Epidemiology and Risk Factors for Cancer After Lung Transplantation.

Cancer is the third most common cause of death among lung transplant (LT) recipients who survive for more than 1 year. The purpose of this study was to analyze the incidence and risk factors for cancer after LT in a Spanish cohort. The epidemiology and risk factors for cancer were retrospectively analyzed in LT recipients from 2 cities in Spain, Madrid and Barcelona. Of the 1353 LT patients initially included in the study, 125 (9.2%) developed cancer after a mean of 3.7 years. This frequency was 5-fold higher than in the general population. The most prevalent tumors were skin cancer (32%), lymphoproliferative disease (18%), and lung cancer (16.5%). In 4 patients, lung cancer was diagnosed on the day of the operation. The risk of cancer increased with age >55 year (hazard ratio [HR] 2.89 [1.64-5.09]; P < .001), in men (HR 2.8 [1.4-5.6]; P = .004), and in heavy smokers (>20 pack-years) (HR 2.94 [1.64-5.27]; P < .001). Other factors such as sun exposure were not found to be risk factors. In conclusion, prevalence of cancer is high in LT recipients in a Mediterranean country. Skin tumors, lymphoproliferative disease, and lung cancer are the most prevalent cancers. Age, male sex, and smoking were the main risk factors for cancer in this population.

Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

Epidemiology of invasive respiratory disease caused by emerging non-Aspergillus molds in lung transplant recipients.

OBJECTIVES: Our aim was to assess the impact of positive cultures for non-Aspergillus molds on the risk of progression to invasive fungal infection (IFI), and the effect of prophylactic nebulized liposomal amphotericin B (n-LAB) on these pathogens. METHODS: This was an observational study (2003-2013) including lung transplant recipients (LTR) receiving lifetime n-LAB prophylaxis, in whom non-Aspergillus molds were isolated on respiratory culture before and after transplantation (minimum 1-year follow-up). RESULTS: We studied 412 patients, with a mean postoperative follow-up of 2.56 years (interquartile range 1.01-4.65). Pre- and post-transplantation respiratory samples were frequently positive for non-Aspergillus molds (11.9% and 16.9% of LTR respectively). Post transplantation, 10 (2.42%) patients developed non-Aspergillus mold infection (4 Scedosporium species, 4 Purpureocillium species, 1 Penicillium species, and 1 Scopulariopsis species); 5 (1.21%) had IFI, with 60% IFI-related mortality. Non-Aspergillus molds with intrinsic amphotericin B (AB) resistance were more commonly isolated in bronchoscopy samples than AB-variably sensitive or AB-sensitive molds (54.5% vs. 25%, P = 0.04) and were associated with a higher risk of infection (56.3% vs. 1.3%%, P < 0.01). CONCLUSIONS: In LTR undergoing n-LAB prophylaxis, pre- and post-transplantation isolation of non-Aspergillus molds is frequent, but IFI incidence (1.21%) is low. Purpureocillium is an emerging mold. AB-resistant non-Aspergillus species were found more often in bronchoscopy samples and were associated with a higher risk of infection.

Prevalence and Diagnosis of Chronic Kidney Disease in Maintenance Lung Transplant Patients: ICEBERG Study.

BACKGROUND: Chronic renal dysfunction (CRD) after lung transplantation (LT) is a common and noteworthy complication associated with increased morbidity and mortality rates. The study objectives were to determine the prevalence of CRD according to different diagnostic criteria and describe its therapeutic management. METHODS: This observational, multicenter, retrospective study included LT patients with ≥ 2 years of evolution. CRD was defined according to 2 different methods: (1) by the physician's subjective clinical criteria and (2) by analytical criteria (estimated glomerular filtration rate [eGFR] by Modification of Diet in Renal Disease of ≤ 59 mL/min). RESULTS: We included 113 patients; 65.5% were men and the mean age at transplant was 49.1 (12.6) years. At 6 months after transplant, approximately half of patients had CRD according to analytical criteria, and, at 2 years after transplantation, the prevalence rose to 80%. Although clinical prevalence and analytical prevalence were similar (68.8% and 78.6%), a weak concordance was observed (Kappa index: 0.6). Among patients who were not classified as having CRD according to clinical criteria, 40.0% (14/35) were diagnosed with CRD according to analytical criteria. None of the patients underwent renal biopsy, and 5.1% of patients required dialysis. In 77.0% of patients with clinical CRD diagnosis, the immunosuppressive regimen was modified: reduction of isolated calcineurin inhibitors (CNIs) (35.0%), CNIs decreased with mycophenolic acid change (23.3%), and CNIs lowering with mammalian target of rapamycin introduction (6.7%). In a multivariate logistic regression model, the independent factors associated with CRD were an older recipient age, low body mass index (BMI) at transplant, treatment with cyclosporine/azathioprine, and low eGFR at the first month after transplant. CONCLUSIONS: We found a high incidence of CRD at the first year after transplantation, which increased subsequently. Moreover, CRD was considerably underestimated by physicians' subjective clinical criteria. End points related to CRD development were older age, low BMI, azathioprine use, and low eGFR during the first month after transplant. The latter finding provides an opportunity to implement prevention strategies.

Biomarkers of pulmonary rejection.

Immunologic complications after lung transplantation (LT) include acute cellular rejection (ACR), antibody-mediated rejection (AMR), and most forms of chronic allograft dysfunction (CAD). ACR is an inflammatory process in which the reaction is mediated by the T-cell population. Most episodes of ACR fully recover with treatment, but repeated bouts are considered to be a risk factor for CAD. Biomarker cytokines interleukin (IL)-10, IL-15, IL-6, CCL5, CCR2 and IFNγ may play significant roles in this complication. Formerly bronchiolitis obliterans syndrome (BOS) or chronic rejection or most forms of CAD were considered to be immunologic complications not amenable therapeutic measures. CAD, the main limitation for long-term survival in LT, is characterized histologically by airway epithelial cell apoptosis and luminal fibrosis in the respiratory bronchioles causing airflow obstruction and, in some cases, lung parenchymal affectations causing restrictive lung disease. Several biomarkers have been studied in CAD, IL-6, IL-8, IL-17, IL-23, IL-13, IFN γ, and TGF ß cytokines, pH, bile acid, and tripsine of gastroesophageal reflux and toll-like receptors of innate immunity. Herein we have reviewed the literature of biomarkers involved in lung rejection.

Inhaled iloprost plus oral sildenafil in patients with severe pulmonary arterial hypertension delays the need for lung transplantation.

BACKGROUND: Accepted treatment for severe pulmonary arterial hypertension (PAH) includes intravenous epoprostenol and lung transplantation (LT). Inhaled iloprost plus oral sildenafil (Ilo-Sil) is an alternative strategy that may also delay the need for LT. PATIENTS AND METHODS: This was a long-term descriptive study in eight patients with PAH functional class (FC) IV with right heart failure, four of them potential candidates for LT, who were treated with Ilo-Sil as an alternative to epoprostenol. RESULTS: At the start of the study, patients (seven women; mean age, 43.8 [range, 34-66] years) were in FC IV and unable to perform the 6-minute walk test. Mean cardiac index was 1.9 (range, 1.4-2.1) L/min/m(2). Treatment with Ilo-Sil provoked a rapid and sustained improvement; mean walking distance at 3 months was 322 ± 90 m and no patient remained in FC IV. Survival at 1 and 5 years was 100% and 75%, respectively. Of the four potential LT candidates, one underwent transplantation after 6.8 years and one died after 1.2 years. CONCLUSIONS: These results suggest that therapy with Ilo-Sil represents an acceptable alternative in patients with severe and unstable PAH.

Recommendations on the use of everolimus in lung transplantation.

The antiproliferative effect of everolimus provides a therapeutic option in the immunosuppression therapy of lung transplantation, by reducing both the risk of acute rejection and the process of progressive fibrosis that determines chronic graft rejection. However, few data on the use of everolimus in lung transplantation have been published to date, and the specific indications of the drug, along with the most adequate time for its introduction or dosing, have not been defined yet. The aim of this article is to propose recommendations for the use of everolimus in lung transplant recipients, including indications, dosing schedules and the use of concomitant immunosuppression. This consensus document has been developed by experts of all the Spanish lung transplant groups from the review of the existing literature and the clinical experience.

A multicenter study of valganciclovir prophylaxis up to day 120 in CMV-seropositive lung transplant recipients.

Seventy-six cytomegalovirus (CMV)-seropositive lung transplant recipients receiving valganciclovir (900 mg/day) for CMV prophylaxis were compared with a group of 87 patients receiving oral ganciclovir (3000 mg/day). Prophylaxis was administered to day 120 post-transplantation and follow-up was 1 year. In addition, a study was conducted on risk factors for CMV infection/disease. CMV disease incidence was 7.9% and 16.1% for valganciclovir and oral ganciclovir, respectively (p = 0.11). Patients receiving valganciclovir had fewer viral syndromes (2.6% vs. 11.5%, p < 0.05), a similar rate of tissue-invasive disease (5.2% vs. 4.6%, p = ns), longer time-to-onset of CMV infection/disease (197.5 vs. 155.2 days, p < 0.05), and a lower probability of infection/disease while on prophylaxis (1.3% vs. 12.6%, p < 0.01). Nonetheless, leukopenia incidence was higher with valganciclovir (15.8% vs. 2.3%, p < 0.01), as was the need for treatment withdrawal due to adverse effects (11.8% vs. 1.1%, p < 0.01). CMV infection was similar in both groups (32.9% vs. 34.5%). Induction therapy with basiliximab and glucocorticosteroid treatment were independent risk factors for developing CMV infection/disease. In conclusion, valganciclovir prophylaxis results in a low incidence of CMV disease in lung transplant recipients and appears more effective than oral ganciclovir. Despite the comparatively higher incidence of adverse events with valganciclovir, the drug can be considered safe for prophylaxis.

Donor-to-host transmission of bacterial and fungal infections in lung transplantation.

The purpose of this study was to evaluate the incidence and etiology of bacterial and fungal infection or contamination in lung allograft donors and to assess donor-to-host transmission of these infections. Recipients who survived more than 24 h and their respective donors were evaluated. The overall incidence of donor infection was 52% (103 out of 197 donors). Types of donor infection included isolated contamination of preservation fluids (n = 30, 29.1%), graft colonization (n = 65, 63.1%) and bacteremia (n = 8, 7.8%). Donor-to-host transmission of bacterial or fungal infection occurred in 15 lung allograft recipients, 7.6% of lung transplants performed. Among these cases, 2 were due to donor bacteremia and 13 to colonization of the graft. Twenty-five percent of donors with bacteremia and 14.1% of colonized grafts were responsible for transmitting infection. Excluding the five cases without an effective prophylactic regimen, prophylaxis failure occurred in 11 out of 197 procedures (5.58%). Donor-to-host transmission of infection is a frequent event after lung transplantation. Fatal consequences can be avoided with an appropriate prophylactic antibiotic regimen that must be modified according to the microorganisms isolated from cultures of samples obtained from donors, grafts, preservation fluids and recipients.

Preemptive therapy with intravenous ganciclovir for the prevention of cytomegalovirus disease in lung transplant recipients.

The most effective strategy for the prevention of cytomegalovirus (CMV) disease in lung transplantation has not been conclusively established. The aim of this study was to determine the efficacy of preemptive ganciclovir therapy for this purpose. Twenty-five consecutive adult patients positive for CMV before transplantation and surviving more than 30 days after the procedure were studied. Mean follow-up was 732.2 days (range, 210-1125). All patients received intravenous (IV) ganciclovir prophylaxis for the first 21 days and subsequently underwent frequent CMV antigenemia monitoring: weekly for the first 3 months, every 15 days between 3 and 6 months, and monthly thereafter. IV ganciclovir was given when antigenemia results were greater than 10 infected cells per 100,000 polymorphonuclears. The study group was compared with a historical group of 30 consecutive patients who had received IV ganciclovir prophylaxis and continued on oral ganciclovir up to day 120 posttransplantation. Eighteen of the 25 patients (72.0%) presented episodes of CMV infection. Six of the 25 patients (24.0%) had CMV disease, including 3 viral syndromes and 3 cases of pneumonitis. Four patients debuted with CMV disease, 1 of them with pneumonitis. CMV resistance to ganciclovir was observed in 2 patients. The incidence of infection was higher than in the historical group (72.0% vs 46.7%; P < .05), but there were no significant differences in the incidence of CMV disease (24.0% vs 40.0%; P = not significant [NS]). Mean time before onset of the first episode of disease was lower in the preemptive therapy group than in the comparison patients (82.8 days; range, 42-240 vs 175 days; range, 90-243; P < .05). In conclusion, preemptive therapy for CMV disease is as effective a prevention strategy as oral ganciclovir prophylaxis. However, the early appearance of CMV disease with preemptive therapy can make this approach inadvisable.

Contamination of the nebulization systems used in the prophylaxis with amphotericin B nebulized in lung transplantation.

The contamination of nebulizer may be the origin of respiratory infections. The aim of this study was to determine the incidence of contamination in nebulizers used to nebulize amphotericin B in lung transplant (LT) patients and the relationship with bacterial isolation in sputum culture. A prospective, cross-sectional study was conducted with 41 LT patients who were administered amphotericin B with a jet nebulizer. Samples were taken from the nebulizers (prior to nebulization). Sputum culture was carried out and patients were asked whether or not they followed a cleaning and disinfection protocol (washing and brushing with soap and water followed by subsequent disinfection with the Milton method after each nebulization). Contamination was defined as such when potentially pathogenic bacteria were isolated in the nebulizer. Seventeen of the 41 nebulizers (41.4%) were contaminated. In 7 of the 17 cases (41.1%) contamination was polymicrobial. The most common microorganism was Pseudomonas aeruginosa. Fourteen of the 41 patients (34.1%) presented positive sputum cultures, most common was P aeruginosa. In 10 patients (24.3%) pathogenic bacteria was isolated both in the nebulizer and in the sputum. In four of these patients (9.7%) the species was the same. The cleaning and disinfection protocol was carried out by 16 of the 41 patients (39.0%). In 2 of the 16 patients (12.5%) who were following the protocol the nebulizer was contaminated, compared to 15 of 25 patients (60.0%) whose nebulizer was not contaminated (P < .05). Two of the 16 patients (12.%) who were following the protocol presented positive sputum culture compared to 12 of 25 (48.0%) who did not (P < .05). In conclusion, the contamination of the nebulizing systems is frequent when no strict cleaning and disinfection protocol is followed. Patients who did not follow the protocol presented a greater isolation of pathogenic bacteria in the sputum.

Blood cyclosporine C0 and C2 concentrations and cytomegalovirus infections following lung transplantation.

The aim of this study was to determine whether cyclosporine levels predose (C0) and at two hours postdose (C2) were higher among patients presenting with cytomegalovirus (CMV) infection or disease. Between days 40 and 365 posttransplantation serial C0 and C2 levels were measured in 15 lung transplant recipients. Nine developed 13 episodes of CMV infection or disease. Both C0 and C2 levels were higher during CMV infection or disease episodes. Eleven of the 13 CMV episodes (84%) displayed C0 >220 ng/mL and none had C0 <200 ng/mL. For C2, 11 of 13 CMV episodes (84%) showed C2 >1200 ng/mL and none had C2 <1000 ng/mL. Among determinations that did not coincide with a CMV episode, 7 of 21 (33%) showed C0 >220 and 9 of 21 (42%) showed C2 >1200, respectively (P<.05). In conclusion, cyclosporine blood levels are higher among patients presenting with CMV infection or disease.

Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors.

BACKGROUND: Aspergillus infection remains a major cause of morbidity and mortality after lung transplantation. Therefore, some strategies have been attempted, one of which is nebulized amphotericin B (nAB); however, the efficacy of this prophylaxis has not been shown clearly. The aim is to study whether nAB can protect against Aspergillus infection in lung transplant recipients. PATIENTS AND METHODS: A study of risk factors was conducted in 55 consecutive lung allograft recipients. Twenty-three potential risk factors were analyzed. In 44 (80%) patients, nAB was indicated as prophylaxis. Multivariate analysis using logistic regression was performed. RESULTS: Eighteen of the 55 patients (33%) developed infection due to Aspergillus spp. Multivariate analysis showed nAB to be a preventive factor (odds ratio: 0.13; 95% confidence interval [CI] 0.02-0.69; p < 0.05) and cytomegalovirus (CMV) disease was an independent risk factor for developing Aspergillus infection (odds ratio: 5.1; 95% CI 1.35-19.17; p < 0.05). Only 1 patient required withdrawal of the prophylaxis owing to bronchospasm. nAB was well-tolerated in the remaining patients with only a few, mild, easily controlled side effects. CONCLUSIONS: The present results show that nAB prophylaxis may be efficient and safe in preventing Aspergillus infection in lung-transplanted patients, and CMV disease increases the probability of Aspergillus infection.

Mycophenolic acid plasma concentrations: influence of comedication.

Mycophenolate mofetil (MMF) in combination with cyclosporine (CsA) or Tacrolimus (TAC) has been show to be a potent immunosuppressive agent. The authors assessed the mycophenolic acid (MPA) plasma levels achieved in clinical practice and evaluated the effect of concomitant administration of CsA and TAC . One hundred forty transplant patients (kidney: 120 and lung: 20) received a triple immunosuppression regimen of CsA or TAC, prednisone and MMF. Twenty-two renal transplant patients received double therapy with MMF and prednisone. There was no correlation between MMF dose and MPA trough concentrations (r = -0.0657). The medians (range) of the MPA dose-to-concentration ratio (D/C) in the CsA and TAC groups were 0.90 (0.11-8.33) and 0.56 (0.11-14.3), respectively (p < 0.0001). According to the post transplant period (1-3, 4-6 and >6 months), D/C values were significantly lower in patients receiving MMF and TAC than those receiving MMF and CsA in all three periods. MPA levels in patients treated with MMF and CsA were significantly lower than those obtained in double therapy. The D/C ratio in CsA-treated patients, increased significantly (p = 0.0005) when CsA level increased. There was no relationship between D/C ratio and TAC blood concentrations. These results suggest that CsA exerts an influence on MPA trough levels, although further work is required to characterize the mechanism of interaction.

Mycophenolate mofetil pharmacokinetics in transplant patients receiving cyclosporine or tacrolimus in combination therapy.

Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, n = 49; lung, n = 11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (n = 45) or tacrolimus (n = 15). Coadministration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose-to-concentration 0.92 (0.11-8.33) (n=167) versus 0.38 (0.11-14.28) (n = 66); P < 0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose-to-concentration in cyclosporine-treated patients increased significantly (P<0.0001) as the cyclosporine level increased, suggesting a possible interaction between mycophenolate mofetil and cyclosporine. No correlation was seen between dose-to-concentration and tacrolimus blood levels (P x 0.215). Further studies are necessary to investigate this issue.

Isoniazid prophylaxis in lung transplantation.

The incidence of tuberculous disease (TD) is higher in lung-transplant patients than in the general population. During a 7-year period, we included 61 patients who underwent lung transplantation in a prospective isoniazid prophylaxis protocol. Isoniazid was prescribed to infected and anergic patients not previously treated when added to the waiting list. Six of 61 patients (10%) developed tuberculosis. We observed no differences in tuberculous disease incidence between infected-anergic and non-infected patients. In our tuberculous-endemic area, isoniazid prophylaxis is safe and offers protection from TD to infected and anergic patients who must be enrolled in a lung transplantation program.

[Lymphangioleiomyomatosis: study of 15 patients]. / Linfangioleiomiomatosis: estudio de 15 pacientes.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is an uncommon disease of not well-known evolution. We describe the clinical features and follow-up of a group of patients diagnosed of LAM in a hospital pulmonary transplantation programme. PATIENTS AND METHODS: 15 women (mean age: 43, range: 36-52) diagnosed of LAM, 9 at the Hospital Vall d'Hebron and 6 referred from other hospitals, for preoperative evolution of lung transplantation, were retrospectively studied. RESULTS: Dyspnea appeared in all cases and it was the main symptom. Pleural problems in the early evolution of the disease were also very frequent (12 out of 15 patients). For this reason, pleurodesis was performed in 7 patients and pleurectomy in 2 (one of them bilateral). Thoracic CT scan showed very characteristic cystic images and abdominal CT proved the presence of extrathoracic associated angiomyolipomas in one case. In two patients, LAM was diagnosed after studying the explanted lung. These two patients had been previously misdiagnosed of emphysema and pulmonary haemosiderosis. Survival since the beginning of symptoms was 82 and 49%, 5 and 10 years later, respectively. Six out of eight patients who underwent lung transplantation had a long postoperative survival. CONCLUSIONS: LAM seems to be as infrequent in Catalunya as in other countries, even if some cases could be misdiagnosed. Lung transplantation is useful in the advanced stages of the disease and, in our experience, it has improved respiratory insufficiency in half of the patients.