Lec 33 CMV EBC other Herpes Flashcards
What are 3 drugs used to treat CMV?
- ganciclovir
- valganciclovir
- cidofovir
What are the common characteristics of herpes viruses?
- large
- enveloped
- double strand DNA
- ubiquitous [except HHV 8]
- chronic/latent infection follows acute
- reactivations common
- mostly transmitted by close contact during asymptomatic reactivation and shedding [except varicella]
What is the one herpes virus that is not ubiquitous?
HHV8
Who is at higher risk for getting herpes viruses?
- immunocompromised particularly with CMI deficiency
What are clinical symptoms of EBV?
causes mononucleosis syndrome
- fever
- pharyngitis
- lymphadenopathy
- hepatosplenomegaly + mild hepatitis
- rash
- atypical lymphocytes
- rarely also: upper airway obstruction, splenic rupture
- resolves in 2-3 wks –> fatigue/malaise may last longer
What causes mononucleosis syndrome?
EBV
What is pathogenesis of mono syndrome?
- resolves in 2-3 wks –> fatigue/malaise may last longer
Who gets mono?
- early childhood usually asymptomatic
- adolescence/early adult hood
- 70% of US population infected by age 30
What happens if you give amoxicillin to pt with EBV?
can trigger a non-allergic rash
What is pathogenesis of EBV?
acute
- get EBV infection from saliva of infected person
- EBV infects resting memory B lymphocytes and establishes latency = main target
- host mounts immune response [humoral and cell mediated]
chronic
- EBV transforms/immortalizes B cells
- cell mediated immunity [EBV-specific cytotoxic T] keep B cells from proliferating out of control
- from time to time: virus can reactivate and enter lytic replication and be shed in saliva
What is pathogenesis of EBV in immunocompromised?
- balance is lost of im
- B cells proliferate out of control –> get lympho-proliferative disorders and cancers
How is EBV transmitted?
- through saliva from subject with acute disease or with asymptomatic reactivation
- through organ transplantation
What is the receptor for EBV infection? where is it located?
CD21 receptor –> on B cells and epithelial cells of oral mucosa and salivary glands
What is immune response to EBV?
- specific cytotoxic T cells control immortalized B cell proliferation
- expansion of this T cell population causes
- – atypical lymphocytosis
- – hyperplasia of lymphatic organs
What is basis of monospot test? who is is sensitive test for?
sensitive for: adolescents/adults, not young children
- basis of test = heterophile antibodies
==== non-specific IgM antibodies that sometimes stick to red blood cells and don’t play a role in controlling the infection
What antibodies initially present in EBV infection? later? after months of time?
initially: high IgM and IgG against viral capsid antigen
later: antibodies against early antigen appear, IgG persists, IgM decreases
fast forward: IgG persists, IgM goes away, EBNA [antibody against epstein barr nuclear antigen] starts to appear
What does a positive EBNA tell you?
patients had mono previously [months or years ago] but it is now resolved
What cancers associated with EBV?
- African [endemic] Burkitt’s lymphoma
- sporadic burkitt’s lymphoma [less closely associated]
- nasopharyngeal carcinoma
- hodgkins lymphoma
- primary CNS lymphoma in AIDS
- post transplant lymphoproliferative disease
What are two symptoms/diseases associated with EBV and HIV co-infection?
- oral hairy leukoplakia [white patch on side of tongue, non-malignant]
- CNS lymphoma
What is chronic active EBV? what types of antibodies do you find?
- begins with infectious mononucleosis but acute infection is not adequately cleared
- high titers of EA and VCA antibodies, lack of appropriate EBNA response
- major organ involvement, persists for months
- high mortality
What is treatment for EBV?
- supportive treatment
- reduce immunosuppression in transplant recipients
- rituximab [anti-CD20] for some EBV related malignancies
What is rituximab? mech of action
- an anti-CD20 monoclonal antibody
- CD20 = a B cell surface receptor
- acts by: directly causing B cell apoptosis, activating complement-dependent cytotoxicity, activating antibody-dependent cell mediated cytotoxicity
- used to treat some EBV related malignancies
What percentage of population of young adults has CMV?
70-90%
How is CMV transmitted?
- through secretions of acutely and chronically infected
- saliva, vaginal fluid, semen, urine
- through blood transfusion, organ transplantation, mother –> infant
What is pathogenesis of CMV infection?
- infects and remains latent in lymphocytes
- down-regulates immune system by down-regulation MHC 1 expression
uses UL 54 protein [ a DNA pol] and UL 97 protein [a viral kinase]
What immune pathway is essential for maintaining control of latent CMV infection?
cell mediated immunity
What is UL 54 protein?
CMV DNA polymerase
What is UL 97 protein?
CMV viral kinase, phosphorylates Gancyclovir which is a viral polymerase inhibitor
What syndrome associated with CMV [non-congenital] infection?
- EBV negative infectious mononocleosis = milder form of EBV that is pretty asymptomatic, most patients are unaware they are infected
- common opportunistic pathogen in transplant recipient and pts with AIDS [retinitis, pneumonia, colitis, hepatitis, esophagitis, kidney graft failure]
- guillain barre syndrome
What happens in congenital CMV infection?
- affects 1% of newborns
- # 1 cause of congenital hearing loss in US
- CNS disease with calcifications
- retinitis
- long lasting lytic infection
What is the biggest cause of congenital hearing loss in US?
congenital CMV infection
How is CMV diagnosed? definitively?
- not usually lab tested in healthy individuals
- use PCR [in immunocompromised]
- IgG seroconversion or IgG avidity test [for pregnant women with acute infection to test for risk of transmission to fetus]
- urine culture [for neonatal disease]
definitively need biopsy: inclusion bodies [owl eyes] or immunohistochemistry
How do you test whether a pregnant woman with acute CMV is likely to pass it on to fetus?
IgG seroconversion or IgG avidity test
How do you diagnose congenital CMV?
urine culture
What are the first line treatments for CMV?
ganciclovir = nucleoside analogue valganciclovir = better orally absorbed ganciclovir prodrug
What is mech of ganciclovir action?
- GCV phosphorylated by UL97 viral prtoein kinase
- then phosphorylated 2x more by cell enzymes
- GCV- tri Phosphate then inhibits DNA polymerase [UL54]
What is mech of resistance to ganciclovir?
mutations in UL97 or UL54
What are the two second line CMV treatments?
- cidofovir
- foscarnet
What is mech of action of cidifovir? how is it administered? side effects?
- cidifovir = cytosine analog that inhibits viral DNA pol
- administered IV
- can be nephrotoxic, give with probenecid to block active tubular renal secretion
What is mech of action of foscarnet? how is it administered? side effects?
- foscarnet = non-nucleoside analog that inhibits viral DNA
- administered IV
- can be nephrotoxic, cause electrolyte abdnormalities
What is disease of HHV-6? pathogenesis?
- exanthema subitum [Roseola]
- start with high fever –> then fever leaves and get rash
- infects lymphocytes/monocytes and other tissues
- most children infected by age 2-3
- occurs in transplantation
What is disease of HHV-7? pathogenesis?
- causes roseola
- infects lymphocytes
- almost all children are infected by age 5
What is diease associated with HHV 8?
karposi sarcoma
What is roseola?
roseola = exanthema subitum
start with high fever for a few days then fever leaves and get rash
occurs in infants/young children
What is karposi sarcoma?
get vascular tumors = HHV8 inside endothelial spindle cells
Where is HHV8 endemic? who gets it?
endemic in africa, mediterranean –> spread person to person and by sexual transmission
not endemic to US –> associated with AIDS in MSM, get by sexual transmission
