Jaime Hook

Selecting lung transplant candidates: where do current guidelines fall short?

In 2010, 1770 lung transplant procedures were performed in the USA, yet 2469 new candidates were added to the waiting list the same year. The shortage of suitable donor lungs requires that transplant professionals select patients for lung transplantation only if they are likely to sustain a survival benefit from the procedure. However, 20% of lung transplant recipients die within the first year of transplantation, suggesting that we are failing to identify those at high risk for severe early complications. In this perspective, we review the current guidelines for the selection of lung transplant candidates, which are based largely on expert opinion and small case series. We also propose the study of new extrapulmonary factors, such as frailty and sarcopenia, that might help improve the prediction of complications and early death after lung transplantation, leading to an improved candidate selection process.

Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis

The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement (TOR) predicted mortality in idiopathic pulmonary fibrosis (IPF). We examined 104 adults with IPF enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases (ILDs). The TOR was defined as the lowest oxygen flow rate required to maintain an oxyhaemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time. A higher TOR was associated with a greater mortality rate independent of forced vital capacity and 6-min walk test results in IPF (adjusted hazard ratio (per 1 L·min−1) 1.16, 95% CI 1.06–1.27). The TOR was at least as accurate as pulmonary function and 6-min walk testing at predicting 1-yr mortality. Findings were similar in other ILDs. The TOR is a simple, inexpensive bedside measurement that aids prognostication in IPF.

Socioeconomic barriers to lung transplantation: balancing access and equity.

edge into clinical practice. However, the present data may be useful in conducting stratified management of comorbidities in patients with COPD: combining results of this set of biomarkers with usual risk factors (age, smoking, systemic hypertension, cholesterol levels, etc.) may prove a useful approach to select a COPD subgroup that may benefit from a systematic diagnostic assessment for major comorbidities, eventually followed by specific intervention. The clinical value of this approach and its cost effectiveness will have to be tested in adequate clinical trials. “Noncommunicable” diseases (e.g., COPD, cardiovascular and metabolic disease, depression, and cancer) represent a major challenge in medicine (13), and are often associated with each other (14). In the general population, the realization that high levels of cholesterol and hypertension were strongly associated with subsequent cardiovascular morbidity and mortality led to early detection and intervention programs and a reduction in events (15). In the COPD population, the early identification of patients at risk for major comorbidities may lead to more aggressive diagnostic evaluation and appropriate preventive therapies that may ultimately reduce comorbidity-related events and mortality. As suggested by the present study and another recent study (12), heterogeneity in systemic inflammation, as reflected by variable results of biomarker combinations, may be a useful contribution to assess the risk of selected comorbidities in patients with COPD. This heterogeneity suggests that not all “inflammatory” events are the same, and individuals with multiple measures of inflammation may be phenotypically different from those with fewer measures and may require more aggressive intervention. One size no longer fits all!

Geographic disparities in donor lung supply and lung transplant waitlist outcomes: A cohort study

Despite the Final Rule mandate for equitable organ allocation in the United States, geographic disparities exist in donor lung allocation, with the majority of donor lungs being allocated locally to lower‐priority candidates. We conducted a retrospective cohort study of 19 622 lung transplant candidates waitlisted between 2006 and 2015. We used multivariable adjusted competing risk survival models to examine the relationship between local lung availability and waitlist outcomes. The primary outcome was a composite of death and removal from the waitlist for clinical deterioration. Waitlist candidates in the lowest quartile of local lung availability had an 84% increased risk of death or removal compared with candidates in the highest (subdistribution hazard ratio [SHR]: 1.84, 95% confidence interval [CI]: 1.51‐2.24, P < .001). The transplantation rate was 57% lower in the lowest quartile compared with the highest (SHR: 0.43, 95% CI: 0.39‐0.47). The adjusted death or removal rate decreased by 11% with a 50% increase in local lung availability (SHR: 0.89, 95% CI: 0.85‐0.93, P < .001) and the adjusted transplantation rate increased by 19% (SHR: 1.19, 95% CI: 1.17‐1.22, P < .001). There are geographically disparate waitlist outcomes in the current lung allocation system. Candidates listed in areas of low local lung availability have worse waitlist outcomes.

Disruption of staphylococcal aggregation protects against lethal lung injury

Infection by Staphylococcus aureus strain USA300 causes tissue injury, multiorgan failure, and high mortality. However, the mechanisms by which the bacteria adhere to, then stabilize on, mucosal surfaces before causing injury remain unclear. We addressed these issues through the first real-time determinations of USA300-alveolar interactions in live lungs. We found that within minutes, inhaled USA300 established stable, self-associated microaggregates in niches at curved, but not at flat, regions of the alveolar wall. The microaggregates released &agr;-hemolysin toxin, causing localized alveolar injury, as indicated by epithelial dye loss, mitochondrial depolarization, and cytosolic Ca2+ increase. Spread of cytosolic Ca2+ through intercellular gap junctions to adjoining, uninfected alveoli caused pulmonary edema. Systemic pretreatment with vancomycin, a USA300-cidal antibiotic, failed to protect mice infected with inhaled WT USA300. However, vancomycin pretreatment markedly abrogated mortality in mice infected with mutant USA300 that lacked the aggregation-promoting factor PhnD. We interpret USA300-induced mortality as having resulted from rapid bacterial aggregation in alveolar niches. These findings indicate, for the first time to our knowledge, that alveolar microanatomy is critical in promoting the aggregation and, hence, in causing USA300-induced alveolar injury. We propose that in addition to antibiotics, strategies for bacterial disaggregation may constitute novel therapy against USA300-induced lung injury.

Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution

Graphical Abstract Figure. No caption available. SUMMARY Regulatory T (Treg) cell responses and apoptotic cell clearance (efferocytosis) represent critical arms of the inflammation resolution response. We sought to determine whether these processes might be linked through Treg‐cell‐mediated enhancement of efferocytosis. In zymosan‐induced peritonitis and lipopolysaccharide‐induced lung injury, Treg cells increased early in resolution, and Treg cell depletion decreased efferocytosis. In advanced atherosclerosis, where defective efferocytosis drives disease progression, Treg cell expansion improved efferocytosis. Mechanistic studies revealed the following sequence: (1) Treg cells secreted interleukin‐13 (IL‐13), which stimulated IL‐10 production in macrophages; (2) autocrine‐paracrine signaling by IL‐10 induced Vav1 in macrophages; and (3) Vav1 activated Rac1 to promote apoptotic cell engulfment. In summary, Treg cells promote macrophage efferocytosis during inflammation resolution via a transcellular signaling pathway that enhances apoptotic cell internalization. These findings suggest an expanded role of Treg cells in inflammation resolution and provide a mechanistic basis for Treg‐cell‐enhancement strategies for non‐resolving inflammatory diseases. HIGHLIGHTSDepletion of Treg cells impairs efferocytosis during inflammation resolutionTreg cell transfer to mice with atherosclerosis improves lesional efferocytosisTreg cells secrete IL‐13, which stimulates IL‐10 production in macrophagesMacrophage IL‐10 induces Vav1, which activates Rac1 and apoptotic cell engulfment &NA; Regulatory T cells suppress inflammation and promote tissue repair in multiple contexts. Proto, Doran, et al. show that Treg cells enhance the ability of macrophages to engulf apoptotic cells (efferocytosis) and thereby promote resolution of inflammation.