Association between cytomegalovirus infection and venous thromboembolism.

1: Am J Med Sci. 2007 Aug;334(2):111-4.Related Articles, Links
Association between cytomegalovirus infection and venous thromboembolism.

Fridlender ZG, Khamaisi M, Leitersdorf E.

Division of Medicine, Hadassah--Hebrew University Medical Center, Jerusalem, Israel. fridlender@hadassah.org.il

It has been suggested that cytomegalovirus (CMV) infection may be associated with thrombosis in immunocompromised patients. In addition, an association between CMV infection and thrombotic events in immunocompetent hosts has been sporadically reported. We report on 1 immunocompromised and 8 immunocompetent adults who were admitted to a tertiary medical center and experienced a venous thromboembolic event during CMV infection. None reported previous thromboembolic events. All patients were diagnosed as suffering from acute CMV infection. Seven of the patients had vein thromboses. Significant additional thrombophilia was identified in 5 patients; 1 had 15.3 U/mL anti-cardiolipin IgM antibodies (elevated >7), 2 others were not evaluated for genetic procoagulant tendency. The exact nature of the procoagulant effect of CMV has not yet been clarified. Even though these mechanistic studies are incomplete, we suggest that from the clinical perspective, the presence of CMV infection should be considered a possible risk factor for thrombophilia, justifying a high index of suspicion for possible thrombotic events and subsequent decisions regarding prophylactic anticoagulation.

Publication Types:
Case Reports

PMID: 17700200 [PubMed - indexed for MEDLINE]

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Cytomegalovirus

Lesia Dropulic, M.D. and Khalil G. Ghanem, M.D.
10-09-2007

MICROBIOLOGY
Prototype of the betaherpesvirus group; establishes latent infection after acute infection.
Transmitted sexually or by close contact (family members, daycare), blood or tissue exposure, perinatally. Cultured from urine, blood, throat, tears, stool, cervix, semen, breast milk.
Seroprevalence increases with age and varies throughout the world; adult seroprevalence rates range from 40-100% and are highest in developing countries.
Exhibits slow growth in cultured cells (can be up to 6 weeks until cytopathic effect is detected in tissue culture) and cytopathology is characterized by large cells with nuclear and cytoplasmic inclusions (nuclear inclusions known as Cowdry owl's eyes inclusion bodies).
Detection of virus in culture indicates presence of virus but does not confirm active disease.
CLINICAL
Immunocompetent adult: ranges from asymptomatic infection to heterophile-negative mononucleosis syndrome, most often characterized by protracted fevers, lassitude, and possibly a rash with absolute lymphocytosis and atypical lymphocytes.
Transplant pts (especially between 30-100d post txp): risk depends on type of transplant (HSCT> solid organ), CMV serostatus of donor and recipient, type (>> risk with antilymphocyte antibody therapy) and depth/duration of immune suppression. Active disease may range from asymptomatic to CMV syndrome (mononucleosis-like with fever, leukopenia, LFT abnls, myalgia/arthralgia), or signs and symptoms related to organ-specific infection.
Reactivation CMV occurs in approximately 70-80% of patients after allogeneic marrow or stem cell transplantation w/o prophylaxis; 35% of these pts get disease.
HIV/AIDS: most cases of CMV disease occur in setting of advanced immunosuppression, CD4 < 50 cells/mL.
Congenital: 90% of newborns with congenital infection are asymptomatic at birth; 10% will have microcephaly, seizures, abnormal neurologic exam, sensorineural hearing loss, feeding difficulties. Greatest risk with primary infection of mother during pregnancy: first trimester (2% risk to fetus) to third trimester (28% risk).
Dx of CMV disease is made by the combination of appropriate clinical syndrome + detection of CMV in blood, plasma, or tissue in the absence of other likely microbial etiology. Without prophylaxis, symptomatic infections occur in approximately 39% of heart-lung recipients, 25% of heart, 29% of liver and pancreas, and in 8% of kidney transplants.
Dx 1: culture in human fibroblasts (time consuming); shell vial (monoclonal Abs to early CMV Ags in cultured cells; often result in 2-3 days); serology (IgM/IgG-used in dx of primary infection only in immunocompetent host); Dx 2: antigenemia (Ag detection in neutrophils w/Ab against CMV matrix protein pp65); PCR using primers for early antigens or for CMV DNA polymerase, PCR can be qualitative or quantitative.
Note that CMV antigenemia and quantitative PCR assay may be negative in the setting of significant disease involving the GI, pulmonary or CNS systems.
SITES OF INFECTION
Organ specific manifestations of CMV are rare in immunocompetent patients, however, pneumonia, gastrointestinal disease (especially colitis), myocarditis, meningoencephalitis have been reported. Liver function abnormalities (transaminitis) are frequently encountered in patients with symptomatic CMV infection. Guillain-Barre syndrome also has been associated with CMV.
TRANSPLANT: the allograft is a "privileged" site for CMV replication given MHC mismatch; pneumonitis (especially lung transplant and BMT; up to 84% mortality in BMT); hepatitis (especially liver txp); nephritis; esophagitis, gastritis, colitis (GI disease common among all solid organ transplants), meningoencephalitis,myocarditis, pancreatitis.
CMV chorioretinitis is a rare manifestation of CMV disease in txp recipients.
CONGENITAL: small infant size, jaundice, hepatosplenomegaly, petechial/purpuric rash, microcephaly, chorioretinitis, .
PERINATAL (via milk or cervical secretions): asymptomatic; subtle effects on hearing and intelligence possible long-term.
AIDS: retinitis (CD4<50),polyradiculopathy and meningoencephalitis, esophagitis, colitis. CMV as a sole cause of pneumonia is not common, but can occur in very late stages of HIV disease.
TREATMENT
Prevention

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The provision of CMV negative bone marrow, stem cells, or solid organs to CMV-negative recipients is recommended, if possible.
Giving CMV-negative or leukocyte-depleted blood products to transplant recipients is highly effective.
Transplant patients who are sexually active and not in long-term monogamous relationships should use latex condoms during sexual contacts.
Handling or changing diapers or wiping oral secretions from toddlers also represents a potential risk for CMV transmission to seronegative individuals and should be avoided.
Prophylaxis vs Pre-emptive Therapy

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Prophylaxis = treat all D+ or R+ patients (universal prophylaxis), or only high-risk patients (solid organ) = D+/R- patients or R+ patients treated with antilymphocyte antibodies (ATG, thymoglobulin, OKT3 or similar); high risk BMT: D+ or R+, mismatched or unrelated txp, GVHD.
Solid organ: ganciclovir is more effective than acyclovir; valganciclovir and IV ganciclovir are as effective as PO ganciclovir.
Solid organ prophylaxis: ganciclovir IV (5mg/kg/day) or valganciclovir (450-900 PO mg/day) x 3-6 mos. Duration depends on depth of immunosuppression.
Pre-emptive (PE): only Rx patients w/ evidence of CMV infection (in blood or lungs) dx as part of viral surveillance monitoring (i.e., CMV antigenemia or PCR) after transplant to prevent active disease. Prophylaxis and pre-emptive both effective in preventing CMV disease.
Preemptive therapy well established for high risk BMT patients: IV ganciclovir 5 mg/kg IV twice daily for 14 days then 5mg/kg/day for 5 days/week until day 100 posttransplant or until antigenemia or PCR is negative. Foscarnet (60 mg/kg IV twice daily for 2 weeks followed by 90 mg/kg IV once daily 5 days per week for 2 weeks) as effective as ganciclovir for PE therapy of allogeneic BMT recipients. Combination not more effective and more toxic.
PE favored by some over routine prophylaxis of all high risk transplant pts: theoretical decrease in incidence of resistance, limits side effects of ganciclovir, decreased incidence of late onset CMV disease.
Valganciclovir is approved for the prophylaxis of CMV disease in high risk kidney, heart, and kidney-pancreas transplant recipients. Valganciclovir is not approved for prophylaxis in liver transplant recipients because of greater incidence of invasive disease in this subgroup in the valganciclovir vs. oral ganciclovir study. However, many experts successfully prophylax liver transplant recipients with valganciclovir because a study bias was identified.
Valganciclovir for pre-emptive treatment looks promising for kidney, lung, and bone and marrow txp patients.
In the setting of treatment of acute rejection (high dose steroids, antilymphocyte antibody therapy, or OKT3), consider prophylactic valganciclovir.
Therapy

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Immunocompetent host: usually self-limited; no specific antiviral therapy necessary.
Solid organ txp, invasive end-organ disease: ganciclovir 5mg/kg IV q12h induction X 14-21 days or until documented clearance of viremia and/or significant clinical improvement.
CMV IVIG often used for severe interstitial pneumonitis, relapsing or resistant CMV infections. No good prospective data in these populations.
HSCT pneumonia: IV ganciclovir 5mg/kg q12 x 21 d then 5mg/kg q24 x 3-4wks PLUS IVIG (500mg/kg) or CMV-IG (150mg/kg) 2x/wk x 2 wks then qwk for 4 wks.
HSCT w/ CMV GI or retinitis: ganciclovir 5mg/kg q12 x 14-21d then q24 x 3-4 wks or until day 100. Substitute foscarnet 90mg/kg q12h for ganciclovir in case of BM suppression.
Cidofovir has documented effectiveness in cases of CMV retinitis. Cross-resistance to ganciclovir-resistant strains relatively common, especially w/ high-level ganciclovir resistance. Limited use in txp pts
Consider valganciclovir 900mg PO bid for induction therapy in the absence of tissue invasive disease, because of excellent bioavailability. Some experts treat asymptomatic viremia or mild disease (clinical symptoms present--CMV syndrome) with valganciclovir for a minimum of 21 days or longer until viremia clears.
Valganciclovir approved for the treatment of CMV retinitis in patients with AIDS.
Discontinue or decrease dose of antimetabolite (azathioprine or mycophenolate mofetil) during treatment of CMV disease. The severity of disease and risk of rejection dictate when/if to restart the antimetabolite.
Choose the drug(s) of interest and see the author's comments.:

Cidofovir
Foscarnet
Ganciclovir
Valganciclovir


FOLLOW UP
Risk factors for late (after day 100) CMV disease in HSCT include unrelated or T-cell depleted transplants, chronic GVHD, steroid use, CD4 counts < 50, and CMV infection before day 100.
Risk for CMV relapse in allogeneic BMT if mismatched unrelated donor and GVHD.
BMT: if antigenemia/positive PCR persists > 4 weeks or levels increase after 3 weeks, assume resistance; discontinue ganciclovir, begin foscarnet.
Solid organ: factors associated with the development of clinically significant ganciclovir resistance: D+R- serostatus, prolonged exposure to ganciclovir, potent immunosuppression, suboptimal ganciclovir levels, and high virus load.
Solid organ: If quantitative PCR does not decrease by 50% 2 weeks into treatment, suspect viral resistance and re-assess recipient immunocompetence.
Continue treatment for one week after finding a negative CMV PCR and after resolution of organ specific signs/symptoms of infection.
Consider secondary prophylaxis for an additional 3 months after initial treatment of CMV infection/disease, especially in those at high risk for recurrence (D+/R- ).
OTHER INFORMATION
CMV (21% ) vs. EBV (79%) causing mono-like sx: CMV associated with LESS tonsillopharyngitis, lymphadenopathy, splenomegaly; MORE systemic symptoms ("typhoidal") and hepatitis.
LATE CMV INFECTIONS: early use of antiviral therapy at time of engraftment delays immune reconstitution against the virus, placing the patient at risk for late (>100d) disease when prophylaxis discontinued.
Valganciclovir (pro-drug of ganciclovir) has 60-70% oral bioavailability. Effective in AIDS CMV retinitis. Clinical use in txp pts increasing.
Cross resistance between ganciclovir and valganciclovir. CLINICALLY, no cross-resistance between ganciclovir & foscarnet (although possible see foscarnet drug specific comment).
Because resistance testing is time consuming, dx of resistance is made clinically based on clinical evidence of Rx failure. Modify Rx while awaiting resistance test.
Basis for Recommendations
Preiksaitis JK, Brennan DC, Fishman J, et al.; Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report.; Am J Transplant; 2005; Vol. 5; pp. 218-27;
ISSN: 1600-6135;
PUBMED: 15643981
Rating: Basis for recommendation
Comments:Partly the basis for recommendations in this module.


Paya C, Humar A, Dominguez E, et al.; Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients.; Am J Transplant; 2004; Vol. 4; pp. 611-20;
ISSN: 1600-6135;
PUBMED: 15023154
Rating: Basis for recommendation
Comments:A phase III randomized, prospective, double-blind, double-dummy study that compared the efficacy and safety of valganciclovir with PO ganciclovir (administered through 100 days after txp) for prevention of CMV disease in high risk (D+/R-) kidney, kidney-pancreas, heart, and liver txp recipients. The incidence of CMV disease was similar in the valganciclovir and ganciclovir study groups at 6 and 12 months after transplant. The safety profile was similar for both drugs.


Preiksaitis J, Green M, Avery RK eds.; Guidelines for the prevention and management of infectious complications of solid organ transplantation.; Am J Transplant; 2004; Vol. 4( suppl.10); pp. 51-58;
Rating: Basis for recommendation
Comments:Partly the basis for recommendations in this module.


Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation; Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.; MMWR Recomm Rep; 2000; Vol. 49; pp. 1-125, CE1-7;
ISSN: 1057-5987;
PUBMED: 11718124
Rating: Basis for recommendation
Comments:Partly the basis for recommendations in this module.