Herpes Flashcards
Herpes Viruses
- related large enveloped DNA viruses
HSV1 - herpes Simplex Type 1 60-90% prevalence in young adults
HSV2 (15-30%)
VZV - Varicella Zoster Virus (shingles, chickenpox) (95%)
CMV - cytomegalovirus (birth defects) 30 - 80% - problem with immunocompromised and birth defects
EBV - Epstein Barr virus. (Mononucleosis) 90%
HH6 - human herpes virus 6 - roseola, cause xanthum, rash in children > 90%
HH7 not a real thing
HHV-8 - kaposi’s sarcoma 5 - 10%
Common Feature of Herpes Virus
Enveloped/not
Proteins
Symptoms
Genome
Hallmark
- morphologically similar, enveloped
- many spike glycoproteins
- make about 100 proteins
- ubiquitous (except HHV-8)
- infection is often asymptomatic
- linear DNA genome; replicate in nucleus
- HALLMARK: all establish latent infections
- life long persistence in cells, reactivation can produce disease, frequently reactivates in immunocompromised host
Common features of herpes viruses: Replication
Productive (lyric) infection
- host cell supports virus growth
- viral genome replicated and viral proteins made
- complete progeny visions produced and released
Latent infection
- virus is ‘hidden’ inside a cell
- expression of viral genes restricted
- no virus particles produced
- reservoir for re-activation and recurrent infection
- reactivation triggered by fever, stress, menses, UV light, trauma immune suppression
Common Features: Cell types
During lyric infection, herpes viruses can infect many different cell types, usually > 2
But herpes virus establishes latent infection in a specific cell type (eg neurons or specific immune cells)
- EBV in B cells, HSV1 in neurons
Common Features: Spread
Close person to person contact: mixing and matching of skin and mucous membranes
- mouth and respiratory tract
- genital tract
- across placenta; during birth
- blood cells (Eg transfusions)
- transplants (eg solid organ and stem cell)
No seasonality or epidemic patterns
No animal reservoir
General Concepts in Herpes virus pathogenesis and disease
Primary infections more severe than recurrent infections that may occur months to years later becuase you have antibodies and immune response against them
Populations with severe infections
- immunodeficiency eg HIV
- immunosuppressed eg transplant recipients, cancer patients
- fetus/newborns
- malnourished
- burn victims
Treatment of Herpes Virus Infections
Two classes of drugs to treat HSV1, 2, VZV, and CMV
Acyclovir (Aciclovir) and its derivatives:
- valacyclovir
- famciclovir
- ganciclovir
- all basically the same- they are prodrugs - must be phosphorylated byviral thymidine kinase, incorporated into growing viral DNA chain, act as chain terminators
- mutations in viral thymidine kinase confers resistance because the drug doesnt get phosphorylated: if it doesnt get phosphorylated it wont resemble nucleotide and get incorporated into the DNA
Foscarnet - inhibits viral DNA pol
- used for acyclovir-resistant HSV and CMV
- used for CMV retinitis
No specific drugs for EBV, HHV6, HHV7, HHV8
Herpes Simples Virus 1
HSV1: respiratory spread in childhood; infect mucosal epithlium; latent focus in trigeminal ganglia; recurrences < HSV2
Encephalitis, conjunctivitis, gingivostomatis, tonsillitis, labialis, pharyngitis, esophagitis, herpes gladiatorum, tracheobronchitis, genital herpes, herpes whitlow
HSV2
Spread by intimate sexual contact
Infects genital mucosa
Latent in lumbosacral dorsal root ganglia
Recurrences > HSV-1
Meningitis, gingivostomatitis; tonsillitis; labialis; pharyngitis; perianal herpes; genital herpes, herpes whitlow
Common vs actual perception HSV1 vs HSV2
Common:
- HSV1 above waist, HSV2 below
Actual
- 20-50% of genital infections are HSV1
- 5 - 20% of oral herpes infections are HSV2
Gingivostomatitis:
HSV-1 > HSV2
- most common primary symptomatic infection HSV1 infection
- generally seen in children and young adults; 13- 30% of affected children
Prodrome of fever, malaise irritability, headache, vomiting, lymphadenopathy 1 - 2 days. Prior to lesions
Small vesicles on the inside of cheeks, gums, tongue, and mucous membranes of mouth that rapidly ulcerate with time ‘dewdrop on a rose petal’
Ulcers are PAINFUL
Perioral vesicular lesions also observed
Strikingly swollen and tender gums
Latency in trigeminal ganglia (bc HSV1)
Recurrence = cold sore (herpes labialis) - oral recurrences more common after HSV1 than HSV2, usually a single crop, shorter lived
SEE PICTURE ON SLIDE 14
Genital herpes; HSV2> HSV1
Pic on slide 16
Most common primary symptomatic HSV2
Incidence > 500,000 cases/yr
Acquisition correlates with number of sexual partners
Women are more susceptible than men: 8% vs 2% annual acquisition rate
70% of cases are acquired from asymptomatic partner
- during active stage, disease contagious by direct contact, excretion of virus can persist for 3 weeks and virus shedding is frequently present in absence of symptoms (can transmit infection to sexual partners)
Antivirals and condom use reduce risk
HSV2 genital ulcers increase risk of acquiring and transmitting HIV1
10 - 21 days of vesiculoulcerative lesions, intense pain and fever, may be associated with malaise, itching and burning dysuria, inguinal lymphadenopathy
HSV2 ulcer disease increases risk of acquiring and transmitting HIV, how? acquiring and Transmitting of genital
Acquiring: ulcer offers an entry site for HIV and attracts CD4= T cells which support HIV replication
Transmitting: higher levels of HIV shedding occur in subjects with genital ulcers
Genital Herpes Recurrences
2/3
Reactivation from latently infected sacral ganglia
More likely after HSV2 than HSV2; immunocompromised vs immunocompetent
Symptoms less severe than primary disease
- shorter shedding duration, lack constitutional symptoms
- fewer lesions, heal sooner
Frequency rates of recurrences
- 90% will have > 1 recurrence per year, 40% will have > 6, 20% will have > 10
Recurrence severity: HSV2> HSV1
Herpes Keratoconjunctivitis
Slide 18
1 cause of infectious blindness in developed world
HSV1 infection of eye
Severe conjunctivitis and keratitis with damage to cornea
Corneal transplants done to replace damaged cornea
Can get dendritic ulcers
Herpes Encaphalitis- primarily HSV-1
Most common acute caus eof sporadic encephalitis
Result of primary or severe recurrent infection
Classic presentation
- fever
- headache
- focal neurological deficits
- temporal lobe involvement
- if you see these Sxs and a temporal lobe lesion, think HSV and treat immediately
FOCAL FINDINGS ARE HALLMARK becuase the virus remains localized to one or more temporal lobes
Other findings: RBCs in CSF, CSF. Pleocytosis, behavioral changes, decreased level of consciousness
High mortality/morbidity if not treated
Treat with acyclovir class of drugs!
HSV Meningitis- Priimarily HSV2
Recurrent episodes of HSV meningitis
Usually caused by HSV2 from genital infections
Present with fever, headache, nausea, vomiting, photophobia, stiff nick - classic meningitis signs
Illness self limited and not life threatening unclear if acyclovir treatment is beneficial
Patients can be quite ill
In presence or absence of genital lesions
No permanent neurological sequelae
Recurrences can be separated by years
Other skin infections- mostly HSV1
Pics 21, 22
Traumatic herpes
Local lesions on fingers and hands (eg suck on thumb, Called hermetic whitlow - primary or recurrent infections in fingers and hands) and on bodies of wrestlers (mat herpes or herpes gladiatorum) and rugby players (scrum pox, or herpes rugbiaforum)
Virus enters through abrasions/openings in skin
HSV1 or HSV2
Seen in hospital personnel, dentists, dental hygienists
Young children form thumb sucking
HERPETIC WHITLOW
Infections in immunocompromised host - slide 23
Everything
- localized invasive skin infx
- extensive at usual sites (oral and genital) or unusual sites (within mouth, esopahgus, or intestinal mucosa)
- lesions progress slowly–> necrosis
- healing slow or negligible
- sever infection can also occur in persons with underlying skin disorders (eczema) or burns
TORCH INFECTIONS
T = toxoplasmosis O = other (syphilis, HIV, VZV,, Parvo B10) R = rubella C = cytomegalovirus H = herpes simplex
Infx cause congenital abnormalities including rash and ocular findings, if fetus exposed to them in utero
Neonatal herpes
HSV2
Transmitted through infected birth canal - most women asymptomatic
Occurs 1 - 2 weeks after delivery
Almost always symptomatic
Primarily (~75%) caused by HSV2
Three syndromes
- 45% skin eye mouth (SEM)
- 33% encephalitis (CNS)
- 25% disseminated disease DIS
Occurrence of lesions: SEM (90%) > CNS (60%) > DIS (20%)
Babies may have disseminated disease without skin lesions, making diagnosis difficult
Varicella Zoster Virus (VZV)
Two distinct diseases
Primary varicella (chickenpox)
Recurrence: herpes zoster (shingles)
VZV pathogenesis
During primary infx, 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
Varicella Epidemiology in US
Prior to vaccine in 1995
- all children infected by 10, highly contagious, complicated in infants < 1
After live attenuated vaccine 90% reduction in chickenpox cases
- two doses given to children at ages of 2 and between 4 and 6
VZV clinical symptoms
Incubation period 10-21 d
Prodrome: fever (100-103 F), malate, pharyngitis
Followed by generalized rash in 24 hours
Rash begins on chest back and face, spreads rapidly and lasts 3 - 5 days
Rash starts out maculopapular and then small fluid filled vesicles with central dimple (umbilication) on a red base; rash is itchy
All stages of rash present at any given moment- avg 300 lesions
Highly contagious at 1-2 days befor rash onset to 4 - 5 d after rash onset
VZV complications
Slide 30
Chickenpox generally self-limited
Bacterial superinfection of skin (Cellulitis) - renders of skin beginning near a lesion and spreading (staph or strep caused)
Encephalitis: VZV spread to cerebellum and cause unsteady gait (ataxia)
PNEUMONIA: majority of morbidity and mortality in teens and adults
Hepatitis
Congenital and perinatal infections (if fetus infected when mother develops chickenpox–> damage to infants Brian or infants born to mother with active chickenpox and can be life threatening)
Immunocompromised: everything more severe, life threatening pneumonia, encephalitis, progressive-disseminated varicella
When VZV reactivates–> Zoster(shingles)
Slide 31
Unilateral vesicular rash that follows a dermatome distribution following reaction of VZV in a single dorsal root ganglion
Rarely crosses midline
Rash involves thoracic and lumbar distribution; ophthalmic distribution can lead to serious eye infection
Post herpetic neuralgia: persistence of pain > 90 days after healing of rash in 20% of patients
Zoster epidemiology - VZV recurrence
Age is most important risk factor although anyone with prior primary VZV can get shingles
Incidence increases with age, dramatic increase after 50
Immunocompromised and underlying disorders are other risk factors
Zoster vaccine recommended in adults > 60 yo; reduces zoster by 50% and post herpetic neuralgia by 67%
Cytomegalovirus
Pic 34 l
Infx common and usually asymptomatic in healthy children and adults
Most adults infected
Large owls eye inclusions, giant cells with intranuclear owls eye inclusion
Clinical link CMV to congenital infections and immunocompromised individuals
What is the #1 congenitally acquired viral infection
CMV
CMV EPi
Infects humans of all ages
Seroprevalence increases with age, 50% by 30, 60-80% by 60
Prevalence peaks 2 - 5 (day care or school) and young adults (sexual)
Crowded living is risk factor
Routes of infection
- oral 30-70% infection rates in daycare
- sexual transmission
- blood transfusions (now blood depleted of WBC)
- organ transplantation - CMV-negative recipients at greatest risk for disease
Epidemiology of congenital CMV
C in torch
Leading infectious cause of birth defects
Primary: maternal infection poses much greater risk to fetus than reactivation
Infection in early pregnancy (first 12 - 16 weeks) poses highest risk to developing fetus
Infx in mother almost always asymptomatic, no warning the fetus is at risk
CMV infection detected in 1% of newborns and is most common identified infectious cause of birth defects
Risk of CMV transmission to fetus and rate of symptomatic fetal infection are much Ghiberti with primary maternal infection
In primary infection 90% of babies become infected and of those, many have congenital abnormalities
Clinical manifestations: congenital CMV
Slide 37
Petechial rash - blueberry muffin baby
CMV retinitis
Brain malformations - periventricular calcification - enlarged ventricles - microcephalic Leads to seizures cognitive deficits
Jaundice with hepatosplenomegaly
Hearing loss - can occur at birth if symptomatic CMV, can occur over first several years if infx asymptomatic
Even if no symptoms at birth can develop sensorineural hearing loss, visual impairment, psychomotor and or intellectual disabilities later in life
CMV in immunocompromised patients pic slide 38
HIV: reactivation with CD4 < 50 less common with HAART
Tranpslants
Any other immunosuppressed
Can get bad viral pneumonia, retinitis
Esophagitis with round solitary ulcer
CMV mononucleosis
Slide 39
Mononucleosis like syndrome
79% EBV, 21% CMV
Frequent manifestation of priamry CMV infx in young adult
Syndrome: fever 2 - 4 weeks, fatigue, mild h epatitis, lymphocytosis and small % of atypical lymphocytes in blood
- exudative pharyngitis frequently absent
- lymphadenopathy less common
Heterophile antibody negative - IgM class antibody that agglutinate RBC from certain species like sheep
Epstein Barr Virus
Infects and transforms B lymphocytes
- binds to cd21 on B cells, some become latently infected
- also infects epithelial cells in oral cavity
EBV diseases
Mono
Cancer: burkitts lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma (B cells affected)
Lymphoproliferative disorders (psottransplant lymphoproliferative disease, oral hairy leukoplakia)
Seroprevalence 50% by age 5, 90 by age 20
Spread by oral secretions - the kissing disease
Often asymptomatic can be shed for years
EBV clinical symptoms: IM
Slide 42
Classic triad
- lymphadenopathy
- splenomegaly - avoid contact sports
- exudative pharyngitis
Fever malaise and rash can appear if mistakenly treated with ampicillin
War b/w infected B cells and the T cell response
- pharyngitis due to respond to infected epithelial cells
- fatigue due to energy needed to power robust T cell response so you are tired al the time
EBV lab finding and diagnosis
Slide 43
Symptoms
Peripheral blood smear: see atypical lymphocytes (Activated T cells, called Downey cells)
CBC; activated T cells, can comprise up to 80% of total WBC
Serology: heterophile AB positive (monospot test) - Ab that cause sheep red cells to clumb
EBV: heterophile + mono
CMV: heterophile - mono
EBV associated malignancies and lymphoproliferative disorders
slide 44
Burkett lymphoma
- jaw tumor of African children, EBV–> chromosomal translocation leading to activation of cmyc oncogene
Other lymphomas- Hodgkin, T cell head and neck, CNS (in HIV infected)
Nasopharyngeal carcinoma - cancer of epithelial cells common in males of Chinese origin
Post-transplant lymphoproliferative disorder (PTLD) - occurs in setting of immunosuppression associated with transplantation, can range from B cell expansion to lymphomas
Oral hairy leukoplakia**: excessive wart like growth of papillae on tongue, in advanced HIVi and othe rimmunosuppressed
- one of most common virally induced oral diseases in HIV patients
- cant be scrapped off like oral thrush
HHV - 6 - Roseola
Most common cause of roseola infantry
- rose red rash of children (sudden rash - exanthum subitum), virtually all children infected by 4 yo
- HHV causes ~10% roseola
Undifferentiated febrile illness without rash
- HHV6 accounts for 5 - 25% of ED visits for fever in infants
HIGH FEVER febrile seizures common with roseola
- responsible or 1/3 febrile seizures in children up to 2 years old
Lymphotropic virus (infects CD4+ T cells in particular); causes transient immunosuppresion and can exacerbate disease with other viruses
HHV6 exanthum subitum
Slide 47
Abrupt onset of high fever (104) that persists 2 to 5 d
Child is normally fussy and irritable
Rash develops coincidental with abatement of fever
- rash first appears on neck, behind ears and on back
- it blossoms
- spread to trunk and abdomen
- some rash on face and arms and legs
- maculopapular in appearance, not itchy or uncomfortable
- no treatment no vaccine
HHV 8 (KSHV)
Slide 49
Cell tropism for CD19+ B cells, macrophages, endothelial cells
Painless purplish macules, nodules or plaques
Tumors mostly on skin, but can involve any organ
Pathology shows spindle shaped tumors with red cells
LAb diagnosis of Herpes Viruses
No point of care ot true rapid tests
For HSV1/2 and VZV molecular is recommended
Serology still primary method for otherwise healthy populations for EBV
For CMV and HSV1/2 serology is limited to pregnant women with fetal abnormalities requiring TORCH investigation or for donor/recipient screening prior to transplant
Old fashioned: culture Tzanck test (look for multinucleated cells in skin vessels)
