Pulmonary Medicine

Infectious Complications in Lung Transplant Recipients

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What every physician needs to know:

Infections after lung transplantation are often challenging to diagnose and treat because of several complicating factors that include presentations of common infections that are due to immunosuppression, uncommon infections that are due to immunosuppression, concomitant allograft dysfunction or rejection-mimicking infection, and significant interactions between anti-infectives and immunosuppressant medications.

The origin of infections in transplant recipients can be classified into four overlapping groups:

  • Donor-derived infections (e.g., CMV, HIV, HCV, West Nile virus)

  • Recipient-derived infections (e.g., CMV, HCV, endemic mycoses, tuberculosis)

  • Nosocomial infections (e.g., catheter-related bloodstream infections)

  • Community-acquired infections (e.g., influenza, community-acquired pneumonia)

During the post-transplant period, the risk for particular infections varies depending on the time since the transplant procedure. These periods can be divided into three time periods.

Transplant to Day 30 - The risks of nosocomial infections and surgical complications that increase the risk of infection are highest in the first thirty days. Donor-derived infections may also manifest during this period. The effect of immunosuppression has not reached its peak during this period, and prophylaxis for some bacterial and viral pathogens has been initiated (usually trimethoprim-sulfamethoxazole and acyclovir or ganciclovir), so opportunistic infections are uncommon.

Months 1 to 6: The risk of reactivation of latent, opportunistic infections is highest during this period, when the net state of immunosuppression is at its peak. Then the risk declines with reduction of immunosuppression to maintenance levels. The continuation of prophylactic antimicrobials can continue to reduce the risk of some bacterial pathogens and herpes viruses. Invasive fungal infections may begin to manifest during this period.

After month 6: The risk of community-acquired infections increases with exposure of the transplant recipient to the outpatient setting, and the cessation of antiviral prophylaxis during this period may increase the risk of CMV and other herpes viruses. Depending on the recipient's overall allograft function (e.g., numerous episodes of acute rejection or the development of bronchiolitis obliterans syndrome or BOS) and corresponding net state of immunosuppression, he or she may be at greater risk for continuing opportunistic infections during this period. The risk of malignancy, including both PTLD and more common cancers, such as skin cancer, increases during this period as well.

Classification:

All manner of infectious agents, including viruses, bacteria, fungi, and parasites, can cause significant complications in lung transplant recipients. Virsuses, especially Cytomegalovirus (CMV) and community-acquired respiratory viruses (CARV), comprise the most frequent pathogens that affect lung transplant recipients. Bacteria, particularly Gram-negative rods, such as Burkholderia species and multi-drug-resistant Pseudomonas aeruginosa and non-tuberculous mycobacteria (NTM), are becoming increasingly recognized as disease-causing entities and as possible prognostic factors for transplant-related outcomes.

Similarly, Candida species, filamentous fungi like the Aspergillus species, and endemic mycoses are often encountered in the post-transplant setting. Finally, with increasing global travel and "transplant tourism," parasitic infections like Trypanosoma cruzi, the vector of Chagas' disease, and Strongyloides should be considered in patients who have the appropriate exposure history. This chapter focuses on the more common and clinically significant infections following lung transplantation.

Viruses

CMV: Among solid-organ transplant (SOT) patients, lung transplant recipients have the highest risk of developing CMV. Rates of CMV infection and disease range from 30 percent to over 80 percent depending on the serostatus of the donor and the recipient and the use of prophylaxis. This high risk is due to several factors, including the large CMV viral loads that may be transmitted via a CMV-positive lung allograft relative to other types of allografts, the more intensive immunosuppression required in lung recipients, the serostatus of the donor and the recipient (a seronegative recipient of a seropositive organ is at the highest risk), the presence of allograft rejection, the use of induction immunosuppression, and the presence of concurrent infections (primarily other viruses).

CMV has both direct and indirect effects on the transplant recipient. Direct effects include CMV syndrome (fever, malaise, leukopenia, or thrombocytopenia) and CMV tissue-invasive disease, which usually involves the gastrointestinal tract and manifests as diarrhea and abdominal pain. However, CMV can affect nearly every organ system and may cause pneumonitis, hepatitis, myocarditis, CNS disease, and (rarely) retinitis. Indirect effects of CMV are believed to occur via the immunomodulatory effects of the virus and may include precipitation of acute or chronic rejection (BOS) episodes and enhancement of the effects of other opportunistic infections. Together, these effects of CMV contribute to increased mortality in SOT patients with CMV infection.

CARV: CARV includes influenza A, B and novel H1N1; respiratory syncytial virus (RSV); adenovirus; parainfluenza; and coronavirus, such as the SARS virus; rhinovirus; enteroviruses; human metapneumovirus; bocavirus; and polyoma viruses, such as KI and WU viruses. Yearly vaccination against influenza for transplant candidates, recipients, and close contacts should be encouraged. Infection with CARV is more likely to progress to lower respiratory tract disease/pneumonia in lung transplant recipients and has been suggested to be a risk factor for the development of BOS.

Gram-negative bacteria:

Burkholderia species, including the B. cepacia complex, notably B. cenocepacia (genomovar III) and B. multivorans (genomovar II), are often colonizers of cystic fibrosis patients and may have implications for post-transplant antibiotic prophylactic choices. Colonization with B. cenocepacia or B. gladioli in particular may predict poorer post-transplant outcomes in these patients, although B. multivorans does not appear to negatively impact survival.

Pan-resistant (PR) or multi-drug-resistant (MDR) Pseudomonas aeruginosa detected post-transplantation are no longer considered absolute contraindications to transplantation, as reflected in the International Guidelines for the Selection of Lung Transplant Candidates. However, post-transplant colonization with P. aeruginosa may be predictive of the development of BOS.

Non-tuberculous mycobacteria (NTM):

Multiple species of NTM, including slow-growing species like Mycobacterium avium complex and M. kansasii isolates, and rapid-growers like M. chelonae and M. abscessus can infect transplant recipients. M. abscessusinfection in particular presents significant problems in terms of the selection of effective and tolerable treatment regimens, and may predict poorer outcomes if it is present as a colonizing organism prior to transplantation.

Fungi:

Endemic mycoses like Histoplasma capsulatum and Coccidiodes immitis typically cause disease via reactivation of latent infection in the immunocompromised host and can present in a variety of ways depending on the organ system involved. Cryptococcal disease also typically represents reactivation of latent disease.

Candida albicans and other Candida species can cause significant nosocomial infections (e.g., catheter-related bloodstream infections) and anastomotic complications in the immediate post-transplant period.

Filamentous fungi like the Aspergillus species can cause invasive pulmonary fungal infections, tracheobronchitis, anastomotic infections, and disseminated disease.

Are you sure your patient has an infectious complication? What should you expect to find?

Viruses:

CMV: A diagnosis of CMV infection requires evidence of CMV viral replication via an accepted form of laboratory testing, such as nucleic acid testing (PCR) or antigenemia testing, while CMV disease requires evidence of CMV viral replication plus attributable symptoms, including fever, malaise, leukopenia, or thrombocytopenia, or evidence of tissue-invasive disease, such as pneumonitis, colitis, hepatitis, or retinitis.

CARV: These viruses may present in a similar manner as in immunocompetent hosts, with fever and upper respiratory tract signs and symptoms, but they can rapidly progress to cause severe lower respiratory tract infections, resulting in significant morbidity and mortality.

Gram-negative bacterial infections, which can present as in immunocompetent hosts, usually affect the lower respiratory tract, the urinary tract, the abdomen, the bloodstream (especially in the context of indwelling catheters), and wounds.

Non-tuberculous mycobacterial infections can present in a variety of ways, including as pulmonary infections, skin and soft tissue infections (which may present as solitary nodules or non-healing ulcers), and disseminated disease with fever, malaise, cytopenias, or other manifestations, depending on the organ(s) involved.

Fungi:

Endemic mycoses: Endemic mycoses may reactivate insidiously and can present with pulmonary manifestations, such as nodules or infiltrates, with skeletal involvement, including osteomyelitis and bone marrow infiltration, and with skin and soft tissue disease, among others. Cryptococcosis often manifests as pulmonary or CNS disease, but it may also disseminate with fungemia in SOT patients.

Aspergillus infections: These infections can manifest in a variety of ways, including pre-transplant airway colonization and infections like aspergilloma, and post-transplant tracheobronchitis, bronchial anastomotic breakdown, invasive pulmonary aspergillosis, and disseminated disease.

Candida infections: These infections, which typically occur in the first thirty days after transplantation, can include bloodstream infections, empyema, mediastinitis, bronchial anastomotic breakdown, and infection of vessel anastomoses with mycotic aneurysm formation.

Beware: there are other diseases that can mimic an infectious complication.

Patients with allograft rejection may have symptoms that mimic infection, including fever, fatigue, cough, shortness of breath, and radiographic abnormalities.

How and/or why did the patient develop an infectious complication?

Lung transplant recipients are uniquely predisposed to infectious complications of the allograft for several reasons, including:

  • the constant exposure of the transplanted lung to the external environment

  • decreased mucociliary clearance and an impaired cough reflex that is due to denervation of the allograft

  • transmission of pathogens from the donor via the allograft

  • infection from a diseased native lung in single-lung transplantation

  • ischemia or other complications of the anastomotic site

  • the relatively high level of immunosuppression required in lung transplantation

In addition to opportunistic infections, transplant recipients are at risk for any of the common pathogens that infect immunologically intact hosts, but because of their immunosuppressed state, recipients may experience a more severe or prolonged course of disease, regardless of whether the site of infection is the allograft or another organ.

Which individuals are at greatest risk of developing an infectious complication?

Viruses:

CMV: Risk factors include the serostatus of the donor and recipient, with a seronegative recipient of a seropositive organ at the highest risk; allograft rejection; the use of induction immunosuppression; and concurrent infections (primarily with other viruses). Areas under recent investigation include defects in CMV-specific cell-mediated immunity, polymorphisms in various components of the innate immune system, and other host factors, such as renal dysfunction. The CMV serostatus of the donor is determined as soon as possible in the post-transplantation period (the recipient should be tested during the transplant evaluation process) so an appropriate antiviral prophylaxis regimen can be initiated.

CARV: Unvaccinated patients are at the highest risk of contracting influenza virus (A, B and H1N1 strains), so yearly vaccination is strongly encouraged for transplant recipients and their household contacts.

Gram-negative bacteria:

Cystic fibrosis patients are at high risk for post-transplant complications with pan-resistant (PR) or multi-drug-resistant (MDR) Gram-negative bacteria because of the likelihood of pre-transplant colonization that is due to bronchiectasis, impaired mucociliary clearance, and prior antimicrobial exposure that may select for colonization with highly resistant organisms over time.

Additional risks include hospitalization (especially in the intensive care setting), indwelling catheters, antibiotic exposure, mechanical ventilation, and concomitant illness.

Non-tuberculous mycobacteria:

Structural lung abnormalities, including cystic fibrosis, COPD, and bronchiectasis, place patients at risk for pre-transplant colonization and subsequent invasive disease after transplant. Impairment in cell-mediated immunity that is due to immunosuppressive medications and chronic rejection can also put patients at risk. Genetic variability of the innate immune system and interleukin-12 and interferon-γ pathways are under investigation as additional risk factors.

Fungi:

Aspergillus: Risk factors include pre-transplant colonization, acquisition of colonizing organisms during the first twelve months after transplantation, and the net state of immunosuppression. Other theorized risks include early airway ischemia, placement of a bronchial stent, single-lung transplantation, hypogammaglobulinemia, CMV infection, use of alemtuzumab or thymoglobulin induction therapies, and acute rejection that requires augmentation of immunosuppression.

Candida: Most candidal infections occur within the first thirty days of transplantation. Risk factors include the use and duration of broad-spectrum antibiotics, the presence of a central venous catheter, the use of renal replacement therapy, parenteral nutrition, and heavy growth of Candida from the donor lung(s).

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Viruses:

CMV: In the last decade, quantitative nucleic acid testing of blood specimens, primarily via polymerase chain reaction (PCR), has become the most widely accepted method of CMV viral load monitoring. CMV antigenemia detection (via pp65 antigen detection in peripheral white blood cells) has fallen out of favor because of its relative insensitivity and labor intensity for laboratory staff. In addition, the relative neutropenia that may occur during CMV infection can limit the utility of the assay.

Lack of standardization of CMV nucleic acid testing platforms and procedures across laboratories produces significant inter-laboratory variability, which makes interpretation and comparison of viral loads obtained from different laboratories problematic and poses problems in establishing uniform viral load cutoffs for positive and negative results. Nucleic acid testing for CMV in other body fluids, such as bronchoalveolar lavage fluid (BAL) or cerebrospinal fluid, is feasible, but care should be taken to ensure a validated methodology is used, as not all centers have implemented routine CMV testing paradigms for non-blood specimens.

A negative blood CMV PCR test does not rule out tissue-invasive CMV disease, so if clinical suspicion for CMV disease remains high, additional testing should be performed. CMV disease is often accompanied by hematological changes, especially leukopenia and thrombocytopenia. Other laboratory abnormalities, such as liver transaminase elevations in CMV hepatitis, may be observed depending on the organ affected.

The diagnosis of tissue-invasive CMV disease should also be supported by cytology and/or biopsy specimens from the affected organ, analyzed by histopathology for characteristic CMV cytopathic changes (e.g., viral inclusions) via immunohistochemistry and in situ hybridization, as well as viral culture.

A promising area in CMV diagnostics is the measurement of CMV-specific cell-mediated immunity (CMI) as a predictor of the development of CMV viremia and disease after the completion of primary post-transplant prophylaxis. The QuantiFERON-CMV test, a CD8+ CMV specific interferon-γ release assay that is commericially available outside the US, was used to test serial CMV-specific CMI in SOT recipients during a three-month post-transplant CMV prophylaxis period. Post-prophylaxis CMV disease (within the first six months after transplant) occurred in 22.9 percent of subjects with no detectable CMV-specific CMI versus 5.3 percent of subjects with a positive QuantiFERON-CMV result, suggesting a possible role in predicting late-onset CMV disease.

CARV: PCR-based quantitative nucleic acid testing for respiratory viruses from BAL or nasopharyngeal aspirates, washes or swabs is the most sensitive modality for the detection of viruses like influenza A and B, RSV, and parainfluenza. Direct fluorescence antibody (DFA) testing is also available for some CARV. Rapid antigen testing is available for influenza virus, but the sensitivity of these tests in immunocompromised patients is unclear, so a negative rapid antigen test does not definitively exclude viral infection. Similarly, rapid antigen tests may not distinguish among the subtypes of influenza A (e.g., H3N2 vs. H1N1), and do not provide any information about antiviral susceptibility.

Gram-negative bacteria: If infection is suspected, sputum and BAL specimens should be submitted for culture and susceptibility testing so antimicrobial therapy can be optimized for highly resistant isolates. Identification to the genomovar level prior to transplantation is critical when B. cepacia infection is suspected/documented in cystic fibrosis patients so appropriate risk stratification can be performed. For infections outside the lung, appropriate specimens of blood, urine, abscess fluid, and so on should be submitted to the microbiology lab.

Non-tuberculous mycobacteria: The IDSA/ATS guidelines published in 2007 are applicable to lung transplant recipients. They recommend the following microbiologic data to support the diagnosis of NTM disease:

  • positive culture results from at least two separate expectorated sputum samples (if the results from the initial sputum samples are non-diagnostic, consider repeat sputum AFB [acid fast bacilli] smears and cultures), OR

  • positive culture results from at least one bronchial wash or lavage, OR

  • transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) AND positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) AND one or more sputum or bronchial washings that are culture positive for NTM.

  • Identification to the species level and susceptibility data are critical, as appropriate antimicrobial regimens vary significantly by species.

Fungi:

Culture remains the gold standard for the diagnosis of fungal diseases, including aspergillosis and candidal infections, to identify the organism to the species level and for performance of susceptibility testing for some candida isolates. Histopathology can suggest the diagnosis of fungal infection, but identification to the species level is often difficult and unreliable.

The use of the galactomannan assay (Platelia Galactomannan EIA) for the detection of invasive aspergillus infection has not been widely adopted in SOT, mainly because of the poor sensitivity of the test when serum samples are used. Testing BAL samples improves the sensitivity to 60-80 percent for detecting invasive aspergillosis, with a specificity of 95 percent. False positives may be seen in the context of beta-lactam antibiotics (especially piperacillin-tazobactam, ticarcillin-clavulanate, and amoxicillin), and the assay may cross-react with other molds or endemic mycoses.

The (1→3)-β-D-Glucan assay tests for a cell wall component present in most fungi, so it is not specific for aspergillus or candida species. The test also has a high false positive rate in critically ill patients and does not appear to have better sensitivity than the galactomannan test.

Candida mannan antigenemia testing does not yet have sufficient sensitivity or specificity to be useful in the clinical setting, and PCR-based methods for detection of aspergillus are in development but are not yet standardized for clinical use. Serologic studies may be helpful in the diagnosis of suspected endemic mycoses (e.g., Coccidiodomycosis), and antigen testing for Histoplasmosis and Cryptococcosis are recommended, but consultation with an infectious diseases specialist should be sought in these circumstances for guidance in establishing the diagnosis.

What imaging studies will be helpful in making or excluding the diagnosis of an infectious complication?

Chest imaging is nearly universally helpful in the workup of suspected pulmonary infection in transplant recipients, and it may serve as a useful guide in targeting additional diagnostic efforts, such as bronchoscopy or biopsy, and to assess the response to therapy. For CARV and pulmonary bacterial infections, chest imaging is useful in determining the extent of involvement of the lower respiratory tract in the lung transplant population.

CMV: A diagnosis of CMV pneumonitis may be supported by chest radiography that demonstrates interstitial patterns with parenchymal consolidation and multiple small nodules. Computed tomography (CT) scans may show patchy or diffuse ground-glass attenuation. Focal consolidations, reticular opacities, thickened intralobular septa, and tree-in-bud abnormalities are also seen. Pleural effusions are present in up to 20 percent of patients.

Given the non-specific nature of these findings, a combination of clinical symptoms, radiographic abnormalities, laboratory, and pathological testing should be used to make the diagnosis. This combination diagnostic strategy is especially important, as periodic shedding of CMV virus in seropositive individuals can occur in the absence of clinically significant disease or in the context of concurrent illness (either infectious or non-infectious).

NTM: The IDSA/ATS guidelines recommend the following radiographic data to support the diagnosis of NTM disease that are applicable to lung transplant recipients: nodular or cavitary opacities on chest radiograph or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules.

Fungal: A diagnosis of invasive pulmonary aspergillosis (IPA) may be supported by CT imaging of the chest, but the findings are typically non-specific and require pathologic and microbiologic confirmation. The finding of a "halo" sign is often characteristic of IPA in bone marrow transplant recipients, but it is not a sensitive indicator of disease in SOT. Numerous radiographic patterns, including nodules, cavitary lesions, focal infiltrates, and consolidation with subsegmental to multilobar involvement, may be seen in patients with IPA. Chest imaging studies remain normal in the majority of patients with tracheobronchial disease.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of an infectious complication?

Changes in pulmonary function tests (including spirometry) are not specific to infection complications but may be caused by a variety of pulmonary disease processes. Therefore, while these tests are not specific for diagnosis of pulmonary infections if they are used in isolation, they may be complementary to other diagnostic procedures.

What diagnostic procedures will be helpful in making or excluding the diagnosis of an infectious complication?

For suspected pulmonary disease that is due to any pathogen, bronchoscopy is typically the procedure of choice to visually assess the airways and anastomoses and to obtain specimens for culture and susceptibility testing, cytologic and pathologic examination, nucleic acid testing, or other supplemental laboratory analyses as appropriate.

Radiologically guided sampling techniques (e.g., CT-guided biopsy) are also helpful in obtaining specimens from peripheral parenchymal or pleural lesions that are not amenable to bronchoscopic sampling. Surgical approaches like video-assisted thorascopic surgery (VATS) should also be considered when appropriate.

For non-pulmonary lesions like skin nodules, abdominal abscesses, or osteomyelitis, sampling of the abnormality for microbiological (and pathological, when appropriate) analysis should always be considered given the broad spectrum of potential causal pathogens and the risk of resistant organisms inherent in the lung transplant population. Careful thought should be given prior to the procedure as to what testing needs should be performed so sufficient material is obtained and proper procedures are followed, as different types of microbiological testing require different types of collection and processing techniques (e.g., aerobic vs. anaerobic bacterial cultures, mycobacterial vs. fungal cultures). A discussion with laboratory personnel for guidance on proper submission of the various types of cultures is often helpful to avoid errors.

CMV: In cases of suspected CMV pneumonitis, bronchoscopy with BAL specimens for cytology, viral culture, and nucleic acid testing (when available), and transbronchial biopsy specimens for pathology, if appropriate, should be collected. Other diagnostic procedures for extra-pulmonary CMV disease may be warranted based on presenting symptoms and may include colonoscopy with biopsies for suspected CMV colitis and a dilated retinal exam by an ophthalmologist for suspected CMV retinitis.

Fungal: For suspected invasive pulmonary fungal infections (e.g., IPA), bronchoscopy with biopsy or CT-guided biopsy with specimens for both pathological and microbiological analysis are preferred due to the potential of BAL contamination from upper airway colonization via environmental exposure that may not be representative of parynchymal disease.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of an infectious complication?

CMV: The diagnosis of tissue-invasive CMV should be supported by cytology and or biopsy specimens analyzed by histopathology for characteristic CMV cytopathic changes (e.g. viral inclusions), via immunohistochemistry, in situ hybridization, and viral culture.

NTM: The diagnosis of NTM disease can be supported by pathological findings like granulomatous inflammation or a positive AFB stain on the tissue specimen. However, cultures should always be submitted in parallel for species identification to rule out tuberculosis (especially in pulmonary disease for public health reasons) and to guide definitive antimicrobial combination therapy, as this therapy differs for each species.

Fungi: While pathological examination can assist in the confirmation of invasive fungal disease (by filamentous fungi or endemic mycoses), identification of fungal organisms to the genus or species level based on pathological assessment is often not definitive given the effects of fixation and sectioning on fungal architecture. Cultures should always be submitted in parallel for species identification to guide definitive anti-fungal therapy.

If you decide the patient has an infectious complication, how should the patient be managed?

CMV:

CMV Prophylaxis: The goal of CMV prophylaxis is to reduce or eliminate the risk of CMV disease and accompanying morbidity and mortality in the early post-transplant period. Prophylaxis strategies in SOT in general are dictated by the serostatus of the donor and recipient (with donor-positive/recipient-negative patients at highest risk) and by the current preferences and practices of the transplant center. These prevention strategies include universal prophylaxis (administration of antiviral medication to all "high risk" patients starting immediately after transplantation for a finite period) and pre-emptive therapy (intensive laboratory monitoring--usually weekly--for evidence of CMV viral replication with initiation of antiviral treatment once viral replication is detected to prevent progression to disease).

Recent guidelines from the American Society of Transplantation (AST) and The Transplantation Society (TTS) provide guidance for providers about prophylaxis strategies: Lung transplant recipients are considered high-risk patients regardless of CMV serostatus. Universal prophylaxis is preferred in lung transplantation, as this strategy may have some benefits in preventing some of the indirect effects of low-level CMV replication. Limited clinical data suggest better graft survival and clinical outcomes with this approach.

The guidelines also point out that pre-emptive treatment has not been well studied in lung transplantation, so this treatment requires careful coordination between the patient and the transplant center to ensure rapid turn-around of test results and action based on those results. This approach may reduce drug exposure, side effects, and drug costs, and may reduce the incidence of late CMV disease (occurring after the discontinuation of prophylaxis), theoretically by allowing low-level CMV exposure to the host immune system, thereby stimulating CMV-specific cell-mediated immunity.

The guidelines recommend oral valganciclovir 900 mg once a day (adjusted for renal insufficiency when appropriate) or intravenous ganciclovir 5 mg/kg once a day (adjusted for renal insufficiency when appropriate) for universal prophylaxis. Oral ganciclovir has poor bioavailability and should be avoided. The use of CMV immune globulin (i.e., Cytogam, CMV-IG) has not been well studied, and there are no current recommendations on its use in CMV prophylaxis. Careful attention must be paid to dose adjustments for renal insufficiency to avoid over-dosing with an accompanying increase in side effects or under-dosing with an accompanying decrease in efficacy (and a theoretical increased risk of inducing ganciclovir resistance).

The duration of prophylaxis should be a minimum of six months. Recent data suggest that extending prophylaxis to twelve months after transplantation may be warranted, but providers should consider each patient individually in terms of his or her post-transplant course (rejection, concurrent illnesses, expected tapering of immunosuppression, etc.) and the tolerability of the prophylaxis regimen, among other factors. Re-initiation of CMV prophylaxis should be considered in certain high-risk patients during treatment of acute rejection with prolonged high-dose steroids, the use of anti-lymphocyte antibody therapy, or other significant enhancement of immunosuppression.

CMV Treatment: Lung transplant recipients who have isolated, low-level CMV viremia, no signs or symptoms of CMV syndrome or tissue-invasive disease, and no other complicating factors (e.g., no concurrent rejection or illness) may be managed initially via reduction of maintenance immunosuppression and careful weekly monitoring of viral response. However, should signs or symptoms of CMV syndrome or disease develop, should CMV viral load levels continue to increase despite reduction of immunosuppression, or should a transplant recipient initially present with confirmed CMV syndrome or disease (evidence of CMV viral replication plus attributable symptoms or evidence of tissue-invasive disease), treatment should be initiated.

Reduction of maintenance immunosuppression is always necessary in conjunction with initiation of antiviral medication. Traditionally, the preferred treatment for CMV disease has been with intravenous ganciclovir 5 mg/kg every twelve hours (adjusted for renal insufficiency when appropriate).

For patients with isolated CMV viremia at levels less than 20,000 copies per milliliter, isolated CMV syndrome, or mild to moderate CMV disease without significant gastrointestinal involvement, recent data from the VICTOR studies suggest that oral valganciclovir 900 mg every twelve hours (adjusted for renal insufficiency when appropriate) is not inferior to intravenous ganciclovir in a mixed population of SOT recipients (mostly kidney transplants). However, caution should be exercised in patients in whom adequate absorption of oral medications is in question (e.g., patients with diarrhea) and in patients who may not be compliant with oral therapy. This approach has not been studied specifically in lung transplant recipients, so careful monitoring is essential with this strategy.

Treatment should be continued for a minimum of two weeks, AND until the cessation of viral replication has been verified AND any symptoms attributable to CMV have resolved. Quantitative nucleic acid testing or antigenemia testing should be performed weekly during treatment to follow the virologic response to therapy. Confirmation of the resolution of viremia with two consecutive negative tests at least seven days apart is recommended prior to stopping therapy.

Secondary prophylaxis with lower-dose valganciclovir 900 mg once a day (adjusted for renal insufficiency when appropriate) can be considered for patients at high risk of relapse after completion of CMV treatment (e.g., patients in whom reduction of immunosuppression was not possible because of concurrent rejection).

The addition of CMV immune globulin (i.e., CMV-IG, Cytogam) to antiviral treatment has not been well studied, but it may be useful in cases of severe CMV disease or CMV pneumonitis. Some providers add CMV immune globulin to the antiviral treatment regimen in cases of documented hypogammaglobulinemia, but the data behind this approach is limited.

Patients who fail to respond to standard antiviral therapy should be evaluated for the presence of ganciclovir-resistant CMV in consultation with an infectious diseases specialist. Testing of the patient's CMV isolate for resistance mutations in the UL97 and UL54 gene products is often necessary to confirm this possibility. Additional therapy with the more toxic antiviral agents foscarnet or cidofovir may be necessary but should be considered only in the context of a consultation with an infectious diseases specialist.

Recurrent CMV disease is not uncommon. Estimates range from 15 percent to 30 percent, despite appropriate antiviral treatment.

The side effects of valganciclovir and ganciclovir usually manifest as cytopenias, especially leukopenia and thrombocytopenia. However, as CMV disease itself often causes these abnormalities, some patients need support with colony-stimulating factors like filgrastim (i.e., Neupogen) until CMV replication is fully suppressed. Renal function must also be carefully monitored, as both ganciclovir and valganciclovir must be dose-adjusted once creatinine clearance decreases below 60 mL/min. The package inserts should be reviewed prior to dosing for a full description of possible side effects.

CARV: Effective antiviral therapies for most CARV are not available, with the notable exception of influenza virus and perhaps RSV, so appropriate infection-control strategies, including hand hygiene and droplet precautions, are mandatory to prevent the spread of disease. These precautions are especially important in the health care setting, as transplant patients may have prolonged viral shedding after infection. Supportive care and reduction of immunosuppression, when possible, remain the mainstays of CARV treatment, and vaccination of transplant recipients and their close contacts should be encouraged.

Suspected cases of influenza A, B or novel H1N1 should ideally be treated within forty-eight hours of symptom onset, but transplant recipients in particular may still benefit if therapy is initiated outside of this window. Symptomatic patients should be treated regardless of the duration of symptoms. Every effort should be made to establish the diagnosis of influenza, including the type, as specific antiviral therapy depends on the resistance pattern of the current circulating viruses.

In most cases, a neuraminidase inhibitor like oseltamivir or zanamivir taken twice daily (adjusted for renal insufficiency when appropriate) is recommended for influenza A or B; an M2 inhibitor (e.g., amantidine or rimantidine) could also be considered for influenza A strains. Treatment should be continued for five to ten days, although there may be a benefit in extending therapy beyond this period for patients slow to clinically respond or who have evidence of continued viral shedding on repeated testing.

Unvaccinated patients with a suspected exposure to an individual with influenza should receive prophylaxis with oseltamivir or zanamivir taken once daily (adjusted for renal insufficiency when appropriate) for five to ten days after the last known exposure contact. It is not known whether vaccinated patients will benefit from prophylaxis. Seasonal or extended prophylaxis is not recommended because of concerns about emerging viral resistance.

For RSV lower respiratory tract disease, supportive care with the reduction of immunosuppression, if possible, is universally recommended. The addition of high-dose corticosteroids in this setting remains controversial, and the use of ribavirin in SOT recipients continues to be debated because of the lack of controlled studies in this population. Aerosolized ribavirin is commonly used in the pediatric population for seasonal RSV bronchiolitis, and limited data suggest benefit in lower respiratory tract disease in the stem cell transplant population. However, this approach has not been embraced in the SOT community.

Two small case series suggest a role for parenteral or oral ribavirin in lung transplantation. Both studies treated patients with ribavirin plus high-dose oral or parenteral corticosteroids until repeated nasopharyngeal swabs were negative for RSV. After median follow-up of more than three hundred days in both studies, all subjects had full recovery of FEV1 after RSV resolution, and only one case of late BOS was identified out of twenty-three subjects. The oral ribavirin study reported no adverse events, and the parenteral study reported mild but reversible hemolytic anemia. Randomized studies are needed to assess fully the utility of ribavirin in the population.

At this time, there are no consensus recommendations for the use of palivizumab, RSV immune globulin, or IVIG for treatment or prophylaxis in transplant recipients.

Gram-negative bacteria: Treatment options for MDR or PR Gram-negative bacterial infections are often limited and must be guided by susceptibility results. Consultation with an infectious diseases specialist should be considered for severe infections. Treatment often requires the use of more toxic anti-microbials, such as colistin or aminoglycosides, in combination with broad-spectrum agents.

NTM: Susceptibility testing should be performed for all clinically relevant isolates because of the evolving resistance patterns of many NTM species and isolates (e.g., M. abscessus) and because of potential drug-interaction issues with immunosuppressant agents (e.g., the use of rifampin for M. avium disease or clarithromycin for rapid-growing NTM). Repeat susceptibility testing should be performed if disease recurrence after treatment has occurred because of inducible mechanisms of drug-resistance in some isolates.

Treatment of NTM infections requires combination therapy with multiple classes of antimicrobials, including parenteral agents like aminoglycosides, for prolonged periods--often twelve months or longer--and may require surgical intervention. Therefore, consultation with an infectious diseases specialist is strongly recommended prior to initiation of therapy. Specific treatment recommendations for NTM isolates are beyond the scope of this review.

Fungi:

Fungal prophylaxis: There are no large-scale multicenter studies to guide antifungal prophylaxis, so practices are vary widely from center to center. Guidelines suggest stratifying patients based on their individual risk factors (some of which remain theoretical), including pre-transplant colonization with Aspergillus, acquisition of colonizing organisms within the first twelve months of transplantation, early airway ischemia, placement of a bronchial stent, single-lung transplantation, hypogammaglobulinemia, CMV infection, the use of alemtuzumab or thymoglobulin induction therapies, and acute rejection that requires augmentation of immunosuppression.

Inhaled amphotericin compounds and oral itraconazole and voriconazole prophylaxis strategies of varying durations have been used with limited supporting data, but voriconazole appears to be emerging as the agent used most often. However, several recent studies have reported unanticipated adverse events, including disabling neuromuscular disorders and periostitis, in lung transplant patients given prolonged courses of voriconazole. In addition, the drug interactions between azole antifungals and calcineurin (e.g., tacrolimus) and m-TOR inhibitors (e.g., sirolimus) must be considered.

Aspergillus tracheobronchitis treatment: Recent guidelines suggest voriconazole as the first-line therapy for biopsy-confirmed Aspergillus tracheobronchitis or anastomotic infections, along with a reduction of maintenance immunosuppression. Voriconazole dosing is weight-based and must be adjusted in patients with liver impairment. In addition, the intravenous formulation may not be used in patients with renal insufficiency (CrCl < 50 mL/min or on any type of dialysis). The typical oral dose for a patient 40 kg or larger is two loading doses of 400 mg, each twelve hours apart, then 200 mg orally every twelve hours subsequently.

Voriconazole has significant drug interactions because of its interactions with a variety of cytochrome P450 enzymes, notably tacrolimus, which requires a significant dose reduction to avoid toxicity (to approximately a third to half of the original dose), and sirolimus, which is contraindicated with voriconazole use.

Liver function tests should be followed. Visual disturbances, including hallucinations, are a common side effect. As above, neuromuscular disorders and periostitis are emerging as long-term sequella of prolonged voriconazole dosing.

With the exception of A. terreus infection because of its intrinsic resistance to amphotericin B, parenteral lipid formulations of amphotericin B deoxycholate remain an alternative in patients who cannot tolerate voriconazole, but there is limited experience using echinocandins (e.g., caspofungin, micafungin) in this setting. Approaches that remain under investigation for aspergillus tracheobronchitis include inhaled formulations of amphotericin and topical instillation of liposomal amphotericin B via bronchoscopy in addition to standard antifungal therapy. Duration of treatment is guided by bronchoscopic surveillance of the trachea and anastomoses until resolution.

Invasive Aspergillosis treatment: Similar treatment guidelines apply for invasive Aspergillosis, with voriconazole recommended as a first-line agent at the doses described above. Parenteral lipid formulations of amphotericin B deoxycholate, echinocandins, posaconazole, and itraconazole are alternatives. Again, reduction of maintenance immunosuppression is an important component of treatment. Combination therapy with two or more agents is not recommended as an initial therapeutic approach because of the lack of evidence for improved outcomes.

Recent guidelines have endorsed therapeutic monitoring of voriconazole levels, as serum concentrations are highly variable among patient populations, especially in cystic fibrosis patients. Trough levels between 1 to 5 μg/μL are recommended for optimal efficacy and prevention of toxicity. Surgical intervention (including debridement and resection) may be necessary for life-threatening hemoptysis, lesions in close proximity to the great vessels or pericardium, sino-nasal infections and intracranial lesions, and in cases of progressive or refractory disease when optimal anti-fungal therapy has failed. Duration of treatment is typically guided by clinical and radiographic resolution of attributable abnormalities, but a minimum of 12 weeks of therapy is recommended.

Immunomodulatory agents such as interferon-γ are still under investigation.

Candidal tracheobronchitis: Treatment should be based on the results of cultures taken at the time of bronchoscopic inspection. Culture data is critical to rule out aspergillus and to identify the candida isolate to the species level, as several species have intrinsic or dose-dependent resistance to certain antifungals, such as C. krusei and C. glabrata resistance to fluconazole and C. lusitaniae to amphotercin B. Choice of antifungal should be determined by the culture results, and duration of therapy should be guided by bronchoscopic resolution of infection. Recent guidelines summarizing the treatment of invasive candidal infections are available from the AST and IDSA.

What is the prognosis for patients managed in the recommended ways?

Viruses:

CMV: The incidence of late CMV disease or CMV disease that occurs after cessation of prophylaxis, usually in two to three months, are concerns with the use of universal prophylaxis. The incidence of late CMV among SOT patients is estimated to be near 30 percent. Risk factors for the development of late CMV disease are still being investigated, but they may include donor-positive/recipient-negative mismatch and the higher levels of immunosuppression that are often used in thoracic and intestinal transplantation.

Extension of CMV prophylaxis in some studies, such as the IMPACT study in renal transplantation and a study by Palmer et al. in lung transplant patients, have resulted in reduced rates of CMV disease twelve months or longer after transplantation. Recent data also suggest that the use of universal prophylaxis may not impair the ability of the immune system to generate CMV-specific T cell responses. Additional studies are needed to determine the optimal duration of prophylaxis for lung transplant recipients.

Recurrent CMV disease may occur in patients who have certain risk factors, including primary CMV infection (e.g., in a recipient seronegative for CMV IgG at disease onset), recipient of a deceased-donor transplant, high baseline CMV viral load, gastrointestinal or multiorgan disease, and concurrent rejection.

Multiple rounds of antiviral treatment may place the patient at risk for the development of resistant CMV infection, especially if renal insufficiency complicates proper dosing of antiviral therapy.

CMV may be a risk factor for the development of BOS, but some studies have shown conflicting results: several studies have shown that the use of CMV prophylaxis is associated with reductions in the incidence of BOS, but many have relied on retrospective designs and historical controls, so additional prospective, randomized studies are needed to define the relationship between CMV and BOS more clearly.

CARV: CARV infection has been noted as a significant risk factor for the development of BOS and the development of acute rejection.

Gram-negative bacterial infections: Persistent colonization with Gram-negative bacteria, especially Pseudomonas aeruginosa, after transplantation has been associated with the development of BOS in several recent studies.

NTM: Transplant patients with disseminated NTM infections are at risk for recurrent disease, usually because of the patient's inability to tolerate the difficult and lengthy antibiotic regimens required. This treatment intolerance may be due to side effects (especially from aminoglycosides), technical issues with long-term parenteral therapy (e.g., maintenance of a central catheter), and the "patient fatigue" that often develops after several months of combination therapy.

What other considerations exist for patients with infectious complications?

Current studies are examining the relationship between genetic polymorphisms in certain genes involved in the immune response, such as mannose-binding lectin and interferon-γ, and risk for infection post-transplantation, but data is not yet sufficient to recommend any type of genetic screening tests for susceptibility to infection.

What’s the evidence?

Reviews:

Fishman, JA. "Infection in solid-organ transplant recipients". N Engl J Med. vol. 357. 2007. pp. 2601-14.

An excellent overview of infectious diseases in solid-organ transplant recipients, emphasizing general concepts applicable to all transplant types.

Remund, KF, Best, M, Egan, JJ. "Infections relevant to lung transplantation". Proc Am Thorac Soc. vol. 6. 2009. pp. 94-100.

Sims, KD, Blumberg, EA. "Common infections in the lung transplant recipient". Clin Chest Med. vol. 32. 2011. pp. 327-42.

Two reviews of the more common infectious complications specific to lung transplant patients.

Christie, JD, Edwards, LB, Kucheryavaya, AY. "The registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report - 2010". J Heart Lung Transplant. vol. 29. 2010. pp. 1104-118.

Summary of the current status of lung transplantation, including donor and recipient demographics, characteristics, and outcomes.

Current Guidelines:

"The American Society of Transplantation Infectious Diseases Guidelines,". Am J Transplant. vol. 9. 2009.

This special supplemental issue provides specific consensus recommendations and guidance from the largest US transplantation society for each type of infection encountered in solid-organ transplantation. Specific chapters of special interest are also highlighted below.

CMV:

Cotton, KN, Kumar, D, Caliendo, AM. "International consensus guidelines on the management of cytomegalovirus in solid organ transplantation". Transplantation. vol. 89. 2010. pp. 779-95.

Humar, A, Snydman, D. "Cytomegalovirus in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. S78-86.

Current CMV diagnosis, prophylaxis and treatment guidelines from The Transplantation Society, the largest European transplantation society, and the American Society of Transplantation.

CARV:

Ison, MG, Michaels, MG. "RNA respiratory viral infections in solid organ transplant recipients". Am J Transplant. vol. 9 Suppl 4. 2009. pp. 166-72.

Kumar, D, Morris, MI, Kotton, C. "Guidance on novel influenza A/H1N1in solid organ transplant recipients". Am J Transplant. vol. 10. 2010. pp. 18-25.

Harper, SA, Bradley, JS, Englund, JA. "Seasonal influenza in adults and children - diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America". Clin Infect Dis. vol. 48. 2009. pp. 1003-32.

Current AST and IDSA guidelines for the treatment of CARV and influenza in both immunocompromised and "normal" hosts.

Gram-negative bacteria:

Van Delden, C, Blumberg, EA. "Multidrug resistant Gram-negative bacterial in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. S27-34.

Current AST guidelines for the management of multidrug-resistant Gram-negative bacteria in solid-organ transplant recipients.

NTM:

Dorman, S, Subramanian, A. "Nontuberculous mycobacteria in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. S63-9.

Current AST guidelines for the management of nontuberculous mycobacteria in solid-organ transplant recipients.

Griffith, DE, Aksamit, T, Brown-Elliot, BA. "An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases". Am J Resp Crit Care Med. vol. 175. 2007. pp. 367-416.

An excellent resource from the American Thoracic Society and the IDSA for the diagnosis and treatment of all significant types of NTM diseases in both "normal" and immunocompromised hosts.

Fungal:

Walsh, TJ, Anaissie, EJ, Denning, DW. "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America". Clin Infect Dis. vol. 46. 2008. pp. 327-60.

Pappas, PG, Kauffman, CA, Andes, D. "Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 48. 2009. pp. 503-35.

Current IDSA guidelines for the treatment of aspergillus and candidal disease in both "normal" and immunocompromised hosts.

Prioa, L, Miller, R. "Endemic fungal infections in solid organ transplant recipients". Am J Transplant. vol. 9 Suppl 4. 2009. pp. S192-98.

Singh, N, Forrest, G. "Cryptococcosis in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. S192-98.

Singh, N, Husain, S. "Invasive aspergillosis in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. S180-91.

Pappas, PG, Silveira, FP. "Candida in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. S173-79.

Current AST guidelines for the management of fungal infections in solid-organ transplant recipients

CMV references:

Eid, AJ, Razonable, RR. "New developments in the management of cytomegalovirus infection after solid organ transplantation". Drugs. vol. 70. 2010. pp. 965-81.

An excellent in depth review of the current literature and recommendations regarding CMV in the transplant population.

Ison, MG, Fishman, JA. "Cytomegalovirus pneumonia in transplant recipients". Clin Chest Med. vol. 26. 2005. pp. 691-705.

A detailed overview of this unique entity ,including epidemiology, radiographic findings, and other diagnostic tools.

Kumar, D, Chernenko, S, Moussa, G. "Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. 258-68.

The first major trial to assess the utility of a commercially available interferon-γ release assay (QuantiFERON CMV) to assess the development of CMV-specific cell-mediated immunity during the post-transplant prophylaxis period and its relationship to the development of late CMV disease.

Synder, LD, Medinas, R, Chan, C. "Polyfunctional cytomegalovirus-specific immunity in lung transplant patients receiving valganciclovir prophylaxis". Am J Transplant. vol. 11. 2011. pp. 553-60.

An assessment of CMV-specific immunity in CMV seropositive patients who receive a median of six months of CMV prophylaxis found comparable levels of CD4- and CD8-dependent cytokine responsiveness to the CMV antigens pp65 and IE-6 to seropositive patients not on prophylaxis and healthy controls, lending support to the extension of prophylaxis in these R+ patients.

Humar, A, Lebranchu, Y, Vincenti, F. "The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant patients". Am J Transplant. vol. 10. 2010. pp. 1228-37.

Humar, A, Limaye, AP, Blumberg, EA. "Extended valganciclovir prophylaxis in D+/R- kidney transplant recipients is associated with long term reduction in cytomegalovirus disease: two year results of the IMPACT study". Transplantation. vol. 90. 2010. pp. 1427-31.

The IMPACT trial was a large, randomized, controlled trial that demonstrated that extension of CMV prophylaxis in kidney transplant patients from one hundred days to two hundred days significantly reduced the incidence of CMV disease without additional safety concerns. This benefit, which was sustained up to two years after transplantation, led to studies in other SOT populations to determine whether extension of prophylaxis will have similar benefits (see next reference).

Palmer, SM, Limaye, AP, Banks, M. "Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial". Ann Intern Med. vol. 153. 2010. pp. 761-69.

Finlen-Copeland, CA, Davis, WA, Snyder, LD. "Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: A single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial". J Heart Lung Transplant. vol. 30. 2011. pp. 990-6.

A recent randomized, controlled trial examining prolonged (twelve months) CMV prophylaxis in lung transplant patients found reduced incidence and severity of CMV disease in these subjects, with no significant safety or resistance concerns. This benefit was sustained through a median of 3.9 years of follow-up.

Asburg, A, Humar, A, Rollag, H. "Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients". Am J Transplant. vol. 7. 2007. pp. 2106-13.

Asburg, A, Humar, A, Jardine, AG. "Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients". Am J Transplant. vol. 9. 2009. pp. 1205-13.

The VICTOR study, the first randomized, controlled trial to compare oral valganciclovir to IV ganciclovir for the treatment of cytomegalovirus disease in a mixed population of SOT recipients (primarily kidney transplant patients), demonstrated that, for selected SOT recipients with relatively low viral loads and mild to moderate, non-GI disease, oral treatment was not inferior to IV treatment in the short term or after one year of follow-up post-treatment.

Chmiel, C, Spiech, R, Hofer, M. "Ganciclovir/valganciclovir prophylaxis decreases cytomegalovirus-related events and bronchiolitis obliterans syndrome after lung transplantation". Clin Infect Dis. vol. 46. 2008. pp. 831-9.

Manuel, O, Kumar, D, Moussa, G. "Lack of association between beta-herpesvirus infection and bronchiolitis obliterans syndrome in lung transplant recipients in the era of antiviral prophylaxis". Transplantation. vol. 87. 2009. pp. 719-25.

Johanssson, I, Martensson, G, Andersson, R. "Cytomegalovirus and long-term outcomes after transplantation in Gothenberg, Sweden". Scand J Infect Dis. vol. 42. 2010. pp. 129-36.

Synder, LD, Finlen-Copeland, CA, Turbyfill, WJ. "Cytomegalovirus pneumonitis is a risk factor for bronchiolitis obliterans syndrome in lung transplantation". Am J Respir Crit Care Med. vol. 181. 2010. pp. 1391-96.

Paraskeva, M, Bailey, M, Levvy, BJ. "Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome". Am J Transplant. 2011.

Some recent publications that highlight the controversy surrounding the relationship of CMV disease and BOS.

CARV references:

Shah, PD, McDyer, JF. "Viral infections in lung transplant recipients". Semin Respir Crit Care Med. vol. 31. 2010. pp. 243-254.

Kumar, D, Humar, A. "Respiratory viral infections in transplant and oncology patients". Infect Dis Clin N Am. vol. 24. 2010. pp. 395-412.

Recent comprehensive reviews of CARV in transplant recipients.

Glanville, AR, Scott, AI, Morton, JM. "Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytical virus infection after lung transplantation". J Heart Lung Transplant. vol. 24. 2005. pp. 2114-19.

Palaez, A, Lyon, GM, Force, SD. "Efficacy of oral ribavirin in lung transplant patients with respiratory syncytical virus lower respiratory tract infection". J Heart Lung Transplant. vol. 28. 2009. pp. 67-71.

Two case series in lung transplant patients support the use of ribavirin for RSV lower respiratory tract disease.

Gram-negative bacteria references:

Lease, ED, Zaas, DW. "Complex bacterial infections pre- and post-transplant". Semin Respir Crit Care Med. vol. 31. 2010. pp. 234-42.

A recent comprehensive review of bacterial infections in lung transplant recipients.

Valentine, VG, Bonvillain, RW, Gupta, MR. "Infections in lung allograft recipients: ganciclovir era". J Heart Lung Transplant. vol. 27. 2008. pp. 528-35.

A large, single-center survey of more than two hundred lung transplant recipients demonstrates that Pseudomonas aeruginosa is the most commonly isolated lung pathogen, and demonstrates an overall decline in CMV infection but an increase in filamentous fungal infections.

Hadjiliadis, D, Steele, MP, Chapparo, C. "Survival of lung transplant patients with cystic fibrosis harboring panresistant bacteria other than Burkholderia cepacia, compared with patients harboring sensitive bacteria". J Heart Lung Transplant. vol. 26. 2007. pp. 834-38.

A multicenter study of more than one hundred CF patients suggests similar survival in CF patients colonized with pan-resistant bacteria as that in patients from the UNOS registry colonized with sensitive bacteria.

Alexander, BD, Petzold, EW, Reller, LB. "Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia cepacia complex". Am J Transplant. vol. 8. 2008. pp. 1025-30.

Boussaud, V, Guillemain, R, Grenet, D. "Clinical outcome following lung transplantation in patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two French centres". Thorax. vol. 63. 2008. pp. 732-37.

Murray, S, Charbeneau, J, Marshall, BC, LiPuma, JJ. "Impact of burkholderia infection on lung transplantation in cystic fibrosis". Am J Respir Crit Care Med. vol. 178. 2008. pp. 363-71.

Selected publications that examine the differential impact of B. cepacia genomovars (e.g., B. cenocepacia vs. others) on lung transplant outcomes in CF.

Vos, R, Vanaudenaerde, BM, Geudens, N. "Pseudomonal airway colonization: risk factor for bronchiolitis obliterans syndrome after lung transplantation?". Eur Resp J. 2008. pp. 1037-45.

Gottleib, J, Mattner, F, Weissbrodt, H. "Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis". Respir Med. vol. 103. 2009. pp. 743-9.

Botha, P, Archer, L, Anderson, RL. "Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome". Transplantation. vol. 85. 2008. pp. 771-74.

Selected publications that examine the relationship between Gram-negative bacterial colonization of the lungs and the development of BOS.

NTM references:

Doucette, K, Fishman, JA. "Nontuberculous mycobacterial infection in hematopoetic stem cell and solid organ transplant recipients". Clin Infect Dis. vol. 38. 2004. pp. 1428-39.

Chernenko, SM, Humar, A, Hutcheon, M. "Mycobacterium abscessus infections in lung transplant recipients: the international experience". J Heart Lung Transplant. vol. 25. 2006. pp. 1447-55.

Chalermskulrat, W, Sood, N, Neuringer, IP. "Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation". Thorax. vol. 61. 2006. pp. 507-13.

Garrison, AP, Morris, MI, Doblecki Lewis, S. "Mycobacterium abscessus infections in solid organ transplant recipients: report of three cases and review of the literature". Transplant Infect Dis. vol. 11. 2009. pp. 541-48.

Morales, P, Gil, A, Santos, M. "Mycobacterium abscessus infection in transplant recipients". Transplant Proc. vol. 42. 2010. pp. 3058-60.

Piersimoni, C. "Nontuberculous mycobacteria infection in solid organ transplant recipients". Eur J Clin Microbiol Infect Dis. 2011.

Selected publications that examine M. abscessus and other NTM infections pre- and post-transplantation.

Fungi references:

Sole, A, Salavert, M. "Fungal infections after lung transplantation". Curr Opin Pulm Med. vol. 15. 2009. pp. 243-53.

Hosseini-Moghaddam, SM, Husain, S. "Fungi and molds following lung transplantation". Semin Resp Crit Care Med. vol. 31. 2010. pp. 222-33.

Selected reviews of fungal diseases in lung transplantation.

Pappas, PG, Alexander, BD, Andes, DR. "Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)". Clin Infect Dis. vol. 50. 2010. pp. 1101-11.

Neofytos, D, Fishman, JA, Horn, D. "Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients". Transpl Infect Dis. vol. 12. 2010. pp. 220-9.

Recent reviews of the epidemiology of fungal infections in SOT recipients.

Wheat, JL. "Approach to the diagnosis of invasive aspergillus and candidiasis". Clin Chest Med. vol. 30. 2009. pp. 367-77.

Wengenack, NL, Binnicker, MJ. "Fungal molecular diagnostics". Clin Chest Med. vol. 30. 2009. pp. 391-408.

Overviews of the current status of diagnostic testing for common invasive fungal infections, including the Platelia Aspergillus EIA (galactomannan) test and (1-->3)-β.-D-glucan test.

Neoh, CF, Snell, GI, Kotsimbos, T. "Antifungal prophylaxis in lung transplantation - a world wide survey". Am J Transplant. vol. 11. 2011. pp. 361-6.

Husain, S, Paterson, DL, Studer, S. "Voriconazole prophylaxis in lung transplant recipients". Am J Transplant. vol. 6. 2006. pp. 3008-16.

Selected publications regarding the use of voriconazole prophylaxis after lung transplantation.

Howard, A, Hoffman, J, Sheth, A. "Clinical application of voriconazole concentrations in the treatment of invasive aspergillosis". Ann Pharmacotherapy. vol. 42. 2008. pp. 1859-64.

Hussaini, T, Ruping, MJ, Farowski, F, Vehreschild, JJ, Cornely, OA. "Therapeutic drug monitoring of voriconazole and posaconazole". Pharmacotherapy. vol. 31. 2011. pp. 214-25.

Recent recommendations regarding therapeutic drug monitoring of voriconazole.
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