Cytomegalovirus Infections

Andrew Nguyen; Mahmoud Shorman

Cytomegalovirus Infections

Author: Andrew D. Nguyen Editor: Mahmoud Shorman Updated: 12/13/2025 9:45:15 PM

Introduction

Cytomegalovirus (CMV) is a double-stranded DNA virus that belongs to the family of Herpesviridae and is also known as human herpesvirus 5.[1] The CMV genome is the largest among human viruses, measuring approximately 230 kb and containing 200 genes that encode proteins.[2][3] Infection with CMV is common in both children and adults, with a worldwide seroprevalence ranging from 24% to 100%, which increases with age.[4] CMV is transmitted through the exchange of bodily fluids, including saliva, fomites, blood transfusions, and sexual contact. CMV can also be transmitted through solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT).[5] As with other herpesviruses, it establishes lifelong latency, remaining dormant in monocytes through specific mechanisms of transcriptional silencing.[1][6][7] CMV is a globally widespread virus that becomes latent after primary infection and can become reactivated in the setting of severe immunosuppression.

In immunocompetent patients, primary CMV typically causes asymptomatic disease or mild-to-moderate mononucleosis-like or flu-like syndromes, characterized by symptoms such as malaise, fever, lymphadenopathy, and arthralgia.[4] Infection with CMV is a leading cause of morbidity in immunosuppressed individuals, eg, due to HIV/AIDS, after receiving SOT and HSCT. In the latter population, CMV can cause severe organ damage and even cause rejection of the transplanted organ.[8] Additionally, mothers who become infected while they are pregnant may pass the virus to the embryo, and in some cases, this can cause congenital CMV.[4]

CMV infection is defined by the detection of active CMV replication in tissue specimens, peripheral blood, or other body fluids, irrespective of clinical manifestations. CMV disease refers to the presence of CMV infection in conjunction with clinically attributable symptoms and signs.[9] CMV disease is subclassified into CMV syndrome, characterized by nonspecific constitutional symptoms, such as fever, malaise, and lymphadenopathy, which are often accompanied by hematologic abnormalities, including leukopenia or thrombocytopenia, as well as tissue-invasive or end-organ CMV disease.[9] CMV syndrome involves direct viral-mediated injury to specific organs, including, but not limited to, the gastrointestinal (GI) tract, lungs, hepatobiliary system, renal parenchyma, myocardium, pancreas, central nervous system, and retina.[9]

Primary, but mostly reactivated, CMV can cause viremia, infecting various organs, including the eyes, stomach, esophagus, and colon, especially in patients with profound immunosuppression.[8] The 2 most common GI tract manifestations of CMV disease include CMV colitis and CMV esophagitis.[10]

Prevention of CMV viremia and CMV end-organ disease is critical, particularly in immunosuppressed patients. Key strategies include assessing CMV serostatus in both donor and recipient, along with regular monitoring for the emergence of viremia via frequent CMV DNA quantification. In high-risk populations, prophylactic strategies may include universal antiviral administration for all at-risk individuals, targeted prophylaxis for those at highest risk, or a pre-emptive approach. The pre-emptive strategy involves initiating antiviral therapy upon early detection of CMV DNAemia, before the onset of clinical disease.[8]

Etiology

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Etiology

CMV is a ubiquitous, double-stranded DNA virus that belongs to the Herpesviridae family and is also known as herpesvirus-5. The virus measures 180 nm in diameter and consists of a protein capsid that encapsulates a DNA core measuring 100 nm, which is further enclosed by a lipid envelope.[11] The assembly of viral proteins is essential for the formation of new capsids. This process begins with the creation of dense bodies that are larger than the virion that contain matrix proteins with CMV DNA. Additionally, there is a second type of structure that lacks CMV DNA but has a high concentration of matrix proteins, known as non-infectious enveloped particles. The DNA polymerase allows further CMV DNA synthesis by cleaving concatemeric molecules into daughter capsids. The DNA sequences are rich in guanine and cytosine, which readily bind host cell DNA. Once CMV infection is acquired, the virus can persist in cells of the myeloid lineage, resulting in lifelong viral latency as it evades the immune system through specific mechanisms of transcriptional silencing.[1][6][7] In immunocompetent individuals, CMV is maintained in a state of balance; however, when immunosuppression occurs, CMV can begin to replicate.[8] Cytotoxic CD8 T cells regularly control CMV reactivation. However, in immunosuppressed patients, such as those who have undergone SOT or HSCT, the failure of immune control and stimulated CMV replication can lead to reactivation.[12] Reactivation can occur locally at a specific organ and may be undetected by serum molecular viral load testing, or it can lead to viremia, also known as CMV DNAemia.[8]

Epidemiology

Infection with CMV is common in both children and adults and is endemic worldwide. Globally, the seroprevalence of CMV infection has been reported to range from 24% to 100%, although the data are heterogeneous.[5][13][14] A more recent systematic review and meta-analysis estimate a global prevalence of 83% in the general population, increasing to 86% among women of childbearing age.[1] Globally, the seroprevalence of CMV infection has been reported to range from 24% to 100%, although the data are heterogeneous and limited.[5][13][14] In the United States, age-adjusted CMV immunoglobulin G (IgG) seroprevalence is approximately 30% in children by age 5 and more than 50% in adults by age 40.[4] While further south in Central America, CMV seroprevalence ranges from 66% to 90% in the general population, with the prevalence increasing with age.[15][16] Further studies have determined CMV exposure to be independently associated with female sex, lower socioeconomic status, older age, lower household education, and increased crowding in households.[4][13][17]

CMV infection can occur as a primary infection, reinfection, or reactivation. CMV can be transmitted through multiple routes, primarily via bodily fluids, including saliva, fomites, blood transfusions, SOT, HSCT, breastfeeding, viral shedding in close-contact settings, perinatal transmission, and sexual contact.[18][19] CMV represents the most common opportunistic viral infection in patients who have received HSCT and SOT, and can cause a life-threatening tissue-invasive disease, most commonly in the GI tract, lungs, liver, eyes, and central nervous system.[20] CMV is the most common viral opportunistic infection in patients with HIV/AIDS and can cause severe disease in patients, especially those with profound immunosuppression with a CD4 count <50 cells/µL.[21]

Reactivation is observed in patients who become immunocompromised and is associated with increased morbidity and mortality.[18][19]. Factors independently associated with CMV reactivation from observational studies have included higher age, lymphoid malignancies, concomitant graft-versus-host disease (GVHD), persistent lymphopenia, use of CMV seronegative donor graft in HSCTs, hypoalbuminemia, higher creatinine level, higher and cumulative doses of prednisolone, and cyclosporine use.[22][23] The most common manifestations of CMV end-organ damage are retinitis, followed by pneumonitis, colitis, esophagitis, encephalitis, and polyneuropathy.[24][25] CMV colitis and esophagitis are the two most frequent CMV-related manifestations leading to end-organ damage.[10]

Cytomegalovirus in Transplant Patients

CMV infection and disease are important causes of morbidity and mortality in transplant recipients. CMV disease can present as CMV end-organ damage, a tissue-invasive disease, and as CMV syndrome, characterized by fever, leukopenia, and malaise.[26] Tissue-invasive disease in this population manifests as end-organ damage, including conditions such as colitis, esophagitis, pneumonitis, gastroenteritis, hepatitis, and rhinitis. Despite strategies to prevent CMV disease, CMV infection occurs in up to 50% of high-risk SOT patients, typically following organ transplantation from a CMV-seropositive donor to a CMV-seronegative recipient (D+/R−), and in 17% of CMV-seropositive recipients (R+).[20][27] Risk factors for CMV infection or disease include a D+/R− serological status, seropositive recipients, induction with mycophenolic acid, steroid or polyclonal antibodies, advanced age of donors and recipients, and a history of acute organ rejection.[28] CMV infection following SOT is associated with a heightened risk of acute rejection and graft failure, increased mortality, and greater healthcare costs due to more frequent hospital readmissions, longer inpatient stays, and overall higher hospitalization costs.[29]

Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients

CMV reactivation is a common complication following allogeneic HSCT (allo-HSCT), particularly during periods of immunosuppression. Positive CMV serology has been linked to reduced overall survival and increased non-relapse mortality, as reactivation can lead to severe end-organ disease, including pneumonia, colitis, and retinitis.[30] Beyond direct organ damage, CMV infection has also been linked to an increased risk of secondary bacterial and fungal infections, as well as a higher incidence of GVHD. This CMV section may be attributed to CMV's immunomodulatory effects, which can influence the dynamics of the immune system post-transplant. CMV serostatus is a critical determinant of post-transplant outcomes. Positive serology, particularly in the recipient, is associated with significant transplant-related morbidity and mortality.[31] The worst outcomes in terms of survival and non-relapse mortality occur in CMV seronegative donor/seropositive recipient (D−/R+) pairs, followed by seropositive donor/seropositive recipient (D+/R+) combinations.[32]

Cytomegalovirus in Patients with HIV Infection

CMV esophagitis is the second most common GI manifestation of CMV in individuals with HIV/AIDS. CMV is the most frequent viral opportunistic infection in this population, particularly when CD4+ T lymphocyte counts fall below 50 cells/mm³.[33] Hallmark symptoms of CMV esophagitis include dysphagia and odynophagia. Endoscopy with biopsy remains the gold standard for diagnosis. Endoscopic findings may include well-demarcated, vertical, single or multiple ulcers, or diffuse esophagitis, most commonly located in the mid-to-distal esophagus.[34] Other manifestations of CMV disease in patients with HIV/AIDS include CMV retinitis (most commonly observed), pneumonitis, and neurological sequelae, such as encephalitis, polyradiculopathy, and multifocal neuropathy (see Image. Cytomegalovirus Retinitis).[35][36]

Cytomegalovirus Colitis

CMV colitis occurs most commonly in immunocompromised hosts, including patients with HIV/AIDS and those who have undergone SOT, HSCT, and chemotherapy. CMV colitis accounts for up to 30% of CMV GI disease in SOT patients. The role of CMV in patients with inflammatory bowel disease (IBD) remains controversial. Whether CMV reactivation contributes to disease exacerbation in individuals with established IBD, occurs as a result of the disease or its treatment, or merely represents an incidental finding without pathogenic significance remains unclear.[37][38] In addition, in patients with IBD, studies have shown that immunosuppression from high-dose systemic corticosteroids is linked to the development of CMV colitis in patients with active ulcerative colitis.[39] Other immunomodulatory therapies used in ulcerative colitis, such as thiopurines and methotrexate, have also been associated with CMV infection, whereas anti-tumor necrosis factor agents have not shown a similar association.[40][41] Patients undergoing allo-HSCT are at increased risk for CMV infection or reactivation. However, distinguishing between GI GVHD and CMV colitis is crucial in this population. CMV reactivation in patients with severe ulcerative colitis is reported to have a prevalence of 4.5% to 16.6% and as high as 25% in patients requiring colectomy for severe colitis.[42] The CMV infection rate in patients with severe corticosteroid-refractory ulcerative colitis ranges from 20% to 40% when infection was diagnosed using antigenemia and histological examination of tissue biopsies.[43][44]

CMV colitis can also occur in healthy immunocompetent patients, and there have been increasing reports, although the incidence is rare.[45] The prevalence of CMV infection in severe acute colitis ranges from 21% to 34% in healthy individuals.[46][47] These patients are typically older adults with underlying comorbidities, and reported cases have shown an association with underlying ulcerative colitis.[39] These patients typically are asymptomatic or have self-limited disease, presenting as gastroenteritis, duodenitis, ileitis, proctitis, or exacerbation of IBD.[45] Colitis may result in a chronic infection or a lifelong carrier state with intermittent reactivation. Symptoms include diarrhea, abdominal pain, and hematochezia or melena. The outcomes are typically favorable, including resolution without antiviral treatment in nearly 25% of these patients.[48] CMV colitis should be a consideration in the differential diagnosis of hematochezia, not only in immunocompromised patients but also in immunocompetent patients, particularly in older adults with underlying comorbidities.[45]

Cytomegalovirus Esophagitis

CMV esophagitis is the third most common cause of infectious esophagitis—after Candida and HSV—and occurs predominantly in patients with profound immunosuppression, including those with HIV/AIDS or those receiving immunosuppressive therapy after SOT or HSCT. [49] Dysphagia and odynophagia are the most common presenting symptoms in CMV esophagitis, especially in the middle to distal esophagus. CMV esophagitis is associated with a poor prognosis, a risk of recurrence, and a high rate of morbidity and mortality at 12 months.[12]

Pathophysiology

The first step in CMV infection involves the binding of highly conserved glycoproteins M and B (gM and gB) to the host cell's heparan sulfate proteoglycans.[50] Glycoprotein B is also crucial for the spread of CMV from cell to cell.[50] Once CMV is transmitted, and the primary infection clears, the virus remains dormant in myeloid cells.[51] CMV can infect a large variety of cell types.[50] Additionally, it can remain latent in bone marrow progenitor cells after primary infection and replicate in various cells and tissues.[17] Viral replication and reactivation are contained primarily by cytotoxic T-cell immunity. However, when reactivation occurs, virions are released into the bloodstream and other body fluids, leading to the presence of symptoms, predominantly in immunocompromised patients.[52][53] Reactivation appears to be driven by inflammatory cytokines that stimulate the differentiation of myeloid progenitor cells into innate immune cells, such as macrophages and dendritic cells, allowing for genetic induction to promote lytic infection.[54][55] Cellular reactivation can occur without viremia, suggesting an element of immune control. When reactivation occurs with concurrent viremia, it is thought to occur most commonly in immunocompromised individuals, often triggered by co-infections or by allogeneic immune-driven responses that lead to end-organ damage.[56] Eye disease, such as CMV retinitis and immune recovery uveitis, is thought to result from lytic infection or an immune response against CMV antigens. Resultant immune activation and cytokine responses are thought to be responsible for CMV-associated promotion of atherosclerotic disease.[57]

In immunocompetent individuals, CMV replication is controlled by antibodies targeting key viral surface glycoproteins, as well as a robust cell-mediated immune response involving natural killer cells, CD4+ T cells, and CD8+ T cells. In immunocompromised patients, CMV disease may result from reactivation of the latent virus, primary infection, or reinfection with a different strain. Reactivation is primarily due to impaired cell-mediated immunity rather than a deficiency in humoral immunity, as these patients typically have sufficient levels of anti-CMV antibodies.[5] The inability to control CMV replication in these patients is mainly due to dysfunctional CD4+ and CD8+ T-cell responses, including impaired mono- and polyfunctional cytokine production. Additionally, CMV encodes proteins that disrupt immune defenses by interfering with class I and class II HLA presentation, natural killer cell activity, the cell cycle, and key apoptotic and inflammatory pathways that generally help contain the virus[17]

Histopathology

Histopathological diagnosis of CMV infection in any tissue can be made by identifying cytomegalic cells and CMV inclusion bodies, which are visible when stained with hematoxylin and eosin (H&E). These cells measure 25 to 35 µm in size, with basophilic intranuclear inclusions that are occasionally surrounded by a clear halo; intracytoplasmic inclusions can also be observed.[5] Finding these cytomegalic cells can be tedious and requires an astute pathologist, as well as a sufficient number of biopsy samples for evaluation.[5] The advent of immunohistochemical staining using anti-CMV monoclonal antibodies is the gold standard for making a diagnosis.[5][58][59]

In CMV-associated pneumonitis, lymphocytes and inflammatory cytokines populate the pulmonary interstitium, impairing gas exchange and leading to hypoxia and oxygen desaturation for the host.[60]

In GI CMV infection, mucosal infection by CMV leads to inflammation and tissue necrosis, vascular endothelial involvement, and, ultimately, ischemic mucosal injury. The occlusion of the vasculature contributes mainly to the cause of tissue injury and ulcer formation.[5] In CMV esophagitis, there are no specific endoscopic features that can confirm the diagnosis; therefore, the definitive diagnosis depends on biopsy findings. The diagnosis of CMV colitis requires histological examination of biopsy tissues taken from the base or edge of the ulcer. Patients with punched-out ulcers typically have a higher number of inclusion bodies on histology.[61] Histological examination can differentiate CMV colitis from other causes, eg, infectious colitis, ulcerative colitis, or drug-induced colitis.[62] Colonic mucosal biopsies stained with H&E may show viral inclusion bodies characteristic of CMV colitis, commonly referred to as owl eye inclusions, which are highly specific for CMV. However, H&E staining has limited sensitivity and is less reliable than immunohistochemistry, which is considered the gold standard for diagnosing CMV colitis.[59]

History and Physical

In healthy individuals, CMV infection is often asymptomatic and subclinical, typically resolving with minimal sequelae and a self-limiting course. When symptoms occur, the infection can present as a mononucleosis-like syndrome, including fever, fatigue, rash, and lymphadenopathy.[5] Rarely, symptoms can be prolonged, and on occasion, severe CMV infection may lead to sequelae, such as myocarditis, pneumonitis, and GI involvement.[63]

CMV infection in immunosuppressed patients can result in viremia and/or end-organ damage, affecting any organ. Clinical signs and symptoms are related to the organ affected by CMV. The affected organ may be the transplanted organ, resulting in impaired function and even graft rejection, or another organ that can exhibit dysfunction. Examples of these may be CMV pneumonitis in the case of a lung transplant recipient who presented with respiratory symptoms or CMV nephritis in a patient who had undergone a lung transplant, who presented with hematuria.[64][65]

CMV infection can occur anywhere in the GI tract in immunosuppressed patients.[5] In CMV esophagitis, the typical large, distal solitary or multiple esophageal ulcers typically produce symptoms such as odynophagia, dysphagia, and substernal chest pain.[5][66][49] Other symptoms include nausea, vomiting, abdominal pain, weight loss, and diarrhea.[10] Rare presentations include GI bleeding and stricture formation.[5][67] Patients with CMV colitis present with nonspecific symptoms, including diarrhea, abdominal pain, fever, rectal bleeding, and weight loss.[45] The symptoms can mimic an exacerbation of IBD, making it challenging to distinguish between ulcerative colitis and CMV colitis solely based on clinical presentation.[68] A high index of suspicion is necessary, and laboratory investigations are essential in diagnosing CMV colitis.

Evaluation

In immunocompetent patients with symptoms of CMV disease, including fever, malaise, and lymphadenopathy, a definitive diagnosis is rarely necessary. In patients who have received SOT or HSCT, serological testing for IgG of the donor and the recipient before the transplantation provides essential information regarding serostatus for risk-stratification of CMV infection. This testing should not be used for the diagnosis of acute infection, but serves to guide close monitoring and inform decisions regarding CMV preventive strategies.[69][70]

In immunosuppressed patients or those for whom a diagnosis is necessary, serum viral DNA identification is the preferred initial test for suspected CMV infection. Quantitative CMV DNA polymerase chain reaction (PCR) assays are the preferred method for viral detection and the most sensitive method for detecting CMV. High levels of DNA in blood in HSCT patients are a strong predictor of CMV disease and end-organ damage.[69][70][71]

CMV pp65 antigenemia, which detects the pp65 antigen in peripheral blood leukocytes, is a rapid and semi-quantitative method for diagnosing CMV infection. In transplant recipients, a positive pp65 assay is a strong predictor of progression to invasive CMV disease.[72][73]

Visualizing pathognomonic CMV inclusion bodies on histopathological examination is the gold standard for diagnosing tissue CMV disease. CMV DNA PCR can also be used to diagnose CMV disease in tissues, such as the detection of CMV in bronchoalveolar lavage fluid or lung tissue samples through virus isolation, histopathologic testing, and immunohistochemical analysis.[65]

Cytomegalovirus Gastrointestinal Disease

For the diagnosis of CMV GI disease, the identification of CMV in biopsy specimens using standard histopathologic or immunohistochemical stains has traditionally been considered the gold standard for confirming proven disease. Quantitative PCR methods are increasingly being evaluated and utilized on tissue specimens to support the diagnosis of tissue-invasive CMV disease.[20]

Cytomegalovirus Esophagitis

Endoscopy with biopsy is the most reliable modality for diagnosing CMV esophagitis.[12] Importantly, CMV can remain latent or be asymptomatic in immunocompetent hosts; therefore, the detection of CMV in tissue or body fluids does not necessarily indicate disease. Relying on serologic testing and anti-CMV antibodies is not helpful, as the disease correlates with defective cell-mediated immunity, rather than humoral immunity. Anti-CMV IgM indicates a recent infection, and anti-IgG can be present in most adults who have previously been infected with CMV. Blood and oropharyngeal viral cultures, even if obtained from patients with risk factors such as organ transplant recipients, can help identify those at high risk for developing the disease; however, they are not sensitive or specific for identifying active disease.[5]

The endoscopic appearance of CMV esophagitis ulcers is well-demarcated, vertical, or horizontal linear shallow ulcers at the mid to distal esophagus.[10] Ulcerations can be single or multiple, deep, and resemble cavitations, with associated features such as mucosal edema and nodularity.[12] The intervening mucosa between the ulcers is typically normal.[5][66] There are no pathognomonic endoscopic or pathological features for CMV disease; therefore, finding cytomegalic cells with CMV inclusion bodies is critical. Successful identification of CMV at a tissue level is associated with having an adequate number of samples and the expertise of the examining pathologist.[5] Immunohistochemistry to label specific CMV antigens is a useful adjunct modality when inclusion bodies are difficult to identify.[58] CMV esophagitis carries a poor prognosis, a high risk of recurrence, and a high rate of 1-year morbidity and mortality.[12]

Cytomegalovirus Colitis

In healthy subjects, CMV colitis is typically asymptomatic or causes self-limited disease but may result in chronic infection or a life-long carrier state with intermittent reactivation. Patients with CMV colitis present with nonspecific symptoms, including diarrhea, abdominal pain, fever, rectal bleeding, and weight loss. The most frequently observed symptoms in these patients include hematochezia and diarrhea. Therefore, a high index of suspicion is necessary, and laboratory investigations are essential in diagnosing CMV colitis. Several methods are possible, including antigenemia, endoscopy, histological examination of biopsy tissues, CMV culture, and quantitative PCR of tissue samples.

The diagnosis of CMV colitis requires histological examination of biopsy tissues taken from the base or edge of the ulcer. One of the significant endoscopic findings in CMV colitis is the presence of ulcerations with a well-defined, punched-out appearance, typically found in 70% to 80% of patients.[68][74] However, ulcerations may be irregular and may also have a cobblestone-like appearance. An ulcer of the cecum involving the ileocecal valve is proposed as a specific finding in CMV colitis in patients with GVHD.[75]

Patients with punched-out ulcers typically have a higher number of inclusion bodies on histology.[61] Histological examination can differentiate CMV colitis from other causes, eg, infectious colitis, ulcerative colitis, or drug-induced colitis.[62] Colonic mucosal biopsies stained with H&E may reveal viral inclusion bodies characteristic of CMV colitis, commonly referred to as owl eye inclusions, which are highly specific for CMV. However, H&E staining has limited sensitivity and is less reliable than immunohistochemistry, which is considered the gold standard for diagnosing CMV colitis.[59] Diagnosis of CMV colitis requires serologic testing and endoscopic biopsies to confirm the diagnosis.

Histopathology

The identification of CMV disease in H&E-stained tissue sections relies on the characteristic presence of viral inclusions, often described as having an owl's eye appearance. These inclusions are highly specific for CMV. However, CMV-specific immunohistochemistry is the gold standard for confirming CMV infection in tissue biopsies. Therefore, if H&E-stained sections are negative but there is a strong clinical suspicion of CMV colitis, immunohistochemistry staining should be performed to enhance diagnostic accuracy.[58]

Real-Time Polymerase Chain Reaction

Qualitative and quantitative PCR for CMV DNA in blood is the diagnostic test of choice due to its high sensitivity and specificity.[20] Efforts are being made to improve standardization and reduce variability across PCR testing platforms and assays. This variability arises due to differences in assays, sample size, extraction methods, amplicon size, and sample types, such as whole blood or plasma.[20]

Generally, caution is required when testing for blood viral load by PCR, as CMV DNA may be compartmentalized in tissue, especially in cases of CMV end-organ damage, and may be absent from the blood. In these cases, clinical utility is limited, as CMV DNA may be present in patients with active disease in tissue but is not detectable in blood. In contrast, serial PCR testing may offer greater clinical value by enabling the monitoring of viral dynamics over time and assessing disease progression or response to therapy.[20]

Cytomegalovirus Culture

CMV culture offers high sensitivity and specificity for diagnosing CMV colitis; however, its major limitation is the prolonged turnaround time, which can delay diagnosis and hinder timely treatment in vulnerable patients.[76]

Serologic Testing

The CMV IgG test helps determine prior exposure to the virus, understand the serostatus of patients, and risk-stratify them, especially immunosuppressed individuals. This test may indicate an acute systemic infection or reactivation, but it lacks specificity and sensitivity for diagnosing tissue-invasive disease.

pp65 Antigenemia Assay

The pp65 antigenemia assay is a laboratory test to detect CMV pp65 antigen, a structural viral protein, in peripheral blood leukocytes. This assay is primarily used to diagnose and monitor active CMV infection, particularly in immunocompromised patients. The pp65 antigenemia assay is valuable for the early detection of CMV viremia and for guiding preemptive antiviral therapy before the onset of clinical disease. This test may aid in the early detection of CMV viremia and help predict clinical outcomes in patients, particularly in cases of tissue-invasive disease, such as suspected CMV colitis. Although many centers now prefer quantitative CMV PCR due to its higher sensitivity and ease of automation, the pp65 assay remains clinically useful, especially in settings with established expertise in its interpretation and in non-neutropenic patients, where adequate leukocytes are available for analysis.[77][78]

Table. Cytomegalovirus Diagnostic Tests

Diagnostic Test	Purpose	Sample Type	Clinical Utility	Limitations
CMV IgM	Identify recent antibody response	Detect recent or current infection	Pregnancy screening, initial exposure	False positives may persist post-infection
CMV IgG	Identify past antibody response	Detect prior exposure and immunity	Pregnancy, transplant evaluation	Does not indicate current infection
IgG avidity	Assess the strength of IgG binding	Distinguish recent versus past infection	Pregnancy (timing of infection)	Only useful early in infection
CMV PCR (DNA test)	Detect viral DNA in blood (quantitative)	Detect and monitor active infection	Immunocompromised patients, treatment response	Does not show tissue involvement
pp65 antigenemia	Viral protein in leukocytes	Detect active infection	Transplant patients	Requires fresh blood; labor-intensive; cannot be neutropenic
Tissue biopsy	CMV inclusions via histopathology	Confirm tissue-invasive disease	CMV colitis, esophagitis, and pneumonitis	Invasive; localized disease may be missed

Abbreviations: CMV, cytomegalovirus; IgM, immunoglobulin M; IgG, immunoglobulin G; PCR, polymerase chain reaction.

Treatment / Management

Immunocompetent patients present with minimal or no symptoms, are self-limited, and do not require specific therapy other than symptomatic management. However, antiviral therapy should be considered in severe cases of CMV mononucleosis, CMV infection, and CMV disease in immunocompromised patients.[79][80] Toxicity is not uncommon when using these agents, and their risks must be weighed against the benefits of initiating treatment. Prophylaxis is considered for all high-risk patients. The treatment of CMV disease or CMV end-organ disease typically involves antiviral therapy. Patients should be monitored for treatment failure, in which cases, the potential causes, such as the emergence of resistance to therapy, should be considered. In such cases, testing for antiviral drug resistance should be performed.[81](B3)

Prophylaxis is administered to prevent primary, reactivation, or recurrence of CMV infection. In contrast, preemptive therapy is given to asymptomatic CMV-infected patients who have had CMV detected on screening tests, as this may reduce CMV viral load.

Immunosuppressed patients, including those with HIV/AIDS, those on immunosuppressants, or those undergoing a SOT or HSCT, should be tested for CMV IgG serostatus, as they are at high risk for complications from CMV infection. Despite advances in CMV prevention and treatment, infection remains a significant complication in solid organ transplant and HSCT recipients, underscoring the importance of effective prophylaxis in these populations. Pre-transplant CMV serology status is the most widely used indicator that predicts the occurrence of CMV infection.[82] CMV infection occurs in up to 50% of high-risk SOT patients, typically when the organ is transplanted from a CMV-seropositive donor to a CMV-seronegative recipient (D+/R−), and in 17% of CMV-seropositive recipients (R+).[20][27] Risk factors for CMV infection or disease include a D+/R− serological status, seropositive recipients, administration of anti-thymocyte globulin due to its potent T–cell-depleting effects, induction with mycophenolic acid, steroid therapy, or polyclonal antibodies, advanced age of both donors and recipients, and a history of acute organ rejection.[28] Other factors affecting the severity of CMV infection include whether it is a primary infection, reactivation, or superinfection; the degree of immunosuppression; and whether the patient has undergone SOT or HSCT.[20](A1)

Prevention

Recipients of solid organ transplants from CMV-seropositive donors (D+) who are at risk for CMV infection should receive prophylactic antiviral therapy, typically with valganciclovir or intravenous (IV) ganciclovir, along with routine virologic surveillance. The duration of prophylaxis is determined by the recipient's risk stratification..

High-risk patients (D+/R−) should receive prophylaxis for a minimum of 6 months, whereas intermediate-risk recipients (R+) are typically treated for 3 months. In low-risk individuals (D−/R−), a prophylactic course of at least 3 months is also generally advised to mitigate the risk of late-onset disease.[82]

Even with prophylaxis, however, CMV infections can still occur, and treatment can be challenging, even with the administration of standard-of-care first- and second-line antivirals.[82] Valganciclovir is the preferred agent due to its oral formulation, good bioavailability, and established efficacy; IV ganciclovir is used when vascular access is available.[82] Newer antivirals, such as letermovir, have shown non-inferiority to valganciclovir in preventing CMV disease. Letermovir is a first-in-class antiviral that has been explicitly approved for this indication.[83][84] Maribavir has also been used for prophylactic treatment and has less toxicity than valganciclovir.[84](A1)

Despite preventive measures, CMV infection following SOT remains linked to a heightened risk of acute rejection and graft failure, increased mortality, and higher healthcare costs due to more frequent hospital readmissions, longer inpatient stays, and overall higher hospitalization costs.[29]

Currently, there are 6 Food and Drug Administration–approved antiviral agents used in the management of CMV infections. Maribavir and letermovir have been most recently added to the armamentarium for the prevention and treatment of CMV infection. Each antiviral targets different aspects of the viral replication cycle, thus inhibiting replication.[19][84][85][86][87](B2)

Ganciclovir: Ganciclovir is the treatment of choice, especially for severe cases of CMV infection. This agent is a guanosine nucleoside analog that is activated by the viral UL97 kinase, inhibiting viral DNA synthesis.
Valganciclovir: Valganciclovir is an oral prodrug of ganciclovir. This agent can be administered orally in less severe CMV infections.
Cidofovir: Cidofovir is a cytidine monophosphate analog that inhibits viral DNA polymerase independent of viral activation.
Foscarnet: Foscarnet is a pyrophosphate analog that directly inhibits the viral UL54 DNA polymerase.
Maribavir: Maribavir is a selective inhibitor of the viral UL97 kinase, with a distinct binding site and resistance profile compared to ganciclovir.[87]
Letermovir: Letermovir was approved in 2017 for both prevention and treatment, and works by targeting the viral terminase complex (UL56-UL89), thereby inhibiting CMV DNA cleavage and packaging.

Treatment of Cytomegalovirus

Valganciclovir and ganciclovir are the first-line treatments for CMV infection. However, their use may be limited by hematologic toxicity or the development of antiviral resistance. Resistance to ganciclovir can occur through mutations in UL97, which impairs drug phosphorylation, or UL54, which encodes the viral DNA polymerase.[84]

Cidofovir and foscarnet are second-line agents, primarily used when resistance or toxicity limits the effectiveness of first-line therapy. Both drugs are administered IV and are associated with significant nephrotoxicity.[84][88][89] All of these antivirals ultimately target the viral DNA polymerase, and mutations in UL54 may confer cross-resistance to ganciclovir, cidofovir, and foscarnet.[84][87](A1)

Letermovir, in contrast, is a CMV-specific antiviral with a different mechanism of action. This agent targets the pUL56 subunit of the terminase complex, inhibiting the final stage of viral DNA processing and packaging. Letermovir is well-tolerated, lacks hematologic or renal toxicity, and is available in both oral and IV formulations.[84][90]

Refractory Cytomegalovirus

Failure to achieve clinical or virologic response after at least 14 days of appropriately dosed antiviral therapy is defined as refractory or resistant CMV infection.[91][92] Although antiviral resistance is a recognized cause, refractory CMV can also occur in the absence of documented resistance, though data on such cases remain limited. Reported rates of antiviral-resistant CMV in SOT recipients range up to 18%, particularly among patients receiving prolonged or subtherapeutic antiviral therapy.[91]

Therapeutic management of CMV infections in SOT recipients remains challenging due to the limited efficacy to toxicity ratio of conventional antivirals and the complexity of transplant-related immunosuppression. Agents such as ganciclovir, foscarnet, and cidofovir are associated with significant adverse effects, including myelosuppression and nephrotoxicity, which can limit their utility. The recent availability of novel anti-CMV therapies, including maribavir and letermovir, along with investigational approaches such as adoptive CMV-specific T-cell therapy, offers promising alternatives that may enhance viral control and improve outcomes in patients with refractory or recurrent CMV infections, respectively.[84][88][89] The benefit of these alternative therapies lies in their distinct mechanisms of action compared to existing antivirals, which reduces the risk of cross-resistance, their lower adverse effects compared to existing antivirals, and their specificity to CMV.[93] Letermovir has traditionally been used for prophylaxis due to the low threshold for resistance developing during CMV replication, whereas mirabavir has evidence in treating refractory CMV.[94][95] Both letermovir and mirabavir have drug-drug interactions that should be reviewed before administration, as letermovir interacts with CYP2C8, CYP3A, and CYP2C19 enzymes, and mirabavir inhibits P-glycoprotein and CYP2C9 activity.[96][97](A1)

Cytomegalovirus Esophagitis

The mainstay of CMV esophagitis treatment is ganciclovir and valganciclovir.[17] The treatment of active disease should begin with induction therapy using IV ganciclovir at a dose of 10 to 15 mg/kg/d, administered in 2 to 3 divided doses daily for 3 to 6 weeks, depending on clinical circumstances.[5][98] Maintenance therapy with IV ganciclovir at 5 mg/kg/d is indicated in cases with concurrent retinitis or recurrent GI disease after discontinuation of induction therapy. Relapse is unfortunately common, as the patients have a baseline, severely persistent immune deficiency most of the time, and treatment only suppresses the infection but does not eliminate it.[5] If recurrence occurs, repeat induction therapy should be performed, followed by maintenance treatment. Foscarnet is an alternative to ganciclovir in cases where resistance to the first-line treatment occurs. Failure of monotherapy calls for an attempt at combination therapy with IV ganciclovir and IV foscarnet.[5] Current treatments still consist of antivirals, such as ganciclovir and valganciclovir, but research into alternatives is ongoing.[5][98][99] (A1)

Cytomegalovirus Colitis

The majority of immunocompetent patients with CMV colitis may require no treatment with antiviral medications. Due to the significant adverse effects associated with antiviral agents such as ganciclovir, including myelosuppression, hepatotoxicity, nephrotoxicity, and central nervous system toxicity, there is mixed evidence that antiviral therapy significantly improves outcomes in this population or attenuates the risk of colectomy.[100][101] However, antiviral treatment may be considered in select cases, particularly in males older than 55 with severe disease and underlying conditions that compromise immune function, such as HIV infection, diabetes mellitus, chronic kidney disease, or steroid- or biologic-refractory IBD.[102][103][104] In these cases, ganciclovir or valganciclovir may be considered for treatment.[59] The British Society of Gastroenterology guidelines recommend initiating antiviral therapy in moderate-to-severe colitis with histological features of high-density CMV in mucosal tissue, particularly in steroid-refractory cases. The American College of Gastroenterology, in its updated 2025 guidelines on the management of adult ulcerative colitis patients, recommends CMV investigation in cases of acute severe ulcerative colitis but does not provide treatment recommendations if CMV is detected.[105](A1)

CMV reactivation, commonly observed in patients with severe or corticosteroid-resistant IBD, does not universally require antiviral therapy, as the virus is often non-pathogenic in these settings, and treatment may not provide clinical benefit. Antiviral therapy should be considered under the following circumstances:

When CMV reactivation leads to CMV colitis and histological examination shows high-grade CMV density [106]
Patients with low-grade CMV density who have corticosteroid-refractory disease or are corticosteroid-dependent
A large endoscopically visible ulcer may indicate the need for antiviral therapy.

Importantly, there is a lack of high-quality evidence regarding the treatment of CMV colitis with antiviral agents, and it remains unclear whether this approach improves colectomy rates or mortality outcomes. Further research, including large randomized trials, is necessary to define subgroups that can benefit from treatment. Concomitant use of anti-tumor necrosis factor therapy with antiviral therapy may be considered to treat CMV reactivation in patients with ulcerative colitis. Ganciclovir is effective in treating and preventing CMV disease in patients undergoing bone marrow transplantation.[107] The identification of high-risk groups and the use of prophylactic therapy are currently topics of research.[108](A1)

Differential Diagnosis

Mononucleosis-Type Cytomegalovirus Infection

Early HIV infection
Human herpesvirus 6 infection
Viral hepatitis
Autoimmune hepatitis
Epstein-Barr virus infection
Infectious mononucleosis

Cytomegalovirus Esophagitis

CMV esophagitis typically presents as a single, large, isolated ulcer in the distal esophagus but can also manifest as diffuse esophagitis.[5] The diffuse presentation can be challenging to distinguish from other disorders, such as herpes simplex virus (HSV) esophagitis and gastroesophageal reflux disease. The differentiating factor is that HSV esophagitis typically presents as multiple, small, shallow ulcers, rather than extensive ulcers. HSV esophagitis also affects the entire esophagus, whereas CMV esophagitis normally affects the mid-to-distal esophagus.[66]

Achalasia
Acid peptic disease
Aphthous ulcers
Barrett's esophagus
Candidiasis
Cryptococcosis
Drug-induced dysphagia
Epstein-Barr virus infection
Esophageal cancer
Gastroesophageal reflux disease
Herpes simplex esophagitis
Histoplasmosis
Tuberculosis

Cytomegalovirus Colitis

The differential diagnosis for CMV colitis includes the following:

Viral or bacterial gastroenteritis
IBD
Colorectal cancer
Toxic megacolon
Diverticulitis
Irritable bowel disease
Celiac disease
GVHD

Prognosis

CMV infection in immunosuppressed patients is associated with significant morbidity and mortality. Recent studies have highlighted the impact of CMV infection across various immunocompromised populations. In many SOT patients, CMV infection has been linked to markedly increased mortality.[109] A study reported a 47% mortality rate in patients with CMV infection compared to 13% in those without.[109] After adjusting for confounding factors, CMV infection remained a strong independent predictor of mortality.[110] In HSCT recipients, CMV infection significantly contributes to mortality.[111] CMV infection often leads to prolonged hospitalization, a higher rate of medical complications, and significantly worse clinical outcomes. These risks highlight the importance of early detection, close monitoring, and, when indicated, timely antiviral therapy in high-risk patients.[112]

Cytomegalovirus Esophagitis

Upper GI CMV disease in immunocompromised individuals is associated with significant morbidity and a high risk of mortality, with some studies reporting 1-year mortality rates as high as 25%.[12] Risk factors for poor outcomes include profound immunosuppression, for example, in SOT or HSCT recipients, individuals with advanced HIV/AIDS, delayed diagnosis, and lack of antiviral treatment.[49] Clinical manifestations can range from odynophagia and GI bleeding to ulceration and perforation, particularly in the esophagus or stomach. Timely diagnosis through endoscopy with biopsy, followed by appropriate antiviral therapy, typically ganciclovir or valganciclovir, can significantly improve patient outcomes and reduce mortality. However, even with treatment, outcomes remain guarded in patients with severe underlying disease or multi-organ involvement.[49]

Cytomegalovirus Colitis

The overall prognosis of CMV colitis is generally excellent. However, certain risk factors have been associated with poorer outcomes and increased mortality. In immunocompetent individuals, prognosis is influenced by age, with those older than 55 experiencing slightly higher mortality rates. The need for surgical intervention is also linked to a less favorable prognosis. Additionally, some studies have increased mortality from CMV colitis is associated with male gender and immunocompromising conditions, such as HIV infection and HSCT, more so than SOT. In immunocompromised patients, early diagnosis and prompt treatment significantly improve outcomes. Biochemically, anemia, elevated C-reactive protein levels, and low albumin levels have been associated with an increased risk of CMV colitis.[113] Patients who experience reactivation of CMV colitis within the context of ulcerative colitis typically have a worse prognosis. However, timely therapy can also greatly enhance clinical outcomes in this group.[106]

Complications

Tissue-invasive CMV disease affects various organ systems and can be life-threatening. CMV colitis presents with diarrhea, abdominal pain, and GI bleeding, and may progress to serious complications such as perforation or toxic megacolon. CMV pneumonitis is another severe manifestation, especially in transplant recipients, and presents with cough, dyspnea, and hypoxia, often with a high mortality rate.[114] Other forms of organ involvement include CMV hepatitis, causing liver dysfunction; esophagitis or gastritis, leading to odynophagia, nausea, and GI bleeding; and CMV retinitis, which causes painless vision loss and retinal necrosis, especially in individuals with advanced HIV/AIDS.[114] CMV encephalitis may also occur, resulting in confusion, seizures, and altered mental status.[114]

In solid organ transplant and bone marrow transplant recipients, CMV infection is strongly associated with graft dysfunction and rejection.[115] CMV infection can contribute to both acute and chronic graft rejection, including bronchiolitis obliterans in lung transplant patients and graft vasculopathy in heart transplant recipients.[115]

CMV infection also predisposes immunosuppressed individuals to secondary infections, as it suppresses overall immune function. This immunosuppressive effect can increase the risk of concurrent bacterial, fungal, and other viral infections, including Epstein-Barr virus–associated post-transplant lymphoproliferative disorder and invasive fungal infections, such as aspergillosis.[116][117]

Additionally, CMV can cause bone marrow suppression, leading to anemia, leukopenia, and thrombocytopenia. These hematologic complications are particularly concerning in patients already dealing with drug-induced cytopenias from immunosuppressive therapy.[112]

Cytomegalovirus Esophagitis

Malnutrition can develop in the setting of dysphagia and odynophagia, which can be devastating in the setting of severe illnesses.[10] If the esophageal CMV ulcerations become extensive and deep enough, perforation and massive GI bleeding can occur spontaneously or as a complication during endoscopy.[5][12] Stricture formation, while uncommon, has been reported to occur despite undergoing treatment with antivirals and even as the initial presentation of CMV esophagitis without prior known ulcers.[21] A case report noted the formation of a stricture severe enough to cause complete obliteration of the esophageal lumen in a patient who had completed antiviral treatment and whose post-treatment pathology samples were negative for CMV and HSV, demonstrating that strictures can form despite disease treatment and resolution.[21]

Complications of CMV infection include the following:[118][119]

Chronic inflammation
Large bowel perforation
Toxic megacolon
Pseudo-membrane formation
Development of ischemic colitis
Patients with CMV colitis complicating IBD may develop severe hemorrhage and colon perforation

Deterrence and Patient Education

Deterrence strategies are essential for preventing CMV infection among immunosuppressed individuals. The use of antiviral prophylaxis remains one of the primary deterrence strategies to prevent CMV reactivation, particularly in high-risk groups such as HSCT recipients. Preemptive therapy is another approach that involves frequent monitoring of CMV viral loads in patients at risk. Antiviral treatment is initiated as soon as viral replication is detected, thereby preventing the progression to symptomatic disease. Additionally, infection control measures, such as rigorous hand hygiene and proper handling of bodily fluids, are crucial, especially in healthcare settings where immunocompromised patients are present.

Patient education is equally important in minimizing the impact of CMV infection. Educating patients about their risk and the potential complications of CMV, such as end-organ damage and increased mortality, is vital, especially for those undergoing immunosuppressive treatments. Patients should be taught to recognize the early symptoms of CMV infection, such as fever, malaise, and organ-specific complaints, which enable timely medical intervention. Ensuring adherence to prescribed antiviral regimens is another key element; patients must understand that consistent medication use can prevent viral reactivation and severe complications. Furthermore, lifestyle counseling should be provided, emphasizing the importance of avoiding contact with individuals who are sick, practicing safe food handling, and maintaining proper hygiene.

Through a combination of medical deterrence strategies and comprehensive patient education, healthcare providers can significantly reduce the incidence, severity, and consequences of CMV infections in immunocompromised populations.

Enhancing Healthcare Team Outcomes

For immunocompromised patients, CMV infection can have significant morbidity and mortality. CMV can affect nearly any organ system, making an interprofessional approach essential for comprehensive care. Immunocompromised patients may be candidates for prophylactic therapy; however, careful consideration must be given to potential drug interactions, toxicity, and the risk of developing antiviral resistance.

Once CMV infection is diagnosed in an immunocompromised patient, long-term follow-up is critical. Ongoing monitoring ensures the timely detection of complications, effective management of medication adverse effects, and regular assessment for disease recurrence. In cases of CMV retinitis, regular follow-up with an ophthalmologist is necessary to prevent vision loss and monitor treatment response.[79]

The involvement of an interprofessional team is essential to improving outcomes in patients at risk for or diagnosed with CMV infections. Key members of this team include primary care providers, infectious disease specialists, transplant surgeons, transplant nurses, and clinical pharmacists and nurses.

This collaborative approach ensures comprehensive, patient-centered care, helping to optimize both prevention and treatment strategies for CMV-related diseases.

Cytomegalovirus Esophagitis

The first step in improving outcomes for patients with CMV esophagitis is identifying those at risk. Primary care physicians play a crucial role in educating immunocompromised patients about potential complications, including CMV esophagitis. This education should also extend to individuals who are about to become immunocompromised, such as patients with newly diagnosed cancer preparing for chemotherapy, or those starting immunosuppressive therapy for autoimmune diseases. Primary care physicians should counsel patients on recognizing key symptoms of CMV esophagitis, including odynophagia, dysphagia, and retrosternal chest pain. For patients with HIV, emphasizing adherence to highly active antiretroviral therapy is critical to prevent CD4 count decline, which significantly increases the risk for opportunistic infections such as CMV esophagitis. All patients at risk should also receive guidance on universal precautions, particularly when handling bodily fluids and other potentially infectious materials.

If CMV esophagitis is suspected, primary care physicians should obtain a detailed history and perform a thorough physical examination, with particular attention to relevant risk factors. Patients should be referred to a gastroenterologist for an upper endoscopy with biopsy, as histopathologic confirmation is essential for diagnosis. A pathologist should review biopsy samples. If challenges arise during treatment or complications occur, infectious disease specialists should be consulted for assistance in management.

Cytomegalovirus Colitis

The diagnosis and management of CMV colitis are complex and require a coordinated interprofessional approach. Key team members may include gastroenterologists, internists, infectious disease specialists, pathologists, clinical pharmacists, specialized nurses, oncologists, and transplant surgeons. A collaborative strategy is crucial for identifying high-risk patients, facilitating early diagnosis, and ensuring the prompt initiation of treatment.

Specialty-trained nurses play a vital role in educating patients on symptom recognition and ensuring adherence to clinical and serologic monitoring protocols, particularly in patients with solid organ transplants, to facilitate the early detection of infections. Clinical pharmacists and infectious disease specialists contribute by managing antiviral therapy, monitoring for toxicity, and identifying potential drug-drug interactions to prevent adverse events.

By working together, the interprofessional team can deliver optimal prophylaxis, monitoring, and treatment, ultimately improving clinical outcomes for patients at the highest risk of CMV colitis.

Media

(Click Image to Enlarge)

Cytomegalovirus Retinitis. The image depicts a view of a fundus affected by cytomegalovirus retinitis.

National Eye Institute, Public Domain, via Wikimedia Commons

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