Complications In Lung Transplant Recipients Research Articles

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV-associated posttransplant lymphoproliferative disorder and worse survival.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P<.02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P=.01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P=.03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P<.0001). Early PTLD (first year) was associated with alemtuzumab use (P=.04), whereas IPF was a predictor for late PTLD (after first year) (P=.002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P=.04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.

Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study.

Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA. We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models. Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates. Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

Ureaplasma spp. and Mycoplasma hominis PCR in Respiratory Samples from Lung Transplant Recipients with Hyperammonemia Syndrome and Cerebral Edema

Hyperammonemia syndrome (HS) is a rare and life-threatening complication in Lung Transplant Recipients (LTRs) resulting in brain edema and death if not promptly treated. An association with Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma hominis (urea splitting organisms) infection has been suggested.

Simkania negevensis and Chronic Lung Allograft Dysfunction in Lung Transplant Recipients

Chronic Lung Allograft Dysfunction (CLAD) is a major complication in lung transplant recipients (LTRs). Underlying mechanisms leading to CLAD are still not well understood. We investigated the association of Simkania negevensis, an intracellular bacteria belonging to the Chlamydiales order, with the occurrence of CLAD in LTRs.

Antifungal Prophylaxis in Lung Transplant Recipients.

Invasive fungal infection remains a serious postoperative complication in lung transplant recipients and is associated with significant morbidity and mortality. Although most lung transplant centers use antifungal prophylaxis, consensus on the strategy, choice of antifungal agent(s), route of administration, and duration of prophylaxis have not been established. This review provides an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluates the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offers recommendations and opportunities for future research. Currently available data evaluating the efficacy of antifungal prophylaxis strategies is limited by a lack of prospective, randomized clinical trial data and variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. There is controversy regarding significant risk factors for invasive fungal infection, which has limited the development and validation of targeted prophylactic strategies. Inhaled formulations of amphotericin B remain the most widely studied option for universal prophylaxis and have been shown to be effective in reducing the incidence of invasive Aspergillosis as compared with no prophylaxis. Concern over early postoperative extrapulmonary infection may suggest a benefit of initial prophylaxis with a systemic azole. Long-term use of systemic antifungals is not optimal due to emerging evidence of long-term toxicities. Multicenter, randomized trials are needed to ascertain the optimal prophylactic strategy in lung transplant recipients. New agents and delivery mechanisms may offer additional opportunities for comparative research.

Tacrolimus-induced, Transplant-associated Thrombotic Microangiopathies after Lung Transplantation

We report a case of tacrolimus-induced transplant-associated thrombotic microangiopathies (TA-TMA) after lung transplantation. A 71-year-old man underwent lung transplantation secondary to idiopathic pulmonary fibrosis. After 4 months, he presented with abdominal discomfort and dyspnea, and was diagnosed with hemolytic anemia and thrombocytopenia. Tacrolimus was considered the cause of the TMA. Tacrolimus was stopped and several sessions of plasma exchange were performed immediately after diagnosis of TA-TMA. However, his platelet count did not normalize, gastrointestinal bleeding was recurrent, and severe pneumonia developed, following which he died. TA-TMA are rare but severe, life-threatening complications in lung transplant recipients. Therefore, the possibility of TA-TMA should be considered in posttransplant recipients.

Infectious Triggers of Chronic Lung Allograft Dysfunction.

Survival after lung transplantation is limited in large part due to the high incidence of chronic rejection, known as chronic lung allograft dysfunction (CLAD). Pulmonary infections are a frequent complication in lung transplant recipients, due both to immunosuppressive medications and constant exposure of the lung allograft to the external environment via the airways. Infection is a recognized risk factor for the development of CLAD, and both acute infection and chronic lung allograft colonization with microorganisms increase the risk for CLAD. Acute infection by community acquired respiratory viruses, and the bacteria Pseudomonas aeruginosa and Staphylococcus aureus are increasingly recognized as important risk factors for CLAD. Colonization by the fungus Aspergillus may also augment the risk of CLAD. Fostering this transition from healthy lung to CLAD in each of these infectious episodes is the persistence of an inflammatory lung allograft environment.

(635) - Impact of Operator and Anesthesia Choice on Bronchoscopic Biopsy Yield and Complications

Flexible bronchoscopy with bronchoalveolar lavage and transbronchial biopsy is the gold standard for the diagnosis of infection, acute rejection, and airway complications in lung transplant recipients. In the hands of an experienced operator, bronchoscopy carries minimal risk. The outcome of all bronchoscopies performed in the first year following lung transplantation at the Hospital of the University of Pennsylvania was recorded retrospectively. Records were included if lung transplantation was performed from January 2011 to December 2013. A total of 549 bronchoscopies were performed on 132 patients. Three hundred bronchoscopies were done on bilateral lung transplants and 249 on single lung transplants. Intravenous conscious sedation managed by the pulmonologist was used in 459 cases and 90 were done under general anesthesia. The bronchoscopy was performed during a rotation with a novice fellow in 168 of the 549 cases. The mean number of samples sent for analysis was 9.09±3.5 pieces, with a mean number of samples with alveolated tissue of 7.08±3.2. With novice fellows, the mean number sent was 8.82 with 6.97 pieces of alveolated tissue. These numbers were 9.10 and 7.12 versus 9.17 and 6.67 under conscious sedation and general anesthesia, respectively. There were complications in 82 (14.9%) of the bronchoscopies. We purposely had a sensitive definition of to be able to capture all unexpected events that were described in the report. These included: Bleeding controlled with suctioning, bleeding requiring the use of iced saline or epinephrine, bleeding requiring an endotracheal tube or bronchial blocker, pneumothorax without need for tube thoracostomy, pneumothorax requiring tube thoracostomy, hypoxemia requiring intervention during the procedure, hypoxemia requiring admission, sepsis linked to the procedure, and death. There was no significant difference in complications based on trainee level. There were more complications when procedures were performed under intravenous conscious sedation, with complications noted in 77 cases (16.8%) versus in 5 cases (5.6%) performed under general anesthesia. Bronchoscopy can be performed safely with no change in procedural yield or complications when novice trainees participate. While it does not affect yield, complications can potentially be reduced by the use of general anesthesia.

The ripple effect of a complication in lung transplantation: Evidence for increased long-term survival risk

ObjectiveLung transplantation is a life-saving procedure for patients who have end-stage lung disease. The frequency and severity of complications have not been fully characterized. We hypothesized that early in-hospital, postoperative complications decrease long-term survival. MethodsWe retrospectively identified in-hospital complications in lung transplant recipients, from the period January 2007 to October 2013. Complications were graded using the extended Accordion Severity Grading System (ASGS). Complications were categorized by event and organ system. Survival analysis was performed (P < .05) using a time-dependent model. ResultsAmong 748 eligible patients, 3381 independent in-hospital, postoperative complications occurred in 92.78% of patients. Median follow-up was 5.4 years. Complications associated with significant decrease in 5-year survival were: renal (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.40-4.48); hepatic (HR 4.08, 95% CI 2.86-5.82); cardiac (HR 1.95, 95% CI 1.56-2.45). The maximum ASGS of ≥5 (18.5% vs 73.8%), and the weighted ASGS sum >10 (2.5% vs 73.8%), were found to be significant predictors of long-term survival. Multivariate analysis identified a weighted ASGS sum of >10, and renal, cardiac, and vascular complications as predictors of decreased long-term survival. ConclusionsRigorous delineation of complications after lung transplantation showed that grade 5 ASGS in-hospital postoperative complications, and a weighted ASGS sum >10, were independent predictors of decreased long-term survival well beyond the initial perioperative period. These results may identify important targets for best practice guidelines and quality-of-care measures after lung transplantation.

Infecciones por mohos en el trasplante pulmonar

Invasive infections by molds, mainly Aspergillus infections, account for more than 10% of infectious complications in lung transplant recipients. These infections have a bimodal presentation: an early one, mainly invading bronchial airways, and a late one, mostly focused on lung or disseminated. The Aspergillus colonization at any time in the post-transplant period is one of the major risk factors. Late colonization, together with chronic rejection, is one of the main causes of late invasive forms. A galactomannan value of 0.5 in bronchoalveolar lavage is currently considered a predictive factor of pulmonary invasive infection. There is no universal strategy in terms of prophylaxis. Targeted prophylaxis and preemptive treatment instead of universal prophylaxis, are gaining more followers. The therapeutic drug monitoring level of azoles is highly recommended in the treatment. Monotherapy with voriconazole is the treatment of choice in invasive aspergillosis; combined antifungal therapies are only recommended in severe, disseminated, and other infections due to non-Aspergillus molds.

Utility of Procalcitonin as a Biomarker for Rejection and Differentiation of Infectious Complications in Lung Transplant Recipients

To evaluate the utility of procalcitonin (PCT) as a biomarker for rejection and differentiation of infectious complications in lung transplant recipients. An English-language literature search was conducted using MEDLINE (1966-September 2013) using the terms procalcitonin, transplantation, and lung transplantation. Additional articles were identified through a manual search of reference lists of the articles obtained. All articles evaluating PCT use in lung transplant recipients, including those where lung transplant patients were a subgroup of immunocompromised patients, were included. Infection and rejection are leading causes of mortality in lung transplant recipients, with similar clinical presentations; PCT could be a valuable biomarker to differentiate between these complications. Five prospective and 2 retrospective single-center observational evaluations were reviewed. Study populations were diverse, with only 3 focused solely on lung transplant recipients. PCT levels were not elevated during episodes of rejection and viral infections, whereas elevations were seen with bacterial infections. The effect of colonization or fungal infection on PCT varied. Current data suggest that PCT can be used to differentiate bacterial infections from rejection in lung transplant recipients, with unclear utility in colonization or fungal infection. It is reasonable to conclude that PCT values more than 8.18 ng/mL and PCT area under receiver operating curve greater than 0.97 indicate bacterial infection in this population, and PCT trends may increase predictive value. Because of the lack of randomized controlled trials, PCT should only be utilized in conjunction with standard tests for infection and rejection diagnosis.

Effect of Hypogammaglobulinemia on the Incidence of Community-Acquired Respiratory Viral Infections After Lung Transplantation

BackgroundHypogammaglobulinemia (HGG) has been associated with an increased risk of infectious complications in lung transplant recipients, but its effect specifically on community-acquired respiratory viruses (CARVs) remains unknown. This study aimed to determine if lung transplant recipients with HGG are at an increased risk of developing CARV infection. Secondary endpoints included the effect of HGG on lung function, incidence of rejection, and mortality. MethodsA retrospective review of all lung transplant recipients from 2008 to 2011 was performed. Patients were stratified as either having HGG after transplantation or having normal IgG titers according to their nadir IgG level. HGG was defined a serum IgG level of <700 mg/dL. CARVs included human metapneumovirus, influenza A/B, respiratory syncytial virus A/B, parainfluenza 1/2/3, rhinovirus, and adenovirus isolated from bronchoalveolar lavage/wash, sputum, or nasal swab. ResultsThe cohort consisted of 263 patients with a mean follow-up time of 612 ± 356 days. The incidence of CARV infection was 27% in patients with normal IgG titers and 23.4% in patients with HGG (P = .62). No difference in rejection, mortality, or lung function was found between the groups. As expected, patients who ever had a CARV infection had a significantly lower 1-second forced expiratory volume % reference on their most recent spirometry than those who had not had a CARV infection (81.6% vs 86.9%; P = .027). ConclusionsAlthough CARV infection has been shown to affect lung graft function, these data suggests that HGG is not associated with the incidence of CARV infection.

Medical Complications in Lung Transplant Recipients with Pulmonary Fibrosis

Lung transplantation is a therapeutic option for selected patients with severe interstitial disease who continue to have progressive clinical deterioration. There is a survival advantage for selected patients who undergo transplant, but it primarily improves quality of life after transplantation. Unfortunately, patients with IPF have worse outcomes following lung transplantation due to various factors. This review article will describe several common postoperative complications including an astamotic complications, allograft dysfunction, cardiovascular complications, thromboembolic phenomenon, renal failure, neurologic complications and complications related to the native lung in the single lung transplant recipients.

Early identification of infectious complications in lung transplant recipients using procalcitonin

The purpose of this study was to determine how sequential measurements of procalcitonin (PCT) could improve the diagnosis of early infectious complications after lung transplantation, and to compare this molecule with other commonly used markers (serum C-reactive protein [CRP] and leukocyte count). Prospective observational study in a 34-bed university hospital intensive care unit (ICU). All lung transplant (LT) recipients between January and November 2010 were included. Biomarkers were measured just before surgery, on ICU admission, and daily on postoperative days 2, 3, 4, and 7. A total of 25 patients were included. Those patients with infectious complications presented with significantly higher levels of PCT as early as the first day after transplantation and during subsequent days. The area under receiver operating characteristic curve for PCT as a predictor of infection ranged between 0.83 and 0.97. PCT cutoff of 8.18ng/mL on day 2 had a sensitivity of 80% and specificity of 100% for prediction of infection development. Neither CRP levels nor leukocyte count could discriminate between the patients with and without infections at any time. In contrast with CRP levels and leukocyte counts, measurement of PCT appears to be a useful diagnostic tool in detecting early infectious complications in LT patients.

717 Increased Distal Airway Nitric Oxide (NO) Release during Acute Complications in Lung Transplant Recipients (LTxR)

717 Increased Distal Airway Nitric Oxide (NO) Release during Acute Complications in Lung Transplant Recipients (LTxR)

Utility of CMR in identification of post lung transplant cardiovascular complications

Background Graft dysfunction after lung transplantation is typically attributable to infection or rejection. In the absence of these entities, structural cardiovascular (CV) abnormalities need to be sought. At our center this evaluation typically includes a myriad of diagnostic tests: echocardiography, chest computed tomographic angiography, nuclear medicine lung perfusion imaging, and right heart catheterization (RHC). This study was designed to evaluate the utility of a novel comprehensive CMR protocol for identification of all post-operative structural CV complications in lung transplant recipients. Methods We enrolled 80 consecutive lung transplant recipients who were referred for CMR evaluation of CV abnormalities. There were 47 men and 33 women; mean age 56.7 ±13.6 years; 55 Caucasians, 9 Hispanic, 13 African American, and 3 Asian. Underlying restrictive disease was present in 39 subjects, obstructive disorders in 22, and other disorders in 19. Forty-three subjects had undergone double lung transplant, while 37 subjects had single lung transplant (23 left lung, and 14 right lung). The comprehensive CMR protocol included complete short and long axis cine imaging (SSFP) to evaluate cardiac size and function; ECG gated spin echo imaging to assess pericardial thickness; contrast enhanced MRA of the pulmonary arterial (PA) and venous (PV) systems to assess for anastomotic site stenosis; phase contrast velocity flow mapping to assess anastomotic site peak velocity and right and left PA flow fraction; and inversion recovery SSFP to evaluate for myocardial fibrosis. Results All 80 subjects completed CMR imaging without difficulty and none were excluded from this analysis for reasons of image quality. The mean LVEF was 66.4±9.23%, mean RVEF was 54.37±10.45%, right and left PAs flow were 2.6±1.21 and 2.6± 1.31 liter/min, respectively. Specific complications identified and the prevalence is shown in Table 1. Patients with moderate or severe PA or PV anastomotic site stenosis underwent RHC and intravascular ultrasound, which confirmed CMR findings; patients with severe stenosis underwent stenting of the respective vessel. Patients with CMR evidence of pericardial constriction underwent pericardiectomy with improvement in symptoms. Conclusions A comprehensive CMR protocol can be a useful single noninvasive test for the detection of structural cardiovascular (CV) abnormalities after lung transplantation. Funding Not applicable.

An analysis of potential risk factors for early complications from fiberoptic bronchoscopy in lung transplant recipients

Several reviews exist describing the safety of bronchoscopy in lung transplant recipients. However, the incidence of bronchoscopic complications in lung transplant recipients in relation to trainee involvement, and clinical characteristics such as pre-transplant diagnosis and transplant type, has not been described. We performed a retrospective cohort study of all lung transplant recipients undergoing flexible fiberoptic bronchoscopy (n = 259) at the University of California, San Francisco, between January, 2003, and June, 2009. Complications included bleeding, pneumothorax, aspiration, oversedation, and hypoxemia. From 2003 to 2009, 3734 flexible fiberoptic bronchoscopies were performed, including 2111 (57%) with transbronchial biopsies. Trainees were involved in 2102 bronchoscopies (56%), including 1046 transbronchial biopsies (49.5%). Complications occurred in 27 bronchoscopies [0.7% (95% Confidence Interval [CI]: 0.4-1.0)], with 10 involving a trainee (37%). Twenty (74%) occurred during bronchoscopies with transbronchial biopsies. Six of these involved a trainee, while 14 involved an attending alone (P = 0.03). We did not find differences in pre-transplant diagnosis, transplant type, lung, or renal function between subjects who suffered a complication and those who did not (P ≥ 0.30). The involvement of trainees, pre-transplant diagnosis, and transplant type do not significantly impact the rate of bronchoscopic complications in lung transplant recipients.

Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients

BackgroundPost-transplant lymphoproliferative disorders (PTLD) are serious complications in lung transplant recipients. No consensus on EBV DNAemia levels predictive of PTLD has been reached. In addition, in many instances EBV DNAemia is determined in patients with suggestive symptoms only.MethodsThe characteristics of five patients with PTLD as well as the prevalence of EBV DNAmia in a cohort of 137 consecutive patients receiving lung transplantation are described.ResultsTwenty-six out of 137 patients (18.9%) were excluded from the analysis because lost at follow-up or dead from PTLD-independent reasons within three months of transplantation. EBV DNA in peripheral blood mononuclear cells (PBMC) was determined in 83/111 patients (74.8%) because of potential PTLD-related symptoms, while 28 patients (25.2%) showed no symptoms and were not examined. EBV DNAemia was positive in 53/83 patients (63.8%), and negative in 30/83 patients (36.2%). PTLD was diagnosed in five (4.5%) patients at a median time of 270 (range 120-870) days following transplantation. All five PTLD (three large B-cell lymphomas, one Hodgkin lymphoma and one possible pre-neoplastic lesion) were potentially associated with EBV infection. However, only 3/5 patients with PTLD had detectable EBV DNAemia: < 1,000 copies EBV DNA/1 × 105 PBMC in one patient and > 1,000 copies EBV DNA/1 × 105 PBMC in two patients.ConclusionA systematic multidisciplinary (clinical, radiologic, virologic and histologic) approach is mandatory for the diagnosis and management of PTLD in lung transplant recipients, while monitoring of symptomatic patients only may provide an incomplete or late picture of the clinical problem. In addition, staining for EBV antigens and quantification of EBV DNA in biopsy specimens should always be performed to understand the role of EBV infection in the pathogenesis of PTLD.

A retrospective study of silicone stent placement for management of anastomotic airway complications in lung transplant recipients: Short- and long-term outcomes

A retrospective study of silicone stent placement for management of anastomotic airway complications in lung transplant recipients: Short- and long-term outcomes

A retrospective study of silicone stent placement for management of anastomotic airway complications in lung transplant recipients: Short- and long-term outcomes

Airway anastomotic complications remain a major cause of morbidity and mortality after lung transplantation (LT). Few data are available with regard to the use of silicone stents for these airway disorders. The aim of this retrospective study was to evaluate the clinical efficacy and safety of silicone stents for such an indication. Data of adult lung transplant recipients who had procedures performed between January 1997 and December 2007 at our institution were reviewed retrospectively. We included patients with post-transplant airway complications who required bronchoscopic intervention with a silicone stent. In 17 of 117 (14.5%) LT recipients, silicone stents were inserted at a mean time of 165 (range 5 to 360) days after surgery in order to palliate 23 anastomotic airway stenoses. Symptomatic improvement was noted in all patients, and mean forced expiratory volume in 1 second (FEV(1)) increased by 672 +/- 496 ml (p < 0.001) after stent insertion. The stent-related complication rate was 0.13/patient per month. The latter consisted of obstructive granulomas (n = 10), mucus plugging (n = 7) and migration (n = 7), which were of mild to moderate severity and were successfully managed endoscopically. Mean stent duration was 266 days (range 24 to 1,407 days). Successful stent removal was achieved in 16 of 23 cases (69.5%) without recurrence of stenosis. Overall survival was similar in patients with and without airway complications (p = 0.36). Silicone stents allow clinical and lung function improvement in patients with LT-related airway complications. Stent-related complications were of mild to moderate severity, and were appropriately managed endoscopically. Permanent resolution of airway stenosis was obtained in most patients, allowing definitive stent removal without recurrence.