Evaluation of Two Different CMV-Immunoglobulin Regimens for Combined CMV Prophylaxis in High-Risk Patients following Lung Transplant.

BACKGROUND: The clinical benefits of the common off-label use of cytomegalovirus (CMV)-specific immunoglobulin (CMV-Ig) combined with antivirals in organ transplantation have not been previously assessed. The objective was to compare the risk of CMV infection and other post-transplantation outcomes between two CMV-Ig prophylaxis regimens in lung transplant recipients; Methods: Retrospective study of 124 donor CMV positive/recipient negative (D+/R-) patients receiving preventive ganciclovir/valganciclovir for 12 months, of whom 62 received adjunctive CMV-Ig as per label indication (short regimen [SR-Ig]; i.e., 7 doses over 2.5 months) and were compared to 62 who received an extended off-label regimen (ER-Ig) consisting of 17 doses over one year after transplantation. RESULTS: The incidence of CMV infection or disease, acute rejection, chronic lung allograft dysfunction, and survival did not differ between the two CMV-Ig schedules. Although the time to the first CMV infection after transplantation was shorter in the ER-Ig than in the SR-Ig adjunctive group (log-rank: p = 0.002), the risk was independently predicted by antiviral cessation (odds ratio = 3.74; 95% confidence interval = 1.04-13.51; p = 0.030), whereas the CMV-Ig schedule had no effect. CONCLUSIONS: Extending the adjunctive CMV-Ig prophylaxis beyond the manufacturer's recommendations up to one year does not confer additional clinical benefits regarding lung post-transplantation outcomes.

Gastroesophageal Reflux and Esophageal Motility Disorder After Lung Transplant: Influence on the Transplanted Graft.

BACKGROUND: Esophageal pathology has been identified as a bad prognostic factor in lung transplantation (LTx). This study aims to assess the esophageal disorders present post-LTx, under treatment with proton pump inhibitors, and their putative impact on the graft. METHODS: Prospective, observational study of LTx patients. Digestive factors were assessed by manometry and pH-metry at 6 months post-LTx and under proton pump inhibitor treatment. We assessed the association between esophageal disorders and graft function and acute rejection (AR) and chronic lung allograft dysfunction (CLAD). RESULTS: Out of 76 post-LTx patients, 27% showed gastroesophageal reflux disease (GERD), 55% showed inadequate gastric inhibition, and 59% showed esophageal motility disorders (EMDs). We observed a greater incidence of AR from 3 months post-LTx in the presence of EMD (P ≤ .05). No significant differences were observed in GERD or EMD prevalence or in survival between patients with or without CLAD. The maximum forced expiratory volume in 1 second (FEV1) achieved after bilateral LTx was significantly (P = .022) lower in patients with EMD vs without EMD. CONCLUSION: At 6 months post-LTx, there is a high percentage of esophageal disorders (GERD and EMDs). No esophageal disorder is associated with CLAD or with survival, although EMDs are associated with a greater incidence of AR and lower graft function.

COVID-19 in transplant recipients: The Spanish experience.

We report the nationwide experience with solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients diagnosed with coronavirus disease 2019 (COVID-19) in Spain until 13 July 2020. We compiled information for 778 (423 kidney, 113 HSCT, 110 liver, 69 heart, 54 lung, 8 pancreas, 1 multivisceral) recipients. Median age at diagnosis was 61 years (interquartile range [IQR]: 52-70), and 66% were male. The incidence of COVID-19 in SOT recipients was two-fold higher compared to the Spanish general population. The median interval from transplantation was 59 months (IQR: 18-131). Infection was hospital-acquired in 13% of cases. No donor-derived COVID-19 was suspected. Most patients (89%) were admitted to the hospital. Therapies included hydroxychloroquine (84%), azithromycin (53%), protease inhibitors (37%), and interferon-ß (5%), whereas immunomodulation was based on corticosteroids (41%) and tocilizumab (21%). Adjustment of immunosuppression was performed in 85% of patients. At the time of analysis, complete follow-up was available from 652 patients. Acute respiratory distress syndrome occurred in 35% of patients. Ultimately, 174 (27%) patients died. In univariate analysis, risk factors for death were lung transplantation (odds ratio [OR]: 2.5; 95% CI: 1.4-4.6), age >60 years (OR: 3.7; 95% CI: 2.5-5.5), and hospital-acquired COVID-19 (OR: 3.0; 95% CI: 1.9-4.9).

Tuberculosis Following Lung Transplantation. A 27-Year Spanish Multicenter Experience. Incidence, Presentation, Prevention and Treatment with Rifampicin.

BACKGROUND: Tuberculosis (TB) represents a diagnostic and therapeutic challenge for solid organ transplant recipients, particularly after lung transplant (LT). Our aim was to determine the impact of TB in LT patients in Spain, considering prevalence, clinical presentation, prevention and therapeutic management. In addition, differences in outcome between rifampicin (RIF) versus non-RIF containing regimens were analyzed. METHODS: Multicenter, observational retrospective study, including all cases of TB diagnosed in recipients after LT, in five pulmonary transplant units in Spain, between January 1990 and December 2017. RESULTS: Among 2962 LT recipients, 45 cases of TB were diagnosed, resulting in a prevalence of 1.52%. Most of them (88.89%) were diagnosed during the first year posttransplantation, 86.67% with pulmonary presentation. Screening for latent TB infection (LTBI) was done in 36 of the 45 patients and LTBI was detected pretransplant in 12 (33.33%). Less than half of the patients with disease (42.22%) received rifampicin (RIF). Lower probability of TB worsening was found in RIF-containing regimens (p=0.049), as well as longer survival (p=0.001). RIF use was not associated with an increased risk in rejection (p=0.99), but doses of calcineurin inhibitors (CNI) had to be raised an average of 215%. CONCLUSIONS: Risk of TB after LT was lower in our series than previously reported. TB should be searched during the first year posttransplant in patients with TB risk factors. Pulmonary presentation was predominant. More sensitive algorithms for detecting LTBI before LT are crucial. It is reasonable to use RIF-containing regimens over non-RIF regimens based on the tendency toward better outcome in our series. RIF regimen requires close monitoring of CNI trough level for 2-3 weeks, until stability is achieved.

Expression profiling of chromatin-modifying enzymes and global DNA methylation in CD4+ T cells from patients with chronic HIV infection at different HIV control and progression states.

Background: Integration of human immunodeficiency virus type 1 (HIV-1) into the host genome causes global disruption of the chromatin environment. The abundance level of various chromatin-modifying enzymes produces these alterations and affects both the provirus and cellular gene expression. Here, we investigated potential changes in enzyme expression and global DNA methylation in chronically infected individuals with HIV-1 and compared these changes with non-HIV infected individuals. We also evaluated the effect of viral replication and degree of disease progression over these changes. Results: Individuals with HIV-1 had a significant surge in the expression of DNA and histone methyltransferases (DNMT3A and DNMT3B, SETDB1, SUV39H1) compared with non-infected individuals, with the exception of PRMT6, which was downregulated. Some histone deacetylases (HDAC2 and HDAC3) were also upregulated in patients with HIV. Among individuals with HIV-1 with various degrees of progression and HIV control, the group of treated patients with undetectable viremia showed greater differences with the other two groups (untreated HIV-1 controllers and non-controllers). These latter two groups exhibited a similar behavior between them. Of interest, the overexpression of genes that associate with viral protein Tat (such as SETDB1 along with DNMT3A and HDAC1, and SIRT-1) was more prevalent in treated patients. We also observed elevated levels of global DNA methylation in individuals with HIV-1 in an inverse correlation with the CD4/CD8 ratio. Conclusions: The current study shows an increase in chromatin-modifying enzymes and remodelers and in global DNA methylation in patients with chronic HIV-1 infection, modulated by various levels of viral control and progression.

Short Communication: p21/CDKN1A Expression Shows Broad Interindividual Diversity in a Subset of HIV-1 Elite Controllers.

The p21/CDKN1A protein has been described in vitro as well as in a small subset of patients as a restriction factor for HIV infection. We evaluated p21/CDKN1A mRNA expression on CD4(+) T cells from HIV-infected individuals with two outcomes (18 elite controllers and 28 viremic progressors). Our results show broad interindividual variation in this factor, which is unrelated to the patient's phenotype. Considering the gene's genetic surroundings in chromosome 6, such as HLA genotype and single nucleotide polymorphisms (SNPs), there was a positive association with carrying HLA-B2705 alleles and the rs733590 SNP. Thus, this natural variation of p21/CDKN1A alone does not appear to be a prognostic indicator of effective viral control in vivo and other factors must be considered.

Oki stenting for anastomotic bronchomalacia in lung transplantation.

Anastomotic airway complications are a frequent cause of disease in lung transplantation. However, there is no consensus on the type of treatment to be performed with prosthetic devices. While some recent gadgets such as the Oki stent have been proposed for main right bronchus stenosis, there are no reports of stenting using this prosthesis in cases where the main complication is malacia rather than stenosis. We present 2 patients diagnosed with main right bronchus bronchomalacia, also involving bronchius intermedius. After several attempts to bypass the anastomosis employing different types of stent, including a T-tube Montgomery device, normal sputum drainage was not possible. Oki stenting was performed without complications, with a remarkable reduction in endoscopic procedures as well as important functional improvement. For both stenosis and bronchomalacia in lung transplantation, we propose Oki stenting as the first choice of treatment.

Point-of-care system for detection of Mycobacterium tuberculosis and rifampin resistance in sputum samples.

Early detection of Mycobacterium tuberculosis complex (MTBC) and markers conveying drug resistance can have a beneficial impact on preventive public health actions. We describe here a new molecular point-of-care (POC) system, the Genedrive, which is based on simple sample preparation combined with PCR to detect MTBC and simultaneously detect mutation markers in the rpoB gene directly from raw sputum sample. Hybridization probes were used to detect the presence of the key mutations in codons 516, 526, and 531 of the rpoB gene. The sensitivities for MTBC and rpoB detection from sputum samples were assessed using model samples spiked with known numbers of bacteria prepared from liquid cultures of M. tuberculosis. The overall sensitivities were 90.8% (95% confidence interval [CI], 81, 96.5) for MTBC detection and 72.3% (95% CI, 59.8, 82.7) for rpoB detection. For samples containing ≥1,000 CFU/ml, the sensitivities were 100% for MTBC and 85.7% for rpoB detection, while for samples containing ≤100 CFU/ml, the sensitivities were 86.4% and 65.9% for MTBC and rpoB detection, respectively. The specificity was shown to be 100% (95% CI, 83.2, 100) for MTBC and rpoB. The clinical sputum samples were processed using the same protocol and showed good concordance with the data generated from the model. Tuberculosis-infected subjects with smear samples assessed as scanty or negative were detectable by the Genedrive system. In these paucibacillary patients, the performance of the Genedrive system was comparable to that of the GeneXpert assay. The characteristics of the Genedrive platform make it particularly useful for detecting MTBC and rifampin resistance in low-resource settings and for reducing the burden of tuberculosis disease.

The Spanish Lung Transplant Registry: first report of results (2006-2010).

The Spanish Lung Transplant Registry (SLTR) began its activities in 2006 with the participation of all the lung transplantation (LT) groups with active programs in Spain. This report presents for the first time an overall description and results of the patients who received lung transplants in Spain from 2006 to 2010. LT activity has grown progressively, and in this time period 951 adults and 31 children underwent lung transplantation. The mean age of the recipients was 48.2, while the mean age among the lung donors was 41.7. In adult LT, the most frequent cause for lung transplantation was emphysema/COPD, followed by idiopathic pulmonary fibrosis, both representing more than 60% the total number of indications. The probability for survival after adult LT to one and three years was 72% and 60%, respectively, although in patients who survived until the third month post-transplantation, these survival rates reached 89.7% and 75.2%. The factors that most clearly influenced patient survival were the age of the recipient and the diagnosis that indicated the transplantation. Among the pediatric transplantations, cystic fibrosis was the main cause for transplantation (68%), with a one-year survival of 80% and a three-year survival of 70%. In adult as well as pediatric transplantations, the most frequent cause of death was infection. These data confirm the consolidated situation of LT in Spain as a therapeutic option for advanced chronic respiratory disease, both in children as well as in adults.

Development of a non-heart-beating lung donor program with «Bithermia Preservation¼, and results after one year of clinical experience.

The number of lung transplantations that are performed in Spain continues to grow, with 235 transplant recipients 2010. Non-heart-beating donations have contributed to this upward progression. Our Lung Transplant Unit began its activity in October 2008 and during these last three years 97% of the transplant interventions performed have been successful. In order to increase the number of donations, we have developed a non-heart-beating donor program as part of the existing organs program in our hospital. In doing so, the development of a multi-organic preservation method (lung, liver and kidney), which we call «Bithermia Preservation¼, was necessary. This paper presents this methodology as well as the first year of clinical application experience. During this time, 3 patients have been transplanted using such non-heart-beating donations. None of them developed primary graft dysfunction; all the patients have been discharged and lead active lives without any evidence of bronchiolitis obliterans syndrome.

Guidelines for the selection of lung transplantation candidates.

The present guidelines have been prepared with the consensus of at least one representative of each of the hospitals with lung transplantation programs in Spain. In addition, prior to their publication, these guidelines have been reviewed by a group of prominent reviewers who are recognized for their professional experience in the field of lung transplantation. Within the following pages, the reader will find the selection criteria for lung transplantation candidates, when and how to remit a patient to a transplantation center and, lastly, when to add the patient to the waiting list. A level of evidence has been identified for the most relevant questions. Our intention is for this document to be a practical guide for pulmonologists who do not directly participate in lung transplantations but who should consider this treatment for their patients. Finally, these guidelines also propose an information form in order to compile in an organized manner the patient data of the potential candidate for lung transplantation, which are relevant in order to be able to make the best decisions possible.

Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety.

BACKGROUND: The main problem with using nebulized liposomal amphotericin (n-LAB) as prophylaxis for Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and its possible adverse effects. The aim of this study was to measure post-inhalation amphotericin B concentration in the respiratory tract and serum of lung transplant patients and assess the effects of n-LAB on respiratory function. METHODS: Thirty-two consecutive bronchoscopies were performed on 27 lung transplant patients at two hospitals. Amphotericin B concentration in the first and third aliquot of bronchoalveolar lavage material was measured in steady state. The first aliquot approximates most closely the true amphotericin B concentrations in the proximal airway, whereas the third aliquot provides an optimum sample from the distal airway. RESULTS: At 2 days, mean amphotericin B concentrations were 11.1 microg/ml (95% confidence interval [CI]: 16.5 to 5.7 microg/ml) and 9.0 microg/ml (95% CI: 14.3 to 3.8 microg/ml) in the first and third aliquot, respectively. Thereafter, concentrations declined progressively. At 14 days, concentrations were 3.0 microg/ml (95% CI: 4.4 to 1.5 microg/ml) in the first aliquot and 4.1 microg/ml (95% CI: 6.1 to 2.1 microg/ml) in the third aliquot (p = not statistically significant). Traces of amphotericin B (0.1 microg/ml) were found in serum samples from only 1 of 27 patients. Mean value of forced expiratory volume in the first second (FEV(1)) was similar before and after n-LAB. CONCLUSIONS: Amphotericin B concentrations after n-LAB remained high for 14 days, at adequate concentrations for prophylaxis of Aspergillus infection. No significant systemic absorption of amphotericin B was detected and no effect was observed on respiratory function. This promising prophylactic regimen warrants assessment in future clinical studies.

[Clinical and functional characteristics of patients prior to lung transplantation: report of experience at the Clínica Puerta de Hierro]. / Características clínicas y funcionales antes del trasplante pulmonar. Experiencia en la Clínica Puerta de Hierro.

OBJECTIVE: The time at which lung transplantation is indicated is determined by clinical and functional criteria that vary according to the particular disease. The aim of our study was to present the criteria according to which patients were placed on waiting lists for lung transplantation in our hospital. PATIENTS AND METHODS: We analyzed retrospectively the clinical characteristics, lung function, heart function, and 6-minute walk test results of patients who had received a lung transplant in our hospital from January 2002 through September 2005. RESULTS: During the study period 100 lung transplants were performed. The mean age of the patients was 45 years (range, 15-67 years) and 57% were men. The diseases that most often led to a lung transplant were chronic obstructive pulmonary disease (COPD) (35%), pulmonary fibrosis (29%), and bronchiectasis (21%). Lung function values differed by disease: mean (SD) forced expiratory volume in 1 second (FEV1) was 20% (11%) and forced vital capacity (FVC) was 37% (15%) in patients with COPD; FEV1 was 41% (15%) and FVC, 40% (17%) in patients with pulmonary fibrosis; and FEV1 was 23% (7%) and FVC, 37% (10%) in patients with bronchiectasis. CONCLUSIONS: The patients who received lung transplants in our hospital were in advanced phases of their disease and met the inclusion criteria accepted by the various medical associations when they were placed on the waiting list.

[Is endoscopic treatment of bronchopleural fistula useful?]. / 'Es útil el tratamiento endoscópico de las fístulas bronquiales?

OBJECTIVE: New endoscopic techniques have been developed as an alternative to surgical treatment of bronchopleural fistula. The objective of this study was to analyze our experience with endoscopic treatment of such fistulas. MATERIAL AND METHODS: We conducted a retrospective study of patients with bronchopleural fistula diagnosed by fiberoptic bronchoscopy. Patient characteristics, underlying disease, fistula size, and outcome of endoscopic treatment were analyzed. The endoscopic technique consisted of injection of fibrin sealants (Histoacryl and/or Tissucol) through the catheter of the fiberoptic bronchoscope. RESULTS: Between 1997 and 2004, 18 patients were diagnosed with bronchopleural fistula by fiberoptic bronchoscopy. All were men with a mean (SD) age of 62 (12) years. Bronchopleural fistula was diagnosed after neoplastic surgery in 16 patients, in the bronchial suture after lung transplantation in 1 patient, and concurrently with pleural effusion due to hydatidosis in the remaining patient. The size of the fistula ranged from 1 mm to 10 mm (mean 3.6 [2.7] mm). Fibrin sealants were applied in 14 patients, 2 underwent direct surgery after diagnosis, and the bronchopleural fistula closed spontaneously in the remaining 2. The fibrin sealant used was Histoacryl in 12 patients and Tissucol in 2. Pleural drainage was employed simultaneously and antibiotic therapy was administered at the discretion of the surgeon. The 4 patients whose bronchopleural fistula was associated with empyema also underwent pleural lavage. In 12 patients the fistulas closed as a result of the endoscopic technique (85.7%), and no complications were observed. For 85.7%, fewer than 3 applications of fibrin sealant were necessary. CONCLUSIONS: The success rate of closure of bronchopleural fistula with fibrin sealants injected under guidance with fiberoptic bronchoscopy is high and there are no complications. This technique can render surgery unnecessary.