Incidence and risk factors for respiratory tract bacterial colonization and infection in lung transplant recipients

Lung transplant (LT) is considered a reasonable treatment option for selected patients with chronic respiratory end-stage diseases. The most frequent indications for adult LT are chronic obstructive pulmonary diseases (COPD) with or without α1-antitrypsin deficiency, interstitial lung diseases, cystic fibrosis, and idiopathic pulmonary arterial hypertension [1, 2]. Each one of these diseases has its own peculiar features in term of transplant list waiting, mortality, and post-transplant survival [3, 4].

Despite post-LT survival rate has increased over the last years, risk of early and late post-surgical complications remains high for transplanted patients [2, 5]. In particular, lung transplant recipients (LTRs) are at higher risk to develop infectious complications compared to other solid organ transplants; this can be due not only to immunosuppressive regimens and changes in anatomical structures after surgery, but also to constant exposure of airways to the outside environment [6, 7]. Infectious complications represent the most frequent cause of death after graft failure within the first 30 days from transplant, and the first cause within the first year [2].

Generally, the most common infections occur following a specific pattern based on the time from LT, as a consequence of the exposure to different risk factors over the time such as hospitalization, immunosuppression, reactivation of latent infection, and community-acquired pathogens exposure. During the early post-transplant period, infections can be related to post-surgical complications, donor or recipient’s pre-existing colonizations/infections, or nosocomial-acquired organisms [6‐9]. Bacterial pneumonia is the most common infection in the first 30 days from LT, related to healthcare-associated or nosocomial bacteria. This risk decreases after 6 months from LT [7, 10] but the possibility to be colonized and infected by a multi-drug resistant (MDR) strain increases with the duration of pre-transplant hospitalizations and post-surgical intubation [1, 8].

Infections are also a major cause of late mortality, and a linkage (especially for bacterial aetiologies) with chronic rejection development is hypothesized, although their pathogenic role is not fully understood [1, 11].

Data on etiologic agents of pneumonia after lung transplant are limited for non-cystic fibrosis patients. Most of the bacteria isolated in post-transplant infections are Gram negative (e.g., Pseudomonas aeruginosa, Klebsiella pneumoniae) with a lower incidence of Gram positive bacteria, mainly represented by methicillin resistant Staphylococcus aureus (MRSA) [8, 12].

Prevalence and type of colonization, occurrence and type of infections and prevalence of MDR bacteria in the first month after transplantation can vary between patients in relation to the type of chronic illness causing end-stage organ disease, as well as to the clinical and microbiological history before and after transplantation [8, 13].

The aim of the study was to evaluate the incidence of and risk factors for respiratory bacterial colonization and infections within 30 days from LT in patients not affected by cystic fibrosis.

Graft colonization and infection in lung transplant recipients represent a common finding [13], with a higher risk observed especially in the first months after surgery [8]. In early post-surgery, the lung allograft is particularly susceptible to infections: the epithelium dysfunction related to the disruption of bronchial circulation and lymphatic drainage, the denervation of the allograft causing a loss of cough reflex and bronchial hyperresponsivity, and the possible stenosis or necrosis of the bronchial anastomosis may facilitate colonization or infection of airways mucosae and/or lung tissue [7]. Infections are the most common cause of death in lung recipients [1]. Most of the related literature on post-transplant infection management is based on experts’ opinion and single center retrospective studies, especially in Europe, but a comprehensive global analysis is difficult to achieve. Every day clinical management in different lung transplant centers may differs due to epidemiological peculiarity [21] and local evidence based medicine. Results from each single center could enrich data analysis and offer confrontation for clinical management.

With the limitations of a retrospective specific cohort analysis, our study revealed a significant increase of respiratory bacterial colonization by both overall bacteria (p < 0.0001) and by MDR/XDR bacteria (p < 0.0001) in the 30 days post-LT. A significantly greater percentage of 30-days respiratory infections occurred in patients with a baseline bacterial colonization (p = 0.03) or infection (p = 0.02).

Donor-derived infections are also of major concern [9]; however, a low risk of donor-recipient MDR transmission has been previously hypothesized [22]. In our cohort, at least 31% of donors had a respiratory bacterial colonization, with a low percentage of MDR bacteria (2.5%), but these observations appeared not to be related to colonization and infection in recipients.

In our cohort, the transplant type seemed to play a role in the prediction of post-transplant infectious risk within the first month after LT. In fact, patients with 30 days pulmonary colonization most frequently received baseline double lung transplant (61.3% vs. 36.5%, p = 0.02). Discordant data are reported in literature regarding correlation between type of LT, infectious complications, and outcome. Meyer et al. observed that single lung transplant in patients with IPF had a better 30-day and 1-year outcome, although the reasons were not clarified, and a role of early events (e.g., infections and colonizations together with surgical technical procedure) was hypothesized [23]. Other studies suggested that bilateral LT did not differ from single LT in terms of overall mortality, even if single LT could have better rates of long-term survival after transplant in > 60-year-old recipients [24, 25] and, on the other hand, that bilateral LT can offer a survival advantage in younger recipients with end-stage emphysema [24, 26]. Our findings can suffer from biases of a retrospective study; however, reported discordant data underline the need of further analysis regarding correlation of type of LT and infectious risk.

We also found that patients with chronic coronary heart disease were more subject to develop lower respiratory tract bacterial colonization in the first month after surgery. Twenty percent of lung recipients had ischemic heart disease as a baseline comorbidity, and these patients had a sixfold increment of bacterial colonization.

Our results showed also that peptic disease (non-ulcerative gastritis; esophagitis; gastric ulcer; and gastroesophageal reflux disease, GERD) was associated to a higher risk of MDR bacteria colonization in the first month after LT. This finding is in line with previous reports [27, 28], which also highlights a high incidence of peptic disease in lung recipients and a more rapid progression to acute and chronic graft rejection after transplant in patients affected by this condition. This can be theoretically explained by various factors, such as continuous asymptomatic aspiration of peptic material which can lead to direct injuries and trigger inflammatory response within the graft, thus facilitating bacterial colonization.

Interestingly, we also found that duration of nebulized therapy was linked to the risk of MDR colonization. In particular, patients who underwent longer periods of aerosolized antibiotic drugs administration were found to be less prone to develop lung MDR colonization within the first 30 days. No benefits were found about the use of aerosolized taurolidine (a topic decontaminant used in many lung transplant centers) as a prophylactic strategy; indeed, aerosolized taurolidine was associated to a higher risk of bacterial infections. This finding should be interpreted with caution due to the small study population and retrospective design of the study, since taurolidine could have been prescribed to patients at higher risk to develop infections: in our center, taurolidine aerosol is indeed commonly used, in combination with systemic antibiotics, as salvage off label therapy in severe respiratory infections after LT. As a consequence, prospective randomized studies are needed to clarify the role of taurolidine as an effective agent used to prevent bacterial respiratory infections. Nebulized administration of antibiotic can be a helpful additional strategy to decontaminate airways after transplant, especially from Gram negative isolates [29], although data from randomized trials are currently not available. This route of administration can be a way to optimize the treatment, reducing the risk of colonization, especially in the first year, with a limited risk of adverse reactions [29].

Even if not confirmed by multivariate analyses, our data revealed a lower 30 days colonization and infection rates (overall and by MDR bacteria) in patients receiving standard systemic antibiotic prophylaxis (extended spectrum cephalosporin plus a glycopeptide) in comparison with atypical regimens, endorsing the clinical relevance to follow guidelines indications [38], in absence of alternative clinical needs.

We also found a significant link between the occurrence of pneumonia in the early post-transplant period and body weight of the recipients. A higher baseline BMI was associated to a reduced risk of developing pneumonia. Our finding could be explained by the fact that a major reservoir of lean and fat mass could permit to bear major stresses, such as the surgery, shortening the ICU stay, and supporting recovery period. In addition, underweight, as well as obesity, can lead to recovery problems during post-surgery period and can be linked to a partially harmed immunity function. Our findings are in line with previous reports [30]: a major incidence of post-LT infections was observed in underweighted patients, together with a shorter survival. Optimal baseline BMI seems to be associated with lower mortality rates, especially at 90 days and 1 year [31]. Underweighted and obese patients also seem to be at higher risk of poor outcome in the first year [32]. Obesity of grades II and III, on the other hand, is an absolute contraindication to transplant, while a less strict approach is adopted with mild obesity (grade I) in which transplant can be considered as an option [33]. An ideal baseline body weight is an important factor to estimate infectious risk and to assess the predicted outcome of lung recipients [30].

We found an association between baseline IPF and the development of pneumonia by MDR bacteria. Previous studies reported high rates of pulmonary and bloodstream infection in person affected by pulmonary fibrosis [34, 35]. In our cohort, patients with baseline IPF were more prone to develop respiratory infections than patients with COPD. This could be related to a higher pre-LT immunosuppression: before 2014 steroidal and immunosuppressive drugs (e.g., azathioprine) were the only therapy for IPF. Therefore, a greater cumulative exposure to these drugs could have been linked to the high incidence of comorbidities and infections. This observation could also partly explain the higher post-transplant mortality in IPF patients, which some authors highlighted [4].

A higher incidence of infections by bacteria harboring MDR is known after solid organ transplant [13, 36]. An active surveillance program during the pre- and post-transplant period including surface swabs and respiratory secretions culture is fundamental to steadily detect colonizing MDR bacteria, thus optimizing post-transplant antibiotic strategies when needed, particularly in patients with PGD. The cause of PGD is likely multifactorial with brain death–related donor lung injury, ischemia-reperfusion injury, infection, and cardiopulmonary bypass representing some of the possible etiologies. Moreover, infections can represent factors that may confound and/or amplify a diagnosis of primary graft dysfunction [15]. In our study, we observed a significantly higher prevalence of PGD (all grades) in MDR infected patients (94.7% versus 63.4% in non-MDR infected patients, p = 0.01).

Our analysis of independent risk predictors identified also a role of pre-transplant respiratory colonization and infection in predicting 30 days pneumonia (respectively AOR 5.43, 95% CI 1.03–28.54, p = 0.04, AOR 22.42, 95% CI 2.22–269.20, p = 0.01), highlighting the role of an accurate pre-transplant microbiological monitoring strategy. Either in pre- and post-transplant period an appropriate use of antibiotics (on the basis of antimicrobial susceptibility testing) is crucial, in order to both prevent possible adverse effects and avoid selective pressure on resistant bacteria [36, 37].

In conclusion, it is well known that anamnestic, clinical, and microbiological pre-transplant features are key factors for planning the post-transplant strategies. Recent guidelines [38] have focused on surgical site infection, but in LT an increasing infectious risk is obviously present for respiratory tract infections. Identification of high-risk patients before the LT could guide to personalize prophylaxis and therapy, when needed, and to lead to shorter and tailored antibiotic treatment, reducing adverse effects and selection of MDR strains. On the basis of our results, the risk of post-transplant lung infectious complications could be stratified by considering several factors such as the indication for LT, the type of LT, the presence of certain comorbidities, and the microbiologic assessment before LT. Importantly, our results suggest that a wider use of early nebulized therapies could be useful to prevent potentially harmful colonization from MDR strains, thus potentially lowering infectious risk.