A 60-year-old previously healthy man was admitted to hospital with COVID-19 pneumonia that was treated initially with noninvasive ventilation, steroids and antibiotics. Six weeks after admission, the ...patient remained dependent on oxygen, using a high-flow nasal cannula combined with a nonrebreather mask. Physical examination found proximal muscle wasting due to the long hospital stay. Computed tomography of his chest showed bilateral dense consolidations with superimposed interstitial and fibrotic changes. Because we thought the fibrosis was unlikely to resolve, we discussed the option of lung transplantation with him and his family, both of whom were interested in the procedure. An acute clinical deterioration subsequently led to his intubation, transfer to our extracorporeal life support centre and placement on veno-venous extracorporeal membrane oxygenation (V-V ECMO) as a bridge to transplantation. Seventeen days after ECMO cannulation, the patient underwent successful double lung transplantation with removal of the V-V ECMO immediately after transplant.
More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung ...can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP.
In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital.
During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP.
Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).
Ex vivo lung perfusion (EVLP) is an effective method to assess and improve the function of otherwise unacceptable lungs, alleviating the shortage of donor lungs. The early results with EVLP have been ...encouraging, but longer-term results, including functional and patient-reported outcomes, are not well characterized.
This retrospective single-center study included all lung transplants performed between September 2008 and December 2012. We investigated whether survival or rate of chronic lung allograft dysfunction (CLAD) differed in recipients of EVLP-treated lungs compared with contemporaneous recipients of conventional donor lungs. We also studied functional (highest forced expiratory volume in 1 second predicted, change in 6-minute walk distance, number of acute rejection episodes) and quality of life outcomes.
Of 403 lung transplants that were performed, 63 patients (15.6%) received EVLP-treated allografts. Allograft survival for EVLP and conventional donor lung recipients was 79% vs 85%, 71% vs 73%, and 58% vs 57% at 1, 3, and 5 years after transplant, respectively (log-rank p = not significant). Freedom from CLAD was also similar (log-rank p = 0.53). There were no significant differences in functional outcomes such as highest forced expiratory volume in 1 second predicted (76.5% ± 23.8% vs 75.8% ± 22.8%, p = 0.85), change in 6-minute walk distance (194 ± 108 meters vs 183 ± 126 meters, p = 0.57), or the number of acute rejection episodes (1.5 ± 1.4 vs 1.3 ± 1.3, p = 0.36). The EVLP and conventional donor groups both reported a significantly improved quality of life after transplantation, but there was no intergroup difference.
EVLP is a safe and effective method of assessing and using high-risk donor lungs before transplantation and leads to acceptable long-term survival, graft function, and improvements of quality of life that are comparable with conventionally selected donor lungs.
Bronchiolitis obliterans syndrome (BOS) with small-airway pathology and obstructive pulmonary physiology may not be the only form of chronic lung allograft dysfunction (CLAD) after lung ...transplantation. Characteristics of a form of CLAD consisting of restrictive functional changes involving peripheral lung pathology were investigated.
Patients who received bilateral lung transplantation from 1996 to 2009 were retrospectively analyzed. Baseline pulmonary function was taken as the time of peak forced expiratory volume in 1 second (FEV(1)). CLAD was defined as irreversible decline in FEV(1) < 80% baseline. The most accurate threshold to predict irreversible decline in total lung capacity and thus restrictive functional change was at 90% baseline. Restrictive allograft syndrome (RAS) was defined as CLAD meeting this threshold. BOS was defined as CLAD without RAS. To estimate the effect on survival, Cox proportional hazards models and Kaplan-Meier analyses were used.
Among 468 patients, CLAD developed in 156; of those, 47 (30%) showed the RAS phenotype. Compared with the 109 BOS patients, RAS patients showed significant computed tomography findings of interstitial lung disease (p < 0.0001). Prevalence of RAS was approximately 25% to 35% of all CLAD over time. Patient survival of RAS was significantly worse than BOS after CLAD onset (median survival, 541 vs 1,421 days; p = 0.0003). The RAS phenotype was the most significant risk factor of death among other variables after CLAD onset (hazard ratio, 1.60; confidential interval, 1.23-2.07).
RAS is a novel form of CLAD that exhibits characteristics of peripheral lung fibrosis and significantly affects survival of lung transplant patients.
Diffuse alveolar damage (DAD) is a non-specific pathologic diagnosis frequently encountered after lung transplantation. We examined the relationship between DAD and different forms of chronic lung ...allograft dysfunction (CLAD).
We reviewed the results of 4,085 transbronchial biopsies obtained from 720 lung transplant recipients. DAD detected in biopsies within 3 months and newly detected DAD after 3 months were defined as early DAD and late new-onset DAD, respectively. Among patients with CLAD (FEV(1) <80% baseline), restrictive allograft syndrome (RAS) was defined by a decline in total lung capacity to <90% baseline and bronchiolitis obliterans syndrome (BOS) as CLAD without restrictive allograft syndrome (RAS). Kaplan-Meier analyses and multivariate proportional hazard models were used.
DAD was observed in 320 of 720 (44.4%) patients at least once; early and late new-onset DAD were observed in 264 of 707 (37.3%) and 87 of 655 (13.3%) patients, respectively. Early DAD was associated with significantly higher 90-day mortality (20 of 264 7.6% vs 11 of 443 2.5%; p = 0.001). Moreover, among 502 bilateral lung transplant recipients who had sufficient pulmonary function tests to distinguish BOS and RAS, early DAD was associated with earlier BOS onset (hazard ratio HR 1.24; confidence interval CI 1.04 to 1.47; p = 0.017; median time of BOS onset: 2,902 vs 4,005 days). Conversely, treated as a time-varying covariate, late new-onset DAD was a significant risk factor for RAS in a Cox model (HR 36.8; CI 18.3 to 74.1; p < 0.0001).
Early DAD is associated with early mortality and BOS, and late new-onset DAD increases the risk of RAS.
Introduction
The significance of granuloma in explanted lungs of lung transplant recipients (LTR) on the development of post‐transplant mycobacterial infection is unclear.
Methods
A retrospective ...review comparing LTRs and heart‐lung transplant (H‐LTR) recipients with granuloma in the explanted lungs between 2000 and 2012 (excluding those LTRs with granuloma due to sarcoidosis) and LTRs or H‐LTRs without granuloma. Patients were followed for 2 years post‐transplant.
Results
A total of 144 LTRs and 4 H‐LTRs with granulomas (75 necrotizing and 73 non‐necrotizing) and a comparator cohort of 144 LTRs and 4 H‐LTRs without granuloma were analyzed. In LTRs with granulomas, identification of infectious organisms was more common by histopathology (35 AFB and 22 fungal) compared to cultures (six NTM and seven fungal) taken around time of the transplant. LTRs with granulomas were more likely to have pre‐transplant non‐tuberculous mycobacteria (NTM) infection compared to LTRs without granuloma; P < .01. In the multivariate analysis, having granuloma or positive mycobacterial cultures at time of transplant were associated with increased risk of post‐transplant mycobacterial infection (HR = 1.8 95% CI 1.024‐3.154; P = .041 and HR = 2.083 95% CI 1.011‐4.292; P = .047). Although there was a trend toward increase mycobacterial disease in those with granulomas P = .056, there was no difference in survival post‐transplantation between those with or without granuloma in the explanted lung; P = .886.
Conclusion
The presence of granuloma in the explanted lungs of LTRs or positive mycobacterial cultures at time of transplant is associated with an increased risk of mycobacterial infection post‐transplant.
Lung transplant recipients are at risk of developing many kinds of lung infection, such as community-acquired, nosocomial, opportunistic, and endemic. Here, we report a young lung transplant ...recipient who developed blastomycosis, which had most likely occurred following eculizumab treatment for atypical hemolytic uremia syndrome. We hypothesize that the agent interfering with C5 would influence the immune response against Blastomyces species. Although eculizumab has opened a new era for treatment of atypical hemolytic uremia syndrome and has led to the understanding that complementmediated pathology is needed, the risk of potentially fatal infections by blocking the complement pathway has not been fully elucidated. Careful follow-up and frequent tests to look for infections are needed after using this monoclonal antibody.
Background
Morbidity and mortality in lung transplant recipients are often triggered by recurrent aspiration events, potentiated by oesophageal and gastric disorders. Previous small studies have ...shown conflicting associations between oesophageal function and the development of chronic lung allograft dysfunction (CLAD). Herein, we sought to investigate the relationship between oesophageal motility disorders and long-term outcomes in a large retrospective cohort of lung transplant recipients.
Methods
All lung transplant recipients at the Toronto Lung Transplant Program from 2012 to 2018 with available oesophageal manometry testing within the first 7 months post-transplant were included in this study. Patients were categorised according to the Chicago Classification of oesophageal disorders (v3.0). Associations between oesophageal motility disorders with the development of CLAD and allograft failure (defined as death or re-transplantation) were assessed.
Results
Of 487 patients, 57 (12%) had oesophagogastric junction outflow obstruction (OGJOO) and 47 (10%) had a disorder of peristalsis (eight major, 39 minor). In a multivariable analysis, OGJOO was associated with an increased risk of CLAD (HR 1.71, 95% CI 1.15–2.55, p=0.008) and allograft failure (HR 1.69, 95% CI 1.13–2.53, p=0.01). Major disorders of peristalsis were associated with an increased risk of CLAD (HR 1.55, 95% CI 1.01–2.37, p=0.04) and allograft failure (HR 3.33, 95% CI 1.53–7.25, p=0.002). Minor disorders of peristalsis were not significantly associated with CLAD or allograft failure.
Conclusion
Lung transplant recipients with oesophageal stasis characterised by OGJOO or major disorders of peristalsis were at an increased risk of adverse long-term outcomes. These findings will help with risk stratification of lung transplant recipients and personalisation of treatment for aspiration prevention.
Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its ...role in BOS.
Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months’ survival. BOS was defined as “early” if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels (≥8 μmol/L).
Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged “early” in 21 (57%) of 36. Median BALF bile acid values were 1.6 μmol/L (range, 0–32 μmol/L) in BOS patients and 0.3 μmol/L (range, 0–16 μmol/L) in non-BOS patients (
P = .002); 2.6 μmol/L (range, 0–32 μmol/L) in early BOS patients and 0.8 μmol/L (range, 0–4.6 μmol/L) in late BOS patients, (
P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3,
P = .0004, and r = 0.3,
P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test,
P = .0001).
Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.
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