Download Infections

Herpesviruses (C54, p541)
Subfamily
Virus
Primary Target Cell
Site of Latency
Means of Spread
Alphaherpesvirinae
Human
herpesvirus 1
Herpes simplex type 1
Mucoepithelial cells
Neuron
Close contact
Human
herpesvirus 2
Herpes simplex type 2
Mucoepithelial cells
Neuron
Close contact (sexually
transmitted disease)
Human
herpesvirus 3
Varicella-zoster virus
Mucoepithelial cells
Neuron
Respiratory and close contact
Gammaherpesvirinae
Human
herpesvirus 4
Epstein-Barr virus
B cells and epithelial cells
B cell
Saliva (kissing disease)
Human
herpesvirus 8
Kaposi's sarcomarelated virus
Lymphocyte and other
cells
B cell
Close contact (sexual), saliva?
Human
herpesvirus 5
Cytomegalovirus
Monocyte, lymphocyte,
and epithelial cells
Monocyte,
lymphocyte, and ?
Close contact, transfusions,
tissue transplant, and congenital
Human
herpesvirus 6
Herpes lymphotropic
virus
T cells and ?
T cells and ?
Respiratory and close contact?
Human
herpesvirus 7
Human herpesvirus 7
T cells and ?
T cells and ?
? (indicates that other cells may
also be the primary target or site
of latency)
Betaherpesvirinae
1.
2.
3.
Cause lytic, persistent, latent/recurrent, and immortalizing infections.
Herpesvirus infections are common, but the viruses are ubiquitous.
Cause serious complications in immunocompromised patients
A. Structure (Fig.1 + Box1)
a. envelope; b. icosahedral capsid made of 162 capsomeres;
c. linear double-stranded DNA (124-235 kb)
B. Replication
regulators
Enzymes:
DNA polymerase,
thymidine kinase
Structure proteins:
glycoproteins
1. Structure
2. Binding
3. Transcription
4. DNA replication
5. Assembly
6. Release
7. Latency
a. Herpes simplex virus means “to creep” and “cold sore”.
type 1 (HSV-1) is normally associated with infection above the waist.
type 2 (HSV-2) is normally associated with infection below the waist.
p. 547
p. 548
Keratitis
Encephalitis (HSV is the most common
viral cause of sporadic encephalitis)
HSV causes serious problems in neonates and
immunocompromised patients.
AIDS patient
Infection at the scaple monitor site
during delivery?
C. Primary (in children is benign) vs. latent infection (latency
associated transcripts, LAT)
2. Clinical
course
3. Recurrence is unpredictable.
BOX 54-3. Triggers of HSV Recurrences
•UV-B radiation (skiing, tanning)
•Fever (hence the name "fever blister")
•Emotional stress (e.g. final examinations, big date)
•Physical stress (irritation)
•Menstruation
•Foods: Spicy, acidic, allergies
•Immunosuppression
•Transient (stress related)
•Chemotherapy, radiotherapy
•Human immunodeficiency virus
4. Epidemiology
--Virus is transmitted by vesicle fluid, saliva,
and vaginal secretions.
-- HSV-1 infects 90% world population.
-- HSV-2 infects 22% adults in US.
(45 million total with up to 1 million
new cases per year)
HSV-1 infection rate
HSV-2 infection rate
5. Lab. diagnosis
Table 54-2. Laboratory Diagnosis of Herpes Simplex Virus (HSV) Infections
Approach
Test/Comment
Direct microscopic examination of cells from base of
lesion
Tzanck smear shows multinucleated giant cells and Cowdry type A
inclusion bodies.
Cell culture
HSV replicates and causes identifiable cytopathologic effect in most cell
cultures.(syncytia?)
Assay of tissue biopsy, smear, cerebrospinal fluid, or
vesicular fluid for HSV antigen or genome
Enzyme immunoassay, immunofluorescent stain, in situ DNA probe analysis,
and polymerase chain reaction (PCR).
HSV type distinction (HSV-1 vs. HSV-2)
Type-specific antibody, DNA maps of restriction enzyme fragments, sodium
dodecyl sulfate-gel protein patterns, DNA probe analysis, and PCR.
Serology
Serology is not useful except for epidemiology.
Syncytia
uninfected cells
Cowdry type A intranuclear inclusions
CPE of infected cells
6. Treatment
BOX 54-5. FDA-Approved Antiviral Treatments for Herpesvirus Infections
Herpes Simplex 1 and 2
•Acyclovir
•Penciclovir
•Valacyclovir
•Famciclovir
•Adenosine arabinoside
•Iododeoxyuridine
•Trifluridine
--- Acyclovir (acycloguanosine; p508)
--- Action of ACV:
ACV

HSV
TK
ACV-P

Cellular
TK
ACV-P-P-P
 block DNA synthesis
HSV
DNA polymerase
(prevent elongation of viral DNA)
Advantage
-- specific (nontoxic), effective for serious presentations during primary infection
and prophylactic treatment.
J. Prevention and control: wearing gloves for medical profession,
restraint sex or use condoms for recurrent genital patients, and
cesarean section for pregnant woman shedding virus in vagina;
no vaccine available.
BOX 54-2. Disease Mechanisms for Herpes Simplex Viruses
•Disease is initiated by direct contact and depends on infected tissue
(e.g., oral, genital, brain).
•Virus causes direct cytopathologic effects.
•Virus avoids antibody by cell-to-cell spread (syncytia).
•Virus establishes latency in neurons (hides from immune response).
•Virus is reactivated from latency by stress or immune suppression.
•Cell-mediated immunity is required for resolution with limited role for
antibody.
•Cell-mediated immunopathologic effects contribute to symptoms.
Primary oral herpes: A 5-year-old boy has an ulcerative rash with
vesicles around the mouth. Vesicles and ulcers are also present
within the mouth. Results of a Tzanck smear show multinucleated
giant cells (syncytia) and Cowdry type A inclusion bodies. The
lesions resolve after 18 days.
Recurrent oral herpes HSV: A 22-year-old medical student studying
for examinations feels a twinge at the crimson border of his lip and
24 hours later has a single vesicular lesion at the site.
Recurrent genital HSV: A sexually active 32-year-old woman has a
recurrence of ulcerative vaginal lesions with pain, itching, dysuria,
and systemic symptoms 48 hours after being exposed to UVB light
while skiing. The lesions resolve within 8 days. Results of a
Papanicolaou smear shows multinucleated giant cells (syncytia) and
Cowdry type A inclusion bodies.
Encephalitis HSV: A patient has focal neurologic symptoms and
seizures. Magnetic resonance imaging results show destruction of a
temporal lobe. Erythrocytes are present in the cerebrospinal fluid,
and polymerase chain reaction is positive for viral DNA.
b. Varicella-zoster virus (VZV)
--varicella (chickenpox; Fig. 10, virus establish latency in dorsal root and
cranial nerve ganglia) zoster (shingle, belt or girdle; Fig.11)
1. Pathogenesis and immunity
* Cell-mediated immunity is essential to control infection.
2. Epidemiology
-- 90% adult population has antibody.
-- Among them, 10-20% develop zoster.
-- VZV vaccine decreases the infection.
3. Clinical syndromes.
--Chickenpox is mild in children and more severe in adults (with
pneumonia and fatal outcome).
--It is one of the five classic childhood exanthems (listed in p551).
--Zoster is painful and causes post-herpetic neuralgia.
--Virus causes serious complications in immunocompromised patients.
4. Lab. diagnosis
--Cytology (Cowdry type A intranuclear inclusions and syncytia by
Tzanck smear), virus isolation, and Ab rising
5. Treatment, prevention and control
p. 549, box 5: VZV
Acyclovir
Famciclovir
Valacyclovir
Varicella-zoster immune globulin
Zoster immune plasma
Live (attenuated) vaccine (Oka strain)
--Drugs are less effective for VZV infection when compared to
HSV infection.
VZV
Varicella (chickenpox): A 5-year-old boy develops a
fever and maculopapular rash on his abdomen 14 days
after meeting with his cousin, who also developed the
rash. Successive crops of lesions appeared for 3 to 5
days, and the rash spread peripherally.
Zoster (shingles): A 65-year-old woman has a belt of
vesicles along the thoracic dermatome and experiences
severe pain localized to the region.
c. Epstein-Barr virus (EBV)
1. Replicates in B or epithelial cells of oro- and nasopharynx.
2. Causes latent infection in B cells (in the presence of competent
T cells).
3. Stimulates and immortalizes B cells (B-cell lymphoma and AfBL)
A
B
AfBL
4. Pathogenesis and immunity
--T cells initiate civil war against virus-infected B cells to produce infectious
mononucleosis (lymphocytosis due to atypical lymphocytes-Downey cells)
and result swelling in lymph glands, spleen, and liver. Adults have severer
symptoms than children.
--Antibody responses to viral antigens, VCA, MA, EA, and self antigens
5. Epidemiology (70% adult population in US is infected by age 30.)
--90% viral infection is spread by saliva (kissing disease).
--Immunosuppression caused by malaria is a cofactor for AfBL
--The cofactor for nasopharyngeal carcinoma may be genetic, food, environment.
--Immunocompromised patients develop hairy oral leukoplakia.
6. Clinical syndromes
--Heterophile antibody-positive infectious mononucleosis-fever, malaise,
pharyngitis, lymphoadenopathy, hepatosplenomegaly, rash, fatigue (rarely,
CNS involvement)
--Chronic disease?
--Lymphoproliferative diseases in patients lack of T cells (X-linked genetic defect
in a T-cell gene, SLAM, or post-transplant proliferative diseases), AfBL,
Hodgkin’s lymphoma, and nasopharyngeal carcinoma
--Hairy oral leukoplakia in epithelial cells.
7. Lab.
--- lymphocytosis (30% atypical lymphocytes in 60-70% of WBC)
--- atypical lymphocytes
--- heterophile antibody
---Antibodies to viral antigens
Table 54-4. Serologic Profile for Epstein-Barr Virus (EBV) Infections
Patient's Clinical Status
Heterophile Antibodies
EBV-Specific Antibodies
VCA-IgM
VCA-IgG
EA
EBNA
Comment
Susceptible
-
-
-
-
-
-
Acute primary infection
+
+
+
±
-
-
Chronic primary infection
-
-
+
+
-
-
Past infection
-
-
+
-
+
-
Reactivation infection
-
-
+
+
+
EA restricted or diffuse
Burkitt's lymphoma
-
-
+
+
+
EA restricted only
Nasopharyngeal carcinoma
-
-
+
+
+
EA diffuse only
8. Prevention, treatment (none), and control measures are not very
effective.
EBV
Infectious mononucleosis: A 23-year-old college student develops
malaise, fatigue, fever, swollen glands, and pharyngitis. After
empirical treatment with ampicillin for sore throat, a rash appears.
Heterophile antibody and atypical lymphocytes were detected
from blood.
d. human cytomegalovirus (HCMV)
1. virus characters
--Virus has the largest genome in herpesviruses.
--Virus only infects humans (species-specific).
--Virus causes cytomegalic effect and basophilic
nuclear inclusion body (Fig. 17).
2. Pathogenesis and immunity
--Virus replicates in epithelial cells, fibroblasts, and macrophages.
--Virus establishes latency in T cells and macrophages.
--Cell-mediated immunity is important for regulating productive
and latent infection. So normal individual develops subclinical
infection and immunocompromised patients suffer severe disease.
3. Epidemiology and clinical syndromes
Table 54-5. Sources of Cytomegalovirus Infection
Age Group
Source
Neonate
Transplacental transmission, intrauterine infections, cervical secretions
Baby or child
Body secretions: breast milk, saliva, tears, urine
Adult
Sexual transmission (semen), blood transfusion, organ graft
Table 54-6. Cytomegalovirus Syndromes
Immunosuppressed
Patients
Tissue
Children/Adults
Predominant
presentation
Asymptomatic
Disseminated disease, severe
disease
Eyes
-
Chorioretinitis
Lungs
-
Pneumonia, pneumonitis
Gastrointestinal tract
-
Esophagitis, colitis
Nervous system
Polyneuritis, myelitis
Meningitis and encephalitis, myelitis
Lymphoid system
Mononucleosis syndrome, post-transfusion syndrome
Leukopenia, lymphocytosis
Major organs
Carditis,* hepatitis*
Hepatitis
Neonates
Deafness, intracerebral calcification, microcephaly, mental
retardation
4. Epidemiology and clinical syndromes
--Congenital infection: Virus infects 0.5-2.5% newborns. Among these,
10% show disease, such as small size, thrombocytopenia,
microcephaly, intracerebral calcification, jaundice,
hepatosplenomegaly, and skin rash (cytomegalic inclusion disease)
--Perinatal infection causes pneumonia and hepatitis in premature
infants, but no serious disease in healthy full-term infants .
--Infection of children and adults (up to 85% population) causes a
heterophile-negative mononucleosis similar to that of
EBV infection but less severe.
--Transplant donors are screened for CMV, because CMV causes
failure of (kidney) transplants.
5. Lab. Test
Table 54-7. Laboratory Tests for Diagnosing Cytomegalovirus Infection
Test
Finding
Cytology and histology*
"Owl's-eye" inclusion body
Antigen detection
In situ DNA probe hybridization
Polymerase chain reaction (PCR)
Cell culture
Cytologic effect in human diploid fibroblasts
Immunofluorescence detection of early antigens (most common)
PCR
Serology:
Primary infection
6. Treatment (p. 549, box 5; Ganciclovir*, Valganciclovir*, foscarnet*
Cidofovir*) and control
-- Safe sex and screening of transplant and blood donors.
--Vaccine is not available.
Cytomegalovirus
Congenital CMV disease: A neonate exhibits microcephaly,
hepatosplenomegaly, and rash. Intracerebral calcification is
noted on the radiograph. The mother had symptoms similar
to mononucleosis during the third trimester of her
pregnancy.
e. Human herpesvirus 6 and 7 (HHV6 & HHV7)
--HHV6 is isolated from AIDS patients;
grows in T-cell cultures (lymphotropic); and
causes exanthema subitum (rosela) in children;
--100% adult population is seropositive.
--HHV7 is isolated from the T cells of a patient with AIDS and shown
to causes exanthema subitum.
Human Herpes Virus 6
Roseola (exanthem subitum): A 4-year-old child experiences a
rapid onset of high fever that lasts for 3 days and then
suddenly returns to normal. Two days later, a maculopapular
rash appears on the trunk and spreads to other parts of the
body.
f. Human herpesvirus 8 (HHV 8) or
Kaposi’s sarcoma-associated herpesvirus (KSHV)
--Viral DNA is found in Kaposi’s sarcoma of AIDS patients.
--Viral DNA is associated with B cells in 10% normal people.
-- A sexually transmitted disease ?
g. Herpes simiae (B virus), is the simian counterpart of HSV
--- transmitted by Asian monkey bites or secretion
--- not pathogenic for monkeys but highly pathogenic for humans
with a death rate of 70%
--- Infected people develop vesicles in virus entry site and
encephalopathy.
--- ACV is recommended for treatment.
CASE STUDIES AND QUESTIONS
A 2-year-old child with fever for 2 days has not been eating and has been crying
often. On examination the physician notes that the mucous membranes of the
mouth are covered with numerous shallow, pale ulcerations. A few red papules
and blisters are also observed around the border of the lips. The symptoms
worsen over the next 5 days and then slowly resolve, with complete healing after
2 weeks.
1. The physician suspects that this is an HSV infection. How would the diagnosis be
confirmed?
2. How could you determine whether this infection was caused by HSV-1 or HSV-2?
3. What immune responses were most helpful in resolving this infection, and when
were they activated?
4. HSV escapes complete immune resolution by causing latent and recurrent
infections.
What was the site of latency in this child, and what might promote future
recurrences?
5. What were the most probable means by which the child was infected with HSV?
6. Which antiviral drugs are available for the treatment of HSV infections? What are
their targets? Were they indicated for this child? Why or why not?