Keith C. Meyer

IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpastures syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease

BACKGROUND The clinical utility of bronchoalveolar lavage fluid (BAL) cell analysis for the diagnosis and management of patients with interstitial lung disease (ILD) has been a subject of debate and controversy. The American Thoracic Society (ATS) sponsored a committee of international experts to examine all relevant literature on BAL in ILD and provide recommendations concerning the use of BAL in the diagnosis and management of patients with suspected ILD. PURPOSE To provide recommendations for (1) the performance and processing of BAL and (2) the interpretation of BAL nucleated immune cell patterns and other BAL characteristics in patients with suspected ILD. METHODS A pragmatic systematic review was performed to identify unique citations related to BAL in patients with ILD that were published between 1970 and 2006. The search was updated during the guideline development process to include published literature through March 2011. This is the evidence upon which the committees conclusions and recommendations are based. RESULTS Recommendations for the performance and processing of BAL, as well as the interpretation of BAL findings, were formulated by the committee. CONCLUSIONS When used in conjunction with comprehensive clinical information and adequate thoracic imaging such as high-resolution computed tomography of the thorax, BAL cell patterns and other characteristics frequently provide useful information for the diagnostic evaluation of patients with suspected ILD.

A new classification system for chronic lung allograft dysfunction

Although survival after lung transplantation has improved significantly during the last decade, chronic rejection is thought to be the major cause of late mortality. The physiologic hallmark of chronic rejection has been a persistent fall in forced expiratory volume in 1 second associated with an obstructive ventilatory defect, for which the term bronchiolitis obliterans syndrome (BOS) was defined to allow a uniformity of description and grading of severity throughout the world. Although BOS was generally thought to be irreversible, recent evidence suggests that some patients with BOS may respond to azithromycin with > 10% improvement in their forced expiratory volume in 1 second. In addition, a restrictive form of chronic rejection has recently been described that does not fit the strict definition of BOS as an obstructive defect. Hence, the term chronic lung allograft dysfunction (CLAD) has been introduced to cover all forms of graft dysfunction, but CLAD has yet to be defined. We propose a definition of CLAD and a flow chart that may facilitate recognition of the different phenotypes of CLAD that can complicate the clinical course of lung transplant recipients.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Neutrophils and low-grade inflammation in the seemingly normal aging human lung

Lung function deteriorates with age and is associated with elastin loss, loss of elastic recoil and decline in diffusing capacity for carbon monoxide. To determine whether increased numbers of neutrophils can be found in the lower respiratory tract in healthy, clinically normal individuals who are more advanced in age, we performed bronchoalveolar lavage (BAL) on individuals in three discontinuous age groups (Group I, 19-36 years; Group II, 45-55 years; Group III, 64 83 years). We found that neutrophils were increased in many individuals in Group III compared to Group I. The neutrophil cell differential count was 1.44+/-0.18% (mean+/-S.E.M.) for Group I versus 3.88+/-0.81% for Group III (P < 0.01) and neutrophils x 10(3)/ml BAL fluid was 1.7+/-0.2 versus 7.2+/-1.7 for Group I versus Group III, respectively (P < 0.01). Similarly, interleukin-8 (IL-8) (8.5+/-1.7 vs 36.8+/-9.4 pg/ml, P < 0.01) and neutrophil elastase (NE) complexed to alpha1-antiprotease (1.2+/-0.1 vs 16.6+/-7.1 ng/ml, P < 0.02) were significantly elevated in the oldest versus youngest age group, although alpha1-antiprotease (582+/-86 vs 1178+/-148 ng/ml, P < 0.01) and elastase inhibitory capacity (EIC) (8.1+/-1.3 vs 17.7+/-1.9 micromol/ml, P < 0.01) were also significantly increased in the oldest age group. This cross-sectional investigation suggests that low-grade inflammation exists in the air spaces of many clinically normal, older individuals.

The role of immunity in susceptibility to respiratory infection in the aging lung.

Abstract Respiratory tract infections, particularly pneumonia, are a leading cause of death in persons 65 years or older in both developed and developing countries. Because many attributes of immunity wane with advancing age, the elderly may be more susceptible to respiratory infections, even if they appear to be in good health. A decline in the ability of lymphoid tissues to mount an antigen-specific response (adaptive immunity) to specific microorganisms such as influenza virus or Streptococcus pneumoniae is thought to be an important factor in increasing susceptibility to respiratory tract infection with advancing age. However, abnormalities in innate immunity may also contribute to increased susceptibility to respiratory infections and have been poorly characterized in the elderly. Although changes in immune parameters such as T cell subsets and immunoglobulin concentrations have been observed in respiratory secretions from older healthy individuals compared to younger subjects, the significance of these changes for protective immunity in the lung is unknown. The incidence of pneumonia may be lessened by measures such as optimizing treatment of comorbid conditions, optimizing nutrition, and addressing swallowing disorders. The use of vaccines directed against the influenza virus and S. pneumoniae appears to have made an impact on the degree of morbidity and mortality, and perhaps, the incidence, of community-acquired pneumonia. However, better stimulation of specific immune responses with improved vaccines and more widespread use of these vaccines for protection of elderly individuals are needed.

Lung transplantation with donation after cardiac death donors: Long-term follow-up in a single center

OBJECTIVE We sought to examine long-term outcomes at the University of Wisconsin for all lung transplant recipients who received lungs from donation after cardiac death donors since the initiation of this program in 1993. METHODS Eighteen (4.2%) of the 424 lung transplantations performed in 406 patients between January 1993 and April 2009 used lungs from donation after cardiac death donors. Outcomes for this recipient cohort were compared with those for recipients who received organs from brain-dead donors. RESULTS Warm ischemic time (from withdrawal of support to reperfusion of organs) was 30 +/- 17 minutes (11-93 minutes). The patient survival rates in the donation after cardiac death group (DCD group) at 1, 3, and 5 years were 88.1% +/- 7.9%, 81.9% +/- 9.5%, and 81.9% +/- 9.5%, respectively. These survival rates were not different from those of the brain-dead donor group (BDD group, P = .66). The incidence of primary graft dysfunction in the DCD group was similar to that of the BDD group (P = .59). However, the incidence of airway complications was somewhat higher in the DCD group. Freedom from bronchiolitis obliterans syndrome at 1, 3, and 5 years in the DCD group was 80.4% +/- 10.2%, 80.4% +/- 10.2%, and 72.3% +/- 11.9%, respectively, and did not differ from the incidence of bronchiolitis obliterans syndrome in the BDD group (P = .59). CONCLUSIONS Our data show that the long-term patient and graft survival rates after donation after cardiac death lung transplantation were equivalent to those after brain-dead donor lung transplantation. Our findings suggest that the use of donation after cardiac death donors can safely and substantially expand the donor pool for lung transplantation.

Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy?

Idiopathic pulmonary fibrosis (IPF) is a distinct clinical entity that generally affects people who are over 60 yrs of age, and median survival ranges from 3 to 5 yrs after the diagnosis is ascertained. The natural course of IPF is well known: the majority of patients with IPF display steady decline in lung function, some patients remain stable for prolonged periods of time, a subgroup of patients rapidly decline, and a subset of patients manifest acute exacerbations of IPF preceding death [1]. While several key cellular and molecular events that are thought to follow “injury” have been identified in the pathogenesis of IPF [2], the ultimate cause of IPF and the triggering factor(s) that injure the lung remain elusive, and none of the currently available pharmacological agents have demonstrated improved outcomes and survival in patients with IPF. The incidence and prevalence of IPF is highly linked to advanced age with an estimated incidence and prevalence of 71 and 271 per 100,000 per year for males and 67 and 266 per 100,000 per year for females aged 75 yrs or greater versus an overall incidence and prevalence of 16.3 and 42.7 per 100,000 per year using broad diagnostic criteria [3]. Interestingly, many observations suggest that the aged lung is more susceptible to injury and fibrosis induced by a variety of stimuli, and this susceptibility may be linked to age-associated changes in gene expression or genetic polymorphisms such as age-associated telomerase dysfunction [4–7]. Advanced age is also accompanied by a decline in oesophageal and gastric motility, diminished upper oesophageal sphincter pressure, and an increase in oesophageal acid exposure [8]. Hiatal hernias appear with advancing age and have been detected in up to 60% of individuals older than 60 yrs [ …

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

RATIONALE The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation. OBJECTIVES To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. METHODS Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa(O(2))/Fi(O(2)) index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. MEASUREMENTS AND MAIN RESULTS We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4(+) T-cell and monocyte mediated, and dependent on IL-17, IL-1beta, and tumor necrosis factor (TNF)-alpha. Pa(O(2))/Fi(O(2)) indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa(O(2))/Fi(O(2)), increased local TNF-alpha and IL-1beta production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts. CONCLUSIONS The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.