History
History varies depending on whether the host is immunocompetent or immunocompromised.
Adult cytomegalovirus infection in the immunocompetent host
Cytomegalovirus (CMV) can cause a wide spectrum of infection in immunocompetent hosts. Sites most often involved include the lung (severe community-acquired viral pneumonia), liver (transaminitis), spleen (splenomegaly), GI tract (colitis), CNS (encephalitis), hematologic system (cytopenias), and multisystem involvement (fever of unknown origin). Uncommon sites of CMV infections in immunocompetent individuals include the kidneys, adrenals, salivary glands, pancreas, and esophagus. [9]
In most cases, primary CMV infection is asymptomatic or produces mild flulike symptoms. Symptoms, when apparent, develop 9-60 days after primary infection. The lymph nodes and spleen may be enlarged, so CMV infection should be included in the differential diagnoses of infections that produce lymphadenopathy. Extreme fatigue may persist after normalization of laboratory values.
CMV may produce a mononucleosis syndrome similar to that caused by Epstein-Barr virus (EBV), primary toxoplasmosis, or acute HIV seroconversion. In a large study of 494 patients with infectious mononucleosis, 79% of cases were due to EBV, and, in the 73 heterophile antibody–negative patients, approximately half of these were CMV positive (rising complement-fixing antibodies). [34] In about a third of patients with CMV mononucleosis, a rash may also be present (macular, papular, maculopapular, rubelliform, morbilliform, or scarlatiniform). [35]
Both CMV and EBV may result in atypical lymphocytes in the blood. Other pertinent test results include negative findings on heterophil antibody studies, mildly or moderately elevated levels of aspartate aminotransferases, and evidence of subclinical hemolysis. [36] Hepatitis and atypical lymphocytes usually disappear after 6 weeks. Despite its great sensitivity, the CMV IgM test is limited by a one-way cross-reaction of acute EBV infectious mononucleosis sera. False-positive reactions have resulted from the presence of rheumatoid factors. [36]
CMV infection should be suspected in patients with clinical mononucleosis or fever of unknown origin. Most cases have a paucity of physical examination findings. Some studies have shown that, as a group, patients infected with CMV have less hepatomegaly, splenomegaly, and pharyngitis than those infected with EBV. Patients with CMV mononucleosis may be older, have a longer duration of fever, and have less cervical lymphadenopathy. However, such clinical findings are inadequate to differentiate between the two viruses.
Transfusion of multiple blood units is a risk factor for CMV mononucleosis and has been implicated in postoperative fever or fever in patients following trauma. Traditionally, CMV antibody tests were performed using complement fixation and showed peak viral titers 4-7 weeks after infection. Multiple tests for CMV antibody are now available, some of which are sensitive enough to detect anti-CMV IgM antibody early in the course of the illness and during CMV reactivation. Reactivation of the virus is not uncommon, sometimes occurring with viremia and a positive IgM result in the presence of IgG antibody. This is usually observed during intercurrent infections or at times of patient stress. The clinical significance, time course, and natural history of reactivation in immunocompetent patients are not known for either virus.
In rare cases, CMV can cause community-acquired pneumonia in immunocompetent hosts [9] and should be considered a possible etiology (along with influenza [human, swine, avian] and adenovirus) in cases of severe viral community-acquired pneumonia. [9] Case reports describe prolonged fever, lack of cough or other respiratory symptoms, bilateral interstitial or patchy infiltrates on chest radiography, relative lymphopenia, atypical lymphocytes, and mild transaminitis. [37] Of note, some patients had negative CMV IgM findings initially but subsequently developed elevated levels of both IgM and IgG, with resolution of the infiltrates over 6 weeks. [37] There are varying degrees of hypoxemia. The prognosis of CMV pneumonia in immunocompetent hosts, even severe cases, is usually good, rarely requires a full course of antiviral treatment, and usually resolves during CMV induction therapy. [9]
Rarer manifestations of CMV infections in immunocompetent individuals include Guillain-Barré syndrome, meningoencephalitis, pericarditis, myocarditis, thrombocytopenia, and hemolytic anemia. Rubelliform or maculopapular rashes are observed with and without administration of ampicillin. GI ulceration may result from acute CMV infection in immunocompetent persons, although this finding is much more likely in immunocompromised individuals.
CMV frequently reactivates in critically ill patients and may be linked to increased length of hospital and/or intensive care stay, [38, 39, 40] duration of mechanical ventilation, [38, 39] morbidity, [40] and mortality. [38, 40, 41] However, an opposing retrospective study looking at the impact of CMV serostatus on outcomes in immunocompetent ICU patients found no association between CMV seropositivity, ICU mortality, in-hospital mortality, time to hospital discharge, duration of mechanical ventilation, or the need for renal replacement therapy. [42]
Further data are required to ascertain if CMV prophylaxis/treatment of critically ill seropositive patients leads to better clinical outcomes.
Adult cytomegalovirus infection in the immunocompromised host
In patients with a history of allogeneic HSCT, CMV infection is a known severe complication, associated with multiorgan disease. Of note, CMV seroposivity is a poor prognostic factor of non-relapse mortality in HSCT recipients. Advanced age is associated with a higher incidence of CMV antigenemia after HSCT. IgG positive recipients from CMV seronegative donors have the worst outcomes. On the other hand, CMV IgG negative recipients from CMV seronegative donors rarely develop severe CMV-related complications. Based on this, patients with hematological diseases who are going to receive allo-HSCT need to have their CMV sero-status checked prior to the procedure. [43]
Of note, about 30% of the seronegative allo-HSCT recipients of sero-positive donor grafts develop reactivation, but more than 80% of sero-positive recipients are likely to develop CMV reactivation regardless of donor CMV status. [43]
Organ transplantation and cytomegalovirus
CMV is an important pathogen isolated in organ transplant recipients, as primary CMV infection in an organ transplant recipient may be quite severe. CMV disease occurs with the highest frequency in donor-positive/recipient-negative transplant recipients. This relationship is true for all organ transplant recipients except those who receive bone marrow, in whom the highest incidence of CMV disease is in donor-negative/recipient-positive individuals. The reason for this is unknown but may be related to the level of immunosuppression observed in patients who have received marrow transplants compared with those who have received other transplants.
Patients who have received marrow transplants undergo ablative chemotherapy and/or radiation. A period of neutropenia and a loss of specific antigen reactivity follow. All transplant recipients have a period of decreased CMV-specific cell-mediated immunity. The next step is unknown; however, patients at greatest risk for CMV disease develop viremia. The role viremia plays in the pathophysiology of CMV disease is unknown.
Life-threatening CMV pneumonia may develop in immunocompromised patients, with the incidence varying based on the type of transplant received. Patients who receive marrow, lung, heart, heart-lung, liver, pancreas-kidney, and kidney transplants have different levels of immunosuppression. Those most at risk include bone-marrow transplant recipients and recipients of lung transplants. In patients who have received marrow transplants, CMV disease is most likely 30-60 days after transplant. Fatal CMV pneumonia is much less common in patients who have received solid organ transplants than in those who have received marrow transplants. Patients may initially present with an asymptomatic infiltrate on chest radiograph.
The most common clinical presentation of CMV pneumonia is fever and shortness of breath, accompanied by an interstitial infiltrate. The differential diagnoses of CMV pneumonia in immunocompromised patients include Pneumocystis pneumonia, viral respiratory infections, pulmonary hemorrhage, drug toxicity, recurrent lymphoma, and other infections. CMV is frequently detected in the lungs of patients with HIV/AIDS but usually represents viral shedding and does not frequently cause clinically significant disease.
CMV pneumonia is difficult to treat, even with the antivirals now available. The mortality rate among bone marrow transplant recipients with CMV pneumonia was approximately 85% prior to the introduction of ganciclovir and CMV-specific immune globulin. The addition of these drugs has decreased the CMV pneumonia mortality rate to 15%-75%. The mortality rate of CMV pneumonia in marrow transplants that requires mechanical ventilation is high, despite treatment with ganciclovir and immune globulin. Poor clinical outcomes are also observed in patients who are also infected with community respiratory viruses (eg, parainfluenza, influenza, respiratory syncytial virus) and those who have received allogeneic marrow transplants. This suggests that the severity of CMV pneumonia is not exclusively secondary to viral characteristics.
The use of immune globulin is based on studies of marrow transplant recipients, which noted improved survival rates in those with CMV pneumonia who received combination therapy (ganciclovir plus immune globulin). [44] This has not been studied in patients with CMV pneumonia who have received solid organ transplants. Some experts believe that the mechanism of CMV pneumonia in patients who have received solid organ transplants may differ from that in marrow transplant recipients, making the addition of immune globulin unnecessary in the former. CMV pneumonia in marrow transplant recipients does not appear to involve a simple and direct viral cytopathic effect on pneumocytes. The addition of CMV-specific immune globulin has not been shown to affect the mortality and morbidity of CMV infection of other organ systems.
Severe CMV disease is likely secondary to synergism between the virus and other factors, such as radiation, chemotherapy, conditioning regimens, a nonimmune inflammatory response, or other infections. The diagnosis of CMV pneumonia depends on recovering CMV from patients with a positive finding on chest radiograph and appropriate clinical signs. CMV may be isolated from the lung with bronchoalveolar lavage (BAL) or open lung biopsy.
In support of the diagnosis, CMV antigen or inclusions are found with histological examination. CMV isolated from clinical samples in the absence of clinical symptoms may represent viral colonization or subclinical replication. In many cases, the detection of subclinical replication in transplant recipients warrants antiviral suppressive therapy. In patients infected with HIV, antiviral therapy is often not required in the absence of clinical apparent disease.
Primary GI CMV disease in solid organ transplant recipients is difficult to treat and may relapse. The relapse rate was recently studied in solid organ transplant recipients following treatment for CMV infection at the Mayo clinic. The investigators found that extensive involvement of the GI tract was significantly associated with CMV relapse but that endoscopic resolution of GI disease did not necessarily translate into a reduced risk of CMV relapse. [45]
Human immunodeficiency virus disease and cytomegalovirus
CMV is often isolated from patients who are co-infected with other bacterial, parasitic, and fungal pathogens. In fact, CMV may be found in the lungs of approximately 75% of individuals infected by both HIV and Pneumocystis. [9] The of CMV infection in Pneumocystis pneumonia is unclear, and treatment of the latter usually leads to resolution of the pneumonia and hypoxemia, meaning that CMV treatment is not typically warranted in most cases.
For unknown reasons, CMV pneumonia without a co-infecting pathogen is uncommon.
In patients with HIV infection, CMV involves the entire GI tract. In the upper GI tract, CMV has been isolated from esophageal ulcers, gastric ulcers, and duodenal ulcers. Patients with upper GI tract esophageal disease can present with painful dysphagia. Patients with CMV disease of the lower GI tract may present with diarrhea (colitis). CMV colitis frequently affects only the right colon, necessitating full colonoscopy and multiple biopsies for accurate diagnosis. [46] Diagnosis of CMV GI disease depends on a biopsy specimen demonstrating the typical CMV intranuclear inclusions.
Recovery of CMV in tissue culture may be helpful but is difficult to interpret because of CMV shedding. CMV may be isolated from many different sites and is not necessarily associated with disease, reinforcing the need for histopathologic examination.
Retinitis is the most common manifestation of CMV disease in patients who are HIV positive. It occurs most commonly in patients with CD4 counts below 50 cells/µL, with rates of up to 40% in this population. Affected patients report decreased visual acuity, floaters, and loss of visual fields on one side. In many cases, it progresses to bilateral involvement that may be accompanied by systemic CMV disease. Ophthalmologic examination shows yellow-white areas with perivascular exudates. Hemorrhage is present and is often referred to as having a "cottage cheese and ketchup" appearance. Lesions may appear at the periphery of the fundus, but they progress centrally.
Ganciclovir has been used to treat CMV retinitis. Unfortunately, it only slows the progression of the disease. Many clinicians switch to foscarnet after ganciclovir fails. Ganciclovir implants have emerged as an important therapy in the management of CMV retinitis. The optimal treatment consists of ganciclovir implants in the vitreous, accompanied by systemic ganciclovir therapy. Oral ganciclovir may be used for prophylaxis of CMV retinitis but should not be used for treatment. The incidence of CMV retinitis has dropped since the widespread use of highly active antiretroviral therapy. During reconstitution of the immune response in patients who are HIV positive and on antiviral therapy, retinitis may worsen for a period. If severe inflammation is present, corticosteroid treatment may be necessary.
In patients who are HIV positive, CMV may cause disease in the peripheral and central nervous system. [47]
Physical
Most patients with CMV infection exhibit few clinical findings on physical examination.
Primary CMV infection may be a cause of fever of unknown origin.
Symptoms, when apparent, develop 9-60 days after primary infection.
Pharyngitis may be present.
Examination of the lungs may reveal fine crackles.
The lymph nodes and spleen may be enlarged, so CMV should be included in the differential diagnoses of infections that produce lymphadenopathy.
Many physicians believe that CMV mononucleosis is less associated with pharyngitis and cervical adenopathy than EBV infectious mononucleosis. A recent study in young children questioned the accuracy of this clinical pearl. The study found that cervical adenopathy was more common in patients infected with EBV than in patients infected with CMV (83% versus 75%). Although statistically significant, relying on this sign for the differentiation between CMV and EBV mononucleosis is difficult.
Causes
See Adult Cytomegalovirus Infection in the Immunocompetent Host and Adult Cytomegalovirus Infection in the Immunocompromised Host.
Complications
Despite long treatment courses with valganciclovir and documented clearance of CMV viremia, CMV relapse remains common among solid organ transplant recipients. [48] A better understanding of the epidemiology of CMV infection among solid organ transplant recipients and risk factors for disease relapse is warranted.
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Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC and Dr Craig Lyerla.
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Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan.
