Composition of Bacteriophages for Therapeutic and Prophylactic Use in Monkeys.

Keeping rhesus monkeys as laboratory animals requires timely prevention and treatment of infections, including diseases of bacterial etiology. Based on our own studies of the microflora of healthy and sick monkeys, as well as analysis of published reports, we identified clinically significant representatives of pathogenic and opportunistic bacteria: E. coli, Staphylococcus aureus, Klebsiella spp., Proteus spp. The isolates of these bacterial species and genera circulating in monkeys kept in the enclosure were isolated, four virulent bacteriophage strains with a wide spectrum of lytic activity against these isolates were selected and newly isolated. The composition based on virulent bacteriophage strains was tested on monkeys with assessment of its safety and its dynamics of detection of phage-specific DNA.

Single lung transplantation from a donor 8 months after double lung transplantation.

Scarcity of donors leads transplant surgeons to consider extended-criteria lungs and occasionally to accept the unlikely. Here we report a case of successful single lung transplantation from a donor 8 months after double lung transplantation.

Preoperative serum uric acid predicts incident acute kidney injury following cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery is a frequent complication and several risk factors increasing its incidence have already been characterized. This study evaluates the influence of preoperative increased serum uric acid (SUA) levels in comparison with other known risk factors on the incidence of AKI following cardiac surgery. METHODS: During a period of 5 month, 247 patients underwent elective coronary artery bypass grafting, valve replacement/ repair or combined bypass and valve surgery. Datas were prospectively analyzed. Primary endpoint was the incidence of AKI as defined by the AKI criteria comparing patients with preoperative serum uric acid (SUA) levels below versus above the median. Multivariate logistic regression analysis was used to identify independent predictors of postoperative AKI. RESULTS: Thirty (12.1%) of the 247 patients developed postoperative AKI, 24 of 30 (80%) had preoperative SUA- levels above the median (≥373 µmol/l) (OR: 4.680, CI 95% 1.840; 11.904, p = 0.001). In the multivariate analysis SUA levels above the median (OR: 5.497, CI 95% 1.772; 17.054, p = 0.003), cardiopulmonary bypass (CPB) time > 90 min (OR: 4.595, CI 95% 1.587; 13.305, p = 0.005), cardiopulmonary bypass (CPB) > 30 kg/m2 (OR: 3.208, CI 95% 1.202; 8.562; p = 0.02), and preoperative elevated serum-creatinine levels (OR: 1.015, CI 95% 1.001; 1.029, p = 0.04) were independently associated with postoperative AKI. CONCLUSIONS: Serum uric acid is an independent risk marker for AKI after cardiac surgery. From all evaluated factors it showed the highest odds ratio.

Association of Higher CD4+ CD25high CD127low , FoxP3+ , and IL-2+ T Cell Frequencies Early After Lung Transplantation With Less Chronic Lung Allograft Dysfunction at Two Years.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung-transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+ CD25high T cells and further analyzed for CTLA4, CD127, FoxP3, and IL-2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+ CD25high CD127low , CD4+ CD25high FoxP3+ and CD4+ CD25high IL-2+ T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.

TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response.

OBJECTIVES: Atherosclerosis is a hallmark of cardiovascular disease. Shear stress on endothelial cells has been linked to atherogenesis and to fibrous cap thinning and rupture. Pericytes reside in the sub-endothelial space of vessels and have vasoprotective effects. They are subjected to shear stress when endothelial cell integrity is disrupted. The aim was to investigate the susceptibility and response of pericytes to shear stress. METHODS: Endothelial cells and pericytes were seeded in two dimensional monocultures and co-cultures, and in a novel three dimensional co-culture system and were subjected to no, low and high shear stress (0, 10, 30 dyne/cm2) for 48 h. The morphological response to flow was assessed by histology and the expression of extracellular matrix proteins was analysed using quantitative polymerase chain reaction, immunoblotting, and ELISA. RESULTS: While endothelial cells aligned into flow direction, pericytes aligned perpendicularly (p < .001), indicating that they must be capable of sensing flow. When pericytes were embedded into a 3D matrix they showed similar alignment and pericytes built long processes towards the lumen. Under shear stress endothelial cells upregulated "a disintegrin and metalloproteinase with thrombospondin motif 1" (ADAMTS-1) (p < .01) and pericytes upregulated "tissue inhibitor of matrix metalloproteinase" (TIMP) 3 (p < .05), an inhibitor of ADAMTS-1, meanwhile differential expression of extracellular matrix (ECM) proteins could be detected in co-cultures of both cells. For TIMP3 expression direct cell-cell contact between endothelial cells and pericytes was required. CONCLUSION: The experiments highlight that pericytes are able to sense direct flow thereby regulating ECM proteins known to be involved in vascular remodelling. Furthermore, pericytes counter-regulate endothelial ADAMTS-1 by protective TIMP3 expression to prevent matrix degradation and maintain vascular stability. For this protective effect direct cell contact was necessary. This observation might represent an adaptive, protective mechanism of pericytes to counteract endothelial damage in the onset of atherosclerosis.

Streptococcus mitis and Gemella haemolysans were simultaneously found in atherosclerotic and oral plaques of elderly without periodontitis-a pilot study.

OBJECTIVES: Local infections may contribute to the initiation and progression of several clinical diseases in humans. Atherosclerotic plaques of subjects suffering from periodontitis are colonized by periopathogens; however, the presence of bacteria in atherosclerotic plaques in patients without severe forms of periodontitis is of high relevance for the general population. MATERIALS AND METHODS: Patients who were electively treated for atherosclerotic lesions of the carotid artery and without clinical signs of periodontitis were eligible for the study. Oral and atherosclerotic plaques were sampled, processed, and analyzed for their microbial composition by 454-sequencing. RESULTS: Seventeen patients were included in the analyses, and 76 % of all atherosclerotic plaque specimens were positive for bacterial DNA. In the oral plaques, 76,532 sequences were identified representing 1 phylum, 17 classes, 112 families, and 263 genera. In atherosclerotic plaques, 6112 sequences representing 1 phylum, 4 classes, 8 families, and 36 genera were found. The bacterial DNAs of the species Gemella haemolysans and Streptococcus mitis were simultaneously found in atherosclerotic as well as oral plaque samples of 3 patients. CONCLUSIONS: These results indicated that in subjects without periodontitis, the transmission of oral bacteria to atherosclerotic plaques of the carotid artery is a feasible event. CLINICAL RELEVANCE: The prevention of transient bacteremia from the oral cavity requires high levels of oral health.

Everolimus Versus Mycophenolate Mofetil De Novo After Lung Transplantation: A Prospective, Randomized, Open-Label Trial.

The role of mammalian target of rapamycin (mTOR) inhibitors in de novo immunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator-initiated single-center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF) or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS-free survival in intention-to-treat (ITT) analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per-protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMF group (p = 0.041). Less biopsy-proven acute rejection (AR) (p = 0.005), cytomegalovirus (CMV) antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR) decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS-free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus-based protocols but also a potentially higher rate of drug-related serious adverse events.

Phenotyping Chronic Lung Allograft Dysfunction Using Body Plethysmography and Computed Tomography.

Restrictive subtype of chronic lung allograft dysfunction (CLAD) was recently described after lung transplantation. This study compares different definitions of a restrictive phenotype in CLAD patients and impact on survival. Eighty-nine CLAD patients out of 1191 screened patients (September 1987 to July 2012) were included as complete longitudinal lung volume measurements and chest computed tomography (CT) after CLAD onset was available. CT findings and lung volumes were quantified and survival was calculated for distinctive groups and predictive factors for worse survival were investigated. Graft survival in patients with total lung capacity (TLC) between 90% and 81% of baseline (BL) (n = 13, 15%) in CLAD course was similar to those with TLC >90% BL (n = 64, 56%; log-rank test p = 0.9). Twelve patients (13%) developed a TLC ≤80% BL and 10 (11%) had significant parenchymal changes on CT, of whom 6 (46%) also had TLC ≤80% BL. CT changes correlated with TLC ≤80% BL (Φ-coefficient = 0.48, p = 0.001). Patients with either TLC ≤80% or significant CT changes (n = 16, 18%) had a significantly reduced survival (log-rank p < 0.001). Forced vital capacity loss at CLAD onset was associated with poorer survival but did not correlate with the TLC or CT changes. A restrictive subtype of CLAD may be defined by either TLC ≤80% BL or severe parenchymal changes on chest CT.

In Vivo Development of Transplant Arteriosclerosis in Humanized Mice Reflects Alloantigen Recognition and Peripheral Treg Phenotype of Lung Transplant Recipients.

Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long-term allograft survival. Here, we study naïve and alloantigen-primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag-/- /IL-2rγc-/- mice reconstituted with peripheral blood mononuclear cells (PBMCs) from the respective lung recipient. Naïve or primed allogeneic PBMCs procured 21 days post-lung transplantation with or without enriching for CD4+ CD25high T cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen-primed PBMCs showed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs (p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen-primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen-primed PBMCs can be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy.

Prolonged Mechanical Ventilation After Lung Transplantation-A Single-Center Study.

This single-center study examines the incidence, etiology, and outcomes associated with prolonged mechanical ventilation (PMV), defined as time to definite spontaneous ventilation >21 days after double lung transplantation (LTx). A total of 690 LTx recipients between January 2005 and December 2012 were analyzed. PMV was necessary in 95 (13.8%) patients with decreasing incidence during the observation period (p < 0.001). Independent predictors of PMV were renal replacement therapy (odds ratio [OR] 11.13 [95% CI, 5.82-21.29], p < 0.001), anastomotic dehiscence (OR 8.74 [95% CI 2.42-31.58], p = 0.001), autoimmune comorbidity (OR 5.52 [95% CI 1.86-16.41], p = 0.002), and postoperative neurologic complications (OR 5.03 [95% CI 1.98-12.81], p = 0.001), among others. Overall 1-year survival was 86.0% (90.4% for LTx between 2010 and 2012); it was 60.7% after PMV and 90.0% in controls (p < 0.001). Conditional long-term outcome among hospital survivors, however, did not differ between the groups (p = 0.78). Multivariate analysis identified renal replacement therapy (hazard ratio [HR] 3.55 [95% CI 2.40-5.25], p < 0.001), post-LTx extracorporeal membrane oxygenation (HR 3.47 [95% CI 2.06-5.83], p < 0.001), and prolonged inotropic support (HR 1.95 [95% CI 1.39-2.75], p < 0.001), among others, as independent predictors of mortality. In conclusion, PMV complicated 14% of LTx procedures and, although associated with increased in-hospital mortality, outcomes among patients surviving to hospital discharge were unaffected.

Augmentation of Transient Donor Cell Chimerism and Alloantigen-Specific Regulation of Lung Transplants in Miniature Swine.

Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4(+) CD25(high+) T cell frequencies were detected in peripheral blood associated with decreased interferon-γ production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third-party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells.

[Impact of guideline adherence on mortality in treatment of left heart failure]. / Auswirkung einer leitliniengerechten Behandlung auf die Mortalität bei Linksherzinsuffizienz.

BACKGROUND: The German national guidelines on chronic heart failure provide treatment recommendations to physicians and reflect the current level of evidence; however, it is questionable to what extent these recommendations are applied in the routine practice and what the effect of guideline adherence on mortality is. METHODS: In this study the claims data of a major German health insurance fund collected over a period of 4 years were analyzed. Using binary logistic regression and Cox regression analyses the influence of drug prescriptions, diagnostic measures, influenza vaccination, the New York Heart Association (NYHA) status, the age and gender on mortality were examined. RESULTS: The study population consisted of 85,465 heart failure patients. Approximately 60 % of the drugs were prescribed according to the guidelines. There was a positive correlation between a higher NYHA status and mortality with an odds ratio (OR) of 3.264. Especially pharmacotherapy with angiotensin-converting enzyme (ACE) inhibitors and beta blockers according to the guidelines was associated with a lower mortality rate (OR 0.448 resp. 0.444). Also patients diagnosed using echocardiography at regular intervals showed a lower risk of dying (OR 0.314). CONCLUSION: The results of this large sample could confirm the results of clinical trials that a therapy according to the guidelines has a significant impact on mortality. By analyzing the claims data evidence was found that in the treatment of heart failure patients the medical results could be improved by adherence to guideline recommendations.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases [Eur Heart Journal (2014) 35, 2873­2926,doi:10.1093/eurheartj/ehu281]. In Table 3, the radiation for MRI is "0" and not "-". The corrected table is shown below.

Suitability and Usability of Claims Data for Review of Guidelines for the Treatment of Chronic Heart Failure.

Background: Guidelines have special importance in medicine, however, it is questionable to what extent these recommendations are applied in daily care, and under which conditions claims data can be used for verification of guideline adherence. Method: Advantages and limitations of claims data for verification of guidelines compliance in the therapeutic area as well as the guidelines themselves were analysed and critically assessed. To substantiate these results, claims data of a major German health insurance fund (Techniker Krankenkasse) were analysed. Results: 104 236 patients were identified. With certain limitations, claims data are useful for verifying guideline adherence; it could be shown that in pharmacotherapy the beta-adrenergic receptor blocker was used to the highest extent (70.5%). In contrast, only 56.4% of patients were treated with pure ACE inhibitors and ACE combined preparation. Conclusion: In order to validate guideline adherence by means of claims data analyses, a number of conditions relating to the database, the therapeutic area and the guidelines themselves have to be considered. Guideline recommendations, which, for example, are based on clinical data, cannot be reviewed by using claims data. Despite these limitations, claims data provide a suitable tool for reviewing selected guideline recommendations. They show that the current use of pharmacotherapy as well as clinical and diagnostic interventions might be increased in accordance with the guideline recommendations.

[Fax Survey to Elucidate the Information Needs of General Practitioners in Lower Saxony Regarding the Topic of Medical Implants]. / Faxumfrage zum Informationsbedarf niedersächsischer Hausärzte zum Thema "Medizinische Implantate".

Background: Medial implants help a multitude of patients to gain more health, mobility and thus, quality of life. In collaboration with a still growing expectation of life especially, i.e., within Western industrial countries, this has led to an increasing use of implants over the last years. However, although biomechanical characteristics of modern implant materials have improved considerably, one big challenge still exists - the implant-associated infection. Early diagnostic and therapeutic interventions could clearly mitigate this issue, but are general practitioners sufficiently informed regarding this topic? Material and Methods: In March 2013 and in close cooperation with the Lower Saxony association of general practitioners, we initiated a survey to elucidate the information demands of general practitioners regarding the topic of medical implants. A total of 939 members of the association were contacted via fax and 101 (10.8 %) responded. Based on the obtained data, we then evaluated which topics are most interesting for this group of medical professionals. Results: The survey clearly indicates that general practitioners request more general implant-related data, e.g., type and specification of an implant as well as its location within the individual patient and contact addresses of the implanting hospital, but also want more specific information regarding diagnostic and therapeutic strategies in the case of implant-associated complications. Conclusion: The present article reports in detail on the conducted fax survey and shows some initial strategies as to how the identified challenges might be faced.

[Organ transplantation in Germany: Critical examination in times of scarce resources]. / Organtransplantation in Deutschland: Kritische Betrachtung in Zeiten knapper Ressourcen.

Organ transplantation over the last 40 years has developed into a standardized successful procedure for the replacement of heart, kidney liver, lung, and pancreas. During this time, treatment strategies have greatly improved and novel procedures such as living related organ donation have been introduced. Despite these improvements, the number of organ transplants has stalled in recent years. In the face of increasing numbers of patients on the waiting list for organ transplantation, this situation is unacceptable and ways to improve the situation of organ transplantation have to be found.The reasons for the stagnant situation in organ transplantation are manifold and include lack of awareness in the general population, insufficient organ procurement in hospitals as well as problems in organ allocation. The criteria for organ allocation have been unfairly reported to EUROTRANSPLANT by some of the presently 44 centers in order of more rapidly receive an organ for their patients on the waiting list. The evolving discussions around this so-called transplantation scandal has further eroded support for organ transplantation in Germany. A critical assessment and a well-defined plan are necessary to improve the situation, increase the number of transplanted organs, and reduce the unacceptably long waiting time for patients in Germany.

Impact of CLAD Phenotype on Survival After Lung Retransplantation: A Multicenter Study.

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re-LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re-LTx for CLAD. Patients who underwent re-LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre- and post-re-LTx were collected and analyzed. A total of 143 patients underwent re-LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re-LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59-4.24; p < 0.0001 and HR = 2.61, 1.51-4.51; p = 0.0006, respectively). Patients waiting at home prior to re-LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23-0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re-LTx for rCLAD is worse compared to BOS. Consequently, re-LTx for rCLAD should be critically discussed, particularly when additional peri-operative risk factors are present.

A new era of ventricular assist device surgery: less invasive procedures.

As the number of patients suffering of congestive heart failure is rising worldwide, the use of mechanical circulatory support to treat these patients has also grown enormously, surpassing the number of annual heart transplants. Moreover latest generation of left ventricular assist devices (LVADs) is characterized by improved technologies. Moreover the size of new LVAD systems is considerably reduced when compared to older generation devices. Therefore, less invasive surgery is now possible for the implantation, explantation, and exchange of LVADs. Although experience with these new techniques is still limited, minimally invasive procedures are thought to improve surgical outcomes by declining the rates of operative complications such as bleeding or wound infection. The miniaturization of LVADs will continue, so that minimally invasive techniques will be used for most LVAD-related procedures in the future. In this article, we summarize and describe minimally invasive surgical techniques, with a focus on the most common LVAD systems in adults.

Paclitaxel-coated balloons in refractory nonanastomostic airway stenosis following lung transplantation.

Airway stenosis represents the commonest airway complication following lung transplantation, affecting between 7% and 18% of patients. Existing treatment options offer limited efficacy and can cause additional patient morbidity. Paclitaxel-coated balloons (PCB) have proved effective in managing postinterventional coronary artery re-stenosis. In a first-in-man study, we evaluated similar PCBs in refractory nonanastomotic airway stenosis in 12 patients. Following a single application, luminal patency was maintained in 50% at 270 days. No significant peri-interventional or early postinterventional complications occurred. Given these encouraging initial findings, further studies appear warranted.

Significance of new lung infiltrates in outpatients after lung and heart-lung transplantation.

BACKGROUND: Infection and rejection represent major complications following lung transplantation and are often associated with pulmonary infiltrates. The differential diagnosis of these infiltrates depends on their timing after transplantation. The aim of this study was to characterize lung transplant recipients (LTR) presenting with new pulmonary infiltrates. METHODS: A retrospective analysis of all LTR and heart-lung transplant recipients attending outpatient follow-up at our institution between September 1, 2006 and October 14, 2011 was performed. All patients presenting with new pulmonary infiltrates on chest x-ray who underwent bronchoscopy were included. RESULTS: A total of 913 patients accounted for 13,156 attendances, with 3,912 bronchoscopies being performed. Seventy-eight patients (9%) exhibited new pulmonary infiltrates and proceeded to bronchoscopy. Infiltrates occurred at a median 15 (interquartile range [IQR] 5-39) months after transplantation. Forty-eight patients (62%) were male, and median patient age was 47 (IQR 29-57) years. Subsequent investigation revealed pneumonia to be the underlying cause in 63 patients (81%). In the remaining patients, chronic lung allograft dysfunction (CLAD) was responsible in 6 (8%), acute rejection in 5 (6%), and toxic pneumonitis in 4 (5%) patients. Overall 1-year survival in LTR presenting with new infiltrates was 97%, compared with 96% for all LTR attending our Outpatient Department. CONCLUSIONS: New pulmonary infiltrates occurring after the first month in LTR are most likely due to infection. Through prompt diagnosis and treatment, early mortality appears unaffected. Late mortality remains attributable to CLAD.