Cmv

Chapter 166 pp. 1049-1053

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CMV & HHV types 6,7,8

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CYTOMEGALOVIRUS DEFINITION • Important pathogen of all age groups • Wide range of dso (asymptomatic, subclinical, mononucleosis syndrome) • Affects healthy to immunocompromised individuals • Produces a characteristic enlarged cells

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Member of β-herpesvirus group dsDNA, icosahedral, replicates in nucleus cause either a lytic & productive or a latent infection viral replication – associated with production of large intranuclear inclusions & smaller cytoplasmic inclusions in vivo – replicates in variety of cells in vitro – prefers to grow in fibroblasts although little evidence that CMV is oncogenic in vivo, it does transform fibroblasts in rare instances & genomic transforming fragments have been identified.

EPIDEMIOLOGY • worldwide distribution • higher in less-developed countries • communcal living & poor personal hygiene facilitates spread • perinatal & early childhood infections are common • present in breastmilk, saliva, feces, & urine • MODE OF TRANSMISSION: 1. children in day care center – infects pregnant mother to developing fetus • when an infected child introduced CMV into a household, 50% of susceptible family members seroconvert w/in 6 mos • NOT READILY SPREAD BY CASUAL CONTACT, requires repeated or prolonged intimate exposure 2. sexual contact – late adolescence & young adulthood • asymptomatic viral carriage in semen or cervical secretions is common • nearly 100% of female prostitutes& homosexual men have detectable CMV antibodies • sexually active adults harbor several strains of CMV simultaneously 3. whole blood transfusion or other blood products containing viable lymphocytes – 0.14-10% per unit 4. organ transplantation • once infected, an individual probably carries CMV for life • infection usually remains latent however, CMV reactivation syndromes develop when T lymphocytemediated immunity is compromised (after organ transplant, lymphoid neoplasms, HIV etc) • most primary CMV infections in organ transplant recipients result from transmission of the virus in the graft itself. • In seropositive transplant recipients – infection due to reactivation of latent virus , or from reinfection by a new strain (less common) • Associated with coronary artery stenosis ff heart transplant or coronary angioplasty PATHOGENESIS • Congenital CMV can result from either primary or reactivation infection of the mother o Clinical dse in fetus or newborn is almost exclusively related to primary maternal infection o A deficient capacity to produce precipitating antibodies & to mount T cell responses to CMV  severe dse • Primary infection in late childhood or adulthood

Associated w/ vigorous T lymphocyte response w/c contribute to mononucleosis syndrome

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Hallmark:: atypical lymphocytes in peripheral blood (CD8+ T cells) o Polyclonal activation of B cells  devt of rheumatoid factors & other autoantibodies Once acquired, CMV persists indefinitely in host tissues like multiple cell types & various organs, salivary glands and bowel Compromised T cell mediated immune response → reactivation of latent virus o Chronic iatrogenic stimulation in the presence of immunosuppresion (ex. ff tissue transplant) o Potent suppressants of T cell immunity (antithymocyte globulin) CMV itself contribute to further T cell hyporesponsiveness, w/c often preceeds superinfection w/ other opportunistic pathogens like Pneunocystis CMV & Pneumocystis – frequently found together in immunosuppressed w/ severe interstitial pneumonia

PATHOLOGY • CMV infected cells (epithelial cells) o 2-4x larger o Contain eccentric intranuclear inclusion surrounded by clear halo  “OWL’S EYE” o Occ. smaller granular cytoplasmic inclusions • Cytomegalic cells are found in salivary gland, lung, liver, kidney, intestine, pancreas, adrenal gland, & CNS • Cellular inflam response consists of plasma cells, lympho & mono-macrophages. • Granulomatous reaction in the liver • Immune-complex glomerulopathy – can be found in infants, patients after renal transplant *see table 166-1 on page 1049 CLINICAL MANIFESTATION 1. CONGENITAL CMV INFECTION • Range from inapparent to severe & disseminated • Cytomegalic inclusion dse is seen almost exclusively in infants born to mothers who develop primary infections during pregnancy • Most common: petechiae, hypatosplenomegaly, & jaundice (60-80%) • Microcephaly w/ or w/o cerebral calcifications, IUGR & prematurity (30-50%) • Less common: inguinal hernias & chorioretinitis

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Lab abn: ↑ALT, conjugated hyperbili, hemolysis, ↑ CSF proteins, thrombocytopenia Mortality rate: 20-30% Those who survive may have intellectual or hearing difficulties later in childhood Diff dx: syphilis, rubella, toxoplasmosis, HSV, enterovirus, bacterial sepsis Most congenital CMV infections – clinically inapparent at birth o 5-25% of asymp infants develop psychomotor, hearing, ocular, dental abnormalities

2. PERINATAL CMV INFECTION • Acquired by: o passage thru infected birth canal o postnatal contact w/ breast milk or other maternal secretions esp if breastfed by >1 mo

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Iatrogenic transmission can also result from neonatal blood transfusion Infected infants usually remain asymptomatic However, protracted interstitial pneumonitis has been associated w/ perinatally acquired CMV infections esp in premature infants & occ accompanied by Chlamydis

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trachomatis, Pneumocystis or Ureaplasma urealyticum infections Poor wt gain, adenopathy, rash, hepatitis, anemia, & atypical lymphocytosis CMV excretion often persists for mos or yrs

3. CMV MONONUCLEOSIS • Heterophil antibody-negative mononucleosis syndrome o Most common manifestation of CMV infection in normal hosts beyond the neonatal period o May dev simultaneously or ff transfusion of leukocyte-containing bld products o Occurs at all ages, most often in sexually active young adults o IP: 20-60 days o Illness lasts for 2-6 wks o S/S:  Prolonged fever, sometimes w/ chills profound fatigue & malaise  Myalgias, headache, splenomegaly  As opposed to EBV infectious mononucleosis, exudative pharyngitis & cervical lymphadenopathy are rare in CMV mononucleosis  Occ: rubelliform rash often after ampicillin exposure  Less common: interstitial or segmental pneumonia, myocarditis, pleuritis, arthritis & encephalitis o Characteristic lab abn: relative lymphocytosis in peripheral blood w/ >10% atypical lympho  Total WBC ct may be low, normal or elevated  ALT/AST & ALP – moderately elevated although significant jaundice is uncommon  Heterophil Ab- negative  Transient immunologic abnormalities • Cryoglobulins • Rheumatoid factors • Cold agglutinins • ANA  Hemolytic anemia, thrombocytopenia, granulocytopenia - rare o Most patients develop w/o sequelae, although postviral asthenia may persist for months o CMV excretion in urine, genital secretions, &/or saliva – months or years o Recurrent episodes of fever & malaise, sometimes ANS dysfunction (attacks of sweating or flushing) in immunocompetent hosts 4. CMV in IMMUNOCOMPROMISED HOST • CMV is the most common & important viral pathogen complicating organ transplantation (kidney, heart, lung, liver) • Variety of syndromes in recipients: fever, leucopenia, hepatitis, pneumonitis, esophagitis, colitis & retinitis • CMV dse may be an independent rish factor for both graft loss & death.

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Period of maximal risk: 1-4 mos after transplant., although retinits may be a later complication Greater likelihood of disease and viral replication in primary infection rather than after reactivation Reactivation infection although frequent, is less clinically significant Risk of clinical disease related to: o Degree of immunosuppression o Use of antibodies to T cell receptors o Co-infections like HHV type 6 CMV hepatitis may follow liver transplantation CMV pneumonitis may follow lung transplantation CMV pneumonia

Occurs in 15-20% of BM transplant receipients; fatality of 84-88% o Greatest risk 5-13 wks after transplant o Other risk factors:  Acute GVHD  Older age  Viremia  Seropositive before transplant In advanced HIV o Causes retinitis or disseminated dse esp when CD4+ is below 50-100/uL o Institution of highly active antiretroviral regimens sometimes leads to acute flare ups or CMV retinitis during 1st few wks of therapy S/S: o Begin w/ prolonged fever, malaise, anorexia, fatigue, night sweats, and arthralgias or myalgias o Tachypnea, hypoxia, unproductive cough signals respiratory involvement Labs: o Liver function abnormalities o Leucopenia o Thrombocytopenia o Atypical lymphocytosis Radio: o Bilateral interstitial or reticulonodular infiltrates which begin in the periphery of lower loves & spread centrally & superiorly o Less common: localized segmental, nodular, or alveolar patters Diff Dx: o Pneumocystis, pulmo hemorrhage, injury 2ndary to irradiation or tx w/ cytotoxic drugs GASTROINTESTINAL CMV o Localized or extensive o Almost exclusively affects compromised hosts o Ulcers of GIT may result in bleeding or perforation o May lead to exacerbation of ulcerative colitis o Hepatitis – frequent after liver transplant o CMV-associated acalculous cholecystitis & adrenalitis ENCEPHALITIS – 2 forms seen in AIDS: 1. resembles HIV encephalitis & presents as progressive dementia 2. ventriculoencephalitis – CN deficits, nystagmus, disorientation, lethargy & ventriculomegaly *in immunocompromised, also cause subacute progressive polyradiculopathy – reversible is txd promptly CMV RETINITIS o Impt cause of blindness o Early lesions: small, opaque, white areas of granular retinal necrosis that spread centrifugally o Later: hemorrhages, vessel sheathing, & retinal edema o Diff dx: toxoplasmosis, candidiasis & HSV Fatal CMV – associated w/ persistent viremia & multi organ involvement Progressive pulmo infiltrates, pancytopenia, hyperamylasemia & hypotension – char features frequently found in terminal bacteria, fungal or protozoan superinfections. o

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DIAGNOSIS • Cannot be made reliably on clinical grounds alone

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Preferred approach: viral isolation, Ag or DNA detection Culture on human fibroblast monolayers o High viral titer(AIDS, congenital disseminated infections)  CPE w/in a few days o Low viral titers  CPE in several wks Shell vial assay (overnight tissue culture method)

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Centrifugation & immunohistochemical detection technique using monoclonal Ab to immediate-early CMV Ag Isolation of virus from urine or saliva is not a proof of acute infection because excretion form these sites may continue for months or years after illness Detection of CMV viremia – better predictor of acute infection Detection of CMV Ag (pp65) in peripheral-blood leukocytes or CMV DNA in blood or tissues o Yield positive result several days earlier than culture thus hastening the dx PCR – CMV DNA amplification o Most sensitive to detect CMV in blood or other fluids o Detection in blood may predict the risk for dse progression o Detection in CSF – useful to dx CMV encephalitis or polyradiculopathy Other methods: o ↑ Antibody level – detectable at 4 wks after primary infection; titers remain high for years thus single-sample antibody assays are of no value in assessing the acuteness of infection o CMV-specific IgM – sometimes useful in dx recent or active infection  False positive: Rheumatoid factors

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TREATMENT • Prophylactic measures: o Use of blood or organs from seronegative donors o Use of blood that has been frozen, thawed, & deglycerolized o Matching or organ or bone marrow transplants by CMV serology o live attenuated & CMV subunit vaccines – not approved for general use o CMV Ig – reduce rates of CMV syndromes & superinfections o Prophylactic acyclovir or valacyclovir – may reduce rates of infection although neither is effective in tx of active CMV disease o Prophylactic or suppressive ganciclovir in high risk bone marrow recipients (seropos before transplantation, or who are culturepositive afterward) • Ganciclovir o Guanosine derivative o After intracellular conversion by a viral phosphotransferase encoded by CMV gene region UL97, gancyclovir triphosphate is a SELECTIVE INHIBITOR OF CMV DNA POLYMERASE o In BM transplant, less effective when given alone thus combine it w/ CMV Ig o In AIDS, persistently low CD4+ counts, CMV dse – maintenance regimens are recommended to prevent relapses o Resistance – common in patients treated for >3 mos & usually related to CMV UL97 gene mutations o Ganciclovir may also be administered via a slow-release pellet sutured into the eye  Although this rovides good local protection, but CL eye dse & disseminated dse are not affected & early retinal detachment is possible  Combi of intraocular & systemic therapy may be better than intraocular implant alone • Valaganciclovir o Oral, prodrug o Rapidly metabolized to ganciclovir in intestine & liver o 60% of oral dose is absorbed

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Oral dose of 900 mg results in similar bioavailability of ganciclovir IV dose of 5 mg/kg o As effective as IV ganciclovir for both CMV retinitis induction & maintenance o *similar adverse events and resistance rates to ganciclovir CMV RETINITIS

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Ganciclovir or valaganciclovir therapy: Ganciclovir Valaganciclovir

Induction course 14-21 days Prolonged maintenance regimen o

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5 mg/kg BID

900 mg BID

5 mg/kg OD Or 6 mg/kg 5x/week

900 mg OD

Adverse effect: peripheral blood neutropenia  Ameliorated by granulocyte colony stimulating factor (CSF) or granulocyte-macrophage CSF D/C of maintenance therapy in AIDS patient who, while receiving antiretrovirals, have a sustained (>6 mos) ↑ CD4 cell counts to >100-150/uL

Foscarnet (sodium phosphonoformate) o Also inhibits CMV DNA polymerase o Doesn’t require phosphorylation to be active, thus also effective for most ganciclovirresistant CMV o Less well tolerated than ganciclovir o Adverse effects:  Renal dysfunction  Hypo-Mg, -K, -Ca  Genital ulcers  Dysuria  Nausea  paresthesia o aggressive hydration & dose adjustment for renal dysfunction to reduce toxicity o Administration requires infusion pump & close clinical monitoring o Avoid when saline load cannot be tolerated (ex. cardiomyopathy) o Induction: 60 mg/kg q 8h for 2 weeks or 90 mg/kg q 12h o Maintenance: 90-120 mg/kg OD o No oral prep available o Foscarnet-resistant viruses may emerge during extended therapy Cidofovir o Nucleotide analogue w/ long intracellular halflife that allows intermittent IV o Induction: 5 mg/kg weekly for 2 wks o Maintenance: 3-5 mg/kg q 2 wks o Adverse effect: nephrotoxicity thru dosedependent proximal tubule cell injury  Ameliorated by saline hydration & probenacid

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