Amit D. Parulekar

Periostin, a novel biomarker of TH2-driven asthma.

Purpose of review Asthma is a heterogeneous disease with multiple, overlapping phenotypes. Biomarkers are currently being investigated to better characterize the disease phenotypes and to identify the responders to specific targeted therapies. This review focuses on the emerging data surrounding the use of one such biomarker for T helper 2 (TH2)-driven asthma: periostin. Recent findings Periostin is an extracellular matrix protein that is induced by interleukin (IL)-4 and IL-13 in airway epithelial cells and lung fibroblasts. It has proven to be an important biomarker of TH2-associated airway inflammation and a potential predictor of airway eosinophilia. It has also been shown to predict response to treatment with inhaled corticosteroids in patients with these characteristics. Furthermore, recent asthma clinical trials have established that serum periostin may have value in predicting the response to targeted therapy with biologic agents such as lebrikizumab and omalizumab. Summary Emerging data suggest a role for periostin in refining asthma phenotypes and predicting the response to targeted therapy. Although early data are promising, further investigations are needed to confirm these findings and to identify other clinical applications in which periostin may be valuable.

Treatment of hyperacute antibody-mediated lung allograft rejection with eculizumab

We report the case of a highly sensitized (cPRA 99%, Class II) 56-year-old white female with a lung allocation score of 38, who underwent double lung transplantation for pulmonary fibrosis and pulmonary hypertension. Pre-transplant desensitization with multiple courses of plasma exchange (PE) and intravenous immunoglobulin (IVIg) was largely unsuccessful. The surgical operation was uneventful; however, the patient was found to have a positive prospective B-cell crossmatch according to both anti-human globulincomplement-dependent cytotoxicity and flow cytometry studies. At the time of transplant, the recipient had the following donor-specific antibodies (DSAs): DR8 (15,000 MFI); DR14 (14,000 MFI); DR52 (15,000 MFI); and DQ7 (3,800 MFI). PE was performed on post-operative days (PODs) 1, 0 and 1, and IVIg was given along with rituximab and bortezomib due to the positive B-cell crossmatch. Repeat DSAs post-implantation/PE were initially negative; however, the patient subsequently developed acute graft dysfunction (Figure 1) and, by POD 2, the P/F ratio had fallen from 106 to 33 and she was initiated on extracorporeal membrane oxygenation (ECMO), nitric oxide, multiple pressors and renal replacement therapy. An open-lung biopsy was performed showing neutrophilic capillaritis and C4d positivity suggestive of antibody-mediated rejection (AMR). An ensuing set of DSAs showed the antibodies against DR8, DR14, DR52 and DQ7 were again present. On POD 2, the decision was made to hold PE and give the anti-C5 antibody, eculizumab, which dramatically halted the disease progression. Extracorporeal membrane oxygenation (ECMO) was discontinued after 3 days and the chest X-ray gradually improved. After the initial 1,200-mg dose, 600 mg of eculizumab was again given on PODs 6, 8 and 9, for a cumulative dose of 3,000 mg, along with 4 doses of bortezomib 1.3 mg/m, 2 doses of rituximab 375 mg/m, 160 g of IVIg and 3 PEs post-transplant (Figure 2). After weaning off ventilator support and hemodialysis, the patient was discharged on POD 47. The 1-month biopsy was 15% positive for C4d, and the 3-month biopsy was unremarkable. The patient is now alive and well at 1 year post-transplant with no re-hospitalizations, infectious complications or

The Asthma COPD Overlap Syndrome (ACOS)

Asthma and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as distinct clinical entities. Recently, however, much attention has been focused on patients with overlapping features of both asthma and COPD: those with asthma COPD overlap syndrome (ACOS). Although no universal definition criteria exist, recent publications attempted to define patients with ACOS based on differences in clinical features, radiographic findings, and diagnostic tests. Patients with ACOS make up a large percentage of those with obstructive lung disease and have a higher overall health-care burden. Identifying patients with ACOS has significant therapeutic implications particularly with the need for early use of inhaled corticosteroids and the avoidance of use of long-acting bronchodilators alone in such patients. However, unlike asthma and COPD, no evidence-based guidelines for the management of ACOS currently exist. Future research is needed to improve our understanding of ACOS and to achieve the best management strategies.

Role of T2 inflammation biomarkers in severe asthma

Purpose of review Severe asthma is a heterogeneous syndrome. Classification of asthma into phenotypes and endotypes can improve understanding and treatment of the disease. Identification and utilization of biomarkers, particularly those linked to T2 inflammation, can help group patients into phenotypes, predict those who will respond to a specific therapy, and assess the response to treatment. Recent findings Biomarkers are present in sputum, exhaled breath, and blood of patients with asthma. These include sputum eosinophils and neutrophils, fractional excretion of nitric oxide, blood eosinophilia, IgE, and periostin. Many of these biomarkers are associated with eosinophilic inflammation propagated mainly by T2 cytokines such as IL-5 and IL-13, which are released from Th2 cells and Type 2 innate lymphoid cells. Biomarkers have been utilized in recent trials of novel biologic agents targeted at T2 inflammation and may contribute to the defining population who would respond to these therapies. Summary Despite advances in the identification and utilization of asthma biomarkers, further studies are needed to better clarify the role of biomarkers, individually or in combination, in the diagnosis and treatment of severe asthma. Future therapeutic trials should include the use of biomarkers in their design, which may lead to a more personalized approach to therapy and improved outcomes.

A Randomized Controlled Trial to Evaluate Inhibition of T-Cell Costimulation in Allergen-induced Airway Inflammation

RATIONALE T lymphocytes are important in the pathogenesis of allergic asthma. Costimulation through CD28 is critical for optimal activation of T cells, and inhibition of this pathway with CTLA4Ig has been shown to be effective in preventing airway inflammation and hyperresponsiveness in animal models of asthma. Abatacept, a humanized version of CTLA4Ig, has been approved for treatment of rheumatoid arthritis, providing the opportunity to test whether inhibition of costimulation is an effective strategy to treat people with asthma. OBJECTIVES To determine if 3 months of treatment with abatacept reduced allergen-induced airway inflammation in people with mild atopic asthma. METHODS Randomized, placebo-controlled, double-blinded study. Bronchoscopically directed segmental allergen challenge was performed on 24 subjects followed by bronchoalveolar lavage 48 hours later. Subjects were randomized 1:1 to receive abatacept or placebo, followed by a second allergen challenge protocol after 3 months of study drug. MEASUREMENTS AND MAIN RESULTS There was no significant reduction in allergen-induced eosinophilic inflammation in the abatacept-treated group compared with placebo (17.71% ± 17.25% vs. 46.39% ± 29.21%; P = 0.26). In addition, we did not detect an effect of abatacept on FEV1, provocative concentration of methacholine sufficient to induce a 20% decline in FEV1, or asthma symptoms. Subjects treated with abatacept had an increased percentage of naive and a corresponding decrease in memory CD4(+) T cells in the blood compared with placebo. CONCLUSIONS Inhibition of CD28-mediated costimulation with abatacept does not seem to alter the inflammatory response to segmental allergen challenge or clinical measures of asthma symptoms in people with mild atopic asthma. Clinical trial registered with ClinicalTrials.gov (NCT 00784459).

CTLA4-Ig inhibits allergic airway inflammation by a novel CD28-independent, nitric oxide synthase-dependent mechanism

The T‐cell response to antigen depends on coordinate signaling between costimulatory and inhibitory receptors. The altered function of either may underlie the pathophysiology of autoimmune and/or chronic inflammatory diseases and manipulation of these pathways is an important emerging area of therapeutics. We report here that the immunosuppressant drug CTLA4‐Ig inhibits the effector phase of allergic airway inflammation through a CD28‐independent, nitric oxide synthase (NOS)‐dependent mechanism. Using mice deficient in both B‐ and T‐lymphocyte attenuator (BTLA) and CD28, we demonstrate that simultaneous deficiency of an inhibitory receptor can rescue the in vivo but not the in vitro CD28‐deficient phenotype. Furthermore, we demonstrate that inflammation in CD28/BTLA‐double‐deficient mice is suppressed by CTLA4‐Ig. This suppression is reversed by treatment with the NOS inhibitor, N6‐methyl‐L‐arginine acetate (L‐NMMA). In addition, CTLA4‐Ig is ineffective at inhibiting inflammation in NOS2‐deficient mice when given at the effector phase. Thus, CD28 and BTLA coordinately regulate the in vivo response to inhaled allergen, and CTLA4‐Ig binding to B7‐proteins inhibits the effector phase of inflammation by a CD28‐independent, NOS‐dependent mechanism.

Role of biologics targeting type 2 airway inflammation in asthma: What have we learned so far?

Purpose of review Severe asthma is a heterogeneous syndrome that can be classified into distinct phenotypes and endotypes. In the type 2 (T2)-high endotype, multiple cytokines are produced that lead to eosinophilic inflammation. These cytokines and their receptors are targets for biologic therapies in patients with severe asthma who do not respond well to standard therapy with inhaled corticosteroids. Recent findings In the last decade, an increasing number of biologic therapies have been developed targeting T2 inflammation. Clinical trials of therapies targeting immunoglobulin E as well as the T2 cytokines interleukin (IL)-4, IL-5, and IL-13 have demonstrated that these treatments improve asthma-related clinical outcomes and/or have steroid-sparing properties. The use of biomarkers of T2 inflammation can help to identify the subset of patients in whom these therapies may be most efficacious. Multiple biologic agents that are directed at other targets are currently in development, including thymic stromal lymphopoietin (TSLP), prostaglandin (PG)D2 receptor, IL-25, and IL-33. Summary Biologics are emerging as a key component of severe asthma management. In patients with T2-high severe asthma, the addition of treatments targeting immunoglobulin E and IL-5 to standard therapy may lead to improvement in clinical outcomes. Other biologic therapies have shown promising preliminary results and need to be studied in further clinical trials. These biologic therapies in conjunction with biomarkers will lead to tailored therapy for asthma.

Targeting the interleukin-4 and interleukin-13 pathways in severe asthma : Current knowledge and future needs

Purpose of review Severe asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics. Interleukin (IL)-4 and IL-13 play a key role in type 2 (T2) asthma. This article reviews the signaling pathway of IL-4 and IL-13 and highlights its targeted therapy in severe asthma. Recent findings Several clinical trials of biologics targeting the IL-4/IL-13 pathway have recently been completed. In patients with severe, uncontrolled asthma, targeting IL-13 alone with biologics including lebrikizumab and tralokinumab has not shown consistent reduction in asthma exacerbations. Simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor &agr; using dupilumab has yielded more consistent results in reducing asthma exacerbations and improving lung function, especially in patients with increased blood eosinophils. Other biomarkers of T2 inflammation such as exhaled nitric oxide and serum periostin may also predict response to biologics targeting the IL-4/IL-13 pathway. Summary No biologic targeting the IL-4/IL-13 pathway is currently available for treatment of asthma, but emerging data suggest that biologics targeting IL-4 and IL-13 together may benefit patients with T2 high asthma. Additional data are needed about long-term efficacy and safety prior to incorporating these drugs into routine clinical practice.

Predictive Biomarkers for Asthma Therapy

Purpose of ReviewAsthma is a heterogeneous disease characterized by multiple phenotypes. Treatment of patients with severe disease can be challenging. Predictive biomarkers are measurable characteristics that reflect the underlying pathophysiology of asthma and can identify patients that are likely to respond to a given therapy. This review discusses current knowledge regarding predictive biomarkers in asthma.Recent FindingsRecent trials evaluating biologic therapies targeting IgE, IL-5, IL-13, and IL-4 have utilized predictive biomarkers to identify patients who might benefit from treatment. Other work has suggested that using composite biomarkers may offer enhanced predictive capabilities in tailoring asthma therapy.SummaryMultiple biomarkers including sputum eosinophil count, blood eosinophil count, fractional concentration of nitric oxide in exhaled breath (FeNO), and serum periostin have been used to identify which patients will respond to targeted asthma medications. Further work is needed to integrate predictive biomarkers into clinical practice.

Age-Related Differences in Health-Related Quality of Life in COPD: An Analysis of the COPDGene and SPIROMICS Cohorts

OBJECTIVE Younger persons with COPD report worse health-related quality of life (HRQL) than do older individuals. The factors explaining these differences remain unclear. The objective of this article was to explore factors associated with age-related differences in HRQL in COPD. METHODS Cross-sectional analysis of participants with COPD, any Global Initiative for Chronic Obstructive Lung Disease grade of airflow limitation, and ≥ 50 years old in two cohorts: the Genetic Epidemiology of COPD (COPDGene) study and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). We compared St. Georges Respiratory Questionnaire (SGRQ) scores by age group: middle-aged (age, 50-64) vs older (age, 65-80) adults. We used multivariate linear modeling to test associations of age with HRQL, adjusting for demographic and clinical characteristics and comorbidities. RESULTS Among 4,097 participants in the COPDGene study (2,170 middle-aged and 1,927 older adults) SGRQ total scores were higher (worse) among middle-aged (mean difference, -4.2 points; 95% CI, -5.7 to -2.6; P < .001) than older adults. Age had a statistically significant interaction with dyspnea (P < .001). Greater dyspnea severity (modified Medical Research Council ≥ 2, compared with 0-1) had a stronger association with SGRQ score among middle-aged (β, 24.6; 95% CI, 23.2-25.9) than older-adult (β, 21.0; 95% CI, 19.6-22.3) participants. In analyses using SGRQ as outcome in 1,522 participants in SPIROMICS (598 middle-aged and 924 older adults), we found similar associations, confirming that for the same severity of dyspnea there is a stronger association with HRQL among younger individuals. CONCLUSIONS Age-related differences in HRQL may be explained by a higher impact of dyspnea among younger subjects with COPD. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00608764 and No.: NCT01969344; URL: www.clinicaltrials.gov.