Version May 2024
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 prevention of CMV infection in lung transplant recipients will be discussed here. The clinical manifestations, diagnosis, and treatment of CMV infection in lung transplant recipients and infectious complications due to agents other than CMV are discussed elsewhere.
●(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 (if the recipient is CMV naïve)
DEFINITIONS — CMV infection and disease are not synonymous terms; not all patients with infection develop overt clinical disease [7-10]:
●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 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.
RISK FACTORS — The most important risk factor for CMV infection and disease in lung transplant recipients is CMV serologic status, with seronegative recipients of seropositive organs (CMV D+/R-) having the highest risk. Immunosuppressive regimens can also play a major role on the impact of CMV replication in lung transplant recipients. In particular, the use of antilymphocyte antibodies as induction therapy or for the treatment of steroid-resistant rejection has been strongly associated with the development of CMV disease in certain recipients (CMV D+/R-, D-/R+, or D+/R+) [11,12]. High doses of glucocorticoids have also been identified as a risk factor for CMV disease [13].
Certain gene polymorphisms involved in innate immunity (toll-like receptor 2 [TLR2], TLR4, mannose-binding lectin, and interferon L3/4 [IFNL3/4]) are associated with an increased incidence of CMV infection or disease following transplantation [14-17]. Evolving research suggests that short telomere defects impair CMV immunity and are risk factors for CMV infection in lung transplant recipients [18].
Serologic status — The overall likelihood of developing CMV infection or disease in lung transplant recipients ranges from 54 to 92 percent in patients without prophylaxis [19-21]. The most important risk factor for CMV infection and disease is organ donor (D) and recipient (R) serostatus, with CMV D+/R- recipients at the highest risk followed by CMV D+/R+; CMV D-/R+ are at lower risk [19,20]. (See 'Universal prophylaxis' below.)
The lung has been identified as a major site of CMV latency and recurrence [22]. Lung transplantation is associated with the transfer of a larger CMV load than other solid organs and, as a result, the risk of CMV infection and disease is greater than in other solid organ transplant recipients. Therefore, most lung transplant programs employ aggressive preventive measures for all D+ or R+ lung transplant recipients.
Serologic status impacts the risk of CMV infection as follows:
●D+/R- − CMV D+/R- recipients are at the greatest risk for CMV, with infection occurring in up to 71 percent of recipients, with 85 percent of infected individuals developing disease (in the absence of prophylaxis). The case-fatality rate of patients with CMV disease has approached 22 percent but, due to the availability of potent antiviral agents, mortality has been substantially reduced [3]. In a single-center series, the survival rate for CMV-mismatched recipients was similar to that for other donor-recipient serologic combinations [23].
●D-/R+ and D+/R+ − Early studies have suggested that CMV infection develops in approximately 58 and 69 percent of CMV D-/R+ and D+/R+ recipients, respectively [24]. The risk is higher in the latter group because reactivation as well as superinfection with a new virus strain can occur. However, more recent reports in the era of valganciclovir prophylaxis found that the risk of infection or disease is much less in D-/R+ and D+/R+ patients, particularly in D-/R+ recipients [25,26]. In one study, during the 180-day period following six months of CMV prophylaxis, the incidence of CMV infection or disease was 6 percent in D-/R+ recipients and 34 percent in D+/R+ recipients [25]. Progression from CMV infection to disease is less common in these recipients who have immunity to CMV, occurring in one-fourth to one-third of cases.
●D-/R- − The risk of CMV infection is lowest in seronegative recipients of seronegative donor lungs (CMV D-/R-).
DIAGNOSTIC TESTS — Serologic testing to assess the risk of CMV infection prior to transplantation as well as the use of appropriate diagnostic tests for the detection of active CMV infection following transplantation are essential for the management of lung transplant recipients.
Pretransplant serologic testing — The recipient should be tested for CMV antibodies prior to transplantation, and the donor should be tested before or at the time of transplantation in order to ascertain the need for postoperative prophylaxis. Seronegative recipients should also be tested on the day of transplantation prior to going to the operating room to correctly assign risk. Only CMV immunoglobulin (Ig)G should be tested for rather than IgM or a combination of IgM and IgG since false-positive IgM results might reduce the specificity of screening [7,8,27-29]. Serology should not be used to diagnose active CMV infection or disease in lung transplant recipients [7]. (See "Overview of diagnostic tests for cytomegalovirus infection", section on 'Serology'.)
Post-transplant monitoring — Quantitative polymerase chain reaction (PCR; ie, viral load testing) is the preferred test for monitoring for CMV reactivation following transplantation [7]. 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 [30,31]. 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. (See "Overview of diagnostic tests for cytomegalovirus infection", section on 'Molecular assays'.)
Historically, the CMV pp65 antigenemia assay was commonly used to diagnose CMV reactivation posttransplantation, 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" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Diagnosis'.)
In general, patients who are receiving antiviral prophylaxis do not require routine viral load monitoring. By contrast, patients who are being managed with a pre-emptive approach should undergo routine viral load monitoring. (See 'Universal prophylaxis' below and 'Pre-emptive therapy' below.)
CMV-specific immunity — Assays for assessing CMV-specific T cell responses have been developed to predict which patients are at increased risk for CMV disease following transplantation and are used at some transplant centers outside the United States [7]. Tests include a QuantiFERON assay, an ELISpot assay, major histocompatibility complex multimer staining assays, and intracellular cytokine staining assays. Such assays may be particularly useful in combination with viral load monitoring in high-risk (eg, CMV D+/R-) solid organ transplant recipients following the completion of antiviral prophylaxis.
As an example, a QuantiFERON CMV assay has been evaluated for assessing CMV-specific cell-mediated immunity in whole-blood specimens by measuring interferon-gamma levels following in vitro stimulation with CMV antigens [32]. In a prospective multicenter cohort study, 127 CMV D+/R- solid organ transplant recipients (including 14 lung transplant recipients) receiving antiviral prophylaxis for a median of 98 days underwent testing at the end of prophylaxis and one and two months later. At 12 months, patients with a positive result had a significantly lower risk of CMV disease than patients with a negative or indeterminate result (6 versus 22 versus 58 percent, respectively). Similar results have been reported in other studies [33-35].
In a cohort study of 263 lung transplant recipients (59 D+/R-, 204 R+), extending the standard 5-month duration of CMV prophylaxis to 11 months for patients who did not have a detectable CMV-immune response based on QuantiFERON testing (at the 5-month mark) was associated with reduced CMV infection (43 versus 60 percent) [36]. Therapy was most often extended in D+/R- recipients who are less likely to develop an immune response and are at the highest risk for CMV infection. Thus, it is unclear whether the risk reduction was attributable to QuantiFERON testing or extending prophylaxis in the highest risk group.
PREVENTION OF DISEASE — Because CMV causes considerable morbidity and mortality and has been identified as a risk factor for chronic rejection in lung transplant recipients, there has been intense interest in prevention [7,19,24,37]. Two strategies have been used:
●Universal prophylaxis of recipients at high risk for infection (ie, all but CMV donor-negative, recipient-negative [CMV D-/R-] recipients). Oral valganciclovir is currently the most commonly used drug for prophylaxis.
●Pre-emptive treatment of recipients with infection in order to abort the development of disease. Using this approach, patients are monitored for CMV in the blood at regular intervals (ie, weekly), and oral valganciclovir is initiated when viral replication has reached a certain assay threshold defined at each institution.
Given the high risk of CMV disease in lung transplant recipients, we favor antiviral prophylaxis over pre-emptive therapy in all lung transplant recipients who are CMV seropositive or who received an organ from a CMV-seropositive donor (CMV D+/R+, D-/R+, D+/R-) [19]. The use of antiviral prophylaxis in seropositive lung transplant recipients is also endorsed by the 2018 international consensus guidelines on the management of CMV in solid organ transplantation [38].
Support for the use of universal prophylaxis is based on a substantial body of published evidence in lung transplant recipients [7,8,19]. There is a paucity of evidence on the safety and efficacy of pre-emptive therapy compared with that of universal prophylaxis in lung transplant recipients. Furthermore, few studies have directly compared universal prophylaxis to pre-emptive therapy in this population.
Several studies have compared pre-emptive and prophylactic strategies in solid organ transplant recipients, but the majority of patients in these studies have been renal and liver transplant recipients, and few lung transplant recipients have been included. The results of these studies might not apply to lung transplant recipients, who have a higher risk of CMV infection and disease than renal transplant recipients. These studies are discussed in detail separately. (See "Prevention of cytomegalovirus disease in kidney transplant recipients", section on 'Preventive strategies'.)
Universal prophylaxis — Antiviral prophylaxis (either alone or in combination with CMV immune globulin) is the most widely used prophylactic approach for lung transplant recipients [39,40]. Oral valganciclovir and intravenous ganciclovir are the drugs of choice for CMV prophylaxis. Acyclovir is ineffective for the prevention of CMV infection after lung transplantation [41-43].
Approach to prophylaxis — The following recommendations are based upon published guidelines and on a randomized trial described below [7,8,19,38,44]. However, the approach to prophylaxis chosen for each patient depends upon protocols developed at each transplant center.
In the immediate posttransplant period, patients who are seropositive for CMV or who received an organ from a seropositive donor (CMV D+/R+, D-/R+, D+/R-) should receive intravenous ganciclovir 5 mg/kg once daily, with dose adjustment for renal insufficiency. Once the patient is absorbing oral medications or at hospital discharge, ganciclovir can be switched to oral valganciclovir 900 mg once daily, with dose adjustment for renal insufficiency.
The 2018 international consensus guidelines recommend 6 to 12 months of prophylaxis for CMV D+/R- lung transplant recipients [8,38]. For CMV D+/R+ and D-/R+ lung transplant recipients, a minimum of six months of prophylaxis is recommended. The decision on duration of prophylaxis depends upon several factors, including the patient's risk of CMV reactivation, development of drug toxicity, and the feasibility of frequent viral load monitoring. (See 'Pre-emptive therapy' below.)
Valganciclovir prophylaxis is preferred over pre-emptive therapy for patients who are seropositive for CMV or who received an organ from a seropositive donor who are receiving antilymphocyte antibodies, high doses of glucocorticoids, or other potent immunosuppressives used for the treatment of rejection, since such patients are at increased risk of CMV infection. Prophylaxis should be continued for one to three months after the antirejection therapy has been completed [7,8]. (See 'Risk factors' above.)
Use of adjunctive cytomegalovirus immune globulin (CytoGam) is controversial. While some experts do add CMV immune globulin to antiviral therapy for high-risk patients (eg, CMV D+/R-, D+/R+, D-/R+; particularly in those receiving a lymphocyte-depleting agent), data supporting this approach are limited. (See 'CMV immune globulin' below.)
Valganciclovir — Valganciclovir, a ganciclovir prodrug with excellent oral bioavailability, has become the drug of choice for the prophylactic management of CMV infection after lung transplantation [8,19,45]. It has proven efficacy in heart, kidney, and kidney-pancreas transplantation compared with oral ganciclovir [46]. One randomized trial and several nonrandomized studies have also shown that valganciclovir is effective for the prevention of CMV infection and disease in lung transplant recipients [44,45,47,48].
The randomized trial included 136 lung transplant recipients with positive donor or recipient CMV serology who received oral valganciclovir (900 mg orally once daily, with dose adjustment for renal insufficiency) for three months, followed by an additional nine months of either valganciclovir or placebo; the following findings were noted [44]:
●Those who received 12 months of valganciclovir prophylaxis were less likely to develop CMV disease than those who received 3 months of valganciclovir prophylaxis (4 versus 32 percent).
●Individuals who received 12 months of prophylaxis were also less likely to develop CMV infection (10 versus 64 percent) and less likely to have invasive disease (2 versus 21 percent).
●There were no significant differences between the groups in the incidence of non-CMV opportunistic infections or acute rejection episodes following randomization.
●There was no difference in the incidence of ganciclovir-resistant CMV infection, and there was a similar incidence of CMV disease during the 6 months following study completion between those who received 12 months of prophylaxis and those who received 3 months of prophylaxis (3 versus 2 percent).
In a subset analysis that included 38 patients who were followed for a mean of 3.9 years, those who received 12 months of prophylaxis continued to have a reduced risk of CMV viremia or pneumonitis compared with those who received 3 months of prophylaxis (12 versus 55 percent; hazard ratio 0.13, 95% CI 0.03-0.61) [49]. White blood cell, neutrophil, and platelet counts were similar between the two groups, demonstrating that the longer duration of prophylaxis did not increase the risk of hematologic toxicity.
Based on these results, many experts favor continuing valganciclovir prophylaxis for 12 months following lung transplantation in patients who are CMV seropositive or who received an organ from a CMV-seropositive donor (CMV D+/R+, D-/R+, D+/R-), but particularly in CMV D+/R- patients, who are at the highest risk for CMV reactivation. Some experts prefer to give prophylaxis for six months followed by a pre-emptive approach with frequent CMV load monitoring in CMV D+/R+ or D-/R+ patients. In a retrospective study that evaluated the risk of late-onset CMV infections during the 180-day period following the discontinuation of CMV prophylaxis (at six months posttransplant) in lung or heart-lung transplant recipients, the proportion of patients with CMV infection or disease differed substantially depending on serostatus [25]. Forty-nine percent of CMV D+/R- patients developed CMV infection or disease (infection: 29 percent; disease: 20 percent), compared with 34 percent of CMV D+/R+ patients (infection: 23 percent; disease: 11 percent), and only 6 percent of CMV D-/R+ patients (infection: 6 percent; disease: 0 percent).
When used for prophylaxis, valganciclovir should be dosed at 900 mg orally once daily, with dose adjustment for renal insufficiency. It is important to give appropriate doses of valganciclovir and ganciclovir, since inadequate dosing may reduce efficacy and lead to resistance, whereas supratherapeutic dosing may lead to toxicity [7,50,51].
The toxicity profile of valganciclovir is similar to that of its parent compound, ganciclovir. Hematologic suppression, in particular leukopenia (including neutropenia), appears to be the most significant and common adverse event associated with these agents. When leukopenia occurs, dose reduction of valganciclovir should be avoided, given the risk of promoting resistance [7]. Patients should be evaluated for other potential causes of leukopenia (eg, mycophenolate mofetil, trimethoprim-sulfamethoxazole). The addition of granulocyte colony-stimulating factor (G-CSF) should be considered before discontinuing valganciclovir. (See 'Ganciclovir' below and "Ganciclovir and valganciclovir: An overview", section on 'Bone marrow suppression'.)
Ganciclovir — As noted above, valganciclovir has replaced ganciclovir as the drug of choice for CMV prophylaxis. (See 'Valganciclovir' above.)
A three-month course of intravenous ganciclovir has been shown to reduce the occurrence of CMV illness in all donor-recipient serologic combinations at risk [52,53]. In contrast, a short course of low-dose intravenous ganciclovir during the first three postoperative weeks failed to prevent CMV illness in a small group of CMV recipient-negative, donor-positive lung transplant recipients [54]. Ganciclovir inhibits viral replication but does not eradicate latent infection. Thus, ganciclovir prophylaxis is effective while it is being administered but does not confer long-term protection [52,53]. However, the delay in onset of CMV infection that it produces is advantageous because the disease is less frequent and less difficult to manage when the recipient has recuperated from surgery, the effects of cytolytic induction have waned, maintenance immunosuppression is less intense, and the highest-risk period for acute rejection has passed. Nevertheless, there is still a substantial rate of CMV infection and disease in individuals who receive only three months of antiviral prophylaxis [44]. A 12-month course of antiviral prophylaxis with oral valganciclovir has been shown to be superior to a three-month course, as discussed below. (See 'Valganciclovir' above.)
Experience with prophylactic oral ganciclovir is limited because oral bioavailability is very low. Some benefit has been suggested in CMV-mismatched recipients when used after an initial period of intravenous ganciclovir [55]. However, oral ganciclovir is no longer routinely available in the United States, and its use has been supplanted by oral valganciclovir, as discussed in the following section.
When intravenous ganciclovir is used for prophylaxis, it should be dosed at 5 mg/kg once daily, with dose adjustment for renal insufficiency.
As discussed above, hematologic suppression, in particular leukopenia (including neutropenia), appears to be the most significant and common adverse event associated with ganciclovir and valganciclovir. When leukopenia occurs, dose reduction of ganciclovir should be avoided, given the risk of promoting resistance [7]. Patients should be evaluated for other potential causes of leukopenia (eg, mycophenolate mofetil, trimethoprim-sulfamethoxazole). The addition of G-CSF should be considered before discontinuing ganciclovir or valganciclovir. (See "Ganciclovir and valganciclovir: An overview", section on 'Bone marrow suppression' and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Clinical manifestations'.)
CMV immune globulin — Use of adjunctive cytomegalovirus immune globulin (CytoGam) is controversial. While some experts do add CMV immune globulin to antiviral therapy for high-risk patients (eg, CMV D+/R-, D+/R+, D-/R+; particularly in those receiving a lymphocyte-depleting agent), data supporting this approach are limited [45]. A retrospective study compared prophylaxis with ganciclovir plus CMV immune globulin in a group of lung and heart-lung recipients to prophylaxis with ganciclovir alone in a group of historical controls at the same center [56]. In this analysis, freedom from CMV disease, freedom from bronchiolitis obliterans syndrome (chronic rejection), and survival were greater in the first three years after transplantation in the group that received the combination of CMV immune globulin and ganciclovir. Adequately powered randomized trials measuring the additive benefit of CMV immune globulin in the lung transplant population have not yet been performed.
Because efficacy data are limited, many experts do not favor the addition of CMV immunoglobulin to treatment regimens; this approach is no longer recommended in the 2018 international consensus guidelines [7].
CMV immune globulin has no role for CMV prophylaxis in lung transplant recipients when given alone [57].
Letermovir — Letermovir (a novel inhibitor of viral terminase subunit pUL56) is not routinely used for prophylaxis in lung transplant recipients. While this agent is US Food and Drug Administration approved for prevention of CMV disease in hematopoietic cell transplant recipients and kidney transplant recipients, its efficacy has not been well studied in lung transplant recipients [58,59]. While one small single-center review suggests that rates of breakthrough viremia are high during letermovir prophylaxis [60], findings from another retrospective review of heart and lung transplant recipients suggest that the agent may be an effective alternative when valganciclovir cannot be tolerated (eg, for profound valganciclovir-induced myelosuppression). In a review of 41 heart and lung transplant recipients who used letermovir for primary or secondary prophylaxis (when other agents could not be tolerated), low-level viremia was detected in 15 percent of cases; one case of clinically significant viremia occurred. Although these findings are encouraging, in most cases, letermovir was initiated late in the post-transplantation period when the likelihood of active CMV infection was lower. Thus, until further data are available, we continue to use valganciclovir as the preferred prophylactic agent [61].
Pre-emptive therapy — Using the pre-emptive approach, patients are monitored frequently (ie, weekly) with a CMV load or antigenemia assay, and antiviral therapy is initiated when viral replication has reached a certain assay threshold defined at each institution [7,8]. For asymptomatic CMV viremia, oral valganciclovir has supplanted intravenous ganciclovir as the drug of choice [38].
The pre-emptive approach is predicated upon a convenient, reliable surveillance test that identifies infection prior to the emergence of disease [38]. The most widely used screening test is the quantitative CMV polymerase chain reaction (PCR) assay (ie, viral load testing). CMV antigenemia assays can also detect CMV DNA in blood but has been largely supplanted by PCR.
Evidence of CMV replication usually precedes overt clinical findings, and therapy given at this point can potentially abort the development of CMV disease [20]. Pre-emptive therapy has some potential advantages over universal prophylaxis. Because only recipients with infection receive pre-emptive therapy, fewer patients are treated for a shorter duration. The net decrease in drug usage and exposure could decrease costs, drug-related toxicity, catheter-related complications, and potentially the evolution of drug-resistant strains of CMV [62,63]. However, pre-emptive therapy is not used commonly in lung transplant recipients during the early posttransplant period, given the high risk of CMV infection in such patients and the limited data about its efficacy in this population. In one trial of renal transplant recipients, prophylaxis was more effective than pre-emptive therapy for preventing CMV disease and resulted in higher rates of graft survival [64].
Given the lack of data regarding the pre-emptive approach and the high risk of CMV infection and disease in lung transplant recipients, we do not recommend the pre-emptive approach during the early posttransplant period. Instead, a pre-emptive approach can be used after the period of prophylaxis has ended. Protocols for pre-emptive therapy should be developed and validated at each transplant center [7]. Recommendations for viral load monitoring are discussed above. (See 'Post-transplant monitoring' above.)
When indicated, treatment should consist of either valganciclovir 900 mg orally twice daily (for mild to moderate disease) or intravenous ganciclovir 5 mg/kg every 12 hours (less common and reserved for severe disease). Treatment should be continued for a minimum of two weeks and until a single viral load is undetectable or less than the lower quantifiable limits (ie, <200 international units/mL) when a highly sensitive assay is used or when two consecutive viral loads drawn one week apart are undetectable when using less sensitive assays [7,8]. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Pre-emptive therapy for asymptomatic viremia'.)
Other approaches
Blood products — CMV-seronegative (CMV D-/R-) lung transplant recipients should receive only CMV-negative or leukoreduced blood products to decrease the risk of transfusion-related CMV transmission [7]. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'CMV-seronegative red cells' and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)
Vaccination — Several CMV vaccines have been developed, but none are available for clinical use [7,65,66]. Use of a live-attenuated CMV Towne strain vaccine in seronegative patients prior to renal transplantation with seropositive organs did not decrease the overall incidence of CMV infection or disease [67]. However, severe cases of CMV disease were less common among vaccinated versus placebo-treated patients.
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".)
SUMMARY AND RECOMMENDATIONS
●Important background – Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in lung transplant recipients. (See 'Introduction' above.)
●Transmission routes – CMV infection following transplantation can be acquired in one of several ways (see 'Epidemiology' above):
•By transmission with the donor organ from a CMV-seropositive donor
•By transfusion of blood products from a CMV-seropositive blood donor
•By reactivation of latent infection in a CMV-seropositive recipient
•By close physical contact with a CMV-infected individual
●Definitions – 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. CMV disease is characterized by evidence of CMV infection with attributable symptoms; 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 'Definitions' above.)
●Risk factors – The most important risk factor for CMV infection and disease in lung transplant recipients is CMV serologic status, with seronegative recipients of seropositive organs (CMV D+/R-) having the highest risk. The use of antilymphocyte antibodies as induction therapy or for the treatment of steroid-resistant rejection is associated with an increase in CMV replication and the development of CMV disease in seropositive recipients. (See 'Risk factors' above.)
●Approach to prophylaxis – We recommend universal prophylaxis against CMV with oral valganciclovir rather than pre-emptive therapy for all lung transplant recipients who are CMV seropositive or who received an organ from a seropositive donor (CMV D+/R+, D-/R+, D+/R-) (Grade 1B).
●Early posttransplantation – In the immediate posttransplant period, patients should receive intravenous ganciclovir 5 mg/kg once daily, with dose adjustment for renal insufficiency (table 1). Once the patient is absorbing oral medications or at hospital discharge, ganciclovir can be switched to oral valganciclovir 900 mg once daily, with dose adjustment for renal insufficiency. (See 'Approach to prophylaxis' above.)
●Duration of prophylaxis – Some experts favor continuing CMV prophylaxis for 12 months following transplantation in lung transplant recipients who are CMV D+/R- and for 6 to 12 months in CMV D+/R+ and D-/R+ patients. The decision of which duration to give to patients who are CMV D+/R+ or D-/R+ depends upon several factors, including the patient's risk of CMV reactivation, development of drug toxicity, and the feasibility of frequent viral load monitoring. (See 'Approach to prophylaxis' above.)
●Other indications for prophylaxis – We recommend CMV prophylaxis with oral valganciclovir for lung transplant recipients who are CMV seropositive or who received an organ from a seropositive donor (CMV D+/R+, D-/R+, D+/R-) with rejection who are receiving antilymphocyte antibodies or high doses of glucocorticoids (Grade 1B). Prophylaxis should be continued for one to three months after the antirejection therapy has been completed. (See 'Approach to prophylaxis' above.)
●Pre-emptive therapy – An alternative to CMV prophylaxis is pre-emptive therapy, in which antiviral therapy is initiated if viral replication has reached a certain assay threshold defined at each institution. However, pre-emptive therapy is not used commonly during the early posttransplant period in lung transplant recipients, given the high risk of CMV infection in such patients and the limited data about its efficacy in this population. A pre-emptive approach is more often used after the period of prophylaxis has ended. (See 'Pre-emptive therapy' above.)
●Adjunctive CMV immune globulin – Use of adjunctive cytomegalovirus immune globulin (CytoGam) is controversial. Some experts favor adding CMV immune globulin to antiviral therapy for selected high-risk patients. However, data supporting this approach are limited and it is no longer recommended by international consensus guidelines. (See 'CMV immune globulin' above.)
●CMV-negative or leukoreduced blood products – CMV seronegative (CMV D-/R-) lung transplant recipients should receive only CMV-negative or leukoreduced blood products to decrease the risk of transfusion-related CMV transmission. (See 'Blood products' above.)
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