Cytomegalovirus (CMV) Infections

The diagnosis, monitoring, and management of cytomegalovirus infection, especially in immunocompromised patients (including solid organ transplant or hematopoietic stem cell transplant recipients), is frequently directed by multidisciplinary teams of infectious disease and transplant specialists familiar with this complex area. The strategies described in this chapter are presented for general orientation.

Definition, Etiology, Pathogenesis

1. Etiologic agent: Human cytomegalovirus (CMV; human betaherpesvirus 5) belonging to the Herpesviridae family. CMV is the largest virus causing infection in humans. It shows resistance to external environmental factors.

2. Pathomechanism: CMV infection can follow different courses:

1) Primary infection: In individuals naïve to CMV exposure.

2) Secondary infection: Reactivated latent infection.

3) Reinfection with a new strain.

Secondary infection and reinfection are referred to as recurrent infections. Following primary infection the latent virus persists in the host’s body throughout their life, and its occasional reactivation may lead to human-to-human transmission. The virus can be detected in multiple tissues. It can infect different types of cells, including dendritic cells, mononuclear cells (monocytes and macrophages, lymphocytes), progenitor cells and hematopoietic precursors (including megakaryocytes), neutrophils, as well as epithelial cells (also renal), endothelial cells, fibroblasts, and smooth muscle cells. The clinical manifestations of infection result from the direct cytopathic effect of CMV on infected cells and the induced inflammatory response, accompanied by tissue infiltration and vasculitis. CMV has an immunomodulatory potential and can have immunosuppressive and/or proinflammatory effect.

3. Reservoir and transmission: Infected humans are the reservoir. CMV may be found in saliva, blood, urine, stool, teardrops, semen, vaginal discharge, and breast milk. Infection can be acquired through droplets, sexual contacts, blood (transfusion of blood components containing infected leukocytes, hematopoietic stem cell transplant [HSCT], solid organ transplant [SOT]), or vertical transmission (intrauterine infection, infection during labor or with breast milk).

4. Risk factors: Close contact with infected individuals shedding the virus (household contacts, nursing, sexual contacts), HSCT or SOT from donors infected with CMV, transfusion of blood components without prior leukocyte reduction.

Occasional reactivation occurs regardless of the immune status, but its probability, replication severity, and risk of symptomatic disease (which can be life threatening) is particularly high in immunosuppressed individuals, especially in patients with AIDS and CD4+ cell count <50/microL, HSCT recipients, SOT recipients, and those receiving immunosuppressive therapy affecting the cellular response (the risk group includes patients with malignancy receiving alemtuzumab, purine analogues, cyclophosphamide, vincristine, doxorubicin, dexamethasone, or idelalisib). CMV disease has also been described in patients receiving other molecular-targeting drugs (dasatinib, ibrutinib, brentuximab vedotin, daratumumab).

5. Incubation and contagious period: From 3 to 12 weeks after blood component transfusion and from 1 to 4 months after SOT.

Epidemiology

CMV infection is common, but the incidence varies depending on economic status (higher in resource-restricted countries) and age (increases with age). A particularly high incidence is observed in densely populated areas and environments with inadequate hygiene and sanitation.

Clinical Features and Natural History

CMV infection can be asymptomatic or present with CMV disease. Clinical features depend on the infected individual’s immune status. In immunocompetent individuals primary infection is most frequently asymptomatic, oligosymptomatic, or manifests as infectious mononucleosis, and rarely affects organs. Infection reactivation and organ involvement may occur in severely ill patients due to other conditions, without additional immunosuppressive factors.

Organ involvement in the course of CMV infection is most often seen in immunosuppressed individuals, and the disease in this group follows a more aggressive course than in other populations. CMV infection poses a particular threat to patients after SOT or HSCT (especially allogeneic) and those with AIDS.

1. Infectious mononucleosis: The most frequent form of CMV infection in immunocompetent individuals. Clinical features resemble those seen in mononucleosis caused by the Epstein-Barr virus (EBV). Compared with EBV infection, splenomegaly and tonsilitis are observed less frequently, and lymphadenopathy is less evident.

2. Asymptomatic viremia: One of the most frequent forms of CMV infection in patients after SOT or HSCT. Biomarkers of active CMV infection (CMV DNA or pp65 antigen) can be detected in serum on posttransplant follow-up. Asymptomatic viremia may precede organ involvement.

3. CMV syndrome in SOT recipients: Active CMV infection defined as viremia accompanied by fever ≥38 degrees Celsius, malaise and weakness (may develop or increase), myalgia, and arthralgia, without organ involvement. Leukopenia (neutropenia), atypical lymphocytes, thrombocytopenia, and increased serum activity of aminotransferases may be present.

4. End-organ CMV disease: The infection is localized and results in pathologies within the affected organ. Organ involvement in CMV disease is most frequently seen in those with cellular immunodeficiency and results from CMV reactivation or infection (viral transmission with graft). The level of viremia varies, and viral presence in blood is not required to establish the diagnosis (viremia may span from undetectable to high level).

1) Gastrointestinal (GI) tract infection is rare in immunocompetent individuals but frequent in those immunosuppressed. Viremia may remain undetectable or low level, particularly in SOT recipients with biomarkers of infection detected before the procedure. In colitis, manifestations are poorly specific and the disease presents with fever, abdominal pain, and diarrhea (sometimes bloody). In those with inflammatory bowel disease (IBD), CMV disease manifests with an exacerbation of IBD.

2) Hepatitis may develop in the course of mononucleosis or independently, as a separate clinical manifestation.

3) Pneumonia rarely occurs in immunocompetent individuals but is the most frequent clinical manifestation in lung transplant recipients and those after HSCT. It presents with cough and dyspnea. Viremia is often undetectable or low level.

4) Retinitis: A specific “pizza-pie” appearance of the eye fundus; extensive inflammatory areas with yellowish exudate and hemorrhage along the vascular arches around the macula and perivascular sheathing. The disease leads to retinal atrophy and blindness.

5) Neurologic manifestations: Encephalitis, Guillain-Barré syndrome, brachial plexus neuropathy, transverse myelitis, Horner syndrome, neuropathy, cranial nerve palsy.

6) Other: Myocarditis and pericarditis, pancreatitis, nephritis, cystitis.

5. Congenital CMV (cCMV) infection is the most frequently reported congenital infection. Clinical forms:

1) Severe symptomatic cCMV (~13% of children born by women with primary CMV infection during pregnancy) is diagnosed in the neonatal period, in newborns with multiple clinical manifestations (jaundice, ecchymosis, microcephaly, hepatosplenomegaly, low birth weight, choroiditis, retinitis) and central nervous system (CNS) involvement.

2) Mild symptomatic cCMV infection is diagnosed in infancy, when ≥1 transient mild manifestation is seen.

3) Asymptomatic cCMV infection with isolated hearing loss.

4) Asymptomatic cCMV infection with hearing preservation.

It is estimated that 10% to 15% of newborns with cCMV infection will experience long-term complications, with hearing loss within the first 3 years of life being the most common one.

Diagnosis

Diagnostic Tests

1. Identification of the etiologic agent:

1) Tests indicating an active infection:

a) Culture on human fibroblasts: Testing material includes blood, cerebrospinal fluid (CSF), throat wash, bronchoalveolar lavage fluid (BALF), urine, biopsy specimens, uterine discharge, amniotic fluid, placenta, and tissue specimens. Culture allows for identification of a virus with infectious potential. A positive result of oral fluid or urine culture should not be the basis for diagnosing CMV disease because of its low specificity (CMV disease is difficult to differentiate from transient viral shedding in the natural history of infection). The American Society of Transplantation (AST) does not recommend viral culture of blood, urine, or oral fluid to diagnose active CMV infection and CMV disease.

b) Molecular studies: Detection of CMV DNA using real-time polymerase chain reaction (RT-PCR). Quantitative tests measuring the level of viremia are typically used in clinical practice (the AST suggests using the term DNAemia instead of viremia to emphasize that what is relevant is the detection of CMV DNA in blood or plasma, regardless of its origin [infectious viral particles vs circulating fragments of the viral DNA]). RT-PCR tests are used to monitor individuals at risk of CMV disease (after SOT or HSCT), diagnose CMV infection, and monitor treatment response. As the viral load may vary depending on the tests and biologic materials used, subsequent follow-up examinations should be performed using the same test and material as previously, preferably by the same laboratory. As recommended by the AST, a difference >0.5 log10 IU/mL or 3-fold increase in the CMV DNA concentration should be regarded as clinically significant in patients after SOT or HSCT. Plasma or whole blood are most frequently used for testing, although CMV DNA can also be detected in other body fluids (CSF, BALF). Absence of CMV DNA in blood or plasma does not exclude CMV disease. The AST does not recommend CMV DNA detection in urine and oral fluids for the diagnosis of CMV disease and follow-up in patients after SOT or HSCT.

c) Detection of the pp65 antigen in leukocytes using immunofluorescence. The result indicates the number of stained cells per the total number of identified cells. The number of infected cells is correlated with the risk of developing active disease. In the case of neutropenia, the result can be falsely decreased, and the AST does not recommend this test in patients with neutrophil count <1000/microL.

d) Histologic studies: Gold standard in the diagnostic workup of end-organ CMV disease; they allow for detection of characteristic CMV inclusion bodies in infected cells (the “owl eye” appearance). CMV infection can be confirmed by immunohistochemistry and/or detection of CMV DNA in tissue by hybridization. Antibody tests and staining procedures vary in sensitivity.

2) Tests indicating contact with CMV:

a) Serologic tests: Identification of specific antibodies (immunoenzymatic and immunofluorescence tests are most frequently used); the tests indicate previous CMV infection. Identification of specific IgM antibodies and/or ≥4-fold increase in the IgG antibody concentration suggests recent CMV infection. IgM antibodies appear within the first 2 weeks of infection and usually circulate in the body for several months (typically 4-6 months). IgG antibodies appear after 2 to 3 weeks from infection onset and can be detected throughout the patient’s life. IgG testing is performed in recipients and donors of solid organs or hematopoietic stem cells to evaluate the risk of posttransplant CMV disease. In immunosuppressed individuals, active infection cannot be diagnosed based on the presence of IgG antibodies. A false result may be caused by low antibody concentration and plasmapheresis (risk of obtaining a false-negative result), transfusion of blood components or blood products (risk of obtaining a false-positive result; blood samples should be collected before transfusion). Serologic tests are also used for screening patients with HIV infection and for diagnosing CMV infection in immunocompetent individuals and pregnant patients. Measurement of avidity allows for differentiation between IgG antibodies from past and recent infections. High IgG avidity, regardless of IgG antibody concentration and the presence of IgM antibodies, excludes recent infection.

b) Detection of specific T cells (detection of cellular response to CMV infection) is not routinely used in the diagnostic workup of CMV infection; it is useful for determination of the patient’s immune status if a false-positive serologic test result is suspected (eg, due to passive transfer of antibodies during transfusion). The test is used in patients after SOT evaluated for pharmacoprophylaxis and preemptive treatment to monitor the response of CMV-specific T cells and indicate individuals at increased risk of infection reactivation and development of CMV disease.

3) Molecular studies: Detection of drug resistance (genotyping); the studies should be performed in individuals with posttransplant CMV disease, particularly if they show no response to ganciclovir or the disease progresses rapidly despite treatment. Sequence variations causing treatment resistance occur in genes encoding CMV proteins pUL97 and pUL54. Specimen: plasma, CSF, BALF. The viral load for testing should be >1000/mL.

2. Other: Diagnostic test results differ depending on disease manifestations:

1) Primary infection: Lymphocytosis, often with atypical lymphocytes; polyclonal hypergammaglobulinemia; rarely thrombocytopenia and hemolytic anemia. In the case of hepatitis, increased serum activity of aminotransferases is observed.

2) Colitis: Often leukopenia, thrombocytopenia, anemia, hypoalbuminemia. Endoscopic examination reveals features of mucositis, but macroscopic lesions are nonspecific; ulceration is frequently seen; pseudomembranes can also develop. Mucosal biopsy is fundamental for diagnosis.

3) Retinitis: Eye fundus examination serves as the basis for diagnosis (the “pizza-pie” sign).

4) Pneumonia: Radiography and computed tomography (CT) scans are nonpathognomonic; diffuse ground-glass opacities, alveolar opacities, nodular lesions, features of pleural effusion.

Diagnostic Criteria

In immunosuppressed individuals, manifestations of organ involvement and CMV detection in blood only, regardless of the method used, are insufficient to diagnose CMV disease (the only instance where clinical features are sufficient to establish the diagnosis is retinitis, in which case CMV identification in tissue is not needed). CMV detection in blood is insufficient to diagnose end-organ CMV disease, except for the CMV syndrome.

Case definitions according to the Drug Development Forum:

1. CMV syndrome refers exclusively to SOT recipients. No definition of proven disease has been established so far. Probable disease: CMV detection in blood (culture, PCR, pp65 antigen) and ≥2 of the following manifestations:

1) Fever ≥38 degrees Celsius persisting for ≥2 days.

2) Development or exacerbation of malaise or fatigue.

3) Leukopenia or neutropenia confirmed on 2 separate measurements performed at an interval of ≥24 hours. If the leukocyte count before clinical onset is ≥4000/microL, leukopenia is defined as a leukocyte count <3500/microL, and neutropenia, as a neutrophil count <1500/microL. If the leukocyte count before infection is <4000/microL, leukopenia and neutropenia are defined as a decrease in the leukocyte or neutrophil count, respectively, by >20%.

4) At least 5% of atypical lymphocytes on peripheral blood smear.

5) Thrombocytopenia. If the platelet count before clinical onset is ≥115,000/microL, thrombocytopenia is defined as platelet count <100,000/microL. If the platelet count before clinical onset is <115,000/microL, thrombocytopenia is defined as a decrease in the platelet count by >20%.

6) Serum activity of aminotransferases 2-fold higher than the upper limit of normal (a criterion to be used in recipients of organs other than the liver).

2. CMV pneumonia:

1) Proven disease: Clinical manifestations and features of pneumonia in diagnostic tests, in conjunction with CMV detection in lung tissue.

2) Probable disease: Detection of CMV (culture) or CMV DNA in BALF in conjunction with manifestations of pneumonia. The probability of CMV pneumonia increases with an increase in the viral load in BALF; a low concentration of CMV DNA may be associated with asymptomatic shedding; a negative BALF test result excludes CMV infection as the cause of pneumonia.

3. CMV-related GI disease:

1) Proven disease: Manifestations suggesting involvement of the upper or lower GI tract as well as macroscopic mucosal lesions and documented presence of CMV in tissue. Exclude graft-versus-host disease (GVHD) in patients after allogeneic HSCT.

2) Probable disease: Manifestations suggesting involvement of the upper or lower GI tract and documented presence of CMV in tissue, without macroscopic mucosal lesions. CMV detection in blood (DNA or pp65 antigen) is insufficient to establish the diagnosis.

4. Hepatitis: Proven disease: Abnormal laboratory test results indicating hepatitis and documented presence of CMV in liver tissue, without other documented causes of hepatitis.

5. Retinitis: Proven disease: Characteristic image of the eye fundus. If the image is atypical, testing for CMV DNA in the aqueous humor should be performed.

6. Encephalitis:

1) Proven disease: CNS manifestations and documented presence of CMV in nervous tissue.

2) Probable disease: CNS manifestations, detection of CMV in CSF not contaminated with blood, and features of encephalitis on imaging or electroencephalography (EEG).

7. Inflammation of the transplanted kidney: Proven disease: CMV detection in tissue and histologic features of CMV infection. CMV detection in urine by PCR testing or culture is insufficient to establish the diagnosis of nephritis, as asymptomatic viral shedding in urine is a frequent finding.

8. Cystitis: Proven disease: CMV detection in a biopsy specimen from bladder mucosa in a patient with manifestations of cystitis. CMV detection in urine is insufficient to establish the diagnosis.

9. Myocarditis: Proven disease: Histologic features of CMV myocarditis on biopsy and CMV detection in tissue.

10. Pancreatitis: Proven disease: Histologic features of CMV infection and CMV detection in tissue.

Diagnostic Workup

Diagnostic tests are selected based on the patient’s immune status and clinical form of the disease. In immunosuppressed individuals, laboratory test results should be interpreted with reference to medical history and clinical features. In some patients, CMV DNA and the pp65 antigen are detected despite the absence of active disease. Negative test results do not exclude CMV disease.

1. Immunocompetent individuals:

1) Diagnostic workup of infectious mononucleosis, diagnostic workup in pregnant patients: Identification of specific IgG and IgM antibodies. Identification of specific IgM antibodies or >4-fold increase in the titer of specific IgG antibodies indicates recent CMV infection. In pregnant patients, if in doubt, measure specific IgG antibody avidity to evaluate whether the infection developed before conception or during pregnancy. High avidity indicates that CMV infection was acquired >20 weeks before testing. Testing should be performed in pregnant patients if congenital defects suggesting intrauterine infection have been found on ultrasonography as well as in those with manifestations of infectious mononucleosis and/or hepatitis. No routine screening is recommended in pregnancy.

2) Patients in severe condition due to other diseases: CMV disease is most frequently associated with infection reactivation; test for CMV DNA (in blood/plasma; in the case of pneumonia, also in BALF).

3) Donors of solid organs and hematopoietic stem cells: Measure the titer of specific IgG antibodies to determine serologic status; a positive result indicates past infection. The serologic CMV status of the donor and recipient is the main risk predictor of posttransplant CMV disease and informs decision on the initiation of antiviral prophylaxis or preventive therapy.

2. Immunosuppressed individuals:

1) SOT or HSCT recipients:

a) Before transplant: Identification of specific IgG antibodies to determine serologic status; a positive result indicates past infection.

b) CMV syndrome (only in SOT recipients): Detection of CMV DNA in blood/plasma or detection of the pp65 antigen in blood (pp65 is not recommended in those with neutropenia <1000/microL).

c) End-organ CMV disease: Culture on tissue/body fluids (BALF in pneumonia, CSF in CMV infection of the CNS), histologic study, CMV DNA detection in blood/plasma, pp65 antigen detection in blood (not in those with neutropenia <1000/microL). Negative results of blood tests for CMV DNA or the pp65 antigen do not exclude the disease.

d) Monitoring (infection prevention, evaluation of treatment efficacy): CMV DNA detection in blood/plasma, pp65 antigen detection in blood. The viral load in the initial phase of infection and rate of its increase help identify persons at risk of CMV disease (the higher the initial viral load, the higher the risk of developing the disease).

In treated patients testing should be repeated at least weekly but not more frequently than every 5 days. If no response to treatment is observed, test for drug resistance.

2) Individuals with HIV infection:

a) Identification of IgG and IgM antibodies against CMV after the diagnosis of HIV infection, before initiation of antiretroviral therapy.

b) Diagnostic workup of CMV disease, if suspected: As in individuals with immunosuppression due to HSCT or SOT.

Differential Diagnosis

1. Infectious mononucleosis: EBV infection, HIV infection, human herpes virus 6 (HHV-6) infection, toxoplasmosis.

2. Colitis: Nonspecific inflammatory bowel disease, GVHD in individuals after allogeneic HSCT.

3. Pneumonia: Pneumonia of other etiology.

Treatment

Antiviral Treatment

1. Infectious mononucleosis: Symptomatic treatment only.

2. Infection in pregnancy: No antiviral treatment is used in asymptomatic or mild disease if there is no threat to the mother’s life (the efficacy of antiviral therapy for the prevention of congenital infection has not been confirmed). If infection is diagnosed in the fetus, valganciclovir or antigen-specific serum antibodies can be used within clinical trials.

3. Treatment of CMV syndrome and end-organ involvement other than retinitis: Antiviral treatment usually starts with an initial high-dose regimen (induction therapy). Duration of the induction therapy varies, but it often lasts ≥3 weeks and continues until the resolution of clinical manifestations, negative results of molecular studies, or both. Following this, experts consider starting a low-dose regimen as secondary prophylaxis (maintenance therapy), but its optimal duration is not well defined.

1) Preferred induction therapy: IV ganciclovir 5 mg/kg every 12 hours or oral valganciclovir 900 mg every 12 hours.

2) Alternative induction therapy: IV foscarnet 90 mg/kg every 12 hours, IV cidofovir 5 mg/kg once a week, oral maribavir 400 mg every 12 hours (approved in 12 countries including Australia, Canada, European Union, and the United States for the treatment of CMV disease resistant to other antiviral agents; ineffective in the treatment of HSV and varicella zoster virus [VZV] infections).

GI infection: Treatment duration ≥3 weeks, until negative results of molecular studies are obtained, absence of the pp65 antigen is reported, or manifestations resolve.

Pneumonia: Treatment duration ≥3 weeks, until negative results of molecular studies are obtained, absence of the pp65 antigen is reported, or manifestations resolve. In addition, intravenous immunoglobulin (IVIG) or specific anti-CMV immunoglobulin can be used in critically ill patients after HSCT.

CNS infection: Ganciclovir is the drug of choice; combined treatment with ganciclovir and foscarnet or addition of IVIG or an anti-CMV immunoglobulin (no proven efficacy) can be considered. Treatment is continued until clinical manifestations resolve or CMV DNA is not detected in serum and CSF.

Note that dose adjustment is required for ganciclovir, valganciclovir, foscarnet, and cidofovir in patients with altered kidney function.

4. Retinitis:

1) Preferred treatment:

a) Lesions increasing the risk of vision loss: Injections to the vitreous body (ganciclovir 2 mg once weekly until lesion inactivity is achieved; or foscarnet 2.4 mg for 1-4 doses injected within 7-10 days) in combination with oral valganciclovir 900 mg every 12 hours for ≥14 to 21 days as induction, then every 24 hours as maintenance therapy.

b) Peripheral lesions: Oral valganciclovir 900 mg every 12 hours for ≥14 to 21 days as induction, then every 24 hours as maintenance therapy.

2) Alternative treatment:

a) IV ganciclovir 5 mg/kg every 12 hours for ≥14 to 21 days as induction, then oral valganciclovir 900 mg every 24 hours as maintenance therapy.

b) IV foscarnet 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for ≥14 to 21 days as induction, then 90 to 120 mg/kg every 24 hours as maintenance therapy.

c) IV cidofovir 5 mg/kg once a week for ≥2 consecutive weeks as induction, then 5 mg/kg every 2 weeks as maintenance therapy (make sure the patient is properly hydrated with each dose: use IV 0.9% NaCl solution and oral probenecid).

5. Preemptive treatment: Antiviral therapy is used in patients after SOT (or treated with alemtuzumab or idelalisib), with biomarkers of CMV replication without clinical manifestations of CMV disease. Treatment aims to prevent progression of infection to CMV disease, and the dosing and choice of antivirals for induction and maintenance therapies are the same as those used for treating CMV syndrome and organ involvement other than retinitis. Management involves regular monitoring for the presence of CMV in blood to detect early viral replication. After a specific CMV DNA concentration threshold is reached, antiviral treatment is started regardless whether manifestations develop or not. So far, no specific DNAemia cutoff point for the initiation of preemptive treatment has been determined (some experts suggest 4000 IU/mL in patients after SOT; however, the AST recommends establishing cutoff points for viremia in every center to initiate preemptive treatment and evaluate its efficacy). Monitoring duration varies. The AST suggests discontinuation of preemptive treatment in patients after SOT if viremia is <200 IU/mL (measured with a high-sensitivity test) or after obtaining 2 consecutive negative results of lower-sensitivity tests.

6. Secondary prophylaxis (maintenance therapy): In individuals with HIV infection and those treated for retinitis and CNS infection caused by CMV, use maintenance doses (eg, oral valganciclovir 900 mg every 24 h) and continue treatment until the CD4+ cell count increases to >100 to 150/microL for ≥6 months and stabilization of lesions is found on the eye fundus examination. Again, note that dose adjustment is required for valganciclovir in patients with altered kidney function.

Complications

1. Infectious mononucleosis: Chronic fatigue syndrome.

2. Colitis: Bowel perforation, bleeding.

3. Retinitis: Blindness.

4. Pneumonia: Respiratory distress requiring ventilatory support.

5. Recurrent infections in immunosuppressed individuals.

6. In infected patients after SOT or HSCT: Increased risk of bacterial, viral, and fungal infections, posttransplant lymphoproliferative disorders (PTLDs), transplant rejection, development of chronic nephropathy in the transplanted kidney, renal interstitial fibrosis, tubular atrophy, development of vascular disease (eg, angiosclerosis involving the transplanted organ).

7. Immune reconstitution inflammatory syndrome: Particularly in CNS infection or retinitis in individuals with HIV infection, after initiation of antiretroviral treatment.

Prognosis

Prognosis in immunocompetent individuals is good. In critically ill patients with other diseases, reactivation of CMV infection prolongs hospitalization and increases mortality.

Pneumonia, GI tract infection, or CNS infection in immunosuppressed individuals after HSCT are associated with a high risk of death not related to recurrence of the underlying disease. In those after HSCT, mortality associated with CMV infection ranges from 10% to 75%.

Prevention

Specific Prevention

1. Vaccination: None available.

2. Passive immunoprophylaxis: Specific anti-CMV immunoglobulin or IVIG in selected groups of patients after SOT or HSCT.

3. Pharmacoprophylaxis: Valganciclovir, ganciclovir, or letermovir in immunosuppressed individuals, used particularly in patients after SOT or HSCT. The choice and duration of pharmacoprophylaxis depend, among other things, on the transplant type (eg, SOT, HSCT), transplanted organ (in SOT), immunosuppressive drug regimen (eg, use of antithymocyte globulin as induction therapy in transplant patients), and the donor/recipient serologic status for CMV. Practices may also differ by transplant center, and each decision for pharmacoprophylaxis should be made in discussion with experts in this area (eg, infectious disease and transplant specialists).

Nonspecific Prevention

1. Seronegative (not previously infected with CMV) immunosuppressed individuals and pregnant patients:

1) For transfusion of blood components (packed red blood cells, platelet concentrate) in patients with immune deficiency (also after transplant) and newborns, use products that are leukoreduced, have inactivated biologic pathogens, or are derived from CMV-negative donors.

2) Allogeneic HSCT from CMV-negative donors.

3) Using condoms during sexual contacts.

4) Hygiene precautions: Inform the patient about:

a) Increased risk of infection during frequent contacts with children (caretaking).

b) Hand hygiene and avoiding the use of shared, unwashed cutlery, mugs, bottles, etc.

c) Necessity to avoid contact with teardrops and saliva when kissing children (kissing, eg, on the forehead instead of the cheek), cleaning surfaces contaminated with saliva, urine, or other body fluids.

2. Patient isolation: Not required.

3. Personal protective equipment (PPE): Standard.