Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients

INTRODUCTION — Cytomegalovirus (CMV), a betaherpesvirus, is an important cause of morbidity and mortality in lung transplant recipients [1]. It is among the most common infections in lung transplant recipients, closely following bacterial pneumonia [2,3]. While the development and availability of potent antiviral agents have decreased CMV-related mortality, there is a growing body of evidence that the indirect effects of CMV may be equally important or even more important than its direct effects of tissue injury and infection [3]. CMV-induced immunosuppression may lead to infection with other opportunistic organisms. In addition, CMV infection and disease have been associated with acute and chronic rejection (chronic lung allograft dysfunction) [4-6]. The approach to the diagnosis and treatment of CMV infections in lung transplant recipients continues to evolve as molecular diagnostic techniques and antiviral therapies advance.

The epidemiology, clinical features, diagnosis, and treatment of CMV infection in lung transplant recipients will be discussed here. Prevention of CMV infection in lung transplant recipients as well as infectious complications due to pathogens other than CMV are discussed separately.

●(See "Prevention of cytomegalovirus infection in lung transplant recipients".)

●(See "Bacterial infections following lung transplantation".)

●(See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

●(See "Tuberculosis in solid organ transplant candidates and recipients".)

●(See "Fungal infections following lung transplantation".)

EPIDEMIOLOGY — Primary CMV infection is acquired through close physical contact involving direct inoculation with infected cells or body fluids. Following primary infection, CMV infection persists for life. Population studies document a gradual increase in CMV seropositivity through young adulthood. Although there is considerable variability, more than one half of adults in the United States have serologic evidence of previous infection. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)

CMV infection following transplantation can be acquired in one of several ways [3]:

●Transmission from the donor organ from a CMV-seropositive donor

●Transfusion of blood products from a CMV-seropositive blood donor

●Reactivation of latent infection in a seropositive recipient

●Close physical contact with a CMV-infected individual

DEFINITIONS — CMV infection and disease are not synonymous terms; not all patients with infection develop overt clinical disease [7-9]:

●CMV infection is characterized by virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs. (See 'Diagnosis' below.)

●CMV disease is characterized by evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome with fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, and/or thrombocytopenia or as tissue-invasive disease. (See 'Clinical manifestations' below.)

CLINICAL MANIFESTATIONS

Spectrum of illness — CMV infection in the lung transplant recipient may range from asymptomatic viremia (CMV infection) to CMV disease manifested as a viral syndrome or as tissue-invasive disease, most commonly pneumonitis. (See 'Definitions' above.)

Most CMV-related illnesses occur in the early post-transplant period when immunosuppression is at its peak. Among lung transplant recipients not receiving antiviral prophylaxis, CMV-related illnesses typically occur within the first three months of transplant, with a mean time to viremia of 40 days post-transplantation [10]. The time to the onset of CMV infection and/or disease can be delayed in those receiving antiviral prophylaxis. Those at highest risk for CMV-related illness are CMV-seronegative recipients who receive allografts from CMV-seropositive donors. (See "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'Risk factors'.)

Asymptomatic viremia — Asymptomatic viremia is among the most common clinical presentations of CMV infection post-transplant. Asymptomatic viremia is typically detected by routine CMV viral load monitoring post-transplantation. Strategies for viral load monitoring and interpretation of results are discussed separately. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

Symptomatic disease

CMV syndrome (symptomatic viremia) — Patients with a CMV syndrome have evidence of clinical disease but without end-organ involvement [8]. Typical symptoms include fever, malaise, weakness, myalgias, and arthralgias. Many patients have leukopenia and/or thrombocytopenia that occur in the setting of viremia.

The following definition of probable CMV syndrome requires detection of CMV in blood (typically by nucleic acid testing) along with ≥2 of the following [8]:

●Fever ≥38°C (100.4°F) for ≥2 days.

●New or increased malaise or new or increased fatigue.

●Leukopenia or neutropenia on two separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count of <3500 cells/mcL if the WBC count prior to the development of clinical symptoms was ≥4000 cells/mcL or a WBC decrease of >20 percent if the WBC count prior to the development of clinical symptoms was <4000 cells/mcL. The corresponding neutrophil counts are <1500 cells/mcL or a decrease of >20 percent if the neutrophil count before the onset of symptoms was <1500 cells/mcL.

●Atypical lymphocytosis of ≥5 percent.

●Thrombocytopenia defined as a platelet count of <100,000 cells/mcL if the platelet count prior to the development of clinical symptoms was ≥115,000 cells/mcL or a decrease of >20 percent if the platelet count prior to the development of clinical symptoms was <115,000 cells/mcL.

●Elevation of transaminases to ≥2 times the upper limit of normal.

Pneumonitis — Pneumonitis is the most common presentation of tissue-invasive CMV disease in lung transplant recipients. Clinical features of CMV pneumonitis are nonspecific and include low-grade fever, shortness of breath, nonproductive cough, and changes in measured pulmonary function. Radiographic features are also nonspecific and varied, including patchy or diffuse ground-glass opacities, patchy consolidation, small nodular opacities, and combinations of these features (image 1 and image 2) [11-13]. Less frequently reported findings include thickened bronchovascular bundles, tree-in-bud opacities, reticular opacities, and small pleural effusions [11,12].

Because the features of CMV pneumonitis and acute allograft rejection overlap, distinguishing these two disorders can be challenging. The timing of presentation can help. CMV disease rarely occurs within the first two weeks following transplantation and the mean time to development of pneumonitis following transplantation is 55 days among patients not taking CMV prophylaxis [14]. In contrast, acute rejection can occur within the first few weeks following transplantation, although its time course is variable. While this timeline serves a helpful rule of thumb, biopsy of the lung is generally needed to definitively distinguish these two disorders. (See 'Pneumonitis' below.)

CMV pneumonitis is a severe form of tissue-invasive disease in lung transplant recipients. In a study of 231 lung transplant recipients, five-year survival was significantly higher in patients who did not develop CMV pneumonitis during the first six months following transplantation compared with those who were treated for CMV pneumonitis during the first six months (71 versus 53 percent) [15].

Other tissue-invasive disease — Other forms of tissue-invasive CMV disease, such as enteritis, hepatitis, and retinitis, are less common than pneumonitis in lung transplant recipients but do occur [10,16]. Clinical features of other tissue-invasive diseases are similar to those that occur in other patient populations. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Organ-specific complications'.)

Indirect effects — In addition to the direct effects of CMV infection and disease, CMV has been associated with chronic rejection (chronic lung allograft dysfunction; previously termed bronchiolitis obliterans syndrome) in lung transplant recipients [15,17-20]. In one study, treated CMV pneumonitis that developed during the first six months after transplantation increased the risk for chronic lung allograft dysfunction (hazard ratio [HR] 2.19, 95% CI 1.36-3.51) and post-transplantation death (HR 1.89, 95% CI 1.11-3.23) [15]. In another study, the use of CMV prophylaxis resulted in a significant decrease in the rate of chronic lung allograft dysfunction following lung transplantation [21]. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

CMV has also been associated with acute rejection in renal and liver transplant recipients [18,22,23].

The immunomodulatory effects of CMV may predispose patients to several opportunistic infections, including those caused by Aspergillus species, Pneumocystis jirovecii, Nocardia species, and Epstein-Barr virus-associated post-transplant-associated lymphoproliferative disease [10].

DIAGNOSIS — The approach to diagnosis varies with the suspected clinical syndrome and site of infection. In general, quantitative polymerase chain reaction (PCR) is the preferred test for detecting CMV in blood [9]. Evidence of CMV infection at the affected site is required for the diagnosis of pneumonitis and other tissue-invasive CMV diseases [9].

Our approach to diagnosis is generally consistent with the 2018 international consensus guidelines on the management of CMV in solid organ transplantation [9]. (See 'Society guideline links' below.)

Asymptomatic viremia — The diagnosis of asymptomatic CMV viremia is typically made during routine CMV viral-load monitoring post-transplantation. Strategies for viral-load monitoring and interpretation of results are discussed separately. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

CMV syndrome — For patients with suspected CMV syndrome (eg, fever, malaise, leukopenia, and/or lymphocytosis in the absence of end-organ disease), we generally obtain a quantitative PCR (ie, viral load) from plasma or whole blood for diagnosis. Because viral-load testing is very sensitive [24,25], assays vary among institutions, and the clinical features of CMV syndrome are nonspecific, interpreting results can be challenging.

●In general, an elevated viral load in a patient with a clinically compatible syndrome (in whom other causes seem unlikely) is considered diagnostic. However, the significance of very low viral loads (ie, detectable but not quantifiable viral loads or viral loads near the lower limit of the assay) is not certain. Thus, we weigh the clinical context heavily when deciding when to repeat the viral load for confirmation and/or starting antiviral treatment.

●A negative test result (eg, an undetectable viral load) is often sufficient to rule out CMV as the cause of a patient's symptoms. However, in some patients with tissue-invasive disease (particularly CMV enteritis), plasma and whole-blood viral loads can be undetectable despite CMV replication in tissue.

Although quantitative PCR has limitations, it is the test of choice for the diagnosis [7,26,27]. In general, a quantitative PCR assay that is calibrated to the World Health Organization (WHO) international standard (with results reported in international units/mL) should be used. Calibration to the international standard reduces some but not all variability among different assays and different institutional testing practices [28,29]. Because sample types (plasma versus whole blood), deoxyribonucleic acid (DNA) extraction techniques, and other factors still vary among testing centers, it is important to use the same assay while monitoring an individual patient over time.

The optimal sample type (ie, whole blood versus plasma) for quantitative PCR testing has not been determined. Both assays are used in clinical practice but are not interchangeable [7,30]. Whole-blood assays may be more sensitive that plasma assays, while plasma assays appear to be more specific. Because the amount of virus detected differs between sample types, neither the sample type nor the assay used should be changed when monitoring patients. (See "Overview of diagnostic tests for cytomegalovirus infection", section on 'Whole blood versus plasma'.)

Historically, the CMV pp65 antigenemia assay was commonly used for the diagnosis of CMV syndrome, but this has now been largely supplanted by quantitative PCR. Serology should not be used to diagnose active CMV infection or disease in lung transplant recipients. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection".)

Pneumonitis — For patients with suspected CMV pneumonitis, we obtain sampling from the lung in addition to quantitative PCR from blood [31-33]. When safe and feasible, we perform bronchoscopy with transbronchial biopsy for tissue diagnosis. The key reason for performing the biopsy is to distinguish CMV pneumonitis from allograft rejection. While the histologic features of these two disorders overlap, the presence of CMV inclusion bodies (image 2) and/or CMV viral antigens (by immunohistochemistry or DNA hybridization) in lung tissue provides a definitive diagnosis of CMV pneumonitis [9,34-37].

When lung tissue cannot be obtained, a presumptive diagnosis can be made based on detection of the virus by PCR or culture in bronchoalveolar lavage (BAL) fluid or bronchial washings, provided that the clinical picture is compatible and other causes have been excluded [9,38-42]. However, caution should be taken when using this approach. Neither PCR nor culture can distinguish viral shedding from tissue-invasive disease. In addition, PCR has not been standardized for use on BAL fluid or bronchial washings.

To help corroborate the diagnosis of CMV pneumonitis, we generally obtain a peripheral quantitative PCR (eg, from whole blood or plasma). Elevated CMV viral loads are common among patients with CMV pneumonitis, but this finding alone is nonspecific and insufficient for diagnosis.

Additional detail on the diagnosis of CMV pneumonitis and the histopathologic findings associated with tissue-invasive CMV disease is provided separately. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Tissue-invasive disease' and "Overview of diagnostic tests for cytomegalovirus infection", section on 'Histopathology'.)

Other tissue-invasive disease — Although other forms of tissue-invasive CMV disease (eg, enteritis/colitis) are less common than pneumonitis in lung transplant recipients, the approach to diagnosis is similar and requires evidence of CMV infection at the affected site in a patient with a compatible clinical picture. Elevated peripheral CMV viral loads are generally corroborative but can be negative even in the presence of active tissue-invasive disease. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Testing based on type of disease'.)

TREATMENT

Pre-emptive therapy for asymptomatic viremia — Most patients with asymptomatic CMV viremia require antiviral treatment. The rationale for treating patients with asymptomatic CMV viremia (ie, pre-emptive therapy) is to prevent the development of invasive disease and the potential indirect effects of CMV viremia, such as rejection.

The diagnosis of asymptomatic CMV viremia is typically made during routine CMV viral-load monitoring post-transplantation. Because viral load assays vary among institutions, the specific viral-load threshold that should trigger the need for treatment is typically determined by the individual transplant center [7]. (See "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'Diagnostic tests' and "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'Pre-emptive therapy'.)

When pre-emptive therapy is indicated, we generally use valganciclovir 900 mg orally every 12 hours (adjusted for renal dysfunction). While on therapy, we monitor the viral load weekly or biweekly. We typically treat until the viral load is undetectable or less than the lower quantifiable limit of the assay (ie, <200 international units/mL) on a single highly sensitive assay or until the viral load is undetectable on two consecutive samples when using less sensitive assays. (See 'Monitoring on therapy' below.)

Our treatment recommendations are largely consistent with the 2018 Transplantation Society international CMV consensus guidelines [9]. (See 'Society guideline links' below.)

Treatment of symptomatic disease — Treatment of symptomatic CMV disease generally involves both reduction of immunosuppression and antiviral therapy, typically with oral valganciclovir or intravenous (IV) ganciclovir [7,9,43,44]. Our treatment recommendations are largely consistent with the 2018 Transplantation Society international CMV consensus guidelines [9]. (See 'Society guideline links' below.)

Reduction of immunosuppression — Immunosuppression should be cautiously reduced (eg, holding or reducing the dose of immunosuppressive medications) in patients with CMV disease to promote the generation of CMV-specific immunity, when feasible [7,45]. The decision to reduce immunosuppression should be made on a case-by-case basis but should be considered most strongly in patients with moderate to severe disease, high viral loads, slow clinical or virologic response to antiviral treatment, ganciclovir-resistant CMV, and/or in those with a high net state of immunosuppression [44,45].

Antiviral therapy — For patients with symptomatic CMV disease, either oral valganciclovir or IV ganciclovir are the drugs of choice. We generally select between these two drugs based on disease severity. Acyclovir, valacyclovir, famciclovir, and oral ganciclovir should not be used for the treatment of CMV infection or disease.

CMV syndrome — Most patients with CMV syndrome (symptomatic viremia in the absence of tissue-invasive disease) have mild or moderate infections that can be treated with oral valganciclovir, provided that the patient is able to adequately tolerate and absorb oral medications. The standard treatment dose is 900 mg orally every 12 hours. For patients who cannot take medications or if there is clinical concern for rapidly progressive or severe disease, IV ganciclovir (5 mg/kg every 12 hours) should be used in place of valganciclovir. Dose adjustments may be needed for changes in renal function but should not be made to manage side effects such as leukopenia. (See 'Monitoring on therapy' below.)

Treatment duration is based on clinical and virologic response to therapy. In general, we monitor CMV viral loads weekly or biweekly on therapy. For patients whose viral loads are declining with treatment, we typically treat until a single viral load is undetectable or less than the lower quantifiable limit of the assay (when using a highly sensitive assay) or until two consecutive viral loads drawn ≥1 week apart are either undetectable (when using a less sensitive assay). The minimum duration of therapy is two weeks [7]. (See 'Viral load' below.)

Oral valganciclovir appears to be equivalent to IV ganciclovir for most transplant recipients with mild to moderate infections, such as CMV syndrome [7,46]. In addition, use of an oral antiviral agent for initial treatment may reduce hospital stays and any adverse events associated with IV therapy. In the valcyte in CMV disease treatment of solid organ recipients (VICTOR) trial, 321 solid organ transplant recipients with non-life-threatening CMV disease were randomized to either oral valganciclovir (900 mg twice daily) or IV ganciclovir (5 mg/kg IV twice daily) [46]. Both groups continued therapy for 21 days before switching to valganciclovir 900 mg once daily for an additional 28 days. Forty-eight percent of patients had a CMV syndrome and 49 percent had CMV disease. The primary endpoint was clearance of CMV viremia at day 21 of therapy, which was achieved in 45 percent of those receiving valganciclovir and 48 percent of those receiving ganciclovir. Clinical resolution of CMV disease was a secondary endpoint and was achieved in 77 percent of those receiving valganciclovir and 80 percent of those receiving ganciclovir. One year following treatment, there were no differences in clinical or viral eradication of CMV disease or in incidence of ganciclovir resistance between the patients who received valganciclovir and those who received ganciclovir [47]. Of note, lung transplant recipients were a minority (6 percent) of the solid organ transplant recipients evaluated. Thus, we do not assume that oral valganciclovir and IV ganciclovir are equivalent for the treatment of more severe CMV disease in lung transplant recipients, particularly for pneumonitis, which involves the allograft.

Pneumonitis and tissue-invasive disease — We treat lung transplant recipients with CMV pneumonitis with IV ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for renal dysfunction, to ensure maximum bioavailability. IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications. While treating with either ganciclovir or valganciclovir, we monitor the serum creatinine at regular intervals in case dose adjustment is needed. (See 'Monitoring on therapy' below.)

As with other forms of CMV disease, treatment duration for pneumonitis is based on clinical and virologic response to therapy. In general, we monitor CMV viral loads weekly or biweekly while on therapy. For patients whose viral loads are declining with treatment, we typically treat until a single viral load is undetectable or less than the lower quantifiable limit of the assay (when using a highly sensitive assay) or until two consecutive viral loads drawn ≥1 week apart are either undetectable (when using a less sensitive assay). The minimum duration of therapy is two weeks [7]. (See 'Viral load' below.)

The addition of cytomegalovirus immune globulin (CytoGam) to antiviral therapy might theoretically improve treatment response and, while this approach is used by some experts, data supporting its use are limited and we do not routinely employ this approach.

Monitoring on therapy

Viral load — We generally monitor CMV viral loads weekly or biweekly while on therapy to assess response to treatment and guide duration of therapy. Because there is variability among assays, we use the same quantitative PCR assay each time the viral load is measured. (See 'CMV syndrome' above and "Overview of diagnostic tests for cytomegalovirus infection", section on 'Molecular assays'.)

During the first week of therapy, the viral load may rise (particularly in heavily immunosuppressed patients) but should fall steadily thereafter [7,48]. For patients whose viral loads continue to rise following the first week of therapy or for patients whose viral loads plateau or slowly decline, we consider the possibility of ganciclovir resistance. (See 'Ganciclovir resistance' below.)

For patients whose viral loads are declining with treatment, we typically treat until a single viral load is undetectable or less than the lower quantifiable limit of the assay (when using a highly sensitive assay) or until two consecutive viral loads drawn ≥1 week apart are either undetectable (when using a less sensitive assay). The minimum duration of therapy is two weeks [7]. However, most patients will require longer treatment courses, particularly those with severe tissue-invasive disease, high initial viral loads, or those who are heavily immunocompromised.

There has been some interest in using CMV-specific immune monitoring assays to help guide the duration of treatment. At this time, there are insufficient data to support the use of these routinely, but further research is being performed to help define whether these assays can help inform the duration of treatment [49]. (See "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'CMV-specific immunity'.)

Renal function — In addition to monitoring CMV viral loads weekly while on therapy, we also check a serum creatinine at routine intervals (eg, weekly or biweekly) to help guide appropriate antiviral dosing. Subtherapeutic dosing raises the risk of developing ganciclovir resistance while on therapy. Supratherapeutic dosing increases the chance of drug-related toxicities.

Blood cell counts — Bone marrow suppression, in particular leukopenia, appears to be the most significant and common toxicity associated with valganciclovir and ganciclovir use. Given this risk, we generally check a complete blood count weekly while patients are on therapy.

If leukopenia occurs while on therapy, antiviral dosing should not be decreased because of the risk of promoting drug resistance [7]. Evaluation for other causes (eg, mycophenolate mofetil, trimethoprim-sulfamethoxazole toxicity, worsening/persistent CMV infection) should be pursued. If valganciclovir or ganciclovir is determined to be an important cause or contributor, the addition of granulocyte colony stimulating factor should be considered before discontinuing or changing antiviral therapy. (See "Ganciclovir and valganciclovir: An overview", section on 'Bone marrow suppression'.)

Ganciclovir resistance — Resistance to ganciclovir should be considered in recipients who fail to improve clinically and/or virologically after two weeks of adequate doses of antiviral therapy or who have recurrent relapses following treatment. Factors that raise the likelihood of ganciclovir resistance include prolonged antiviral use, lack of prior CMV immunity (CMV D+/R-), and inadequate antiviral drug selection or dosing (eg, treatment with oral ganciclovir or subtherapeutic dosing of IV ganciclovir or valganciclovir) [9,50-52].

●Resistance testing – Genotypic resistance testing should be performed in patients with suspected ganciclovir resistance [7,9,43,53-56]. In patients who have been treated with ganciclovir, the most common mutations are UL97 phosphotransferase mutations [9,51,56,57]. Certain UL97 mutations confer ganciclovir resistance by diminishing the enzyme's ability to phosphorylate GCV, a modification needed for antiviral activity [58,59]. The degree of ganciclovir resistance conferred varies among UL97 mutations. In most cases, treatment with an alternate antiviral agent is needed; in a minority of cases, resistance can be overcome with higher dose ganciclovir.

UL54 DNA polymerase mutations may occur, usually as second-step mutations in patients who already have a UL97 mutation. UL54 mutations rarely are the first mutation to occur, and alone are not always associated with clinical antiviral resistance. CMV isolates possessing both UL97 and UL54 mutations often have high-level ganciclovir resistance [10,60-62]. The resistance conferred by UL54 mutations cannot be overcome by increasing the dose of ganciclovir. UL54 DNA polymerase mutations confer various combinations of resistance to ganciclovir, foscarnet, and/or cidofovir [58].

●Treatment – Data on the treatment of ganciclovir-resistant CMV infection are mixed and limited [9,63-68], and the approach to treatment varies based on disease severity, viral gene mutation, antiviral drug availability and safety profile, and host immune status.

Reduction of immunosuppression is particularly important in patients with resistant CMV disease [7]. Although the approach to reducing immunosuppression should be individualized, switching the immunosuppressive regimen to one that includes an mTOR inhibitor (eg, sirolimus, everolimus) can be considered because of the reportedly lower risk of CMV disease in patients receiving mTOR inhibitors [69].

In patients with severe disease and/or a substantial degree of immunosuppression, we typically use foscarnet 60 mg/kg IV every 8 hours (or 90 mg/kg IV every 12 hours), with adjustment for renal dysfunction [70]. It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet. An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity. (See "Foscarnet: An overview" and "Cidofovir: An overview".)

In patients treated empirically for presumed ganciclovir-resistant CMV, the regimen should be adjusted as indicated based upon the results of genotypic resistance testing. UL97 mutations that confer low-level ganciclovir resistance (less than twofold; eg, C592G mutation) may respond to an increase in the dose of IV ganciclovir up to 10 mg/kg IV every 12 hours (twice the US Food and Drug Administration [FDA]-approved dose), with adjustment for renal dysfunction [7,9,64].

Some experts have used foscarnet and ganciclovir in combination for the treatment of ganciclovir-resistant CMV disease [63], but it is unclear whether there is benefit to this approach. Maribavir, benzimidazole antiviral agent, is a potential option for salvage treatment, but efficacy data for these agents in lung transplant recipients are mixed and limited [7,44,68,71-74]. While its toxicity profile is favorable (no bone marrow or renal toxicity), resistance has been reported to emerge during therapy [75,76].

Letermovir, a viral terminase inhibitor, is approved by the FDA for CMV prevention in allogeneic hematopoietic stem cell transplant (HCT) recipients and kidney transplant recipients [77]. Although letermovir has been reported to successfully treat ganciclovir-resistant CMV disease in a few lung transplantation recipients [67,78,79], it is not approved for this indication, optimal dosing has not yet been determined, and resistance can emerge while on therapy [80]. Letermovir is not recommended for treatment of ganciclovir-resistant CMV due to its low barrier to resistance. Evidence supporting the use of letermovir in other populations is discussed separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'CMV prevention'.)

Experimental agents include leflunomide, an immunosuppressive agent [81-83], and artesunate, an antimalaria drug [84,85]. Both have some in vitro activity against CMV, but further study is needed before either agent can be recommended.

PREVENTION

Primary prophylaxis — CMV disease is associated with increased mortality rates among solid organ transplant recipients, and the use of antiviral prophylaxis against CMV is associated with a reduction in all-cause mortality after transplantation [10,23,86-90]. Methods to prevent CMV infection and disease following transplantation, including universal prophylaxis and pre-emptive therapy, are discussed separately. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

Secondary prophylaxis — Secondary prophylaxis (ie, continuing antiviral medications at prophylactic doses after completion of treatment for symptomatic disease) has not been associated with lower recurrence rates and is not routinely recommended [7,91].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cytomegalovirus in solid organ transplant recipients".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Cytomegalovirus (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Cytomegalovirus (CMV) is an important cause of morbidity and mortality in lung transplant recipients. CMV infection is characterized by virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs. CMV disease refers to CMV infection with attributable symptoms or signs. (See 'Introduction' above and 'Definitions' above.)

●Spectrum of illness – The spectrum of illness associated with CMV ranges from asymptomatic viremia to severe tissue-invasive disease. CMV syndrome and pneumonitis are among the most common manifestations in lung transplant recipients. (See 'Clinical manifestations' above.)

●CMV syndrome – CMV syndrome refers to symptomatic viremia without evidence of tissue-invasive disease. The signs and symptoms that most commonly accompany viremia include fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, and/or thrombocytopenia. (See 'CMV syndrome' above.)

●Pneumonitis – Clinical features of CMV pneumonitis are nonspecific and include low-grade fever, shortness of breath, nonproductive cough, and changes in measured pulmonary function. Because these features overlap with acute allograft rejection, distinguishing these two disorders can be challenging and biopsy is typically needed for diagnosis. (See 'Pneumonitis' above.)

●Diagnosis – The approach to diagnosis varies with the suspected clinical syndrome and site of infection. In general, CMV quantitative polymerase chain reaction (ie, viral-load testing) is the preferred test for detecting viremia. Evidence of CMV infection at the affected site is required for the diagnosis of pneumonitis and other tissue-invasive CMV diseases. (See 'Diagnosis' above.)

●Pre-emptive therapy for asymptomatic viremia – Most lung transplant recipients with asymptomatic CMV viremia should be given pre-emptive antiviral therapy to prevent the development of symptomatic and/or invasive disease as well as any potential indirect effects of CMV viremia, such as rejection. The viral load cut-off for which antiviral treatment should be given varies among institutions. When therapy is indicated, we typically use oral valganciclovir 900 mg orally every 12 hours, adjusted for renal dysfunction. (See 'Pre-emptive therapy for asymptomatic viremia' above.)

●Management of symptomatic disease – For lung transplant recipients with symptomatic CMV disease, we generally reduce immunosuppression (when feasible) and recommend treatment with antiviral therapy. Typically, we use either oral valganciclovir or intravenous (IV) ganciclovir, depending on the severity of illness. (See 'Treatment of symptomatic disease' above and 'Reduction of immunosuppression' above.)

•Treatment of CMV syndrome – For most patients with CMV syndrome, we suggest treatment with oral valganciclovir (900 mg orally every 12 hours, adjusted for renal dysfunction) rather than IV ganciclovir, provided that the patient is able to adequately tolerate and absorb oral medications (Grade 2B). Patients with CMV syndrome typically have mild to moderate infections, and clinical outcomes are similar when comparing IV ganciclovir with oral valganciclovir in solid organ transplant recipients. (See 'CMV syndrome' above.)

•Treatment of pneumonitis or other tissue-invasive disease – We generally consider lung transplant recipients with pneumonitis or other tissue-invasive disease to have severe infection and recommend treatment with IV ganciclovir 5 mg/kg IV every 12 hours over oral valganciclovir (Grade 1C). IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications. Some experts give CMV immune globulin (CytoGam) in addition to antiviral therapy, but data supporting this approach are limited. (See 'Pneumonitis and tissue-invasive disease' above.)

●Duration of therapy – Treatment duration is based on clinical and virologic response to therapy. In general, we monitor CMV viral loads weekly or biweekly on therapy. We treat until the patient's symptoms have resolved and the viral load is undetectable or less than the lower quantifiable limit of the assay (when using a highly sensitive assay). The minimum duration of therapy is two weeks, but courses are frequently longer. (See 'Viral load' above.)

●Monitoring on therapy – For patients being treated with ganciclovir or valganciclovir, we check a serum creatinine at regular intervals to help guide appropriate antiviral dosing. We also routinely check a complete blood count to monitor for bone marrow suppression. (See 'Monitoring on therapy' above.)

●Ganciclovir resistance – For patients whose viral loads fail to decline while on therapy, we test for ganciclovir resistance. For most patients with confirmed ganciclovir resistance, we suggest foscarnet (Grade 2C). Foscarnet should be dosed at 60 mg/kg IV every 8 hours (or 90 mg/kg IV every 12 hours), with dose adjustment for renal insufficiency and close monitoring for associated drug toxicities. (See 'Ganciclovir resistance' above.)