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1 Advanced Lung Disease and Lung Transplant Programme, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
Correspondence and requests for reprints should be addressed to Professor J. J. Egan, Department of Respiratory Medicine, Mater Misericordiae University Hospital, University College Dublin, Eccles Street, Dublin 7, Ireland. E-mail: jegan{at}mater.ie
ABSTRACT
Allograft infection after lung transplantation has a significant impact on the outcome and can be a diagnostic challenge. The increased susceptibility of the pulmonary allograft to infection is due to its direct contact with environmental microbes by inhalation, concurrent immunosuppression, and the impaired clearance mechanisms after denervation of the transplanted lung. The possible spectrum of microorganisms infecting the allograft after lung transplantation is broad, but commonly includes Pseudomonas aeruginosa, cytomegalovirus, community-acquired respiratory viruses, and Aspergillus species. Prophylactic antimicrobial treatment regimens after surgery reduced the incidence of infections. However, preventive strategies for reducing infectious complications used by different transplant centers are still heterogeneous, and many questions regarding efficacy remain unanswered.
Key Words: lung transplantation • infection • prophylaxis
Infectious complications remain one of the most important causes of morbidity and mortality in lung transplant recipients (1). After lung transplantation, the pulmonary allograft is the most common infection site (2). Reasons for this susceptibility include the continuous and direct exposure of the pulmonary allograft to microbes; the denervation of the allograft with subsequent impaired cough reflex and abnormal mucociliary clearance; the impaired lymphatic drainage; complications associated with the anastomosis site; transmission of infection from the donor lungs; infection from the native lung in single lung transplantation; and the immunosuppression involved in transplantation (1). Preventive antimicrobial strategies have reduced the incidence and altered the timing of infections from different microbes after lung transplantation (3). With this short review, we intend to give an overview of the most frequent pathogens after lung transplantation.
BACTERIAL INFECTIONS
Bacterial Infection of the Lung Allograft
Bacterial pneumonia is a frequent complication after lung transplantation. After introducing routine preventative postoperative antimicrobial therapy, the incidence of bacterial infections has changed over the last decades (1, 4–6). In recent studies bacterial microbes were isolated in up to 80% of transplant recipients (1, 4, 5). A prospective Spanish multicenter study with inclusion of 236 lung transplant recipients, with a median follow-up of 180 days, revealed an incidence of 72 pneumonic episodes per 100 lung transplant recipients per year. In two thirds (57 cases), the microbiological etiology was established, and 82% were bacterial infections. Pseudomonas aeruginosa was isolated in 24.6% (n = 14); Acinetobacter baumannii and Staphylococcus aureus each in 14%; Escherichia coli, Klebsiella pneumoniae, and Stenotrophomonas maltophilia each in 5.3% of cases; and Pseudomonas putida, Serratia marcescens, and Burkholderia cepacia were also isolated (each 1.8%, n = 1). Mycobycterial infections were found in 5.3% of cases (3.5% Mycobacterium tuberculosis, 1.8% Mycobacterium avium) (4).
The highest risk of pneumonia is during the first month after lung transplantation, and this risk reduces after 6 months (4, 6).
A significant number of the early episodes of bacterial pneumonia are derived from donor lungs (6). However, microbiological screening of donor lungs followed by an adapted prophylactic postoperative antibiotic treatment improved the recipient outcome (7). Late onset of bacterial pneumonia has an association with bronchiolitis obliterans. Episodes of pulmonary infection in lung transplant recipients with diagnosed bronchiolitis obliterans syndrome (BOS) have been associated with a faster progression through BOS stages and to death (8).
P. aeruginosa
Recipients with cystic fibrosis (CF) have a higher susceptibility to pulmonary P. aeruginosa colonization/infection compared with recipients without CF (9–13). The higher incidence of pulmonary Pseudomonas colonization in patients with CF after lung transplantation is believed to be due to spread from extrapulmonary reservoirs in the recipient (12–14).
Later in the time course after lung transplantation, the frequency of P. aeruginosa colonization in airways increases and can be associated with chronic graft rejection, the BOS. The Newcastle Transplant group have shown an association between de novo colonization of P. aeruginosa with the subsequent development of BOS in lung transplant recipients (13). Vos and colleagues observed in their single-center study that post-transplant P. aeruginosa colonization was, in univariate analysis, an independent risk factor for BOS and responsible for a worse survival of BOS, although the multivariate analysis showed only a trend for colonization as an independent risk factor (15).
B. cepacia Complex
B. cepacia complex can be further divided into different genomovars. B. cepacia complex may cause multi- or panresistant invasive infections in patients with CF and is associated with a pretransplant mortality of up to 50%. Burkholderia cenocepacia (genomovar III) is the most frequent isolated subtype worldwide; however, significant local differences exist in prevalences of the B. cepacia complex and its subgroups (16). B. cenocepacia is associated with an increased early post-transplant morbidity and mortality, while the other genomovars, under adapted antimicrobiotic protocols, have been reported to have similar outcomes compared with patients with P. aeruginosa colonizations (16, 17). However, the virulence factors of B. cepacia complex are still poorly understood and differ between the strains of each genomovar. Whether colonization with B. cepacia is an absolute contraindication to transplant remains controversial (18).
Chlamydia pneumonia
Chlamydia pneumonia is an intracellular bacterium, and limited data relating to C. pneumonia infections exist in lung transplant recipients. Glanville and coworkers have investigated 232 bronchoalveolar lavages (BALs) of 80 lung transplant recipients performed over a 1-year period (19). Thirty-six recipients were studied during the first month after lung transplantation, and nine (25%) had a positive nested PCR for C. pneumonia. Three of these nine patients had C. pneumonia in their native remaining lung and responded to treatment with a macrolide, while the BALs of three other patients stayed positive for C. pneumonia and died due to airway disease within 1 year after transplantation. Seventy-one patients were studied after the first month after lung transplantation. Again, 25% (n = 18) tested positive for C. pneumonia between 48 and 2,620 days after transplantation. Five of these 18 recipients had acute bronchopneumonia. In 15 of the 18 patients transbronchial biopsies were performed, and acute pulmonary allograft rejection was found in 11. Recipients of single lung transplants with underlying diagnosis of chronic obstructive pulmonary disease were more likely to test positive for C. pneumonia in either their native lung or their allograft when compared with patients with interstitial lung disease. The authors concluded that persistent C. pneumonia infection in lung transplant recipients was associated with early mortality and allograft dysfunction (19).
Mycobacterium Species
Infection with M. tuberculosis may occur due to reactivation, occult disease in the remaining native lung after single lung transplantation, transmission by transplantation, or nosocomial infection (4, 20–23). Infections with nontuberculous Mycobacteria (NTM) are only occasionally reported. However, two retrospective studies identified a particular frequent occurrence of NTM infections (23, 24). Chalermskulrat and colleagues identified in a retrospective study of lung transplant recipients with CF that the prevalence for NTM disease was 3.4%. However, overall rates of invasive disease were low, and the increased risk for post-transplant NTM disease were restricted largely to those with pre-transplant Mycobacterium abscessus isolates. Medical treatment effectively controlled NTM disease after lung transplantation and did not affect survival (24).
Bacteremia in Lung Transplant Recipients
Bacteremia after lung transplantation is associated with a high mortality rate. A recent prospective multicenter study identified 56 lung transplant recipients with bacteremia, with a mortality rate of 25% at 28 days. Of these 56 patients, 35 underwent lung transplantation during the study period, and an incidence rate for bacteremia of 11.5% was calculated. Pulmonary infections followed by catheter-related infections were the leading portal of entry. After 1 year, the leading source of bacteremia changed to catheter-related infections. P. aeruginosa was the most common cause (14/56), followed by S. aureus (9/56) B. cepacia (5/56), Enterococcus faecalis (5/56), Staphylococcus epidermidis (4/56), and Klebsiella pneumoniae (4/56). Multiple antibiotic resistance was documented in 48% (27/56) of the isolates (25).
VIRAL INFECTIONS
Cytomegalovirus and Other Human Herpes Viridae
Cytomegalovirus (CMV) is one of the most important pathogens after lung transplantation (26). Like other herpesviridae, CMV has the ability to develop a life-long latency in the host with possible reactivation. Transplantation of CMV-seropositive donor lungs transmits a significant viral load to recipients (27). Recipients with evidence of previous/latent CMV infection (seropositive recipients) are at risk, while seronegative recipients transplanted with a seropositive pulmonary graft are at highest risk of developing CMV infection and disease after lung transplantation (primary infection). Further risk factors for CMV infection include induction therapy with antilymphocytic therapy and coinfection with human herpes virus (HHV) 6 and 7 (28).
The incidence and timing of CMV infections and disease has changed over the last decade with the introduction of preventative strategies (see CMV PROPHYLAXIS) (29). A Spanish prospective multicenter study has revealed an incidence of CMV pneumonitis in 5 per 100 lung transplant recipients per year in patients with CMV prophylaxis (4). Given the definition of CMV infection (isolation of virus or evidence of active viral replication either by molecular or immunologic techniques or by seroconversion) and CMV disease (histologic evidence of tissue invasion, positive tissue culture, or by characteristic syndrome after exclusion of other causes), the incidence is reported to range from 30 to 86%, with an associated mortality range of 2 to 12% (26–30, 31). With prevention strategies, the presentation of CMV infection and disease occurs later after transplantation. Without prophylaxis, the symptoms of CMV reactivation occur typically between the first and fourth month after transplantation. Prophylaxis has led to the emergence of antiviral-resistant CMV strains that can be categorized into two major genotype groups: UL 97 and UL 54. While the UL 97 region corresponds to a phosphotransferase essential for activating ganciclovir, mutations of the UL 54 region lead to DNA polymerase changes, which can cause resistance to foscarnet, cidofovir, and/or ganciclovir. Different mutations of the regions are possible and are associated with variable strength of the resistance. Risk factors for developing CMV-resistant strains are CMV mismatch with seronegative recipient and seropositive donor, prolonged prophylaxis with oral ganciclovir, and intense immunosuppression (29).
Beside direct effects of CMV disease leading to organ damage, CMV provokes additional alteration of the immune system, referred to as indirect effects of CMV infection (32). Indirect effects of CMV can lead to increased opportunistic infections and are thought to be associated with acute rejection episodes.
The impact of CMV on chronic allograft rejection in lung transplantation remains unclear. Given (1) the bi-directional relationship of CMV replication and allograft injury through proinflammatory cytokines and intracellular mediators, (2) molecular mimicry of CMV antigens with HLA-DR, and (3) that ongoing graft injuries may lead to bronchiolitis obliterans, an association of CMV with BOS would be expected. However, clinical studies have failed to show a uniform relationship of CMV infection or disease and chronic allograft rejection (8, 33, 34).
HHV 6 and 7, like CMV, belong to the Betaherpesviridae group. Both viruses are lymphotropic, and primary infection occurs during early childhood, with a seroprevalence up to 100% in adulthood. Reactivation early after solid organ and lung transplantation is reported to be common. HHV 6 may be associated with skin rashes, hepatitis, bone marrow suppression, pneumonitis, and encephalopathy; however, most reactivations are believed to be asymptomatic. The clinical impact of HHV 7 is less well understood. Co-infection of the three Betaherpesviridae can lead to interactions of the viruses and facilitate reactivation of each (35).
The Alphaherpesviridae include herpes simplex virus (HSV 1 and 2) and Varicella zoster virus (VZV). Two decades ago, infection with HSV had been a feared complication within the first weeks after lung transplantation and was associated in up to 10% of such transplantations with severe pneumonitis and a high mortality rate (1). Today, however, with effective antiviral prophylaxis, organ infection with HSV has became a rare complication. Primary VZV infection causes chickenpox. Reactivations cause herpes zoster, with painful vesicular skin lesions usually in a dermatomal distribution. A retrospective single-center study in 239 lung transplant recipients with a median follow-up of 722 days calculated an incidence of 55.1 cases per 1,000 person-years for herpes zoster episodes and a cumulative probability of 20.2% after 5 years. 5.7% of the patients had disseminated cutaneous infection, and reinfection occurred in 13.8%. Post-herpetic neuralgia was observed in 20%. None had a visceral infection. CMV prophylaxis was protective against herpes zoster (36).
The Gammaherpesviridae, including HHV 8 and Ebstein Barr Virus (EBV), are oncogenic viruses. HHV 8 causes Kaposi sarcoma. EBV is strongly associated with post-transplant lymphoproliferative disease (PTLD). PTLD is a heterogeneous group of lymphoproliferative disorders ranging from reactive, polyclonal hyperplasias to aggressive non-Hodgkin's lymphomas. The development of PTLD is linked to immuosupressant-induced deficient EBV-specific cellular immune response (37). The incidence of PTLD after lung transplantation is between 1 and 20%. Major risk factors for developing PTLD in solid organ transplantation are intense and/or prolonged immunosuppression and EBV mismatch (transplantation of an EBV-positive donor into a EBV-negative recipient) (36–38). A continuous increase of EBV load is indicative of imminent PTLD (39). The EBV-DNA load is paralleled with the strength of the immunosuppression. The Groningen group used the EBV-DNA load as surrogate marker of the degree of immunosuppression. In their report they included 75 lung transplant recipients for a routine quantitative EBV-DNA PCR in whole blood samples twice per year with a follow-up of 4.5 years. The median time after transplant at the beginning of the study was 4.25 years. They reduced the antimetabolite therapy of their standard triple immunosuppression stepwise and started antiviral therapy with valaciclovir if the patients had an increased EBV-DNA load of greater than 10,000 copies per milliliter. With this treatment regime they observed a significant reduction of EBV-DNA load. Only one patient developed PTLD and died. Interestingly, no patient developed acute rejection after reduction of immunosuppression. The authors concluded that their approach was safe regarding reducing immunosuppression and might prevent PTLD development (40).
Community-acquired Respiratory Viruses
Different viruses are pooled into the community acquired respiratory viruses (CARV) group. This includes the Picornaviridae (rhinovirus and enterovirus); the Coronaviridae (coronavirus); the Paramyxoviridae (respiratory syncytial virus, parainfluenza virus, human metapneumovirus); the Orthomyxoviridae (influenza A and B); and the Adenoviridae (adenovirus). Airway infections with CARV are common in lung transplant recipients. The incidence of CARV infection in lung transplant recipients with symptoms of airway tract infections can be up to 57% (41). The presentation of CARV infection varies from being asymptomatic to mild upper airway tract infections to severe pneumonia. The severity of the infections is also related to the type of virus. Adenovirus infections of the pulmonary graft can be associated with a high mortality rate (42). However, even rhinoviruses (thought to be less virulent) can cause lower respiratory tract infections and have been persistently detected in two lung transplant recipients with graft dysfunction in a study by Kaiser and colleagues (43). Bacterial and fungal super infections are a feared complication of CARV infections.
CARV infection of pulmonary grafts has been associated with onset of acute and chronic rejection (44, 45). A prospective study of the Toronto group enrolled 50 lung transplant recipients with symptoms of viral respiratory tract infection (patients with positive sputum cultures or CMV antigenaemia were excluded) and, as a control group, 50 stable lung transplant recipients. In 66% of the patients with symptoms of respiratory tract infections, CARV (respiratory syncytial virus, parainfluenza virus 1–3, influenza virus A and B, adenovirus, human metapneumovirus, rhinovirus, enterovirus, and coronavirus) were detected in nasopharyngeal and oropharyngeal swabs. In the control group, only rhinovirus was detected in 8% (4 patients). Three months after enrollment, episodes of acute rejection occurred in 16% and FEV1 decline of more than 20% in 18% of transplant recipients with a respiratory tract infection, while none experienced an acute rejection nor a decline in FEV1 more than 20% in the control group (46).
However, another prospective study by Milstone and colleagues revealed no increased incidence of bronchiolitis obliterans in lung transplant recipients with CARV-mediated respiratory tract infections (47). They enrolled 50 lung transplant recipients during a single respiratory viral season (November–March). Thirty-two patients had symptoms of respiratory tract infections. In 17 patients, CARV (respiratory syncytial virus serotype A and B, parainfluenza virus 1–3, influenza virus A and B, and adenovirus were analyzed) were detected. After one year, bronchiolitis obliterans (BOS) occurred in 1 out of the 17 patients with CARV detection compared with 3 out of 33 patients with no CARV detection.
Other Viruses
West Nile virus belongs to the Flaviviridae virus family. The transmission to humans is mainly through mosquito vectors from avian hosts. Transmission also occurs through blood transfusions or infected donor organs (48). The West Nile virus is widespread in Africa, Europe, and Asia. Since the outbreak in 1999 in New York, the virus has spread rapidly over the Western hemisphere (49). Infections with West Nile virus can lead to neuroinvasive disease with meningitis, encephalitis, and flaccid paralysis, and fatal outcomes are not uncommon. Infected transplant recipients are at increased risk of developing neuroinvasive disease (up to 40%) compared with the general population (< 1%) (50, 51).
BK virus is a human Poliomavirus with a seroprevalence in healthy adults up to 80 to 100%. In kidney transplant recipients, reactivation of BK virus occurs in 10 to 45% and can cause three different lesions: hemorrhagic cystitis, urethral stenosis, and tubulointerstitial renal disease, termed BK virus–associated nephropathy. In lung transplant recipients, only a few cases with BK virus–associated nephropathy of the native kidney have been reported (52). In a prospective longitudinal study by Doucette and colleagues, the serum and urinal BK viral load was measured by real-time PCR in 60 nonrenal solid organ transplant recipients (7 heart, 25 liver, and 28 lung transplant recipients) at the time of transplantation and every 3 months until 9 months after transplantation (53). BK viruria was detected in nine patients. However, an association with renal dysfunction was not observed and BK viremia was not detected at all (53). Similar results were found on another prospective study involving 50 lung transplant recipients. Viruria was detected in 24%, with no association with renal failure. On average, patients were enrolled 3.7 ± 2.7 years after lung transplantation, and urinary samples were analyzed every 3 to 4 months over a period of 17 months (54).
Parvovirus B19 can cause pure red cell aplasia, which is a rare complication after lung transplantation and is more common in renal transplant recipients (55).
Emerging viruses can be very harmful for transplant recipients. The outbreak of the West Nile virus showed how vulnerable and predisposed transplant recipients are to infections with emerging viruses. Kumar and Humar recently proposed a potential classification with three categories. A first group includes old, known microbes infecting recipients but with previously unrecognized pathogenicity to patients after transplantation (e.g., HHV 6 and 7). A second category includes established microbes with known disease states, in which the infection rate is increasing or becoming associated with more severe disease states (West Nile viruses, Poliomavirus). The third group includes new pathogens with new diseases (SARS, Xenotransplantation) (56).
FUNGAL INFECTIONS
Infection with Aspergillus spp. is the most common fungal infection among lung transplant recipients. Fungal infections occur in 15 to 35% recipients after lung transplantation; Aspergillus spp., together with Candida spp., are responsible for over 80% of these infections (57).
Risk factors for fungal infections include complicated postoperative course, early fungal colonization of the airways, frequent bacterial infections, coexisting CMV infection, bronchiolitis obliterans, renal failure, age of recipient, and environmental factors. The mortality rate of fungal infections can be over 80%. Early recognition is essential for successful treatment; however, establishing the diagnosis of fungal infection is challenging.
Aspergillus Species
Aspergillus infections can be further divided into infections of the bronchial anastomosis and the tracheobronchial tree, invasive pneumonia or disseminated infection (4, 58–60). A review of the literature of Singh and Husain has revealed a incidence of Aspergillus infection of 6.2% in lung transplant recipients (58). Fifty-eight percent had tracheobronchitis or anastomotic infections, while 32% had invasive pulmonary aspergillosis and 10% had disseminated infections. Three months after lung transplantation, 75% of Aspergillus infections occurred in the tracheobronchial tree, compared with 18% invasive pulmonary and 7% disseminated infections. Interestingly single lung transplant recipients had a later onset of Aspergillus infection compared with double lung transplant recipients.
The most common Aspergillus species is Aspergillus fumigatus (91%), while infections with Aspergillus flavus and Aspergillus niger occurred in 2% and mixed Aspergillus species were detected in 5%. The overall mortality after invasive Aspergillus infection was 52%, and 82% of patients with invasive pulmonary aspergillosis died (59).
The diagnosis of invasive aspergillosis is difficult. The airways of up to 55% of lung transplant recipients can be colonized with Aspergillus species. Detection of Aspergillus in lung transplant recipients with invasive aspergillosis has a low sensitivity, as isolation in sputum cultures ranges from 8 to 34%, and isolation and cultures from BALs are positive in only 62% of cases (2, 60).
Nodular opacities and areas of consolidation observed on computer tomogram that may indicate invasive pulmonary Aspergillus infections may also represent other diagnoses (58, 60, 61). The halo sign, which is a highly specific finding for invasive Aspergillus pneumonia in neutropenic patients, is infrequently present in lung transplant recipients (61, 62). New rapid laboratory methods can also be used for diagnosing invasive aspergillosis. Galactomannan is a cell wall component and is released during Aspergillus growth. In lung transplant recipients the sensitivity of measuring serum galactomannan was low (30%) (63). More promising has been a study in lung transplant recipients where the galactomannan presence was analyzed in BAL. The Platelia enzyme immunoassay was used, and with a cutoff index of 1 or greater revealed a sensitivity of 60% and specificity of 98% for the diagnosis of invasive aspergillosis. However, antifungal prophylaxis (false negative results) and antibiotic treatment with pipercillin-tazobactam (false positive results) can reduce the quality of the test results (64). Other emerging rapid laboratory methods are diagnostic tests for 1
3-Beta-D-Glucan. This fungal cell wall polysaccharide is not specific for Aspergillus spp., and currently no data in lung transplant recipients are available.
Last, but not least, surveillance bronchoscopies are helpful for diagnosing invasive aspergillosis. Tracheobronchitis and anastomotic Aspergillus infections can be visualized and appropriate samples for culture or histology taken.
Candida Species
Candida species often colonize the airways of lung transplant recipients. Most invasive infections appear during the first month after transplantation, either after postoperative complications with a prolonged stay in the intensive care unite or as a transmission of a heavily colonized donor organ. Invasive infections with Candida species include candidemia, mediastinitis, and necrotic infections of the anastomosis (1, 65, 66). Pre-emptive antifungal treatments/prophylaxis can prevent the progression of benign candidal colonization of the airways to fatal invasive disease; however, severe candidal growth in donor airways can still lead to invasive candidal infections (1, 57, 67).
Zygomycetes, Scedosporium Species, and Fusarium Species
Zygomycosis is an invasive fungal infection with ubiquitous found saprophytic fungi, including Rhizopus, Rhizomucor, Mucor, and Absidia. Less frequent are Cunninghamella, Saksenaea, and Apophysomyces. In a retrospective study, Almiroudys and colleagues identified Zygomycosis in 14 of 1,000 lung transplant recipients (68). The overall mortality was approximately 50%. A favorable outcome was associated with limited and surgically accessible disease. Prognosis of disseminated infections and rhino-cerebral infections were associated with a high mortality up to 100% (68).
Scedosporium species are filamentous fungi, and morphologically resemble Aspergillus species. The most clinically relevant species are Scedosporium apiospermum (the asexual anamorph of Pseudallescheria boydii) and Scedosporium prolificans. They can colonize the airways, and disseminated infections occur in periods of increased immunosuppression and neutropenia. The mortality with disseminated infection is believed to be poor. However, a recent report has described two lung transplant recipients with disseminated S. apiospermum with prolonged survival after treatment with the newer triazole voriconazole, although the fungi could not be eradicated. S. prolificans is resistant to all known antifungal drugs (69, 70).
Fusariosis is a very uncommon syndrome in lung transplant recipients (1). Fusarium species are hyaline molds and have a high potential for hematogenous dissemination. A few reports have been published dealing with Fusarium solani and Fusarium proliferatum infections. In severely immunocompromised patients, Fusarium species are highly invasive with a high rate of positive blood cultures. Compared with hematologic stem cell transplant recipients, patients after solid organ transplantation tend to have more localized infections and a better outcome. Voriconazole alone or in combination with Amphotericin B can be an effective treatment in patients with localized disease or recovered neutropenia (71–73).
PREVENTIVE STRATEGIES FOR REDUCING INFECTIVE COMPLICATIONS
A successful antimicrobial prophylactic regimen in lung transplant recipients starts with promoting lifestyle changes aimed at preventing transmission to the recipient of microbes from the environment, food and water, or from other patients. In general, three different treatment strategies can be used for prophylaxis: vaccination, general prophylaxis therapy, and pre-emptive therapy (1).
Vaccination
The American Society of Transplantation guidelines for vaccination (and other recommendations) advise primary immunization in the pre-transplant setting followed by boosting after transplantation as required (e.g., pneumococcal vaccine) or yearly adapted epitopes (e.g., influenza vaccine) (74–76). However, a recent survey of pediatric lung transplant centers revealed heterogeneous vaccination practice (77). Live vaccines, containing live, attenuated microorganisms, should generally be avoided after lung transplantation. The theoretical concern of triggering episodes of acute rejection with vaccinations has never been substantiated by clinical data. However, the immunologic protection of vaccination in patients after lung transplantation may be limited not only in extent also in duration (3).
Post-surgical Antibacterial Prophylaxes
Routine post-surgical broad-spectrum antibiotic therapy aimed at gram-negative microbes, including treatment targeted according to culture findings from donor lungs, has been recommended for several years and is widely used. Adapted antimicrobial prophylaxis directly after surgery are recommended in recipients with known resistant microbes (1).
PCP prophylaxis
One of the most successful antimicrobial prophylaxes is probably the administration of sulfamethoxazole and trimethoprim for the prevention of Pneumocystis jirovecii pneumonia, with additional antimicrobial effects against Toxoplasma gondii, many nocardia, Listeria species, and bacteria of the respiratory and urinary tract (3).
CMV prophylaxis
A recent Cochrane review by Hodson and colleagues analyzed antiviral medications for preventing CMV-related events in solid organ transplant recipients. Antiviral prophylaxis reduced the risk significantly for CMV disease (relative risk [RR], 0.61; 95% confidence interval [CI], 0.48–0.77) and CMV infection (RR, 0.42; 95% CI, 0.34–0.52), with the highest effectiveness with either intravenous ganciclovir or oral valganciclovir (78). The CMV Expert Advisory Committee recommended in 2005 to consider prophylaxis with valganciclovir for at least 100 days for all lung transplant patients at risk of CMV. Also recommended was consideration of additional administration of intravenous CMV-directed immunoglobulins, as well as monitoring of CMV viremia (31). The optimal duration of CMV prophylaxis after lung transplantation remains unclear. Short courses of prophylaxis, for approximately 1 month, were tending to delay CMV reactivation, although recently published single-center data with long-term prophylaxis showed more promising results. In their study, Zamora and colleagues prolonged the postoperative prophylaxis. They used intravenous ganciclovir in combination with CMV immune globulins (30 d for D+/R+ and D–/R+, and 90 d for D–/R+), then changed to valganciclovir. They planned, prospectively, treatment for 180 days, 270 days, or 365 days after transplantation, with each group comprising 30 lung transplant recipients at risk of developing CMV-related events. However, because of side effects (neutropenia, elevated liver function tests, central nervous system symptoms) they defined post hoc five different groups of lung transplant recipients based on the amount of time they received prophylaxis: less than 100 days (n = 18), 100 to 179 days (n = 11), 180 days (n = 21), 270 days (n = 20), or 365 days (n = 20). The lung transplant recipients who tolerated the prophylaxis had an incidence of CMV infection and disease of 6.6% (patient groups: 180 d, 9.5%; 270 d, 5%; and 365 d, 10%) compared with the discontinued patient groups of 41.4% (patient groups: < 100 d, 44%; 100–179 d, 27%) or compared with their historical group (prolongation with aciclovir) of 35% (79). The Zurich group included in their study 104 lung transplant recipients who were at risk of developing CMV-related events (either CMV infection or CMV disease); they excluded 64 recipients with CMV-negative seromatch and 7 recipients who died within 30 days after transplantation. Ninety-six patients received prophylaxis (valganciclovir or ganciclovir) for an average of 507 (± 398) days, and were either compared with 8 historical control subjects (who received transplant before 1994) or with 274 recipients pooled from the Medline who received no prophylaxis. The cumulative incidence for CMV-related events was 27% for the prophylaxis group compared with 75% of the control groups. They also reported a significant lower cumulative incidence of BOS and an improved survival compared with the historical control subjects or the pooled Medline data of recipients with no prophylaxis (BOS I at 5 yr, 43% versus 60% or 78%; survival at 5 yr, 73% versus 47% or 50%) (31). A retrospective study by Valentine and colleagues examined the onset of CMV pneumonitis; BOS and survival in 130 CMV donor or recipients seropositive lung transplant recipients. Ninety patients who received indefinite prophylaxis were compared with 40 patients with discontinued prophylaxis. The reasons for discontinuation were: prophylaxis stopped by outside physicians (n = 10), Leucopoenia (n = 6), cost (n = 6), drug study protocol (n = 6), renal insufficiency (n = 5), noncompliance (n = 3), GIT/hepatic complications and nausea (n = 3), or presumed CMV resistance (n = 1). The cumulative incidence for CMV pneumonitis at 5 years was 2% for the patients with indefinite prophylaxis and 57% for patients with discontinued prophylaxes; the BOS-free survival and survival was similar in both groups. However, two thirds of patients (n = 10) with discontinued prophylaxis who had CMV pneumonitis developed BOS with a median onset time of 116 days (80).
Antifungal prophylaxis
Different antifungal prophylactic regimens have been reported to be effective in preventing fungal disease after lung transplantation. Cross-sectional survey data of 43 lung transplant centers across the world in 2002 revealed a practice of universal antifungal prophylaxis in the postoperative period in 69% of the centers, and in 31% a pre-emptive approach for fungal airway colonization was used (81). Aerosolized Amphotericin B deoxicholate alone or in combination with itraconazole were the most commonly used drugs for antifungal prophylaxis. More recently, a study by Husain and colleagues outlined antifungal prophylaxis with voriconazole, a third generation azole, in lung transplant recipients (82). Sixty-five patients were treated directly postoperatively with voriconazole for 3 months (or high-risk patients for 6 mo) and compared with 30 patients receiving a targeted prophylaxis with fluconazole alone or in combination with itraconazole and/or inhaled amphotericin B for 3 to 6 months. The rate of invasive aspergillosis 1 year after transplantation in the patients with voriconazole after was 1.5% compared with 23% in the targeted prophylaxis group. Overall 40% of the lung transplant recipients had 73 episodes of fungal colonization. The incidence of total fungal colonizations did not differ between patient groups. While Candida species were significantly more common in the voriconazole prophylaxis group, colonization with Aspergillus species was not significantly different between patient groups. However, a threefold or higher increase of liver enzymes was noted in 37 to 60% of the patients in the voriconazole group compared with 15 to 41% in the targeted prophylaxis group, and 14% had to stop the prophylaxis with voriconazole due to side effects (8% in the targeted prophylaxis group) (82).
FOOTNOTES
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form September 30, 2008; accepted in final form October 10, 2008)
REFERENCES
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