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A. Characteristics navigator

  1. Opportunistic Infection
  2. Epidemiology
    1. Seroprevalence 40-100% in adults
    2. Variable seroprevalence strongly related to socioeconomic status
    3. Asymptomatic infection or mononucleosis like syndrome in healthy non-infants
    4. Serious infection including pneumonia, hepatitis, rash is rare in healthy persons [6]
    5. Clinically apparent in immunocompromised patients and infants
    6. Serious infection in ~1% of all neonates
  3. Risk Factors for Significant Infection
    1. HIV Infection
    2. Organ or Bone Marrow Transplantation
    3. Prolonged (usually high dose) glucocorticoid or immunosuppressive therapy
    4. Congenital CMV: "C" in TORCHS series of congenital infections
    5. Infants
  4. Increasing problem as more patients are immunosuppressed

B. Organ Involvement [1]navigator

  1. CMV Retinopathy is most common problem [2,3]
    1. Mainly in patients with HIV [15]
    2. Less common in organ transplantation
    3. Retinitis (ultimately leads to blindness) - up to 40% of patients with AIDS
    4. Conjunctivitis also occurs, particularly in HIV
  2. Pneumonia
    1. Severe interstitial pneumonitis
    2. Common in organ / bone marrow transplant patients
    3. Very rare in healthy persons, but can present with negative gram stain [6]
  3. CMV Encephalitis
    1. Majority of cases occur in patients with advanced AIDS; <5% are immunocompetent
    2. In advanced HIV, pathology shows ventriculoencephalitis, a unique entity
    3. Over 50% of patients also have CMV retinitis
    4. Lethargy and confusion are most common symptoms
    5. Average CD4 count at presentation was 20/µL
    6. Spinal fluid analysis should include a polymerase chain reaction for CMV DNA
    7. Combination ganciclovir and foscarnet therapy is recommended but unproved
  4. Cauda Equina Syndrome (Polyradiculopathy)
    1. CD4+ T cell count usually <50µL
    2. Caused by CMV
    3. Severe and rapid loss of lower extremity strength ± sensation
    4. Bladder and bowel incontinence are common presenting symptoms
    5. Poor response to single agent anti-CMV Therapy
    6. Ganciclovir (DHPG) + Foscarnet may be used (poorly tolerated)
  5. Hepatitis
    1. Probably cause of hepatitis in immunocompromised persons
    2. Probably not a cause of hepatitis in immunocompetent persons
    3. May cause high fevers when found with liver disease
    4. Particularly dangerous in setting of liver transplantation
    5. CMV positivity (donor and/or recipient) predicts poor liver transplant outcome [5]
  6. Gastrointestinal Disturbances
    1. Usually colitis [4], esophagitis, particularly in HIV infection [7]
    2. Colitis in solid organ transplant (>1 month after transplant) [11]
    3. HIV, other immunodeficiency, or immunosuppressive drugs increase risk [4]
    4. Occasionally seen in elderly patients without overt immunodeficiency
    5. Erosive or ulcerative process
    6. Mucosal biopsy required for diagnosis
  7. Bone Marrow Infiltration
    1. Severe bone marrow suppression (pancytopenia)
    2. High Fevers
  8. Vascular Inflammation
    1. CMV seropositivity is associated with high restenosis rates post-atherectomy [8]
    2. CMV also plays a key role in damage to transplanted organs [19]
  9. CMV infection of HIV+ infants increases rate of progression of HIV-1 disease [22]
  10. Congenital CMV [16,21]
    1. Occurs in ~40% neonates in ~40% of women with primary CMV infection
    2. Symptomatic in ~10% of infected neonates
    3. Significant neurologic deficits in 50% of these
    4. Sensorineural hearing loss (leading cause in USA)
    5. Cognitive impairment
    6. Cerebral palsy
    7. Visual impairment
    8. Thrombocytopenia [17]
    9. Virus transmitted to fetus during primary maternal infection during pregnancy
    10. Naturally acquired immunity leads to ~70% reduction in risk of congenital CMV infection

C. Diagnosisnavigator

  1. Seropositivity is major method for detection of prior infection
    1. IgM titers acutely
    2. IgG titers for previous infection (most persons are positive)
  2. Seropositive perons are considered to have latent CMV
  3. CMV is reactivated with immunosuppression
  4. Culture of virus possible, with generation of bizarre large cells
  5. In situ hybridization on biopsy specimens is diagnostic
  6. Polymerase Chain Reaction (PCR)
    1. CMV DNA test based on hybridization is now commercially available
    2. These are ~99% sensitive
    3. Likely that the PCR based test will supplant culture and biopsy for diagnosis

D. Treatment [1,9] navigator

  1. Overview
    1. Prophylaxis in organ and bone marrow transplantation (see below)
    2. Treatment with Ganciclovir and/or Foscarnet, or resistant strains with cidofovir
    3. Cidofovir intravitreous injection for initial CMV retinopathy therapy
    4. Patients with immunodeficiency may require lifelong treatment
    5. However, highly active anti-HIV therapy may reverse CMV disease and need for therapy
    6. Anti-CMV agents can be stopped in patients with stable CMV disease and CD4 counts >150/µL [23]
    7. CMV hyperimmune globulin reduces transmission in pregnant women with primary CMV infection and CMV or CMV DNA in amniotic fluid [16]
  2. Ganciclovir (Cytovene®)
    1. Indications: CMV retinitis, CMV organ infections (except pneumonia)
    2. Dose: 5mg/kg IV bid for 2-3 wks or oral therapy for prophylaxis in HIV [10]
    3. Dose must be adjusted for renal dysfunction; 1 hour infusion time requred
    4. Side Effects: granulocytopenia, thrombocytopenia, severe myelosuppression with AZT
    5. G-CSF and/or erythropoietin may be given for cytopenias
    6. Oral ganciclovir 4500-6000mg/day is efficacious and has fewer side effects than IV
    7. Oral ganciclovir is recommended for maintenance therapy after IV induction [1]
    8. Oral or IV ganciclovir reduces risk of Kaposi's sarcoma in HIV+ patients as well
    9. Ganciclovir resistant CMV is an emerging problem in solid-organ transplants [24]
  3. Valganciclovir (Valcyte®) [9,25]
    1. Valgancyclovir is L-valyl ester of ganciclovir with excellent oral availability
    2. Valgancyclovir should replace both IV and PO ganciclovir for CMV retinitis [25]
    3. Induction 900mg po bid (usually for 3 weeks for CMV retinitis)
    4. Maintenance 900mg po qd
  4. Intraocular Ganciclovir (Vitrasert®) [14]
    1. Intraocular implant with sustained release ganciclovir
    2. Duration of efficacy very long; overall more effective than IV therapy
    3. Intraocular ganciclovir leads to more CMV systemic disease in HIV than IV drug
    4. Requires surgical implantation and complications of surgery can occur
    5. Effects can last >7 months in implanted eye
    6. Retinitis in contralateral eye occurred in ~55% of persons over 7 months
    7. Combination of implant with oral ganciclovir reduces recurrence of CMV retinitis
  5. Foscarnet (Foscavir®)
    1. Indications: acyclovir resistant HSV, VSV; CMV retinitis, pneumonia, others
    2. Dose: 60mg/kg IV q8hr for 2-3 weeks
    3. Maintenance dose is 120mg/kg IV daily (2 hour infusion times requred)
    4. Side Effects: azotemia (50%), renal failure, nausea, vomiting, anemia, fatigue, seizures
    5. Side Effects: hypokalemia, hypomagnesemia, hypo- and hypercalcemia, abnormal phosphate
    6. This agent is not myelosuppressive
  6. Cidofovir (Vistide®) [3,12]
    1. Nucleoside analog highly active against CMV given intravitreous or intravenous
    2. Intravitreous injections of 20µg cidofovir is safe and effective in CMV retinitis [13]
    3. Low risk of retinal detachment with multiple injections
    4. Intravenous dose 5mg/kg weekly for 2 weeks, then 3-5mg/kg every two weeks
    5. Given with probenecid (4gm peri-infusion) and saline hydration
    6. Main side effects of IV therapy are proteinuria, creatinine elevation and neutropenia
    7. For systemic disease, this is the easiest agent to administer
  7. Fomivirsen (Vitravene®)
    1. Antisense oligonucleotide for intravitreal treatment of CMV retinitis
    2. Used for patients resistant to other therapies
    3. Should not be used within 2-4 weeks of cidofovir treatment
    4. Adverse effects: iritis, vitritis, increased intraocular pressure, vision changes
    5. Development of resistance by CMV has not been documented
  8. Combination Therapy
    1. Combined ganciclovir and foscarnet may be required in severe infections
    2. Consider for cauda equina syndrome other serious infections
    3. In vitro data suggest that cidofovir and other anti-CMV therapy are synergistic [2]
  9. HIV associated Retinitis requires indefinite therapy in many patients

E. Prophylaxis navigator

  1. Given to all persons at high risk for CMV disease (immunocompromised persons)
  2. Solid organ transplantation and bone marrow / stem cell transplantation
  3. Universal prophylaxis reduced bacterial infections 50% and death 38% in solid organ transplant recipients (both acyclovir and ganciclovir were effective) [26]
  4. Drugs for Prophylaxis [18]
    1. Oral ganciclovir is expensive and fairly effective [10]
    2. Oral valacyclovir is highly effective and well tolerated [20]
    3. Oral valganciclovir is likely more effective than oral ganciclovir [9]
    4. Overall, prophylaxis reduced risk of any CMV disease ~60%, mortality ~40% in solid organ transplant patients [18]
  5. Patients with late stage HIV (decreasing numbers due to active anti-HIV therapy)
  6. High-titer (Hyperimmune) Anti-CMV Immune Globulin
    1. Reduces risk of disseminated CMV in high risk transplant patients original modality
    2. Significantly (~68%) reduces risk of congenital CMV infection without adverse effects [16]

References navigator

  1. Whitley RJ, Jacobson MA, Friedberg DN, et al. 1999. Arch Intern Med. 158(9):957
  2. Jacobson MA. 1997. NEJM. 337(2):105 abstract
  3. Studies of Ocular Complications of AIDS Research Group. 1997. Ann Intern Med. 126(4):264 abstract
  4. Babyatsky MW, Keroack MD, Blake MA, et al. 2007. NEJM. 357(20):2068 (Case Record) abstract
  5. Falagas ME, Snydman DR, Griffith J, et al. 1997. Ann Intern Med. 126(4):275 abstract
  6. Amory JK, Rosen H, Sukut C, et al. 2006. NEJM. 354(14):1516 (Case Discussion) abstract
  7. Ives DV and Smith RN. 1996. NEJM. 334(22):1461 abstract
  8. Zhou YF, Leon MB, Waclawiw MA, et al. 1996. NEJM. 335(9):624 abstract
  9. Drugs for Non-HIV Viral Infections. 2002. Med Let. 44(1123):9 abstract
  10. Spector SA, McKinley GF, Lalezari JP, et al. 1996. NEJM. 334(24):1491
  11. Rubin RH, Gilman MD, Kradin RL. 2006. NEJM. 354(2):180 (Case Record) abstract
  12. Lalezari JP, Stagg RJ, Kuppermann BD, et al. 1997. Ann Intern Med. 126(4):257 abstract
  13. Rahhal FM, Arevalo JF, de la Paz EC, et al. 1996. Ann Intern Med. 125(2):98 abstract
  14. Musch DC, Martin DF, Gordon JF, et al. 1997. NEJM. 337(2):83 abstract
  15. Whitcup SM. 1996. JAMA. 275(2):142 abstract
  16. Nigro G, Adler SP, La Torre R, Best AM. 2005. NEJM. 353(13):1350 abstract
  17. Modlin JF, Grant PE, Makar RS, et al. 2003. NEJM. 349(7):691 (Case Record) abstract
  18. Hodson EM, Jones CA, Webster AC, et al. 2005. Lancet. 365:2105 abstract
  19. Fishman JA and Rubin RH. 1998. NEJM. 338(24):1741 abstract
  20. Martin DF, Kuppermann BD, Wolitz RA, et al. 1999. NEJM. 340(14):1063 abstract
  21. Fowler KB, Stagno S, Pass RF. 2003. JAMA. 289(8):1008 abstract
  22. Kovacs A, Schluchter M, Easley K, et al. 1999. NEJM. 341(2):77 abstract
  23. Whitcup SM, Fortin E, Lindblad AS, et al. 1999. JAMA. 282(17):1633 abstract
  24. Limaye AP, Corey L, Koelle DM, et al. 2000. Lancet. 356(9230):645 abstract
  25. Martin DF, Sierra-Madero J, Walmsley S, et al. 2002. NEJM. 346(15):1119 abstract
  26. Kalil AC, Levitsky J, Lyden E, et al. 2005. Ann Intern Med. 143(12):870 abstract