Herpes Viruses Flashcards
1
Q
List the 8 herpes viruses of this lecture.
A
- HSV-1
- HSV-2
- VZV
- CMV
- EBV
- HHV-6
- HHV-7
- HHV-8
2
Q
What type of immunity is required to control herpes?
A
-cell-mediated immunity
3
Q
Describe the structure of herpesviruses
A
- large enveloped icosahedral capsids
- large double stranded DNA
- encode many proteins to manipulate host and host IS and promote viral replication
- limited DNA homology
4
Q
2 functions of non-structural genes herpesviruses encode
A
-modulators of host cell gene expression and host immune responses
5
Q
List the subfamilies of herpes viruses, their biological properties, and the official names of the viruses
A
- Alpha-herpesviruses: fast growing, cytolytic; infect mucoepithelial cells; latent in neurons; HSV1, HSV2, VZV
- Beta-herpesviruses: slow growing, cytomegalic, infects and latent in epithelial cells, endothelial cells, and leukocytes; CMV, HHV 6, HHV 7
- Gamma herpesviruses: lymphoproliferative, infects and latent in lymphocytes and other cells; transformative; EBV, HHV-8
6
Q
What is the Herpes B virus? What is unique about this?
A
- alphaherpesvirus transmitted to humans by bite of macaque monkey
- only nonhuman primate herpes virus causing severe pathogenicity in humans
7
Q
Name and describe the 2 modes of replication of herpesviruses
A
- Productive (lytic) infection: host cell supports virus growth, viral genome replicated and viral proteins made, complete progeny virions produced and released
- Latent infection: virus is hidden inside cell, expression of viral genes restricted, no virus particles produced, reservoir for reactivation and recurrent infection
8
Q
What can trigger reactivation of latent herpetic infection?
A
-fever, stress, menses, UV light, trauma, immunesuppression
9
Q
4 steps of herpes lytic infection
A
- viral entry via envelope FUSION with cell membrane
- Nucleocapsid transport to nucleus
- Nuclear events: viral gene transcription, genome replication, progeny nucleocapsid assembly
- Nucleocapsids bud from nucleus, viral envelope formed from nuclear membrane, release by exocytosis
10
Q
Where do herpes viruses replicate? Where do they get their envelope from?
A
- nucleus
- nuclear membrane
11
Q
Describe what occurs in terms of gene expression during the lytic lifecycle
A
- occurs in temporal cascades that are tightly regulated
1. Alpha: immediate early (IE) regulators of viral gene expression
2. Beta: early- proteins required for genome replication
3. gamma (late): virion structural proteins
12
Q
Describe gene expression in latency vs. lytic lifestyles
A
- lytic: temporal cascades that are highly regulated
- latent: RESTRICTED, only kept around is used to maintain latency
13
Q
Compare the cell types infected in a latent vs. lytic herpes infection
A
- latent: infects few ( 1 or 2) cell types
- lytic: infects many cell types, usually >2
14
Q
Spread of herpes viruses and examples of transmission
A
- person to person in close contact
- no animal reservoirs
- transmission: mouth and respiratory tract, genital tract, across placenta or during birth, blood cells during transfusions, transplants
15
Q
Give the spectrum of disease severity: when and who is it better or worse in? Who gets severe infections?
A
- high severity: primary infection and immune impairment
- low severity: recurrent infection and immune competent
- Severe infection populations: immunodeficient (HIV), immunosuppressed (cancer, transplant), fetus/newborn, malnourished, burn victims
16
Q
What immune response is of prime importance in herpes viruses?
A
- cell-mediated and especially T cells
- antibodies are somewhat effective, but complement is not
- immunity helps control reactivation
17
Q
2 ways herpesviruses evade immune system
A
- viral glycoproteins evade antibody and complement
2. encode proteins that interfere with MHC Class I antigen presentation
18
Q
Serotypes of herpes simplex virus, where they infect, and where they are latent.
A
- HSV-1 and HSV-2
- infect mucosal epithelium
- HSV1: latent focus in trigemical ganglion
- HSV2: latent in lumbosacral dorsal root ganglion
19
Q
How many HSV infections are asymptomatic?
A
-75%
20
Q
Describe gingivostomatitis presentation; what causes it; who gets it?
A
- most common primary symptomatic HSV1 infection
- generally seen in children and young adults (10-30%)
- prodrome of fever, malaise, irritability, headache, vomiting, lymphadenopathy 1-2 days before lesions
- then small, vesicles on inside of cheeks, gums, tongue and mucous membranes of mouth that rapidly ulcerate with time
- very painful
- perioral lesions also observes
- swollen and tender gums
- latency in trigeminal ganglion
21
Q
Recurrent cold sore (herpes labialis) is usually caused by what HSV?
A
-oral recurrences more common after HSV-1 than HSV2
22
Q
What can cause genital herpes infections? 3 types of genital infections? Risk of other illnesses? How to prevent?
A
- HSV-1 or HSV-2, but HSV-2 is more common
- 3 infection types: primary, primary first episode, recurrent
- acquisition correlates with # of sexual partners; women more susceptible
- antivirals and condom use reduce risk
- HSV-2 genital ulcers increase risk of acquiring and spreading HIV
23
Q
Describe the course of a primary genital herpes lesion
A
- 10-21 days of vesiculoulcerative lesions, intense pain, and fever
- may be associated with malaise, itching and burning, dysuria, and inguina lymphadenopathy
24
Q
Genital herpes recurrences
A
- 2/3 have them
- reactivation from infected sacral ganglia
- more likely after HSV-2 infection and in immunocompromised
- symptoms less severe than primary disease
- HSV2 recurrence severity is worse than HSV1
25
Neonatal herpes: when do they get it? when does it present? 3 syndromes
- transmitted through infected birth canal when most women are asymptomatic
- 1-2 wks after delivery
- almost always symptomatic
- 75% due to HSV2
- 3 syndromes: skin, eye, mouth (SEM); encephalitis (CNS); disseminated disease (DIS)
* *not congenital, acquired during birth**
26
How can herpes impact the eyes? Which form causes this? Why is it so serious? What may recurrences eventually form?
- Herpes keratoconjunctivitis
- HSV-1 infection of eye
- #1 cause of infectious blindness in developed world
- severe conjunctivitis and keratitis with damage to cornea
- recurrences are common and may cause dendritic ulcers
27
What is the most common cause of acute sporadic encephalitis? How will patients present?
- HSV-1
- result of primary or severe recurrent infection
- fever, headache, focal neurologic deficits, temporal lobe involvement
- RBCs in CSF, CSF pleocytosis, behavior changes, decreased level of consciousness
* *deadly**
28
What usually causes HSV meningitis? What do patients present with? Is it life-threatening?
- usually due to HSV-2 from genital infections
- fever, headache, nausea, vomiting, photophobia, stiff neck
- self-limited and not life threatening
- can occur in presence or absence of genital flare
- no permanent neurologic sequelae
29
Eczema herpeticum: what causes it? what is it? who gets is?
- locally invasive skin infections due to HSV1- or HSV2
- any person with deficient cellular immunity or people with underlying skin disorders or burns
- infections may be extensive at usual sites or may appear at unusual sites
- lesions progress slowly and cause necrosis with slow/neglible healing
30
Herpetic witlow: what is it? what causes it? who gets it?
- traumatic herpes
- local lesions on fingers and hands
- virus enters through abrasions/openings in skin
- HSV-1 or HSV-2
- seen in hospital personnel, dentists, dental hygientists
31
If a wrestler or rugby player comes in with herpes all over one side of their face, what is the diagnosis?
- Herpes gladiatorum (mat herpes)
| - herpes rugbiaforum or scrum pox
32
What does VZV stand for?
-Varicella-Zoster virus
33
2 diseases caused by VZV
1. primary: varicella (chickenpox)
| 2. recurrence: herpes zoster (shingles)
34
Pathogenesis of VZV; where is latency established?
- during primary infection, virus infects respiratory mucosa through oral cavity
- replicates in oral cavity and regional nodes
- primary viremia leads to replication in liver and spleen
- secondary viremia results in infection of lymphocytes that carry virus to skin and other areas
- latency established within sensory neurons of dorsal root ganglia
35
Who is varicella particularly complicated in? What age group was is commonly in (before vaccine)?
-adults and infants <10
36
Varicella attach rates among susceptible household contacts in 80-90%. How is it transmitted?
-person to person via respiratory route or direct cutaneous contact
37
Varicella clinical symptoms
- incubation period is 10-21 days
- prodrome: fever, malaise, pharyngitis
- generalized rash within 24 hours: begins on chest, back and facel spreads rapidly and lasts 3-5 days
- all stages of rash present at any given time
- contagious 1-2 days before rash and 4-5 days after rash onset
38
Describe the rash associated with varicella
- begins on chest, back, and face and spreads rapidly
- starts out maculopapular and then small, fluid-filled vesicles with central dimple (umbilication) on a red base
- rash is itchy!!
- all stages present at any given time (unlike smallpox)
39
Varicella complications
- chickenpox is usually self-limited
- bacterial superinfections of skin (cellulitis)
- Encephalitis: spread to cerebellum and cause unsteady gait (ataxia)
- pneumonia
- hepatitis
- congenital and perinatal infections
- immunocompromised: pneumonia, encephalitis, progressive-disseminated varicella
40
What is the common cause of death in adults and teens due to varicella?
-pneumonia
41
Although anyone with a prior primary VZV infection can have zoster, what is the most important risk factor? What are other risk factors?
- age
- incidence progressively increases with age with a dramatic increase over 50 y.o
- immunocompromised and underlying disorders are other risk factors** zoster recurrences more common in immunocompromised
42
Zoster clinical features
- unilateral vesicular rash that follows a dermatomal distribution
- does not cross midline
- rash most commonly involves thoracic and lumbar distribution; ophthalmic distribution can lead to serious eye infection
- when tip of nose is involved, eye is often infected
43
What is Ramsay Hunt Syndrome? What are clinical features and complications?
- Herpes zoster oticus
- affects facial nerve near infected ear
- causes facial paralysis and hearing loss on same side as affected ear; vesicular lesions on external ear
- difficulty closing 1 eye, ringing in ears, vertigo, change in taste perception or loss of taste
- more common in adults over 60, but can be seen in children
- complications: permanent hearing loss and facial weakness; postherpetic neuralgia, possible cornea damage is eyelid will not fully close
44
Post-herpetic neuralgia (PHN)
- zoster complications
- persistence of pain (>90 days) after healing of rash
- occurs in 20% of adults
- more common if over 60
- risk factors: age, severity of pain before rash heals, number of lesions, ophthalmic distribution, comorbid conditions like cancer
45
Granulomatous angiitis
- a vasculitis of small vessels in CNS
| - zoster complication
46
5 zoster complications
1. severe pain
2. Post-herpetic neuralgia
3. Zoster in immunocompromised
4. eye infection in 10-25%
5. granulomatous angiitis
47
How to prevent VZV? Who is vaccine not given to?
- Live attenuated vaccine
- Varicella: 2 doses; side effect is rash
- Zoster: adults over 60, and 50-59 is recommended; same virus but with 14x potency
- avoid giving to immunocompromised (live attenuated!!)
48
Who is cytomegalovirus problematic in?
-newborns and those with compromised immune systems
49
What cells does CMV infect and remain latent in? What will these cells look like?
-epithelial cells, endothelial cells, and leukocytes (monocytes and macrophages)
50
CMV infects humans of all ages, but its prevalence peaks in what age ranges?
- 2-5 (day care or school)
| - young adults (sexual)
51
What is a major risk factor for CMV and what are 4 common routes of infection?
- crowded living is risk factor
| - oral, sexual transmission, blood transfusions, organ transplantation
52
Discuss epidemiology of congenital CMV
- leading infectious cause of birth defects
- prenatal, natal, and post natal spread
- primary maternal infection poses much greater risk to fetus than reactivation
- infection in early pregnancy poses highest risk to developing fetus
* *infection in mothers, like most CMV infections, are asymptomatic**
53
What is the leading cause of infectious cause of birth defects?
Congenital CMV, highest risk if infected early in pregnancy and it is the primary infection
54
1-4% of pregnant women will develop a primary CMV infection, and about 40% of them will transmit the infection to the fetus. Describe what happens to that 40% statistically.
- 10-15% will show the disease; of these 10% will be normal, but 90% will have sequelae
- 85-90% of fetuses will be asymptomatic, of which 5-15% will develop sequelae and 85-95% will be normal
55
What are the clinical manifestations of a fetus that congenitally contracts CMV from a mother's primary infection? What about from the mother's reactivation during pregnancy?
- Primary: any combination of intrauterine growth retardation, jaundice, hepatosplenomegaly, microcephaly, petechial rash, thrombocytopenia purpura, deafness, myocarditis, pneumonia, cerebral calcifications, chorioretinitis, motor disability; death may occur in first months of life, but more commonly infants survive but are neurologically damaged
- Reactivation: late onset hearing loss (15%)
56
What is the term commonly given to babies born with congenital CMV from their mother's primary infection?
-blueberry muffin babies
57
Discuss perinatal and postnatal CMV infection: how is it acquired, who gets it, what are symptoms?
- Perinatal: babies can acquire CMV at time of delivery due to maternal cerical excretion (10-15% shed from cervix, 4% shed virus in urine);
- highest among young mothers and lower SES
- most infants are asymptomatic; may see interstitial pneumonia
- post-natal transmission through breast milk is common and low-birth-weight infants are at greatest risk (premies)
58
A lot of CMV focuses on neonatal transmission, but what can it cause in other ages?
- Mononucleosis-like syndrome in normal host
- Infection in immunocompromised can be frequent and severe, but symptoms being worse if primary infection; disease in transplant/cancer differs from HIV patients
59
What is the frequent manifestation of a primary CMV infection in a young adult? Give the symptoms.
- CMV mononucleosis
- fever (2-4 wks), fatigue, mild hepatitis, lymphocytosis and small % of atypical lymphocytes in blood; exudative pharyngitis is absent and lymphadenopathy is less common
- heterophil antibody negative
60
2 huge causes of Mononucleosis and how you can differentiate the causes.
- EBV (79%) and CMV (21%)
| - In CMV, exudative pharyngiti is frequently absent, lymphadenopathy is less common, heterophil antibody negative
61
What is heterophil antibody and what syndrome is this key of?
- IgM class antibody that agglutinates RBCs from certain species
- seen in EBV mono, but not CMV mono
62
CMV is particularly common in what 2 groups of immunocompromised patients? Describe their clinical presentations.
- HIV: reactivation and diseases when CD4+ <50; retinitis, encephalitis, GI Tract-itis, uncommon in HAART era
- Transplants: prolonged fever (2-4 wks), malaise, lethargy, myalgia or arthalgia, leukopenia, thrombocytopenia, mild hepatitis, pneumonia (diffuse, bilateral infiltrate); onset 1-3 months posttransplant
63
What is retinitis?
-hemorrhages and exudates often around blood vessels
64
What cells does Epstein-Barr virus infect and transform?
- B-lymphocytes
| - also infects epithelial cells in oral cavity and monocytes and T cells
65
Clinical diseases of importance due to EBV
- infectious mononucleosis (IM)
- PTLD
- X-linked LPS
- Burkitt Lymphoma
- Nasopharyngeal carcinoma
- Lymphomas of CNS and others
- Hemophagocytic lymphohistiocytosis (HLH)
66
EBV is often asymptomatic except in what age group? What do these individuals get? How is it spread? What nickname has this acquired due to these facts?
- 10-30 y.o. get IM
- spread via oral secretions
- the kissing disease
67
Clinical symptoms of IM due to EBV; describe their blood cells.
- symptoms in over 50% of infections
- fever, exudative pharyngitis, lymphadenopathy, and fatigue; petechial rash on palate in 25-60%; facial edema in children
- can also have hepato and splenomegaly, and rash
- Lymphocytes will be 50-70% of WBVs with atypical lymphocytes comprising >20% of lymphocytes
- atypical lymphocytes: reactive CD8+ T cells that contain abundant cytoplasm and lobulated nuclei
68
EBV IM complications are uncommon in normal hosts, but include what issues?
- hepatitis
- maculopapular rash with antibiotic treatment!!!
- splenic rupture (why athletes should refrain from sports)
- autoimmune hemolytic anemia
- thrombocytopenia
- encephalitis
- overwhelming infection and death in X-linked LPS
69
5 categories of EBV-associated Malignancies
- Posttransplant lymphoproliferative disorder (PTLD)
- Burkitt Lymphoma
- Nasopharyngeal carcinoma
- Other lymphomas (Hodgkin, T cell, head and neck, CNS in HIV-infected)
- Oral Hairy Leukoplakia
70
What is Oral Hairy Leukoplakia associated with? (give 2 viruses) and describe it.
- excessive wart-like growth of papillae on tongue
- occurs in advanced HIV infection and other immunosuppressed patients
- one of the most common virally-induced oral diseases in HIV patients
71
EBV-Associated PTLD
- serious complication of organ transplantation and a common malignancy in transplanted children***
- usually associated with primary EBV infection, of which the donor organ can be the source
- B cell expansion ranging from reactive hyperplasias to aggressive large cell lymphomas
- rapidly fatal if not caught
72
Risk factors for PTLD
- type of organ transplanted
- primary vs. reactivated infection after transplantation
- type and degree of immunosuppression
- HLA mismatching
- history of symptomatic CMV
73
Treatment(s) of PTLD and why is it necessary to get it right!!
- PTLD necessitates decreased immunosuppression and/or removal of graft
- it may look similar to acute cellular rejection, which needs heightened immune suppression. They look alike but required different things!!!
74
2 ways to diagnose Oral Hairy Leukoplakia
1. visual diagnosis: tongue lesions consisting of thin white plaques on tongue
2. incisional biopsy: verrucous hyperplasia with EBV PCR positive and HSV and VZV negative; culture should be normal respiratory flora with no fungal growth
75
Human Herpesvirus-6 (HHV-6): what is it most closely related to? what does it infect? what are variants?
-closely related to CMV and HHV-7
-lymphotropic virus that infects CD4+ and CD8+ T cells, NK cells, macrophages and neural and epithelial cells
2 variants: A and B with B causing most primary infections in children
76
HHV-6 clinical manifestations
1. Most common cause of roseola infantum (exanthum subitum) rose rash of infants aka sudden rash
2. undifferentiated febrile illness without rash
3. febrile seizures common with roseola in children up to 2 y.o.
4. may also see IM, hepatitis, and neurologic syndromes
5. can contribute to HIV disease progression and exacerbate disease with other viruses
77
HHV-6 clinical manifestations with transplant
-fever, hepatitis, leukopenia, delayed engraftment, neurologic disease, skin rashes, pneumonia, bone marrow suppression
78
HHV-6 Exanthum subitum
- abrupt onset of high fever (104) that persisted for 2-5 days
- fussy and irritable child
- rash develops coincidentally with abatement of fever
- right as fever comes down, rash will appear on neck, behind ears, and on back where it will then spread to abdomen and trunk with some on face and legs/arms
- maculopapular in appearance and not itchy or uncomfortable
79
HHV-8: tropism, what it causes
- Tropism: CD19+ B cells, macrophages, endothelial cells
- Identified in all 4 types of Kaposi's sarcoma: classic KS, endemic, KS in transplantation, AIDS-related KS
- primary effusion lymphomas
- Multicentric Castleman disease
80
HHV-8 KS clinical features
- painless purplish macules, nodules or plaques
- tumors mostly on skin, but can involve any organ
- pathology shows spindle shaped tumors with RBCs
81
5 ways to diagnose herpesviruses
1. virus isolation in cell culture
2. nucleic acid amplification (NAAT)
3. Direct cytology or histology assays
4. detection of antibodies
5. genotyping/phenotyping
82
Cautions of using EBV Heterophil Antibody tests
- not specific to EBV, but uncommon in other conditions
- replies on polyclonal B cell stimulation
- Agglutinates RBCs (most sensitive in horse, least in sheep)
- False negatives common early in disease
- age specific development
- FALSE POSITIVES UNCOMMON
83
At presentation, EBV may not be detected in the blood, but is usually found in large quantities where?
- in oral cavity
| - virus cleared from blood much more rapidly than from oral compartment
84
Antivirals are commonly used to treat what herpesvirus infections? which ones do not have specific antiviral therapies? List the drugs and what they are prescribed for.
- Primarily used to HSV, VZV, and CMV
- Acyclovir or valacyclovir for HSV or VZV
- Famciclovir for HSV or VZV
- Ganciclovir or valganciclovir for HIV with CMV retinitis, GI tract infections or transplant with CMV pneumonia, hepatitis
- Foscarnet: mucocutaneous acyclovir-resistant HSV infections and CMV retinitis
- Cidofovir; Fomivirsen for CMV retinitis
85
Acyclovir mechanism of action and how resistance arises
- must be triphosphorylated to be active
- first phosphorylated by viral Thymidine kinase (TK)
- then p-lated to di- and tri- phosphate forms by cellular enzymes
- P-lated drug can then act as substrate for viral DNA polymerase and drug is incorportated into viral DNA to act as chain terminator and prevents elongation of viral DNA
- Resistance results from mutations that inactivate viral TK which prevents activation of drug
86
Compare common primary HSV oropharyngeal infections between adults and children.
Children: gingivostomatitis
| -primary infections in adults commonly cause pharyngitis and tonsillitis
87
Recurrent disease of oropharyngeal HSV infections is called what?
-herpes labialis (cold sores)
88
3 types of genital HSV infections and their definition.
1. primary infection: result of infection in patient who has never been exposed to either HSV-1 or HSV-2 and has no preexisting antibodies
2. Non-primary first episode: have previous infection with HSV and acquire other strain; fewer lesions due to some protective cross immunity
3. Recurrent infection: reactivate of genital HSV with HSV type that previously established infection in genital tract
