A Large Subgroup of Mild-to-Moderate Asthma is Persistently Non-Eosinophilic

A large percentage of patients with mild-to-moderate asthma have persistently non-eosinophilic disease which may not respond to currently available anti-inflammatory treatments, according to a new study.

In a cross-sectional study of 995 asthmatic subjects enrolled in nine clinical trials conducted by the NHLBI’s Asthma Clinical Research Network, sputum eosinophilia (≥2% eosinophils) was found in only 36% of asthmatics not using an inhaled corticosteroid (ICS) and 17% of those using an ICS. Among patients who achieved good asthma control, 26% had sputum eosinophilia, compared with 15% among patients who had not achieved good control.

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

Among asthmatic subjects not taking an ICS who had repeated induced sputum samples, 22% had sputum eosinophilia on every occasion (persistent eosinophilia), 31% had eosinophilia on at least one occasion (intermittent eosinophilia), and 47% had no eosinophilia on every occasion (persistently non-eosinophilic). Two weeks of treatment with a combination of anti-inflammatory drugs resulted in significant improvements in airflow obstruction in subjects with eosinophilic asthma, but not in those with persistently non- eosinophilic asthma. Bronchodilator responses to albuterol, however, were similar in eosinophilic and non-eosinophilic asthma.

“Prevalence estimates for non-eosinophilic asthma in earlier studies were based on single sputum samples,” said John Fahy, MD, MSc, professor of medicine and director of the Cardiovascular Research Institute/University of California San Francisco Airway Clinical Research Center. “Here we show for the first time that sputum eosinophilia is persistently absent in a large percentage of patients with mild/moderate asthma when sputum is analyzed repeatedly over time.”

The poor response to intense combined treatment seen in patients with persistently non-eosinophilic asthma suggests that these patients have a unique disease phenotype for which new treatments need to be developed. Treatment responses in patients with intermittent eosinophilia were similar to those of patients with persistent eosinophilia.

“A large subgroup of patients with mild-to-moderate asthma do not have the usual eosinophilic subtype that is responsive to steroid treatment,” concluded Dr. Fahy. “In addition to the implications for the care of these patients, our results have important implications for future asthma research. In clinical studies, the eosinophil phenotype of patients should be characterized to better understand treatment responses and disease mechanisms. In addition, appropriate in vitro and animal models for the study of the mechanisms of non-eosinophilic airway disease need to be developed.”

To read the article in full, please visit http://www.thoracic.org/media/press-releases/mcgrath.pdf.

Contact for article: John V. Fahy, MD, MSc, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd South, San Francisco, CA 94158-9001
Phone: 415-476-9940
Email: john.fahy@ucsf.edu

Statins May Increase Risk of Interstitial Lung Abnormalities in Smokers

Use of statins may influence susceptibility to or the progression of interstitial lung disease (ILD) in smokers, according to a new study.

While some studies have suggested that statins might be beneficial in the treatment of fibrotic lung disease, others have suggested that they may contribute to the progression of pulmonary fibrosis by enhancing secretion of inflammasome-regulated cytokines, and numerous case reports have suggested that statins may contribute to the development of various types of ILD.

“Based on earlier case reports of statin-associated ILD and data suggesting that smoking is associated with the interstitial lung abnormalities (ILA) which underlie ILD, we hypothesized that statins would increase the risk for ILA in a population of smokers,” said George R. Washko MD, MMsC, and Gary M. Hunninghake MD, MPH, of the Division of Pulmonary and Critical Care at Brigham and Women’s Hospital in Boston. “Accordingly, we evaluated the association between statin use and ILA in a large cohort of current and former smokers from the COPDGene study. In addition to the association between statin use and ILA we found in humans, we also demonstrated that statin administration aggravated lung injury and fibrosis in bleomycin-treated mice.” Bleomycin has been shown to induce lung inflammation and fibrosis.

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

Assessment included pulmonary function testing and CT scanning for radiologic features of ILA. Among 1,184 subjects with no evidence of ILA, 315 (27%) used statins, compared with 66 of 172 (38%) subjects with ILA. After adjustment for a number of covariates, including a history of high cholesterol or coronary artery disease, statin users had a 60 percent increase in the odds of having ILA , compared to subjects not taking statins. No other positive associations between ILA and cardiovascular medications or disorders were detected. The association between statin use and ILA was greatest with statins with higher hydrophilicity (readily absorbed or dissolved in water), such as pravastatin, and in higher age groups.

The effects of statins on lung injury and fibrogenesis were also examined in a study in mice, which were pretreated with pravastatin prior to intratracheal bleomycin administration. Statin use was found to exacerbate bleomycin-induced lung fibrosis. In a further in vitro study, statin pretreatment was shown to enhance Nlrp3-inflammasome activation through mitochondrial reactive oxygen species generation in macrophages. “These results implicate activation of the NLRP3 inflammasome in fibrotic lung disease,” said Jin-Fu Xu MD, and Augustine M. K. Choi, MD, of the Department of Pulmonary Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, in Shanghai, China and the Division of Pulmonary and Critical Care at Brigham and Women’s Hospital in Boston, respectively.

There were some limitations to both studies. Findings in the mouse model were not replicated in human samples. All study subjects were current or former smokers, perhaps limiting the applicability of the results to others. Cigarette smoking by itself may lead to pulmonary inflammation. Finally, the duration and dosage of statin therapy was not available for the majority of patients.

“While statin use was associated with ILA in our study, caution should be used when extrapolating these findings to the care of patients,” concluded Dr. Hunninghake. “The significant benefits of statin therapy in patients with cardiovascular disease probably outweigh the risk of developing ILA, and statin use may benefit some patients with respiratory disease. Clinicians should be aware, though, that radiological evidence of ILD can develop in some patients treated with statins.”

To read the article in full, please visit http://www.thoracic.org/media/press-releases/xu.pdf.

Contacts for article: Augustine M. K. Choi, MD, Gary M. Hunninghake MD, MPH, Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Phone: 617-732-7599, 617-525-9687
Email: amchoi@rics.bwh.harvard.edu, ghunninghake@partners.org

ATS Issues Joint Statement on Key Issues and Recommendations for Critical Care Research

To reduce mortality and improve patient care in the nation’s ICUs, a task force formed by the Critical Care Societies Collaborative (CCSC), in conjunction with the US Critical Illness and Injury Trials Group (USCIITG) has recommended that research in the field become less fragmented and better account for patient heterogeneity and the complexity of critical illness.

The CCSC comprises the American Thoracic Society (ATS), the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP) the Society of Critical Care Medicine (SCCM).

The task force recommendations were published in the January 1, 2012 issue of the American Journal of Respiratory and Critical Care.

The task force was formed because identifying common challenges and establishing priorities in the field of critical care research have proven difficult, given the broad range of stakeholders involved in the rapidly growing field.

“Critical care is one of the fastest growing areas in medicine, accounting for approximately $80 billion in healthcare expenditures in the United States annually,” said the lead ATS representative on the task force, Polly Parsons, MD, chair of the Department of Medicine at the University of Vermont College of Medicine. “This enormous cost, along with the high mortality rates seen in intensive care units, point to the urgent need for new treatments and systems of care, implementation of new research findings and identification of priorities for critical care research.”

Key themes and challenges identified by the task force include the need to alter the fragmented approach to critical care research and more effectively link diverse research areas, the need to account for the complexity of critical illness and injury and patient heterogeneity in research, and the need for an enhanced clinical research infrastructure.

General principles for research priorities in critical care identified by the task force include:

• Clearer classification and separation of clinical entities in critical illness;
• Identification and testing of novel biomarkers, such as protein markers, metabolites, RNA and DNA;
• Development of improved models of critical illness and novel approaches to bench research that take into account variations in patient characteristics, care strategies and therapeutic interventions;
• Enhanced access to clinical research data; and
• Integration of new research areas, scientific disciplines and technology into the study of critical illness

Key critical care research priorities were identified in the specific areas of:

• Basic science/cellular research, including definition of factors that transform normal stress responses into critical illness;
• Translational research, including integration of studies of mechanism and intervention and application of standardized methodology to study design;
• Clinical research, including development of methods for early recognition of acute, severe disease in patients at risk for imminent deterioration and improved organ support techniques;
• Health service and delivery research, including improved mechanisms for knowledge transfer; and
• Education research, including the incorporation of other disciplines and the use of simulation.

In addition to these areas, the task force recommended process improvements in:

• Research environment, including improvements in the infrastructure of research facilities and greater interdisciplinary collaboration;
• Preclinical modeling to more fully capture data on the wide range and severity of critical care conditions;
• The characterization of both individual patients and patient cohorts;
• Regulatory challenges, including improvements in consent procedures for critical care patients;
• Research networks, including expansion of existing multidisciplinary networks; and
• Funding to encourage increased collaboration across funding sources to ensure adequate support for critical care research, which crosses disease- and age-specific boundaries;

Dr. Parsons noted that the increasing demand for resources in response to outcome challenges has created a need for greater investment in critical care research. “These recommendations will help facilitate the progress of research across the spectrum of critical care,” she said. “Their implementation will require new initiatives, shifts in national research priorities and enhanced cooperation within the critical care community. The agenda for critical care research outlined in these recommendations provides a blueprint for future initiatives.”

To read the article in full, please visit http://ajrccm.atsjournals.org/content/185/1/96.abstract

Contact for article: Polly E. Parsons, MD, Department of Medicine, University of Vermont/FAHC, Fletcher 311, 111 Colchester Avenue. Burlington, Vermont 05401
Phone: 802-847-2550
Email: polly.parsons@vtmednet.org

Duration of Red Blood Cell Storage Does Not Affect Short-Term Pulmonary, Immunologic, or Coagulation Status

There is no difference in early measures of pulmonary function, immunologic status, or coagulation status after fresh versus standard issue single-unit red blood cell (RBC) transfusion, according to a new study from the Mayo Clinic.

“Longer duration of RBC storage is thought to increase the risk of transfusion-related pulmonary complications,” said Daryl J. Kor, assistant professor of anesthesiology at the Mayo Clinic College of Medicine. “In our study of 100 intubated, mechanically ventilated patients, we did not see an increased risk associated with RBC storage duration.”

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

In the double-blind trial, 50 patients were randomized to receive fresh (median storage duration = 4.0 days) RBC and 50 were randomized to receive standard issue RBC (median storage duration = 26.5 days). The primary outcome measure was change in pulmonary gas exchange, as measured by the partial pressure of arterial oxygen to fraction of inspired oxygen concentration ratio (ΔPaO2/FiO2). Post-transfusion measurements were performed upon completion of the transfusion and within two hours of the transfusion (median 1.9 hours in the fresh RBC group and 1.8 hours in the standard issue RBC group).

No significant differences between groups were seen in the primary outcome measure of change in PaO2/FiO2 ratio (2.5 +/- 49.3 vs. -9.0 +/- 69.8; fresh RBC vs. standard issue RBC; p = 0.22). Similarly, no significant differences were seen for any of the other outcome measures of pulmonary function (fraction of dead space ventilation, dynamic and static pulmonary compliance), immunologic status (tumor necrosis factor-alpha, interleukin-8, C-reactive protein) or coagulation status (fibrinogen, anti-thrombin consumption).

“Our data do not support a significant effect of RBC storage duration on respiratory, immunologic or coagulation parameters in the immediate post-transfusion period,” said Dr. Kor. “Previous observational studies linking RBC storage duration and respiratory complications may have suffered from bias and unmeasured confounding, which were addressed in our double-blind, randomized trial.”

The study did have some limitations, including the short duration of follow-up, the study’s limited sample size and the single center, tertiary care setting, which may limit the generalizability of the results.

“Given the lack of an association between RBC storage duration and transfusion-related pulmonary complications in our study, randomization to fresh or standard issue RBC in clinical trials can be performed ethically,” said Dr. Kor. “Further study will clarify the impact of RBC storage duration on other patient outcomes.”

To read the article in full, please visit http://www.thoracic.org/media/press-releases/kor.doc

Contact for article: Dr. Daryl J. Kor, Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905
Phone: 507-255-6051
Email: kor.daryl@mayo.edu

Accelerated Infant Growth Increases Risk of Future Asthma Symptoms in Children

Accelerated growth in the first three months of life, but not fetal growth, is associated with an increased risk of asthma symptoms in young children, according to a new study from The Generation R Study Group at Erasmus Medical Center in the Netherlands.

“We know that low birth weight is associated with an increased risk of asthma symptoms in children, but the effects of specific fetal and infant growth patterns on this risk had not been examined yet,” said researcher Liesbeth Duijts, MD, PhD. “In our study, weight gain acceleration in early infancy was associated with an increased risk of asthma symptoms in children of preschool age, independent of fetal growth patterns, suggesting that early infancy might be a critical period for the development of asthma.”

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

This study was embedded in the Generation R Study, a population-based prospective cohort study, and included 5,125 children who were followed from fetal life through the age of four. Information on asthma symptoms was obtained by questionnaires at the ages of 1, 2, 3, and 4.

No consistent relationships between fetal length and weight growth during different trimesters and the development of asthma symptoms were observed. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms, including wheezing (overall odds ratio (OR) 1.44 (95% confidence interval (CI): 1.22, 1.70), shortness of breath: 1.32 (1.12, 1.56), dry cough: 1.16 (1.01, 1.34), and persistent phlegm: 1.30 (1.07, 1.58)). The associations between accelerated infant growth and risk of developing asthma symptoms were independent of other fetal growth patterns and tended to be stronger among children of atopic mothers.

“Our results suggest that the relationship between infant weight gain and asthma symptoms is not due to the accelerated growth of fetal growth-restricted infants only,” said Dr. Duijts. “While the mechanisms underlying this relationship are unclear, accelerated weight growth in early life might adversely affect lung growth and might be associated with adverse changes in the immune system.”

The study had a few limitations, including the possibility of measurement error in the estimation of fetal weight and the use of self-report for asthma symptoms.

“Further research is needed to replicate our findings and explore the mechanisms that contribute to the effects of growth acceleration in infancy on respiratory health,” concluded Dr. Duijts. “The effects of infant growth patterns on asthma phenotypes in later life should also be examined.”

To read the article in full, please visit http://www.thoracic.org/media/press-releases/Sonnenschein-vanderVoort.doc

Contact for article: Dr. Liesbeth Duijts, MD, PhD, Erasmus Medical Center - Sophia Children's Hospital, Sp-3435; PO Box 2060, 3000 CB Rotterdam, The Netherlands.
Email: l.duijts@erasmusmc.nl

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation

Extracorporeal membrane oxygenation (ECMO) support in awake, non-intubated patients may be an effective strategy for bridging patients to lung transplantation, according to a new study from Germany.

“As waiting times for donor organs continue to increase, so does the need for bridging strategies for patients with end-stage lung disease awaiting transplantation,” said Marius M. Hoeper, MD, professor of medicine at the Hannover Medical School in Hannover, Germany. “Our study shows that ECMO support in awake and non-intubated patients may be an alternative to intubation and mechanical ventilation, and may result in better survival.”

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

In the retrospective, single-center study of consecutive lung transplantation candidates with terminal respiratory or cardiopulmonary failure, 26 patients received awake ECMO and 34 control patients received conventional mechanical ventilation (MV) as a bridge to transplant. Median duration of ECMO support was 9 days (range 1-45) and median duration of MV was 15 days (range 1-71). Veno-arterial ECMO was used primarily in patients with right ventricular failure and/or profound hypoxemia while the veno-venous approach was used primarily in patients exhibiting hypoxemic and/or hypercapnic respiratory failure but stable hemodynamics.

Of 26 patients in the ECMO group, six (23%) died before a donor organ became available, compared with 10 of 34 (29%) patients in the MV group. Among the patients who reached transplantation, the survival rate at six months post-transplantation was significantly (p=.02) higher in the awake ECMO group (80%) compared with the MV group (50%). The six-month survival rate among awake ECMO patients who required secondary intubation dropped to 43%. Awake ECMO patents required significantly (p=.04) shorter postoperative mechanical ventilation and showed a trend towards shorter postoperative hospital stays.

ECMO-related complications included a fatal cardiac arrest after insertion of the venous ECMO cannulae in one patient. Intubation and mechanical ventilation was required 1-7 days after ECMO insertion in six patients. Blood transfusions due to bleeding complications were needed in eight patients. Of five patients who developed a sepsis-like syndrome, one recovered.

“Ours is the largest series of patients who underwent awake ECMO as a bridge to lung transplantation,” said lead author Thomas Fuehner, MD. “In addition to the possibility that this approach may improve survival, one of the main benefits of using awake ECMO is the avoidance of the complications associated with general anesthesia, intubation, and long-term ventilation.”

The study had a few limitations, including the small number of patients included and the retrospective nature of the analyses.

“Awake ECMO may be an effective bridging strategy for lung transplantation candidates,” said Dr. Hoeper. “This strategy, however, remains investigational and must be studied further to improve its safety and efficacy and examine how to tailor its use for specific patient populations.”

To read the article in full, please visit http://www.thoracic.org/media/press-releases/fuehner.pdf

Contact for article: Professor Marius M. Hoeper, MD, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany
Phone: +49 511 532 3537
Email: hoeper.marius@mh-hannover.de