary infection (who does not have protective
antibodies), classic cytomegalic inclusion disease
develops
 the disease resembles erythroblastosis fetalis
 infants suffers with:
o intrauterine growth retardation,
o present with jaundice
o hepatosplenomegaly,
GEN PATHOLOGY 2018 2 ND BI MASONG|6
o anemia,
o bleeding due to thrombocytopenia,
o encephalitis
 In fatal cases the brain is often smaller than normal
(microcephaly) and may show foci of calcification
 Complications includes: interstitial pneumonitis, hepatitis,
hematologic disorder

PERINATAL INFECTIONS of CMV

 Infection acquired during passage through the birth

canal or from breast milk is usually asymptomatic due
to protective maternal anti-CMV antibodies, which are
transmitted to the fetus across the placenta
 Subtle effects on hearing and intelligence
 Less common: interstitial pneumonitis, failure to thrive,
rash, or hepaitis

CYTOMEGALOVIRUS MONONUCLEOSIS

 Nearly always asymptomatic

 The most common clinical manifestation of CMV infection in
immunocompetent hosts beyond the neonatal period
 is an infectious mononucleosis-like illness,
o with fever,
o atypical lymphocytosis,
o lymphadenopathy,
o hepatitis, marked by hepatomegaly and
abnormal liver function tests
 diagnosis is made by serology
 infected individuals remain seropositive for life and the
virus is never cleared, in leukocytes

CMV in Immunosuppressed Individuals

 individuals who are: transplant recipients, HIV-

infected, are susceptible
 disseminated CMV infections in immunosuppressed people
primarily affect:
o the lungs (pneumonitis)  an interstitial
mononuclear infiltrate with foci of necrosis
develops + typical enlarged cells with inclusions
o gastrointestinal tract (colitis)  intestinal
necrosis and ulceration develops leading to
formation of pseudomembranes and debilitating
diarrhea
 diagnosis:
 demonstration of characteristic morphologic
alterations in tissue sections,
 viral culture,
 rising antiviral antibody titer,
 detection of CMV antigens
 PCR-based detection of CMV DNA