Epidemiology and Immediate Indirect Effects of Respiratory Viruses in Lung Transplant Recipients: A 5-Year Prospective Study.

The epidemiology of respiratory viruses (RVs) in lung transplant recipients (LTRs) and the relationship of RVs to lung function, acute rejection (AR) and opportunistic infections in these patients are not well known. We performed a prospective cohort study (2009-2014) by collecting nasopharyngeal swabs (NPSs) from asymptomatic LTRs during seasonal changes and from LTRs with upper respiratory tract infectious disease (URTID), lower respiratory tract infectious disease (LRTID) and AR. NPSs were analyzed by multiplex polymerase chain reaction. Overall, 1094 NPSs were collected from 98 patients with a 23.6% positivity rate and mean follow-up of 3.4 years (interquartile range 2.5-4.0 years). Approximately half of URTIDs (47 of 97, 48.5%) and tracheobronchitis cases (22 of 56, 39.3%) were caused by picornavirus, whereas pneumonia was caused mainly by paramyxovirus (four of nine, 44.4%) and influenza (two of nine, 22.2%). In LTRs with LRTID, lung function changed significantly at 1 mo (p = 0.03) and 3 mo (p = 0.04). In a nested case-control analysis, AR was associated with RVs (hazard ratio [HR] 6.54), Pseudomonas aeruginosa was associated with LRTID (HR 8.54), and cytomegalovirus (CMV) replication or disease was associated with URTID (HR 2.53) in the previous 3 mo. There was no association between RVs and Aspergillus spp. colonization or infection (HR 0.71). In conclusion, we documented a high incidence of RV infections in LTRs. LRTID produced significant lung function abnormalities. Associations were observed between AR and RVs, between P. aeruginosa colonization or infection and LRTID, and between CMV replication or disease and URTID.

Early identification of infectious complications in lung transplant recipients using procalcitonin.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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 8.18 ng/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. CONCLUSIONS: 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.

[Lung transplantation using donors 55 years and older]. / Trasplante pulmonar con donantes de edad marginal (≥ 55 años).

OBJECTIVE: We analyzed short, medium and long-term mortality in transplant recipients who received lungs from donors aged 55 years or more. PATIENTS AND METHODS: All patients who underwent lung transplantation from donors aged 55 years or more were included. The association between the different study variables and early death and death at 1 year and 5 years was studied. A logistic regression model was used to study the association between early death and variables with a trend towards significance (P<.2) in the bivariate analysis. The risk factors for mortality at 1 year and 5 years were analyzed with a Cox regression model. The Kaplan-Meier method was used to analyze survival. RESULTS: A total of 33 patients were included. The probability of survival was 90.9%, 78.5% and 44.8% at 1 month, 1 year, and 5 years after lung transplantation, respectively. The elevated age of the recipient (P=.16) and single-lung transplantation (P=.09) were the variables associated to or with a trend towards significant associations with mortality. CONCLUSIONS: The final decision to accept a lung graft should be based on individual evaluation of each donor and recipient. However, given the lack of lung donors, donors aged 55 years or more should be considered for lung transplantation.

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.

Early outcome after single vs bilateral lung transplantation in older recipients.

BACKGROUND: Lung transplantation (LT) has been increasingly performed in patients older than 60 years. The outcome of LT in this recipient age group has not been extensively analyzed. The purpose of this study was to evaluate the early death (30 days) in LT recipients older than 60 years according to the type of procedure, that is, single vs bilateral LT. METHODS: We retrospectively reviewed our experience with older recipients between January 1999 and August 2007. Probability of survival was compared using the two-tailed Fisher exact test. The odds ratio for death at 30 days was estimated using multiple logistic regression. RESULTS: During the study, 167 LT procedures were performed in 164 patients, of whom 51 (30.5%) were aged 60 years or older (age range, 60-70 years; mean [SD], 63.3 [2.4] years). Thirty-seven recipients aged 60 years or older underwent single LT, and 14 underwent bilateral LT. The 30-day survival was 81% (95% confidence interval [CI], 65%-92%) in patients who underwent single LT, and 92% (95% CI, 64%-100%) in patients who underwent bilateral LT. No differences were observed in the survival probability between the two groups (P = .42). Logistic regression analysis for death at 30 days showed an odds ratio of 1.10 (95% CI, 0.08-14.5; P = .94) in the unilateral LT group. CONCLUSIONS: Early survival in LT recipients aged 60 years or older who underwent bilateral LT was comparable with that in who underwent single LT. The type of procedure is not a predictor of death in this age group. Recipients older than 60 years should not be excluded from consideration for bilateral LT.

Conversion from cyclosporine to tacrolimus stabilizes the course of lung function in lung transplant recipients with bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) continues to be the main factor limiting the long-term survival of lung transplant recipients. The objective of this study was to prospectively assess the impact of conversion from cyclosporine (CsA) to tacrolimus on lung function in patients who developed BOS while receiving CsA-based immunosuppressive therapy. A total of 79 patients with BOS were included in the study. Sixty percent of patients had stage II or III BOS according to the International Society for Heart and Lung Transplantation criteria. Mean time from transplantation was 30.4 +/- 21.9 months and all patients were on CsA therapy at enrollment in the study, with mean trough levels of 232.75 +/- 98.26 ng/mL. After conversion, tacrolimus trough levels were 11.0 +/- 3.6 ng/mL at 3 months and 9.0 +/- 3.4 ng/mL at 12 months. Sixteen deaths occurred during the first year postconversion, 56% of which were due to respiratory failure. Comparison of forced expiratory volume in 1 second (FEV(1)) preconversion versus postconversion showed a change in the slope of the FEV(1)-time curve. The slope of the preconversion curve was -0.44 versus a zero slope, whereas the slope of the postconversion curve was 0.005, with a statistically significant difference between both slopes. This change in slopes, which was also seen in FEV(1%), suggests that lung function loss closed after conversion from CsA to tacrolimus supporting this therapeutic strategy in lung transplant recipients with BOS treated with CsA.

[What the family doctor must know about lung transplant (Part 1)]. / Qué debe saber el médico especialista de familia sobre el trasplante pulmonar (Parte 1).

Lung transplant is a therapeutic, medical-surgical procedure indicated for pulmonary diseases (except lung cancer), that are terminal and irreversible with current medical treatment. More than 3,500 lung transplants have been performed in Spain, with a rate of over 6 per million and increasing. In this review, an analysis is made of the types of transplants, their indications and contraindications, the procedures, immunosuppressive treatments, their side effects and medical interactions, current prophylaxis. A list of easily accessible literature references is also include, the majority being by national authors.

[What the family doctor must know about lung transplantation. Complications, health promotion, and outcomes (Part 2)]. / Qué debe saber el médico de familia sobre el trasplante pulmonar. Complicaciones, promoción de la salud y supervivencia (Parte 2).

The lung transplantation is a therapeutic procedure indicated for lung diseases that are terminal and irreversible (except lung cancer) despite the best medical current treatment. It is an emergent procedure in medical care. In this review, an analyse is made of the most frequent complications of lung transplant related to the graft (rejection and chronic graft dysfunction), immunosuppression (infections, arterial hypertension, renal dysfunction, and diabetes), as well as others such as gastrointestinal complications, osteoporosis. The most advisable therapeutic options are also included. Specific mention is made of the reviews and follow-up for monitoring the graft and the patients, as well as the lifestyle recommended to improve the prognosis and quality of life. An analysis is also made on the outcomes in the Spanish and international registries, their historical evolution and the most frequent causes of death, in order to objectively analyse the usefulness of the transplant.

Lymphoproliferative disease after lung and heart-lung transplantation: first description in Spain.

Lymphoproliferative syndromes are the most common tumors in transplant recipients. More than 90% of posttransplantation lymphoproliferative syndromes (PTLS) are considered to be associated with Epstein-Barr virus, and 86% are of the B-cell line. Histopathology ranges from polymorphic-reactive to monomorphic forms. Clonality should be studied using molecular biology techniques. Clinically, a differentiation is usually made between early PTLS (occurring within 1 year after transplantation) and late PTLS, which occur as localized or disseminated nodal lymphomas. In localized forms, immunosuppression should be discontinued or decreased, and the involved area should be subsequently resected or irradiated. In disseminated cases, immunosuppression should be decreased and administration of acyclovir/ganciclovir should be considered. If this is not effective, treatment should be started with anti-CD20 monoclonal antibodies (rituximab). If no response occurs, use of chemotherapy, possibly with interferon, should be considered. Our aim was to report the incidence, clinical signs, and treatment in a series of patients undergoing lung transplantation (LTx).

Urgent lung transplantation in Spain.

BACKGROUND: Lung donors are scarce and lung transplantation resources are limited. Because urgent lung transplantation (ULT) is assumed to yield poor results, its use is controversial. We assessed the outcome of patients who received ULT seeking to determine effectiveness and risk factors. PATIENTS AND METHOD: We collected data from every ULT performed in Spain during 5 years (1998-2002). The survival of patients was studied using Kaplan-Meier, Cox regression, and chi-square statistical analyses. We compared outcomes and perioperative mortality (over 30 days) for ULT procedures, analyzing the influence of certain variables (age, type of transplant, diagnosis, indication, and time on waiting list). RESULTS: Among 109 patients proposed for the procedure, 73 ULT were performed during the period. The most frequent indications were pulmonary fibrosis (19 cases) and cystic fibrosis (19 cases), showing the worst and the better survival rates, respectively. The bad prognosis, determined mainly by per operative mortality rate (35.62%), was significantly affected by age (worse for patients older than 40 years) and type of LT (single worse than double; P < .05). A longer time waiting for ULT also showed a worse prognosis (P < .005). CONCLUSIONS: Long-term survival after ULT shows that the procedure is effective and efficient for a select group of patients, despite the high per operative risk. ULT should be reserved for younger patients. It also requires performance in a short period (just a few days), initially rejecting a single lung transplant, provided that the patient is adequately monitored.

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.

Invasive pulmonary aspergillosis prior to BMT in acute leukemia patients does not predict a poor outcome.

Eight patients with acute leukemia (AL) and invasive pulmonary aspergillosis (IPA) developing during previous antileukemic therapy underwent BMT (autologous in 6 cases and allogeneic 2). IPA was treated prior to BMT with full doses of amphotericin B, associated with surgical resection in three cases. One patient was treated with amphotericin B and itraconazole. Prior to BMT, seven patients had minimal residual pulmonary lesions. All patients received amphotericin B (0.5 mg/kg/day) during the aplastic period prior to engraftment. One patient died of Gram-negative septic shock before engraftment. Seven patients achieved complete hematological engraftment without any evidence of IPA reactivation. Amphotericin B was well tolerated with only minimal transient renal dysfunction in three patients. Later pulmonary complications related to IPA were observed in only one patient who developed a self-limited episode of hemoptysis. One patient died of CMV pneumonitis and two of leukemia relapse. Four patients survive disease-free and without complications related to IPA. We conclude that the reactivation of correctly treated IPA can be successfully prevented in BMT patients by use of prophylactic amphotericin B. With this approach, prior IPA is not a contraindication to BMT.

Influence of preservation solution on early lung function (Euro-Collins vs Perfadex).

BACKGROUND: This clinical study was performed to evaluate the efficiency of 2 different preservation solutions (Euro-Collins [EC] vs Perfadex [P]) on organ function in human lung transplantation. METHODS: The donor lungs for 46 patients were flushed either with EC solution (25 cases, EC group) or Perfadex (21 cases, P group). Transplant function was assayed using PaO2/FiO2 ratio after transplantation upon intensive care unit (ICU) arrival and at 12 and 24 hours later (T1, T2, and T3, respectively). We also compared the duration of mechanical ventilatory support and ICU stay. RESULTS: The PO2/FiO2 ratio was significantly better in the P than EC group at T1, T2, and T3. The duration of mechanical ventilatory support and ICU stay were lower also in P group, whereas age, sex, aetiology of lung disease, donor, PaO2/FiO2 ratio, and ischemia time did not show differences between the 2 groups. CONCLUSIONS: Our data on graft function tend to confirm better graft preservation using the P preservation solution.

[Chronic eosinophilic pneumonia in a patient treated with allogenic bone marrow transplantation]. / Neumonía eosinófila crónica en un paciente tratado con trasplante de médula ósea alogénico.

A 39 year old patient diagnosed of severe aplastic anemia and treated with allogenic bone marrow transplantation and who presented chronic eosinophilic pneumonia eight months after the transplant is presented. The patient had no previous history of asthma or atopy. Conditioning was performed with cyclophosphamide and total body irradiation. Prophylaxis of the graft versus host disease was carried out with cyclosporin and short course of methotrexate. At day 30 mild graft versus host disease appeared which spontaneously resolved. A progressive increase in the number of eosinophils was observed from day +40 reaching 1.05 x 10(9)/l at day +180 coinciding with suspension of the cyclosporine. The patient remained asymptomatic with no evidence of chronic graft versus host disease. At 8 months following allogenic transplantation the patient developed three episodes of fever, cough, moderate dyspnea and pulmonary infiltrates. Respiratory tests showed a restrictive pattern. Bronchoalveolar lavage contained 20% of eosinophils. Upon lung biopsy alveolar infiltration by eosinophils, lymphocytes and mononuclear cells was observed. Diagnosis of chronic eosinophilic pneumonia was made with initiation of steroid treatment. A drastic response was observed. The patient remained asymptomatic without recurrence and without evidence of chronic graft versus host disease. This picture may have been caused by the donor eosinophils given that retrospective evaluation demonstrated a persistent moderate eosinophilia in the donor.

[Acute eosinophilic pneumonia: presentation of a case and review of the literature]. / Neumonía eosinófila aguda: presentación de un caso y revisión de la literatura.

Pulmonary eosinophilias are characterized by the appearance of lung infiltrates by eosinophils and the presence, commonly, of peripheral blood eosinophilia. Among idiopathic pulmonary eosinophilias, with no evidence of any cause or underlying disease, chronic eosinophilic pneumonia is the most characteristic. Recently, there has been described a few cases of eosinophilic pneumonia with many similarities to chronic eosinophilic pneumonia but with a shorter clinical course, a very good response to corticoid therapy, and without tendency to relapse. This process has been named acute eosinophilic pneumonia. We present a case of this entity and review the literature, emphasizing on the potential severity of this disease, which often conduce to progressive respiratory failure, and its excellent prognosis after appropriate treatment.

[Reimplantation edema in the transplanted lung. Reperfusion-ischemia or hydrostatic edema?]. / Edema de reimplantación en el trasplante pulmonar. ¿Isquemia-reperfusión o edema hidrostático?

The development of non cardiogenic pulmonary edema or pulmonary reimplantation response after lung transplantation has been well described. The cause is ischemic vascular injury of the allograft, results in increased permeability of the lung after reperfusion, in turn leading to interstitial and alveolar edema. We report two cases of pulmonary reimplantation response after bilateral sequential lung transplantation. Massive pink frothy fluid was noted in the orifice of the double-lumen endobronchial tube. Blood and endobronchial fluid samples were collected for protein electrophoresis. We conclude that, in spite of the severity of reimplantation response, this complication can be resolved early when the cause is mainly hydrostatic.

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.

Study of B-cell subpopulations in lung transplant recipients with posttransplant infection.

BACKGROUND: Posttransplant infection after lung transplantation is a common feature due to the immunodeficiency induced by the immunosuppressive load. AIM: To assess B-cell subsets in lung transplant recipients suffering at least one episode of infection within the first year posttransplantation. METHODS: Twenty-eight lung transplant recipients were enrolled in the study. Their overall mean age was 56.6 ± 10.7 years and 10 were women (35.7%). All recipients were treated with steroids, tacrolimus, and mycophenolate mofetil. B-cell subset levels were measured in peripheral blood before as well as 7, 14, 30, 60, 90, and 180 days posttransplantation. RESULTS: No difference in the absolute number of B-cell subsets was observed within the first year of follow-up. However, pre-germinal center-activated naïve B cells (Bm2'), defined as IgD(+)CD38(++), were increased among patients displaying infections within the first year. The increased Bm2' subset was accompanied by a decrease in the double negative (CD27(-)IgD(-)) B-cell population. CONCLUSION: Infections in lung transplant recipients were associated with an increase in the Bm2' subset even before transplantation. It is possible that Bm2' cells have a role in response to infection in lung transplantation.

A retrospective 12-month study of conversion to everolimus in lung transplant recipients.

BACKGROUND: Everolimus has potent antifibrotic effects that may potentially affect the clinical course of bronchiolitis obliterans syndrome (BOS) or provide nephroprotective immunosuppressive regimens for lung transplantation. METHODS: We retrospectively assessed the 12-month outcomes of the conversion to everolimus among lung recipients in six Spanish centers. RESULTS: From March 2005 to December 2007, 65 lung recipients who were at a mean posttransplantation time of 10.2 ± 7.9 months were converted to everolimus, mainly because of BOS (64.6%) or renal insufficiency (RI; 12.3%). The initial dose of everolimus was 1.9 ± 0.6 mg/d and the mean blood trough levels were stable over time (6.4 ± 2.8 ng/mL at 12 months). Conversion to everolimus allowed us to eliminate the calcineurin inhibitor (CNI) in 21% of patients. Among the overall population, the forced expiratory volume at 1 second (FEV(1)) and renal function remained stable. Mean FEV(1) did not change among the 35 (81%) patients surviving BOS at 12 months: preconversion FEV(1): 1.449.5 ± 641.9 mL vs 12-month FEV(1): 1420.0 ± 734.6 mL (P = .866). There was a significant improvement in renal function among the RI patients with mean glomerular filtration rates of 42.2 ± 15.2 mL/min/1.73 m(2) (P = .043) at 6 and 44.4 ± 18.8 mL/min/1.73 m(2) at 12 months, (P = .063) and a decrease in the use of CNIs from 1% of RI patients preconversion to 57% at 6 and 75% at 12 months. With a mean of 8.1- months follow-up (range: 1-31.3) overall survival was 84.6% at 1 year and 50% at 22.3 months. Progressive BOS was the main cause of death. Reasons for everolimus discontinuation were patient death (n = 10), lack of efficacy (n = 4), gastrointestinal adverse events (n = 2), and edema (n = 2). CONCLUSIONS: BOS and RI were the main indications for conversion to everolimus among lung recipients. Conversion to everolimus improved renal function among patients converted because of RI. The present results were inconclusive regarding effects of everolimus on BOS.