Viral infections following lung transplantation

INTRODUCTION — A wide range of viral infections complicate lung transplantation. This topic review will focus on community respiratory viruses (eg, influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, human metapneumovirus, rhinovirus), herpes simplex virus, and varicella-zoster virus.

Cytomegalovirus infection in lung transplant recipients is covered in detail separately. Likewise, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is covered in detail separately. Bacterial, mycobacterial, and fungal infections in solid organ transplant recipients are also discussed in the following topics:

●(See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)

●(See "COVID-19: Issues related to solid organ transplantation".)

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

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

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

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

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

COMMUNITY RESPIRATORY VIRUSES

Overview — Among immunocompromised patients, community respiratory viruses (CRVs) have been best studied in hematopoietic cell transplant and lung transplant recipients. Historically, studies defining the epidemiology and clinical virology of CRVs in lung transplant recipients have been retrospective, have involved inpatients only, and have used culture-based diagnostic techniques in patients with severe respiratory symptoms. As a result, these studies may underestimate the incidence and overestimate the severity of CRVs in lung transplant recipients. A few more contemporary studies have used molecular techniques applied prospectively to all lung transplant recipients, including outpatients and asymptomatic individuals; these studies are summarized in the following table (table 1) [1-10].

Our understanding of CRVs in lung transplant recipients has improved over time. Nonetheless, there are several significant gaps in our knowledge that warrant further investigation. Additional prospective studies carried out over several years and in different geographic regions are needed to best define the epidemiology and clinical impact of CRVs in lung transplant recipients. Such studies should include both healthy outpatients and those with clinical disease and should be correlated with clinical course and pulmonary function testing. These studies would ideally use a broad array of molecular diagnostic tests to identify the widest range of viruses. In patients with documented infection, serial monitoring using quantitative molecular testing should be performed to define the natural history of the CRVs in this population. In addition, studies of available and investigational antiviral agents are needed to define the optimal antiviral regimen, dosing, and duration of therapy as well as the impact of therapy on secondary infections and on the development of acute and/or chronic rejection.

Epidemiology and risk factors — Because of the lung's exposure to the environment, inhaled viruses are of particular concern and can be divided into pathogens that primarily affect the respiratory tract (CRVs, such as influenza, respiratory syncytial virus [RSV], parainfluenza virus [PIV], adenovirus, human metapneumovirus [hMPV], rhinovirus, and coronaviruses) and pathogens that predominantly affect other tissues (eg, cytomegalovirus [CMV], varicella-zoster virus [VZV], herpes simplex virus [HSV], measles). Adenovirus can be either a primary respiratory pathogen or the lungs can be involved as part of a disseminated infection.

The incidence of disease with CRVs varies in individual patient populations, depending in part on the incidence of disease in different geographic regions. Children tend to have more CRV infections than adults. Lung transplant recipients with exposure to children, particularly in the household, are at greater risk of CRV infection. Risk factors for progression to lower respiratory tract disease or severe illness among lung transplant recipients include being a child, having received recent lymphodepletion or treatment for rejection, and having had early post-transplant infections [11,12].

The epidemiology of individual viral infections and the coronavirus disease 2019 (COVID-19) pandemic are discussed in greater detail separately. (See "Influenza: Epidemiology and pathogenesis" and "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Epidemiology' and "Parainfluenza viruses in adults", section on 'Epidemiology' and "Parainfluenza viruses in children", section on 'Epidemiology' and "Epidemiology of varicella-zoster virus infection: Chickenpox" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Epidemiology' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Epidemiology' and "COVID-19: Epidemiology, virology, and prevention", section on 'Epidemiology' and "Respiratory syncytial virus infection in adults".)

Seasonal patterns — The seasonal patterns of the individual CRVs in lung transplant recipients are similar to those seen in immunocompetent hosts:

●Outbreaks of influenza generally occur during the winter months in the northern and southern hemispheres (which occur at different times of year). In the temperate northern hemisphere, influenza predominates from November through April with variable peaks that typically occur in January or February. In tropical regions, influenza occurs throughout the year. (See "Seasonal influenza vaccination in adults".)

●RSV causes seasonal outbreaks throughout the world; the typical season of outbreak activity depends upon the geographic region. The pattern in the United States is summarized in the following figure (figure 1). (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Epidemiology'.)

●hMPV appears to cause infections with seasonal variation in different regions: late winter and early spring the United States and northern Europe, and late spring and summer in Asia. (See "Human metapneumovirus infections", section on 'Epidemiology'.)

●PIV infections occur throughout the world and throughout the year, with certain serotypes predominating during the spring or fall (figure 1). (See "Parainfluenza viruses in adults", section on 'Seasonality'.)

●Adenovirus has a worldwide distribution, and infections occur throughout the year. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Epidemiology'.)

●SARS-CoV-2 transmission dynamics are discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Epidemiology'.)

Clinical manifestations — CRVs can cause both upper and lower respiratory tract infections in lung transplant recipients. There are no pathognomonic signs or symptoms associated with a single CRV, and there is almost always cocirculation of multiple viral pathogens [13]. It is therefore impossible to determine the etiology on clinical grounds alone, and respiratory samples must be tested to make a definitive virologic diagnosis, as discussed below. (See 'Diagnosis' below.)

Signs and symptoms associated with upper respiratory tract infections caused by CRVs are often muted in lung transplant recipients because the inflammatory response is impaired by immunosuppressive therapy. Most lung transplant recipients with viral upper respiratory tract infections present with respiratory complaints or objective changes in pulmonary function test (PFT) results compared with baseline values. Rarely, isolated changes in PFTs are the only sign of infection. (See "Infection in the solid organ transplant recipient", section on 'General principles'.)

Asymptomatic infections have been recognized with certain viruses, especially rhinovirus [14-17].

Lung imaging — In patients with pneumonia caused by a CRV, high-resolution chest computed tomography (CT) may reveal interstitial infiltrates, ground-glass opacities, nodules (image 1), tree-in-bud opacities, and/or airspace consolidations (image 2 and image 3), which may be indistinguishable from findings noted with other viral and nonviral pathogens [18].

High-resolution CT of the lungs is discussed in greater detail separately. (See "High resolution computed tomography of the lungs".)

Potential complications

Secondary infections — Lung transplant recipients are at increased risk of secondary infectious complications of CRV infections, such as bacterial and fungal pneumonias [11,19]. In a retrospective review of 132 lung transplant recipients at a single center, 15 percent developed an invasive fungal infection (mostly invasive aspergillosis) [20]. Secondary invasive fungal infections were associated with chronic lung allograft dysfunction (CLAD) progression and death. CRVs may cause local mucosal defects and changes in cell surface peptides, which in turn may predispose to colonization and local invasion of colonizing fungi and bacteria.

Rejection — Transplanted lungs are susceptible to several different types of rejection. These include acute cellular rejection, humoral rejection, and CLAD. There are two types of CLAD, bronchiolitis obliterans syndrome and restrictive allograft syndrome. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Definition'.)

CRVs, particularly when associated with lower respiratory tract involvement, may be associated with rejection, the most common type of which is CLAD, previously referred to as bronchiolitis obliterans syndrome [8,12,21-34]. While the link between CRVs and CLAD is strong, the link between CRVs and acute rejection is less clear; most later studies have not demonstrated a correlation. Lymphocytic infiltrates are the expected response to viral infections and likely the reason that rejection has been diagnosed in some patients with CRV infection.

CLAD has been associated with several CRVs, particularly when the virus involves the lower respiratory tract [1,21-28,31,33,34]. Lower respiratory tract CRV infection causes local mucosal damage, exposing the host to alloantigen. There is at least one animal model that has demonstrated a correlation between lower respiratory tract infection with Sendai virus, a virus related to PIV, and CLAD [35]. Viruses that more commonly replicate in the lower respiratory tract, including hMPV, influenza, PIV, and RSV are more strongly linked with development of CLAD. A study found an association between CLAD and coronavirus infections, although this finding needs confirmation by other groups [36].

In a retrospective study that included 250 lung transplant recipients, 50 (20 percent) were diagnosed with CLAD and 79 (32 percent) had 114 episodes of CRV infection; most CRV infections were lower respiratory tract infections (85 percent) [31]. On multivariate analysis, rejection (adjusted hazard ratio [aHR] 2.2, 95% CI 1.2-3.9) and CRV infection (aHR 1.9, 95% CI 1.1-3.5) were independently associated with CLAD. The association of CRV infection with CLAD was stronger the more proximate the CRV infection (aHRs 4.8, 3.4, and 2.4 for 3 months, 6 months, and 9 months following CRV infection, respectively).

In a separate study of 139 lung transplant recipients that prospectively monitored CRV infections, the risk of CLAD was increased among those with CRV pneumonia (HR 3.94, 95% CI 1.97-7.90) but not symptomatic CRV infection or asymptomatic CRV infection [32]. The risk of graft loss was not increased by asymptomatic or symptomatic CRV infection.

A systematic review of observational studies, which included 1060 of CLAD, reported low 30-day mortality (0 to 3 percent) in lung transplant recipients with RSV, hMPV, and PIV infection. However, the incidence of CLAD was 19 to 24 percent 180 to 365 days after infection with these viruses [37].

The association between CRVs and acute rejection has not been established, with studies showing conflicting results [38]. One reason that it has been difficult to evaluate this potential association is that the cellular infiltrates observed in patients with CRVs may represent the host's appropriate response to the viral infection rather than rejection [39]. Several prospective studies have failed to find an association between CRV infection and acute rejection [17,39,40]. On the other hand, one study reported a 33 percent acute rejection rate in patients who had had a CRV infection within the past three months compared with 7 percent of those who did not have a recent CRV infection [8]. A limitation of this study is that the patients considered to have acute rejection included not only those with grade ≥2 biopsy-proven acute rejection but also those with a ≥20 percent decline in forced expiratory volume in 1 second (FEV₁), which could be caused by conditions other than acute rejection. No significant difference was seen in the incidence of acute rejection between symptomatic and asymptomatic patients.

Cytomegalovirus has also been associated with CLAD. This is discussed in greater detail separately. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Indirect effects'.)

Other viruses, such as human herpes virus 6 and Epstein-Barr virus, have been associated with an increased risk of bronchiolitis obliterans syndrome in some but not all studies [41-43].

Rejection in lung transplant recipients is discussed in detail separately. (See "Evaluation and treatment of acute cellular lung transplant rejection" and "Evaluation and treatment of antibody-mediated lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Diagnosis

Approach to diagnosis — CRVs should be tested for in any lung transplant recipient presenting with fever, respiratory symptoms, or changes in pulmonary function testing results. In lung transplant recipients with mild to moderate respiratory illness, we start by obtaining nasopharyngeal samples (swabs or washings) for CRV testing. Available tests and techniques vary by institution. Some institutions use individual tests for each CRV, whereas others use a multiplex polymerase chain reaction (PCR) to test for a panel of CRVs. The multiplex PCRs frequently include rhinovirus and coronaviruses, which are less clinically significant and may be shed for long periods of time after clinical recovery from infection. Further, these assays detect common coronaviruses associated with the common cold but not the rare, more lethal SARS, Middle East respiratory syndrome (MERS); most assays do detect SARS-CoV-2 and COVID-19 (see "Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis" and "COVID-19: Clinical features" and "COVID-19: Diagnosis"). We typically test for COVID-19, influenza, PIV, RSV, adenovirus, and hMPV in lung transplant recipients presenting with a respiratory illness. We have a low threshold for repeating testing for certain CRVs (eg, influenza) if initial testing is negative but the virus is known to be circulating locally; this is particularly important if effective antiviral therapy is available. Likewise, if molecular testing is only performed for SARS-CoV-2, repeating testing for a wider range of viruses should be performed as cocirculation of multiple viruses does occur.

In patients who have evidence of pneumonia and who are severely ill and in whom the diagnosis has not been made by less invasive techniques, we generally favor bronchoscopy with bronchoalveolar lavage (BAL). Up to 20 percent of patients with pneumonia or lower tract disease may not have virus detected in upper airway samples. The following table lists various tests that can be performed on BAL fluid (table 2). The decision of which studies to perform depends upon the individual patient's epidemiologic exposures and clinical findings and on availability at specific hospital laboratories. When the diagnosis is not established by studies of BAL fluid or noninvasive testing, histopathology of lung tissue can be helpful.

The diagnosis of specific CRVs and community-acquired pneumonia is discussed in greater detail separately. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Diagnosis' and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Diagnosis' and "Human metapneumovirus infections", section on 'Diagnosis' and "Parainfluenza viruses in adults", section on 'Diagnosis' and "Parainfluenza viruses in children", section on 'Diagnosis' and "COVID-19: Clinical features" and "COVID-19: Diagnosis", section on 'Diagnostic approach' and "COVID-19: Diagnosis" and "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

The approach to the immunocompromised patient with fever and pulmonary infiltrates is also presented elsewhere. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Diagnostic tests — Given how nonspecific the clinical findings of CRVs are, it is useful to test for a wide range of viruses. Molecular diagnostic techniques (eg, PCR) are preferred. Nearly every study in immunocompromised patients, including those focusing on lung transplant recipients, has demonstrated that PCR provides greater yield and sensitivity than culture or direct florescent antibody (DFA) [2,5,6,12,21,44,45]. Similarly, several PCR methods are quantitative or semiquantitative, which allows for serial monitoring of the clinical course and response to therapy.

Although rapid antigen detection systems have been developed for influenza, RSV, and adenovirus, their sensitivity is limited, particularly in immunocompromised adults [11,46]. SARS-CoV-2 rapid antigen testing is also available but has improved sensitivity. Nonetheless, negative rapid antigen results should therefore never be used to rule out the presence of disease. If rapid antigen testing is used, positive results should guide therapy, whereas negative results should mandate additional testing.

Culture is insensitive for some viruses (eg, PIV, rhinovirus, hMPV infections), and there are limited reagents to allow routine DFA testing for other viruses (eg, rhinovirus, coronavirus).

Some transplant centers routinely test for CRVs whenever a bronchoscopy is performed. However, the relevance of respiratory viruses detected from asymptomatic lung transplant recipients remains to be defined, particularly rhinovirus and seasonal coronaviruses.

Specimen type — The optimal specimens for CRV testing are nasopharyngeal aspirates, washings, and swabs. Nasopharyngeal washings are generally more sensitive than nasopharyngeal swabs for the detection of CRVs [47], but nasopharyngeal swabs are easier to obtain. In hospitalized patients with suspected CRV infection, specimens can be collected from different respiratory sites and on more than one day to increase the likelihood of detection [48]. In particular, in mechanically ventilated patients, upper (nasopharyngeal aspirates, washings, and/or swabs) and lower (BAL fluid, endotracheal aspirates and/or washes) respiratory tract samples should be obtained if CRV infection is suspected but not yet confirmed [49].

A video reviews the proper technique for nasopharyngeal swab collection.

The optimal specimen type has been best studied for influenza infection. This is discussed in greater detail separately. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Differential diagnosis — Both the clinical and radiographic findings associated with CRVs are nonspecific. In lung transplant recipients presenting with signs and symptoms that are suggestive of a CRV infection (eg, fever, cough, shortness of breath, reduced pulmonary function testing results), a variety of viral and nonviral causes should be considered:

●Viral causes include the CRVs (influenza, RSV, PIV, hMPV) and other viruses (adenovirus, CMV, VZV, HSV, SARS-CoV-2). (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in children: Clinical features and diagnosis" and "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children" and "Parainfluenza viruses in adults" and "Parainfluenza viruses in children" and "Human metapneumovirus infections" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Clinical features of varicella-zoster virus infection: Chickenpox", section on 'Pneumonia' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Respiratory tract infections' and "COVID-19: Clinical features" and "COVID-19: Diagnosis".)

●Clinicians should have a high index of suspicion for CMV in patients who have recently discontinued CMV prophylaxis or who have recently been treated for rejection. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)

●Other infections (bacterial, mycobacterial, fungal, parasitic) also cause pneumonia that can sometimes be difficult to distinguish from viral causes but often have distinguishing radiographic features:

•Lobar consolidation is suggestive of bacterial (eg, pneumococcal) pneumonia. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

•Atypical bacterial causes (eg, Mycoplasma pneumoniae, Chlamydia pneumoniae) may have a radiographic appearance that is similar to the appearance of viral pneumonia. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Mycoplasma pneumoniae infection in adults" and "Mycoplasma pneumoniae infection in children" and "Pneumonia caused by Chlamydia pneumoniae in adults" and "Pneumonia caused by Chlamydia pneumoniae in children" and "Clinical manifestations and diagnosis of Legionella infection".)

•Nontuberculous mycobacteria can cause a range of lung imaging findings, including nodular or cavitary opacities and multiple small tree-in-bud opacities. (See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Overview of nontuberculous mycobacterial infections".)

•Tuberculosis in lung transplant recipients can cause focal infiltrates, a miliary pattern, nodules, pleural effusions, diffuse interstitial infiltrates, and cavities. (See "Tuberculosis in solid organ transplant candidates and recipients", section on 'Radiographic findings'.)

•Fungal pathogens (eg, Aspergillus spp) typically cause nodules with surrounding ground-glass opacities. (See "Fungal infections following lung transplantation", section on 'Pulmonary aspergillosis' and "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Imaging'.)

●Acute or chronic rejection can cause similar signs and symptoms as CRVs. The diagnosis of rejection is established by lung biopsy. (See 'Rejection' above and "Evaluation and treatment of acute cellular lung transplant rejection" and "Evaluation and treatment of antibody-mediated lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Pulmonary infections in immunocompromised patients are discussed in greater detail separately. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Viral shedding — Prolonged shedding is typical of CRVs in lung transplant recipients [30]. This has been best demonstrated with rhinovirus, in which shedding has been documented for months [21]. Patients with prolonged shedding may benefit from longer durations of therapy, as discussed below. (See 'Therapy' below.)

Studies that evaluate the kinetics of viral shedding using quantitative assays are needed for most CRVs to elucidate the natural history of treated and untreated infection in lung transplant recipients.

Management — The management of CRVs varies with the specific virus causing the infection [50]. Effective antiviral agents are available for certain CRVs (eg, influenza) but not for others. Among the CRVs, a vaccine is available only for influenza virus.

An overview of the approach to management in lung transplant recipients is provided here. Management for each virus is discussed in greater detail in the disease-specific topic reviews.

Influenza

Therapy — Since ongoing replication of influenza virus may be correlated with secondary infections and rejection, antiviral therapy should be given to all lung transplant recipients with influenza virus infection, irrespective of the severity of infection or the interval between onset of symptoms and diagnosis [30,51]. If influenza is strongly suspected, antiviral therapy should be started while awaiting test results [30].

The usual treatment is a neuraminidase inhibitor (eg, oseltamivir), but, because of the potential for resistance in circulating strains of influenza, the appropriate antiviral agent should be guided by the recommendations of local and national health agencies (table 3) [52]. Baloxavir, a new influenza antiviral agent, has been approved for influenza treatment in healthy adults in the United States [53]. However, we do not use this agent for influenza treatment in immunocompromised patients, including lung transplant recipients, because it has not been studied in this population and because resistance can emerge during therapy [54]. (See "Seasonal influenza in nonpregnant adults: Treatment".)

We continue antiviral therapy in lung transplant recipients with influenza until shedding is no longer detected by real-time reverse-transcriptase PCR; this will typically require more than the five days of therapy recommended for immunocompetent individuals [30]. We typically start with 10 days of therapy and extend therapy if the patient remains PCR positive within a day of the planned stop date. The optimal duration of therapy has not been prospectively studied. If the patient continues with prolonged symptoms and signs with shedding or has clinical deterioration with ongoing replication, antiviral drug resistance should be considered. When there is clinical concern for resistance, appropriate testing should be performed and alternative therapy considered. (See "Antiviral drugs for influenza: Pharmacology and resistance".)

The best evidence for the efficacy of antiviral therapy for influenza comes from randomized trials and meta-analyses of immunocompetent patients. In otherwise healthy immunocompetent adults and children, there is little benefit to the use of antivirals greater than 48 hours after symptom onset; this may not be the case with lung transplant recipients. Some studies have suggested that antiviral therapy reduces the severity and incidence of complications of influenza, the duration of hospitalization in patients with severe influenza, and influenza-associated mortality. (See "Seasonal influenza in nonpregnant adults: Treatment".)

There have been few prospective studies of the optimal timing, dose, or duration of antivirals in lung transplant recipients with influenza infection [10,55-57]:

●In one prospective study, 228 immunocompromised patients (including transplant recipients) were randomized to receive standard-dose or double-dose oseltamivir [57]. Adverse event rates were lower (50.5 versus 59.1 percent) in patients receiving standard-dose therapy, but most of the difference was attributable to an increased rate of headaches. Resistant variants emerged on therapy more commonly with conventional-dose than double-dose therapy (12 versus 3 percent patients) and duration of shedding was shorter with double-dose therapy.

●In a retrospective study of antiviral therapy in 237 solid organ transplant patients infected with 2009 pandemic influenza A/H1N1, 33 (14 percent) were lung transplant recipients [55]. Antiviral therapy (primarily oseltamivir monotherapy) was associated with improved outcomes, particularly if it was started early. Seven patients (8 percent) given antiviral drugs within 48 hours of symptom onset were admitted to an intensive care unit (ICU) compared with 28 (22 percent) given antivirals later.

●In a retrospective study of antiviral therapy in 616 solid organ transplant patients over a five-year period, including 116 transplant recipients, antiviral therapy (primarily oseltamivir monotherapy) was associated with improved outcomes, particularly when it was started early [58]. Influenza vaccination within the same influenza season was associated with reduced disease severity, pneumonia, and ICU admission.

●In a retrospective study of nine lung transplant recipients, oseltamivir was associated with clinical and radiographic response and a reduced risk of bronchiolitis obliterans syndrome compared with historical controls [56]. Of note, most of the patients were previously vaccinated against influenza, and most had symptoms for ≥48 hours prior to starting antiviral therapy. Oseltamivir was generally well-tolerated and treatment interruptions were not reported.

●In another series that included 10 lung transplant recipients with influenza, all patients tolerated oseltamivir and most did well despite prolonged shedding [10].

Several experimental antiviral agents are under investigation for influenza infection. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Investigational approaches'.)

Immunocompromised patients, including lung transplant recipients, are at greater risk for developing infection with drug-resistant influenza. Antiviral resistance should be suspected in patients who fail to improve clinically and have evidence of ongoing viral replication after 5 to 10 days of treatment (eg, patients with persistently reverse-transcriptase PCR). When resistance is suspected, resistance testing should be performed and antiviral therapy with two agents can be considered while awaiting results. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Antiviral resistance' and "Seasonal influenza in nonpregnant adults: Treatment", section on 'Patients with persistent symptoms'.)

In addition, patients who fail to improve often have other causes or complications (eg, bacterial or fungal superinfection, rejection, acute respiratory distress syndrome), which should be evaluated.

The treatment of influenza infection is discussed in greater detail separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Prevention — Prevention of influenza depends on vaccination and, in some cases, on the use of antiviral prophylaxis.

Vaccination — Annual influenza vaccination is recommended for all lung transplant recipients (after the early post-transplant period) and their close contacts [30,59]. It is common to wait three to six months after transplantation before giving vaccines, once maintenance immunosuppression levels have been attained [60]. An exception is that during influenza outbreaks, it is reasonable to give the inactivated influenza vaccine as early as one month following transplantation [61]. It is strongly recommended that all close contacts of lung transplant recipients be vaccinated against influenza annually to provide a protective ring around the patient.

In lung transplant recipients, inactivated influenza vaccination has been shown to be safe without associated risk of rejection [62-65]; the live-attenuated intranasal vaccine is contraindicated in transplant patients because of the risk of infection by the vaccine strain. Although influenza vaccines are less immunogenic in lung transplant recipients when compared with immunocompetent individuals, they still appear to be effective [66,67]. The high-dose vaccine may augment immune response and does not appear to be associated with increased rates of rejection, though data are limited [58,68,69]. (See "Immunizations in solid organ transplant candidates and recipients", section on 'Influenza'.)

Despite its safety and efficacy, influenza vaccination rates among lung transplant recipients and their close contacts remain poor. Interventions, such as letters sent to transplant recipients specifically recommending vaccination for both the recipient and his or her close contacts, should be considered to increase the uptake of vaccination in these patients.

Seasonal influenza vaccination is discussed in greater detail separately. (See "Seasonal influenza vaccination in adults" and "Immunizations in solid organ transplant candidates and recipients", section on 'Influenza'.)

Antiviral prophylaxis — We generally do not give pre-exposure prophylaxis to lung transplant recipients who are unlikely to have immunity out of concern that prolonged use of an antiviral agent could increase the risk of resistance. However, in the setting of significant influenza activity, we are most likely to give pre-exposure prophylaxis to those who underwent transplantation within the past month. The American Society of Transplantation states that, for lung transplant recipients in whom influenza vaccination is contraindicated or for those who are likely to have an inadequate response to the vaccine (eg, those receiving therapy for acute rejection or who underwent transplantation recently), pre-exposure antiviral prophylaxis for 12 weeks starting at the beginning of influenza season may be proposed (table 3) [30].

In patients who meet criteria for pre-exposure prophylaxis described above but who are not receiving it and who have been exposed to a patient with influenza within the past 48 hours, the United States Advisory Committee on Immunization Practices recommends giving postexposure prophylaxis [51]. However, we prefer to either give such patients treatment dosing for five days or to closely observe such patients for signs and symptoms of infection and initiate treatment if they develop. We are most likely to offer treatment to exposed patients who underwent transplant within the past month. Our rationale for avoiding postexposure prophylaxis in most patients is that it might lead to the development of resistance. Postexposure prophylaxis and the development of antiviral resistance are discussed in detail separately. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention", section on 'Postexposure antiviral prophylaxis' and "Antiviral drugs for influenza: Pharmacology and resistance".)

In a randomized trial, oseltamivir or placebo was given for 12 weeks during periods of local influenza circulation to kidney, liver, and hematopoietic cell transplant recipients [70]. Oseltamivir was well tolerated and was associated with a significant reduction in PCR-proven influenza infections compared with placebo (1.7 versus 8.4 percent). Although lung transplant recipients were not included in the trial, the results are likely to apply to this group.

Studies of neuraminidase inhibitors in immunocompetent patients have demonstrated protective efficacy when used for short-term prophylaxis. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

SARS-CoV-2 — The management of SARS-CoV-2 in lung transplant patients is generally similar to other patients with a few notable exceptions:

●The threshold to use approved and investigational therapies is lower but practice varies among transplant centers. Consideration of drug interactions and renal function should inform selection of agents. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)

●The efficacy of vaccination is considerably lower. For messenger ribonucleic acid (mRNA) vaccines, additional doses are recommended as part of the primary series as well as booster dosing. (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

Respiratory syncytial virus — RSV is a major cause of CRV infection in lung transplant recipients, particularly children [71]. Risk factors for severe RSV disease include age less than one year, acquisition of RSV infection during the early post-transplant period, and recent exposure to augmented immunosuppression [72].

Despite limited data, some centers give symptomatic patients with documented RSV pneumonia ribavirin, which has in vitro activity against RSV. Oral ribavirin is most frequently used because of ease of use and lower cost compared with aerosolized ribavirin [73-78]. The author of this topic review agrees with this approach. However, it should be noted that some experts give supportive care only rather than antiviral therapy given the lack of clear evidence of benefit of antiviral therapy and the potential toxicity of ribavirin (most notably anemia). Oral ribavirin is typically dosed at 600 to 800 mg twice daily. Despite broad use of oral ribavirin in lung transplant recipients, clinical studies demonstrate drug levels in the lung during therapy are generally lower (8.3 mcg/mL) than when aerosolized (249 to 1379 mcg/mL); levels with oral therapy are well below the IC50 of ribavirin for RSV (17 to 30 mcg/mL) [79]. Duration is usually seven days or until clear improvement in symptoms.

There are limited observational data on the role of antiviral therapy in the management of RSV infection in lung transplant recipients. Traditionally, aerosolized ribavirin was advocated for the treatment of RSV infections, particularly pneumonia, but it is not clear that its use leads to improved outcomes [71,80-85]. Major drawbacks of aerosolized ribavirin include extremely high cost, intolerance, bronchospasm, and risk to the caretakers exposed to the therapy (because it is a teratogen) [77].

It is not clear whether glucocorticoids are beneficial for the management of RSV, but they are frequently used in combination with ribavirin by transplant clinicians because it is difficult to distinguish infection from rejection on biopsy and both may coexist. One study of five RSV-infected lung transplant recipients treated with glucocorticoids and oral ribavirin (15 to 20 mg/kg in three divided doses for a total of 10 days) concluded that the intervention was well-tolerated and less costly than aerosolized ribavirin [77]. No patients died.

There has also been interest in intravenous (IV) ribavirin. However, it is not available. In one study, IV ribavirin plus oral prednisolone were given to 18 RSV-infected lung transplant recipients until repeat nasopharyngeal and throat swabs were negative for RSV on indirect fluorescent antibody testing in one retrospective study [86]. No patients died and all had a return to near baseline pulmonary function testing. Treatment was continued for a median of eight days and was well-tolerated except for mild hemolytic anemia in several patients.

There are some data suggesting improved outcomes for the treatment of RSV with aerosolized or oral ribavirin plus antibody-based therapy in hematopoietic cell transplant recipients [87]. However, there is insufficient evidence in lung transplant recipients to support the routine use of intravenous immunoglobulin (IVIG), high RSV titer IVIG, or the monoclonal antibodies (eg, palivizumab). Such therapy may be considered in lung transplant recipients with severe pneumonia. However, because of the prohibitive cost of palivizumab in adults, when antibody therapy is desired, adults are typically treated with commercially available IVIG or by using the investigational high RSV titer IVIG product, RI-001 [88].

Several antivirals, including a novel small interfering RNA preparation, ALN-RSV01, and presatovir, a fusion inhibitor, have been studied for RSV but are no longer in clinical development [89-91]. Other agents are actively undergoing investigation, mostly in populations other than lung transplant patients.  

Prevention of RSV is evolving with the availability of novel monoclonal antibodies and vaccines.

●Two vaccines against RSV have been approved for use in adults ≥60 years old by the US Food and Drug Administration (FDA) [92-94]. While the studies that support the FDA approval did not include lung transplant recipients, we expect the benefit of vaccination to extend to transplant recipients and recommend their use in lung transplant recipients ≥60 years of age. Further efficacy data are needed to support use in younger transplant recipients. (See "Overview of preventive care in adults", section on 'Immunization'.)

●Nirsevimab (a human recombinant monoclonal antibody that is active against RSV) has been studied for the prevention of RSV in infants [95]. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis'.)

Studies in immunocompromised infants are ongoing and studies in other immunocompromised populations are planned.

Parainfluenza virus — There are no antiviral agents that have been proven in prospective studies to be effective for treating PIV infections. The mainstay of therapy for PIV infection in immunocompromised hosts is reduction of immunosuppression, particularly reduction in the dose of glucocorticoids, when possible [11]. We do not use ribavirin or IVIG for the treatment of PIV pneumonia given the lack of proven benefit.

Ribavirin has been used in a few isolated cases of severe PIV infection in lung transplant recipients with reportedly successful outcomes [71,81]. The possible benefit of IVIG has not been proven in humans [96]. DAS181, an investigational sialidase fusion inhibitor, has been studied in hematopoietic cell transplant patients, and the results of this trial are pending.

The treatment of PIV infections is discussed in greater detail separately. (See "Parainfluenza viruses in adults" and "Parainfluenza viruses in children", section on 'Treatment'.)

There are no proven strategies other than infection control to prevent PIV in lung transplant patients. Hospitalized patients with PIV infection should be placed on standard and contact precautions and should have a private room whenever possible [97]. Respiratory precautions are not necessary because the droplets are large and do not aerosolize. (See "Infection prevention: Precautions for preventing transmission of infection".)

Adenovirus — Adenovirus can cause pneumonia in lung transplant recipients [98]. As noted above, adenovirus can be either a primary respiratory pathogen or the lungs can be involved as part of a disseminated infection.

Cidofovir has been the antiviral agent most frequently used to treat adenovirus infections, but severe nephrotoxicity is a major dose-limiting toxicity. Cidofovir can also cause a Fanconi-type syndrome, with proteinuria, glucosuria, and bicarbonate wasting. Brincidofovir, a lipid ester of cidofovir, was studied for adenovirus [99]. Although the drug has been approved for the treatment of human smallpox, the label states that it cannot be used for other indications and is not available by compassion use [99,100]. An infectious diseases specialist should be consulted when treatment is being considered.

For lung transplant recipients with severe adenovirus pneumonia or disseminated disease, we generally give cidofovir. However, the decision of whether to give cidofovir should be made on a case-by-case basis, carefully weighing the potential risks and benefits. If cidofovir is given, it is usually dosed 5 mg/kg IV once together with probenecid and aggressive hydration. Renal function, urine protein, and electrolytes must be monitored closely. After the initial dose, repeated doses can be given at weekly intervals if the patient has not experienced significant toxicity and if it is deemed to be clinically necessary. There is experience with the use of 1 mg/kg three times a week in pediatric lung transplant patients where efficacy appears similar to higher dose but is associated with less renal toxicity; dosing with probenecid is also required with this approach [101]. Specific recommendations regarding the use of probenecid and hydration in patients receiving cidofovir are presented separately. The management of adenovirus infection is also discussed in greater detail separately. (See "Cidofovir: An overview", section on 'Toxicity' and "Diagnosis, treatment, and prevention of adenovirus infection".)

When using antivirals, the patient should be monitored with weekly quantitative viral load assessment of blood (if viremic) and respiratory specimens to guide decisions about the duration of therapy.

Human metapneumovirus — We do not recommend antiviral therapy for the treatment of hMPV infections, as no studies have prospectively studied therapeutic interventions for hMPV in lung transplant recipients. Ribavirin has been used in a few cases of severe hMPV infection in lung transplant patients with successful outcomes reported [102,103]. (See "Human metapneumovirus infections".)

There are no antiviral agents that have been proven effective for the prevention of hMPV infections.

Other community respiratory viruses — Data on other respiratory viruses in lung transplant recipients are limited [9,21,104-107]. Therapeutic interventions are either unproven or lacking. The respiratory polyomaviruses WU and KI have been associated with lower airway disease and symptoms in lung transplant recipients in some reports; confirmation of these findings may elucidate the clinical importance of this group of pathogens [9,104,108]. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections", section on 'Classification'.)

The role of rhinoviruses in lung transplant recipients has not been well studied, but it is likely that they can cause pneumonia in such patients. Prolonged shedding, even in the absence of symptoms, has been documented with rhinovirus infection [21]. The clinical significance of prolonged shedding warrants further study. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Rhinovirus'.)

Coronaviruses have been documented in both upper and lower tract specimens and are typically the second or third most commonly detected viruses in lung transplant patients [17,36,109]. While most studies suggest that infected patients are symptomatic, only one study has associated coronavirus with chronic rejection (CLAD). SARS, MERS, and SARS-CoV-2 generally result in severe in transplant recipients, particularly lung transplant recipients [110-112]. When the lung transplant is performed for COVID-19-associated lung injury (ARDS or fibrosis), recipients have longer hospital stays, higher risk of early infections, but have similar one-year patient survival (COVID, 86.6 versus non-COVID, 86.3 percent). Post-transplant, COVID-19-associated deaths were 9.2 percent of all deaths among lung transplant recipients, highlighting ongoing risk of infection despite severe infection prior transplantation [113]. (See "COVID-19: Issues related to solid organ transplantation" and "Middle East respiratory syndrome coronavirus: Treatment and prevention".)

Organ donation — There are few prospective studies of donor-derived infections and, as a result, the true incidence of donor-derived respiratory virus transmission is unknown [114]. Nonetheless, lung transplantation presents a unique risk for transmitting respiratory viruses of donor origin, since the lungs are constantly exposed to the environment. At least two confirmed cases of transmission of influenza of donor origin have been reported [115,116]. Because of the risk of transmission, guidelines recommend against the use of donors with recognized influenza infection for lung transplantation [117]. Donors with documented current pneumonia secondary to other CRVs should generally also be excluded from lung donation. Transmission of SARS-CoV-2 through lung transplantation has been documented and testing of the lower airway by PCR is required by Organ Procurement and Transplantation Network policy in the United States [118,119]. Similarly, lung transplantation should generally be delayed in candidates with a documented CRV until they have cleared the virus.

HERPES VIRUSES — The herpesviruses (eg, cytomegalovirus [CMV], herpes simplex virus [HSV], varicella-zoster virus [VZV]) are important causes of infection in lung transplant recipients because they commonly reactivate in the setting of immunosuppression when prophylaxis is not used. However, herpesvirus prophylaxis is effective at preventing these infections. Few studies of herpes viruses other than CMV have focused on lung transplant recipients. Treatment and prophylaxis recommendations are derived mostly from data in other transplant populations.

Cytomegalovirus — CMV, a member of the betaherpesvirus group, is an important cause of morbidity and mortality in lung transplant recipients. 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. Oral valganciclovir is used to prevent CMV reactivation in lung transplant recipients who are at risk. The prevention and treatment of CMV in lung transplant recipients are discussed in detail separately. (See "Prevention of cytomegalovirus infection in lung transplant recipients" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Treatment'.)

Herpes simplex virus — Prevalence rates of HSV-1 and -2 in adults in the United States are 80 and 26 percent, respectively [120,121]. HSV-seropositive lung transplant recipients are at risk for post-transplant reactivation. Although the classic findings of vesicular lesions in the oral or genital regions occur frequently, atypical presentations may occur, so suspicious lesions should be tested for the presence of HSV by direct florescent antibody testing, culture, or polymerase chain reaction [122]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)

Prophylaxis — Prophylaxis for CMV will effectively prevent most cases of HSV reactivation. (See 'Cytomegalovirus' above.)

We give HSV prophylaxis to all lung transplant recipients who are not receiving CMV prophylaxis (ie, patients who are seronegative for CMV and received an allograft from a CMV-seronegative donor) or who are receiving letermovir for CMV prophylaxis. Appropriate regimens for HSV prophylaxis in patients with normal renal function include acyclovir 400 or 800 mg orally twice daily, valacyclovir 500 mg orally twice daily, or famciclovir 500 mg orally twice daily (table 4) [122]. We continue prophylaxis for three to six months following transplantation as well as during periods of lymphodepletion for the treatment of rejection.

The evidence to support prophylaxis to prevent the reactivation of HSV comes from trials and a meta-analysis in solid organ transplant recipients [123-125], a trial and a cohort study in hematopoietic cell transplant recipients [126,127], and a trial in human immunodeficiency virus (HIV)-infected patients [128].

Treatment — For patients with mucocutaneous HSV and normal renal function, acyclovir 400 mg three times daily, valacyclovir 1 g orally twice daily, or famciclovir 500 mg orally twice daily should be initiated promptly and continued until all lesions are fully healed [122]. For severe or visceral disease, intravenous acyclovir should be used [122].

Varicella-zoster virus — Over 90 percent of adults have had chickenpox or have been vaccinated [129]. VZV reactivation occurs in approximately 8 to 11 percent of solid transplant recipients during the first four years following transplantation [122].

Pre-exposure prophylaxis — CMV prophylaxis with valganciclovir or ganciclovir will effectively prevent most cases of VZV reactivation. (See 'Cytomegalovirus' above.)

We give VZV prophylaxis to all lung transplant recipients who are not receiving CMV prophylaxis (ie, patients who are seronegative for CMV and received an allograft from a CMV-seronegative donor) or who are receiving letermovir prophylaxis for CMV. Appropriate regimens are the same as those used for HSV prophylaxis (acyclovir, valacyclovir, or famciclovir) (table 4). Prophylaxis is typically continued for three to six months as well as during periods of lymphodepletion for the treatment of rejection. (See 'Prophylaxis' above.)

The evidence to support prophylaxis to prevent the reactivation of VZV comes from a trial and meta-analysis in solid organ transplant recipients [123,125] and a trial in hematopoietic cell transplant recipients [126].

Postexposure prophylaxis — If nonimmune transplant recipients are exposed to a patient with documented primary VZV, immunoprophylaxis with VZV-specific immune globulin if available or intravenous immunoglobulin if VZV-specific immune globulin is not available should be given; addition of pre-emptive antiviral therapy can also be considered [122]. Detailed recommendations are provided separately. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)

In adult immunocompetent transplant candidates who are seronegative for VZV, two doses of varicella vaccine should be given four to eight weeks apart; because the vaccine is a live-virus vaccine, patients should not undergo transplantation for at least two weeks, but preferably four weeks, after receipt of the vaccine [122,129]. Some experts recommend waiting at least four weeks after receipt of live vaccines before proceeding to transplantation [61].

Treatment — Patients with primary VZV infection (chickenpox), multidermatomal zoster, and zoster affecting the trigeminal or geniculate ganglion should be treated with intravenous acyclovir. Patients with localized dermatomal zoster can be treated orally with valacyclovir or famciclovir as long as close follow-up is assured. Patients with progressive or new lesions despite two to three days of oral therapy should be admitted for intravenous acyclovir therapy. (See "Treatment of varicella (chickenpox) infection" and "Treatment of herpes zoster", section on 'Immunocompromised patients'.)

Infection control — All hospitalized patients with primary VZV or herpes zoster should be placed on airborne and contact precautions; this should be continued until all lesions are crusted, which can be delayed in immunocompromised hosts [122]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Airborne precautions' and "Prevention and control of varicella-zoster virus in hospitals".)

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: Infections in solid organ transplant recipients".)

SUMMARY AND RECOMMENDATIONS

●Range of viral infections – A wide range of viral infections complicate lung transplantation. Important viruses in lung transplant recipients include the community respiratory viruses (CRVs; eg, influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, human metapneumovirus, rhinovirus), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). CMV infection in lung transplant recipients and SARS-CoV-2 infection is covered in detail separately. (See 'Introduction' above and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Prevention of cytomegalovirus infection in lung transplant recipients".)

●Respiratory tract infection and disseminated disease – Because of the lung's exposure to the environment, inhaled viruses are of concern and can be divided into pathogens that primarily affect the respiratory tract (CRVs, such as influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus, and rhinovirus) and those that predominantly affect other tissues (eg, CMV, VZV, HSV, measles); adenovirus can be either a primary respiratory pathogen or the lungs may be involved as part of a disseminated infection. (See 'Epidemiology and risk factors' above.)

●Seasonal pattern for CRVs – The seasonal patterns of the individual CRVs in lung transplant recipients are similar to those seen in immunocompetent hosts. As an example, outbreaks of influenza generally occur during the winter months in the northern and southern hemispheres (which occur at different times of the year). In the temperate northern hemisphere, influenza predominates from November through April and typically peaks in February. In tropical regions, influenza occurs throughout the year. (See 'Seasonal patterns' above.)

●CRV symptoms are nonspecific – CRVs can cause both upper and lower respiratory tract infections in lung transplant recipients. There are no pathognomonic signs or symptoms associated with a single CRV, and there is almost always cocirculation of multiple viral pathogens. It is therefore impossible to make a virologic diagnosis clinically, and respiratory samples must be tested to make a definitive virologic diagnosis. (See 'Clinical manifestations' above.)

●CRV association with rejection – CRVs, particularly when associated with lower respiratory tract involvement, may be associated with rejection, particularly chronic lung allograft dysfunction. The association between CRVs and acute rejection has not been established, with studies showing conflicting results. (See 'Rejection' above.)

●Testing required for CRV diagnosis – CRVs should be considered and tested for in any lung transplant recipient presenting with fever and respiratory symptoms and/or changes in pulmonary function testing results. In lung transplant recipients with mild to moderate respiratory illness, we start by obtaining nasopharyngeal samples (swabs or washings) for CRVs. We favor molecular diagnostic techniques (eg, the polymerase chain reaction) and typically test for SARS-CoV-2, influenza, parainfluenza virus, RSV, adenovirus, and human metapneumovirus. We have a low threshold for repeating testing for certain CRVs (eg, influenza) if initial testing is negative but the virus is known to be circulating locally; this is particularly important if effective antiviral therapy is available. (See 'Approach to diagnosis' above and 'Diagnostic tests' above.)

●Role of bronchoscopy – In patients who have evidence of pneumonia and who are severely ill and in whom the diagnosis has not been made by less invasive techniques, we generally favor bronchoscopy with bronchoalveolar lavage (BAL). The following table lists various tests that can be performed on BAL fluid (table 2). The decision of which studies to send depends upon the individual patient's epidemiologic exposures and clinical findings and on availability at specific hospital laboratories. When the diagnosis is not established by studies of BAL fluid or noninvasive testing, histopathology of lung tissue can be helpful. (See 'Approach to diagnosis' above.)

●CRV management – The management of CRVs varies with the specific virus causing the infection. Effective antiviral agents are available for certain CRVs (eg, influenza, SARS-CoV-2) but not for others. (See 'Management' above and 'Therapy' above.)

•When treating influenza, we typically use a neuraminidase inhibitor (eg, oseltamivir) but antiviral selection should be guided by the recommendations of local and national health agencies because of the potential for resistance in circulating strains. We continue antiviral therapy in lung transplant recipients with influenza until shedding is no longer detected by the real-time reverse-transcriptase polymerase chain reaction; this will typically require more than the five days of therapy recommended for immunocompetent individuals. The management of other CRVs is discussed above.

•The management of COVID-19 in lung transplant recipients is similar to the general population, although the threshold to treat with monoclonal antibodies is lower than in nonimmunocompromised patients (algorithm 1). Similarly, the threshold to use investigational therapies may also be lower but practice varies among transplant centers. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy' and "COVID-19: Management of adults with acute illness in the outpatient setting".)

●CRV vaccination – Among the CRVs, a vaccine is available for influenza virus and SARS-CoV-2. Annual influenza vaccination should be given to all lung transplant recipients (after the early post-transplant period) and their close contacts. An inactivated influenza vaccine should be used in lung transplant recipients; the live attenuated intranasal vaccine is contraindicated. (See 'Vaccination' above and "Seasonal influenza vaccination in adults" and "Immunizations in solid organ transplant candidates and recipients".)

●CRV pre-exposure prophylaxis – For lung transplant recipients in whom influenza vaccination is contraindicated or for those who are likely to have an inadequate response to the vaccine (eg, those receiving therapy for acute rejection or who underwent transplantation recently), we suggest pre-exposure antiviral prophylaxis for 12 weeks starting at the beginning of influenza season (table 3) (Grade 2B). We are most likely to give pre-exposure prophylaxis to those who underwent transplantation within the past month. In patients who meet criteria for pre-exposure prophylaxis but who are not receiving it, we give postexposure prophylaxis following exposure to a patient with influenza. (See 'Prevention' above and "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention", section on 'Postexposure antiviral prophylaxis'.)

●Herpes viruses – The herpesviruses (eg, CMV, HSV, VZV) are important causes of infection in lung transplant recipients because they commonly reactivate in the setting of immunosuppression when prophylaxis is not used. Specific herpesvirus prophylaxis is effective at preventing these infections. (See 'Herpes viruses' above.)

●Prevention of CMV reactivation – Oral valganciclovir is used to prevent CMV reactivation in lung transplant recipients who are at risk. The prevention and treatment of CMV in lung transplant recipients are discussed in detail separately. (See "Prevention of cytomegalovirus infection in lung transplant recipients" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients".)

●HSV and VZV prophylaxis – We recommend prophylaxis against HSV and VZV for all solid organ transplant recipients who are not receiving CMV prophylaxis (ie, patients who are seronegative for CMV and received an allograft from a CMV-seronegative donor) or who are receiving letermovir for CMV prophylaxis (Grade 1B). Appropriate regimens for HSV and VZV prophylaxis in patients with normal renal function include acyclovir 400 to 800 mg orally twice daily, valacyclovir 500 mg orally twice daily, or famciclovir 500 mg orally twice daily. We continue prophylaxis for three to six months following transplantation as well as during periods of lymphodepletion for the treatment of rejection. (See 'Prophylaxis' above.)

ACKNOWLEDGMENT — The views expressed in this topic do not necessarily represent the views of the National Institutes of Health or the United States Government.