Update and Arizona Thoracic Society Position Statement on Stem Cell Therapy for Lung Disease

Summary

Infusions of stem cells are increasingly being offered for a variety of diseases, including chronic lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. However, the potential for harm, the lack of any proven benefit, and the high fees that many of these programs charge make recommending stem cell therapy untenable. At the time of this writing (April 2019) it appears that stem cell therapy can be safely performed, although the long-term side effects remain unknown. However, the little data available show no benefit in meaningful outcomes, such as mortality, morbidity or patient well-being, for stem cell treatment of chronic lung disorders. Patients with severe, incurable diseases may be motivated to seek innovative therapies. We encourage such patients to contact their primary care physician or pulmonologist. Clinical trials in the United States and Canada investigating stem cell therapy for lung diseases can be found on the website of the National Institutes of Health at Clinicaltrials.gov. The Arizona Thoracic Society encourages regulatory agencies to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

Introduction

A central component of the mission of medical societies is to translate new scientific information into patient education. There appears to be increasing direct-to-consumer advertising of untested, unapproved, and potentially ineffective “stem-cell” treatments for a variety of diseases, including lung disorders (1). One may come across information regarding stem cell therapy for chronic obstructive pulmonary disorders and fibrotic lung disease, in the United States and worldwide, on the internet, patient support groups, or other sources. Recently, a direct mailing to the home of one of the members of the Arizona Thoracic Society was received (Figure 1).

Figure 1. Direct mailing for stem cell therapy for several diseases including COPD received by one of the members of the Arizona Thoracic Society.

These programs are often characterized by:

• Exorbitant fees
• Misrepresentation of risks and benefits
• Overreliance on, and advertisement of, patient testimony
• Poor patient follow-up
• Absence of regulatory oversight and objective clinical evidence for claimed benefits

Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies.

Chronic Obstructive Pulmonary Disease (COPD)

Stem cells can differentiate into several different lung cell types, including the alveolar epithelial cells. Since COPD is a disease associated with destruction of alveoli induced by cigarette smoke, the concept of rebuilding the alveoli through stem cell therapy is attractive. Pre-clinical trials in animal models have suggested regeneration of alveolar-like structures, repair of emphysematous lungs, and reduction of inflammatory responses, with the greatest success being in acute lung injury models.

Currently, regenerative therapies are divided into extrinsic therapeutic strategies and intrinsic cell therapy methods. Extrinsic cell therapy refers to the vascular infusion of (or endotracheal installation) of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), mesenchymal stem cells (MSCs), and human lung stem cells (hLSCs). Intrinsic therapy refers to the delivery of small molecules (retinoid compounds have been the most studied) that can stimulate the endogenous lung stem/progenitor cells to regenerate and replace damaged structures.

A number of recent review articles have summarized the current state of research in the use of stem cells in COPD (2-4). These review articles all contain summaries of trials conducted to date using both extrinsic and intrinsic therapies. There have been several phase I clinical trials, primarily assessing safety, and a handful of small phase II clinical trials that have been negative for meaningful clinical outcomes. Sun et al. (3) point out that the available trials have all been conducted on patients with advanced COPD. The authors suggest that further research is required on how to enhance the engraftment of exogenous mesenchymal stem cells in damaged lungs. Further, considering the anti-inflammatory and immunomodulatory effects of exogenous mesenchymal stem cells, they may be most effective potentially in treating acute lung disease, as opposed to chronic progressive disease with severe structural damage.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease of unknown etiology characterized by a combination of histological changes, including extracellular matrix (ECM) deposition, phenotypic changes of fibroblasts, and alveolar epithelial cells, the formation of fibroblastic foci, and scattered areas of aberrant wound healing interspersed with normal lung parenchyma (5).

There are two approved compounds for the treatment of IPF: pirfenidone and nintedanib. Pirfenidone is an antifibrotic compound with an unclear mechanism of action, targeting several molecules, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin 6 (6). Nintedanib is a tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR) (7). While the use of pirfenidone and nintedanib has been shown to slow the progression of IPF, neither is curative and morbidity and mortality from IPF remains high (8,9).

Because of the inadequacy of therapy in IPF, the use of mesenchymal stem cells (MSCs) has attracted interest as a potential option. Early clinical studies have shown that the MSCs can be safely administered (5,10-12). A phase Ib study of endobronchially administered autologous adipose-derived MSCs showed not only acceptable safety outcomes, but also improvements in quality of life parameters (12). However, there were no significant differences in any of the studied functional parameters (FVC, FVC%pred. and DLCO% pred.) at baseline and 6 and 12 months following 3 endobronchial infusions of MSCs.

Cystic Fibrosis

Cystic fibrosis (CF) is a genetic syndrome usually resulting in a high mortality rate due to progressive lung disease. Several drugs targeting specific mutated cystic fibrosis transmembrane regulator (CFTR) proteins are already in clinical trials. However, new therapies, based on stem cells, are also emerging. Interest has focused on induced pluripotent stem (iPS) cells. It is possible to make iPS cells using cells from people with CF, and then use gene editing to correct CFTR mutations in those cells (13). This suggests the possibility of re-implanting the corrected iPS cells into the lungs of people with CF to generate healthy lung cells. Currently, three trials examining the safety of stem cells in cystic fibrosis are ongoing according to Clinicaltrials.gov. 

Adult Respiratory Distress Syndrome (ARDS)

Four clinical trials are listed on Clinicaltrials.gov for ARDS and stem cells; one, which involved 3 patients, has been completed (14). No outcome information is available.

Other Lung Diseases

We are unaware of any human trials at this time with outcomes in other lung diseases.

Regulatory and Legal Actions

The Food and Drug Administration (FDA) and the Attorney General of New York have both expressed concern over stem cell therapy. The concerns follow reports of three patients becoming blind after receiving injections of stem cells into the eye and twelve patients who became seriously ill after receiving injections that purportedly contained stem cells from umbilical cord blood (15,16). The FDA has issued warning letters to stem cell clinics, including one letter claiming violation of Federal law, and another 20 warnings to clinics of that their claims and actions were subject to FDA approval. The NY Attorney has filed a lawsuit against a for-profit stem cell clinic, Park Avenue Stem Cell, claiming it performed unproven procedures on patients with a wide range of medical conditions, from erectile dysfunction to heart disease (17).

The Arizona Thoracic Society encourages further investigation into stem cell transplantation in lung disease. However, we do not at this time encourage non-investigational use of stem cells since the therapy has not been shown to have meaningful patient benefits. We also encourage state and local regulatory agencies in the Southwest to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

References

1. American Lung Association. Statement on Unproven Stem Cell Interventions for Lung Diseases (July 2016). Available at: https://www.thoracic.org/members/assemblies/assemblies/rcmb/working-groups/stem-cell/resources/statement-on-unproven-stem-cell-interventions-for-lung-diseases.pdf (accessed 4/5/19).
2. Balkissoon R. Stem Cell Therapy for COPD: Where are we? Chronic Obstr Pulm Dis. 2018;5(2):148-53. [CrossRef] [PubMed]
3. Sun Z, Li F, Zhou X, Chung KF, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. J Thorac Dis. 2018 Feb;10(2):1084-98. [CrossRef] [PubMed]
4. Cheng SL, Lin CH, Yao CL. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science. Stem Cells Int. 2017;2017:8916570. [CrossRef] [PubMed]
5. Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal stem cells for the treatment of idiopathic pulmonary fibrosis. Front Med (Lausanne). 2018 May 15;5:142. [CrossRef] [PubMed]
6. Kolb M, Bonella F, Wollin L. Therapeutic targets in idiopathic pulmonary fibrosis. Respir Med. 2017;131:49–57. [CrossRef] [PubMed]
7. Fletcher S, Jones MG, Spinks K, et al. The safety of new drug treatments for idiopathic pulmonary fibrosis. Expert Opin Drug Saf. 2016;15:1483–9. [CrossRef] [PubMed]
8. King TE, Bradford WZ, Castro-Bernardini S, et al. Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92. [CrossRef] [PubMed]
9. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82. [CrossRef] [PubMed]
10. Tzouvelekis A, Ntolios P, Karampitsakos T, et al. Safety and efficacy of pirfenidone in severe idiopathic pulmonary fibrosis: a real-world observational study. Pulm Pharmacol Ther. 2017;46:48-53. [CrossRef] [PubMed]
11. Tzouvelekis A, Koliakos G, Ntolios P, et al. Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal. J Transl Med. 2011;9:182. [CrossRef] [PubMed]
12. Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171. [CrossRef] [PubMed]
13. The Cystic Fibrosis Foundation. Stem cells for cystic fibrosis therapy. Available at: https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Stem-Cells-for-Cystic-Fibrosis-Therapy/ (accessed 4/5/19).
14. Clinicaltrials.gov. Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START). Available at: https://www.clinicaltrials.gov/ct2/show/results/NCT01775774?term=Stem+cells&cond=ARDS&rank=4 (accessed 4/5/19).
15. Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med. 2017 Mar 16;376(11):1047-53. [CrossRef] [PubMed]
16. Grady D. 12 People hospitalized with infections from stem cell shots. NY Times. Dec. 20, 2018. Available at: https://www.nytimes.com/2018/12/20/health/stem-cell-shots-bacteria-fda.html?action=click&module=RelatedCoverage&pgtype=Article&region=Footer (accessed 4/9/19).
17. Abelson R. N.Y. attorney general sues Manhattan stem cell clinic, citing rogue therapies. NY Times. April 4, 2019. Available at: https://www.nytimes.com/2019/04/04/health/stem-cells-lawsuit-new-york.html (accessed 4/9/19).

Cite as: Arizona Thoracic Society*. Update and Arizona Thoracic Society position statement on stem cell therapy for lung disease. Southwest J Pulm Crit Care. 2019;18(4):82-6. doi: https://doi.org/10.13175/swjpcc020-19 PDF

*The below contributed to the update and position statement on stem cell therapy

• Bhargavi Gali, MD
• Michael B. Gotway, MD
• Kenneth S. Knox, MD
• Timothy T. Kuberski, MD
• Stuart F. Quan, MD
• George Parides, DO
• Richard A. Robbins, MD
• Gerald F. Schwartzberg, MD
• Allen R. Thomas, MD
• Lewis J. Wesselius, MD

Evaluating a Scoring System for Predicting Thirty-Day Hospital Readmissions for Chronic Obstructive Pulmonary Disease Exacerbation

Vanessa Yap, MD¹

Diahann Wilcox, APRN, DNP¹

Richard ZuWallack, MD²

Debapriya Datta, MD¹

¹Division of Pulmonary & Critical Care Medicine

University of CT Health Center

Farmington, CT USA

²Division of Pulmonary & Critical Care Medicine

St Francis Hospital & Medical Center

Hartford, CT USA

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) results in 700,000 hospitalizations annually in the United States and 12-25% of patients are readmitted within 30 days of hospital discharge. A simple scoring system to risk-stratify these patients would be useful in allocating scarce resources.

Objective: The objectives of this study were to identify possible predictor variables to develop a clinically-useful instrument that can predict 30-day hospital readmissions in COPD patients.

Methods: Fifty patients hospitalized for a COPD exacerbation at two hospitals over a one-month period were studied prospectively. Demographics, disease severity, symptoms, functional status, psychological, and co-morbidity variables were assessed during the hospitalization. Patients were contacted telephonically thirty days post-discharge to determine readmission. Baseline variables were tested as predictors of 30-day readmissions.

Results: Mean age was 71 ± 11 years; 77% were female, 60% had Medical Research Council dyspnea 3 or 4; mean FEV1 was 41 ± 13% of predicted. Mean length of stay was 4.3 ± 3.2 days. Sixty percent had ≥ 1 clinical exacerbations in the preceding year, 52% had been hospitalized at least once for a respiratory exacerbation; 61% had been hospitalized at least once; 26% were on chronic prednisone. Thirty-day readmission rate was 24%. Three variables were found to be predictive of hospitalization: Clinical exacerbations in the previous year, chronic prednisone use, and functional limitation from dyspnea predictive of hospitalization.

Conclusions: Exacerbations in the previous year, chronic prednisone use, and functional limitation from dyspnea hold promise in a scoring system used to predict 30-day re-hospitalization and could be quickly assessed from a review of hospital record or a brief interview.

Introduction

Chronic obstructive pulmonary disease (COPD) is a common disease and is a leading cause of mortality in the United States (1). Much of the cost of care in COPD involves expenses related to exacerbations of this disease (2). Hospital readmissions within 30 days in COPD are frequent – with approximately 9-20% being readmitted (3-6). Hospitals will soon be financially penalized for 30-day readmissions for COPD. Risk stratification would be useful in directing scarce medical resources toward those patients most likely to be readmitted. The objectives of our study were: 1. To evaluate predictors of 30-day hospital readmission in patients hospitalized for an exacerbation of COPD and 2. To develop a simple, clinically-useful instrument that can predict any-cause 30-day hospital readmissions in COPD patients. To this end, the final tool would have to be brief (taking < 10 minutes to complete), convenient to use and have sufficient predictive power to predict hospital readmission.

Methods

This was a prospective study, performed by means of review of medical records and patient interview. Approval for the study was obtained from the IRBs of both participating institutions. There was no extramural funding for the study.

Fifty patients admitted with acute exacerbation of COPD over a 3-month period were studied. The primary inclusion criterion was a clinical diagnosis of a COPD exacerbation resulting in hospitalization. Patients with primary diagnosis of acute exacerbation of COPD exacerbation but with concomitant diagnosis of heart failure or pneumonia were included in the analysis. Inability to effectively communicate with the investigator, including language barrier or cognitive defect was the exclusion criterion.

The hospitalist physician, after receiving verbal approval from the hospitalized COPD patient of his/her potential willingness to see an investigator for a clinical research study, was then seen by an investigator, and informed consent was obtained. Following this, an interview and review of medical records were performed to obtain demographic and disease variables. Variables (from interview or record review) included: demographics (age, gender), disease severity, all-cause and respiratory-related hospitalizations over the preceding year, outpatient treated respiratory exacerbations over the preceding year, functional status, co-morbidities, psychological status, treatment upon admission. COPD assessment test (CAT) (7), Charlson Comorbidity Index (CCI) (8) and LACE Index (9) were determined for all patients. We also measured the treating physician’s “gut feeling” of the likelihood of a 30-day readmission. The treating physician was blinded as to the specific variables we measured. (All variables tested are detailed in Appendix. Post-bronchodilator forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were obtained from previous spirometry (within 3 years), if available. The patients without a historical spirometric diagnosis of COPD had spirometry before hospital discharge. Consented patients were then contacted at 30-days to determine whether they had readmissions and if so, for what cause.

General statistics are reported as means ± standard deviations (SD). Univariate logistic regression analyses were used to determine which of our tested variables predicted 30-day admission for exacerbation of COPD. Following this, multivariate forward logistic regression, incorporating variables that were predictive in univariate analyses, was utilized to determine which variables were predictive of 30-day hospitalization for COPD exacerbations.

Hospitalizations were analyzed as binary variables (yes-no). Based on the univariate analysis, two scoring systems were developed to predict readmission. The 2 scoring systems, each including three variables, significantly predicted 30-day readmissions.

The first scoring system (scoring system I) was as follows:

1. MRC dyspnea. This score ranges from 0 (least) to 4 (greatest) dyspnea. Our scoring was dichotomized to 0 (MRC 0, 1, 3, or 3) or 1 (MRC 4: “too short of breath to leave the house or short of breath dressing/undressing.”
2. Exacerbation history: Those with 1 or more hospitalizations for exacerbations in the preceding year were given a score of 1; those below this threshold had a score of 0.
3. Chronic prednisone use prior to admission: Chronic prednisone use was defined as prednisone used on all or most days for at least three months prior to admission. Those meeting this criterion were given a score of 1, those without chronic prednisone use had a score of 0.

The second scoring system (scoring system II) was as follows:

1. MRC dyspnea. This was identical to # 1 in the first scoring system.
2. Exacerbation history: Those with 2 or more outpatient -treated exacerbations (some of these could result in hospitalization) in the preceding year were given a score of 1; those below this threshold had a score of 0.
3. Chronic prednisone use prior to admission: This was identical to # 3 in the first scoring system.

Scores for each of the above scoring systems could, therefore, range from 0-3. The relationship between the above scores and 30-day hospital readmissions were evaluated using receiver operating characteristic (ROC) curves, which plot the true-positive rate (sensitivity) versus the false-positive rate (1-specificity).

A receiver operating characteristic (ROC) curve, plotting the true-positive rate (sensitivity) versus the false-positive rate (1-specificity) was used to characterize the relation. The ROC model was used to predict the likelihood of readmission for scoring system I and scoring system II.

Results

Of the 50 studied patients, 77% were female; mean age was 71 ± 11 years. The body mass index (BMI) was 29.65 + 9 kg/m2. Clinical characteristics of subjects are shown in Table 1.

Table 1. Clinical characteristics of studied subjects.

Sixty percent had Medical Research Council (MRC) dyspnea 3 or 4 (moderate to severe). Mean length of stay was 4.3 ± 3.2 days. Thirty-four percent lived alone at home.  

In our study, all patients readmitted within thirty days had respiratory exacerbations of COPD as principal diagnoses (i.e., the frequency of respiratory-related and all-cause 30-day readmissions was identical). Thirty-day readmission rate for exacerbation of COPD was 24%. Of the studied parameters, the ones that did not predict rehospitalization in univariate logistic regression analyses are shown in Table 2.

Table 2. Variables that did not predict 30-day readmission.

Variables that significantly predicted or tended to predict readmission included: 1) two or more clinical exacerbations (not necessarily resulting in hospitalization) in the previous year (OR 4.6, p= 0.04); 2) prednisone use (chronic or prior to admission) (OR 4.4, p< 0.04); 3) MRC = 4 (OR 2.7, p = 0.16); 4) one or more respiratory hospitalizations in the preceding year (OR 3.1, p = 0.08).

Using scoring system I, 16 patients had a score of 0; 16 had a score of 1, 14 patients had a score of 2, and 4 had a score of 3. Readmission rates for each of these categories were as follows: 13%, 19%, 29%, and 75%, respectively. Using the ROC model (Figure 1), odds ratios for readmission for- Score 0 versus 3 was 18; (2) odds ratios for readmission for score 1 versus 3 was 16 and (3) odds ratios for readmission for score 2 versus 3 was 6.7.

Figure 1. Receiver operating characteristic (ROC) curve for scoring system I, showing odds ratio for readmission for Score 0 versus 3, Score 1 versus 3 and Score 2 versus 3.

In scoring system II, 19 had a score of 0, 16 had a score of 1, 11 had a score of 2, and 4 had a score of 3. Readmission rates for each of these categories were as follows: 11%, 19%, 36%, and 75%, respectively.  Using the ROC model (Figure 2), odds ratios for readmission for- Score 0 versus 3 was 24; (2) Score 1 versus 3 was 15 and (3) Score 2 versus 3 was 4.5.

Figure 2. Receiver operating characteristic (ROC) curve for scoring system II, showing odds ratio for readmission for score 0 versus 3, score 1 versus 3 and score 2 versus 3.

In both scoring systems, the combined score of 3, with all 3 variables present, was associated with a high rate of readmission. The odds ratio was calculated for the clinical scores as it provides a valid effect measure and allows comparison of the clinical scores with regards to outcome, i.e. the readmission for COPD exacerbation, in a small study such as this.

The closer AUC is to 1, the better the predictive performance of the test, with the practical lower limit for the AUC of a predictive test being 0.5. In this study, scoring system I with an AUC of 0.69 (Figure 1) and scoring system II, with an AUC of 0.73 (Figure 2), indicate fair strength as predictors for COPD readmission.

Discussion

The purpose of our study was to create a simple scoring system that might predict 30-day readmissions in patients hospitalized with COPD exacerbations. Data regarding factors which predisposes to hospital readmissions within 30 days of discharge after hospitalization for acute exacerbations of COPD is variable and remains limited (4-6, 10,11). Our study aimed at identifying potential risk factors and evaluating probable predictors of hospital re-admission in COPD patients within a month of discharge.

In our study, three variables held promise in a scoring system used to predict re-hospitalization within 30 days: exacerbations (either clinically-treated or hospitalized), chronic prednisone use, and functional limitation from dyspnea. These three variables could be assessed within a few minutes from a review of the inpatient hospital record or from a brief interview.

Previous studies evaluating readmission risk factors in COPD up to one year have identified several variables. These include: a lower FEV1 (12- 16), reduced physical activity, functional limitation and poor health-related quality of life (2,4,17-19), need for self-care assistance, active/ passive smoking, long term supplemental O2-requirement (12,16-18), and presence of selected co-morbid conditions (20, 21).

More recent studies found low physical activity to be a significant factor (5,18). Minutes of physical activity per day in the first week following discharge was lower in those readmitted (42 + 14 minutes vs. 114 + 19 minutes, p = 0.02) (5). Ngyuen et al. (19) reported an 18% readmission rate in 4000 patients, with independent predictors of increased readmission including reduced activity, anemia, prior hospitalizations, longer lengths of stay, more comorbidities, receipt of a new oxygen prescription at discharge, use of the emergency department or observational stay before the readmission. In another retrospective study, multivariate analysis showed the following risk factors to be associated with early readmission within 30 days of discharge- male gender, history of heart failure, lung cancer, osteoporosis, and depression; no prior prescription of statin within 12 months of the index hospitalization and no prescription of short-acting bronchodilator, oral steroid and antibiotic on discharge; length of stay, <2 or >5 days and lack of follow-up visit after discharge (10). Another study found these variables to have a significant association with 30-day readmissions: age, diastolic blood pressure, COPD severity score, length of stay, pH, paCO2, FEV1< 50%, number of previous days until exacerbation (6). This study also found an increased mortality at 6 months and one year in patients readmitted within 30 days of discharge (6).

In our study, the most influential variable 30-day readmission was the history of two or more exacerbations in the preceding year (OR: 2.47, CI= 1.51-4.05, p< 0.001). This variable was also found in our study to be significantly associated with 30-day readmission, following discharge for a COPD exacerbation hospitalization.

Our study found steroid use (chronic or prior to admission) to be a significant predictor of COPD readmissions. Steroid use has been associated with a significantly increased risk of readmission in a few other studies (12,13,16,22). We hypothesize chronic prednisone use reflects instability and variability in the chronic respiratory disease or a recent exacerbation prior to the index hospitalization- hence its relatively strong relationship to re-hospitalization.

The second significant predictor in our study, exacerbations resulting in hospital admission in the preceding year, has been found to be a risk factor readmission in prior studies (6,12,13,23). Three admissions in the year preceding recruitment was found to increase risk for readmission for COPD exacerbation (12,13,23). Frequent exacerbations in the preceding year likely reflect the severity of disease in these patients. A retrospective study found no association between the number of previous hospital COPD admissions and readmission (24).

Our third significant predictor, the severity of dyspnea has also been reported in some studies to be an independent risk factor for hospital admission for an acute exacerbation of COPD. Kessler et al. (14) reported that COPD patients with a dyspnea of grade 3, 4 or 5 (defined as breathlessness with mild, minimal or limited exertion respectively), had a significant risk of hospitalization at one year but those with dyspnea of grade 2 did not. Patients with “severe dyspnea” have been found to be more likely to be readmitted to hospital in studies (15,18). Our study using the MRC rating for dyspnea and found patients with an MRC rating of 4, which is equal to the most severe grading of dyspnea in this scale. The severity of dyspnea by MRC dyspnea being a predictor for readmission in COPD indicates that the severity of the disease predisposes to exacerbations of COPD and consequent readmissions.

A systematic review of studies on risk factors for readmission for patients with COPD exacerbation found 3 predictive factors similar to our study, namely- previous hospital admission, dyspnea and oral corticosteroids (25). This review also identified other variables including use of LTOT, having low health status or poor health related quality of life and reduced routine physical activity as risk factors for admission and readmission for COPD exacerbation (25).

A scoring system similar to ours, using 3 the significant predictors of COPD readmission (chronic prednisone use, MRC dyspnea rating and prior exacerbations, either clinical or requiring hospitalizations) has not been studied in predicting the 30 day- readmission for COPD exacerbation. This scoring system was a fairly strong predictor of readmission for COPD and may serve as a useful tool in risk-stratifying patients and directing medical resources toward those patients most at risk for readmission. This is especially of relevance at the present time when hospitals will face financial penalties for 30-day readmissions for COPD.

The risk factors identified for COPD readmission in this study are not modifiable. However, if patients more at risk for readmissions can be identified based on these risk factors, more resources can be directed to these group of patients- such as closer outpatient follow-up, VNA services, inpatient and outpatient pulmonary rehabilitation, more gradual steroid taper and institution of anti-inflammatory therapy such as azithromycin.

One limiting factor of this study is the small number of patients. The scoring system generated by the study using the 3 identified predictors, though fairly predictive of readmissions for COPD exacerbations, cannot be used without corroboration. The validity of the scoring system using needs to be established in a larger group of patients. Based on the results of this study, we intend to assess these variables as part of a quality assurance study on a larger number of hospitalized COPD patients. We plan to attempt to refine the scoring system, if possible, with an emphasis on simplicity in assessing data, brevity in data collection and predictive power for 30-day and subsequent hospitalization.

Conclusions

A simple 3-point scoring system, incorporating three variables: 1) chronic prednisone use; 2) MRC dyspnea rating; and 3) prior exacerbations (either clinical or requiring hospitalizations) has a fairly high predictive value for 30 -day readmission due to COPD exacerbation. This can be easily assessed within a few minutes from a review of the inpatient hospital record or from a brief patient interview. It can serve as a useful tool in risk-stratifying patients and directing medical resources toward those patients most at risk for readmission. This scoring system using these three variables holds promise for future validation studies.

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18. Chawla H, Bulathsinghala C, Tejada JP, Wakefield D, ZuWallack R. Physical activity as a predictor of thirty-day hospital re-admission after a discharge for a clinical exacerbation of COPD. Ann Am Thorac Soc. 2014;11:1203-9. [CrossRef] [PubMed]
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Cite as: Yap V, Wilcox D, ZuWallack R, Datta D. Evaluating a scoring system for predicting thirty-day hospital readmissions for chronic obstructive pulmonary disease exacerbation. Southwest J Pulm Crit Care. 2018;16(6):350-9. doi: https://doi.org/10.13175/swjpcc054-18 PDF

Reducing Readmissions after a COPD Exacerbation: A Brief Review

Richard A. Robbins, MD¹

Lewis J. Wesselius, MD²

¹The Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ

²Mayo Clinic Arizona

Scottsdale, AZ

Abstract

CMS' Hospital Readmissions Reduction Program (HRRP) was extended to chronic obstructive pulmonary disease (COPD) exacerbations in October 2014. HRRP penalizes hospitals if admissions for COPD exacerbations exceed a higher than expected all-cause 30-day readmission rate. Recently, a review of 191,698 Medicare readmissions after a COPD exacerbation reported that COPD explained only 27.6% of all readmissions. Patients were more likely to be readmitted if they were discharged home without home care, dually enrolled in Medicare and Medicaid, and had more comorbidities (p<0.001 compared to patients not readmitted). Data on interventions is limited but recently a study of bundled interventions of smoking cessation counseling, screening for gastroesophageal reflux disease and depression or anxiety, standardized inhaler education, and a 48-h postdischarge telephone call did not result in a lower readmission rate. We conclude that there is limited evidence available on readmission risk factors, reasons for readmission and interventions that might reduce readmissions. In the absence of defined, validated interventions it seems likely that CMS's HRRP will be unsuccessful in reducing hospital readmissions after a COPD exacerbation.

Introduction 

To address rising costs and quality concerns, the Hospital Readmissions Reduction Program (HRRP) was enacted, targeting inpatient discharges in the Medicare fee-for-service population for congestive heart failure (CHF), acute myocardial infarction (AMI), and pneumonia in 2012. HRRP was extended to chronic obstructive pulmonary disease (COPD) exacerbations in October 2014.

Correlation of Readmissions with Outcomes

There were about 800,000 hospitalizations for COPD exacerbations annually, with about 20% of patients needing to be rehospitalized within 30 days of discharge (2,3). The cost of readmissions is about $325 million for the U.S. Centers for Medicare and Medicaid Services (CMS) (4). Therefore, it is hardly surprising that CMS is attempting to reduce COPD readmission to reduce costs. The implication is that care was incomplete or sloppy on the first admission, and that better care might reduce readmissions.

However, a number of concerns have been raised questioning the wisdom of the HRRP. Hospitals with better mortality rates for heart attacks, heart failure and pneumonia had significantly greater penalties for readmission rates (5). If this correlation is found to be true with randomized trials, then CMS is financially encouraging hospitals to perform an action with potential patient harm and suggest that CMS continues to rely on surrogate markers that have little or no correlation with patient-centered outcomes. Until this question is resolved, we cannot recommend programs that discourage hospital readmissions.

Differences between COPD Exacerbations and CHF, AMI and Pneumonia Methodology

Several aspects of COPD exacerbations differentiate it from other conditions included in HRRP. AMI, CHF, pneumonia and COPD exacerbations are all defined by discharge ICD-9 codes. Examination of ICD-9 coding against physician chart review found profound underestimation of COPD exacerbations, with sensitivities ranging from 12% to 25% and positive predictive values as low as 81.5% (6). In contrast, coding data to identify pneumonia and AMI have a sensitivity and positive predictive value of over 95% (7,8). Therefore, there is a high probability of misclassification of COPD exacerbations used to calculate the readmissions penalty.

COPD exacerbations are clinically defined while AMI and CHF are defined by biomarkers (plasma troponin, B-type natriuretic peptide) and pneumonia is defined by not only a compatible clinical situation but by consolidation on chest radiography. Because COPD symptoms overlap with many other diseases, biomarker and radiograph evidence can make accurate diagnosis difficult. Furthermore, this uncertainty in diagnosis may provide an opportunity for hospitals to game the system by excluding sicker patients who present with COPD from the readmission measure (9).

COPD may also require prolonged times for recovery as opposed to AMI, CHF, and pneumonia patients who seem to require shorter recovery times. One quarter of patients with a COPD exacerbation had not returned to preexacerbation peak expiratory flow rate by day 35 (10).

There is also a suggestion of a frequent exacerbation phenotype of COPD independent of disease severity (11). The single best predictor of exacerbations was a history of exacerbations, although a history of gastroesophageal reflux (GERD) was also associated with increased exacerbations. A hospital with higher numbers of patients with the frequent exacerbation phenotype or with GERD would be expected to have a higher readmission rate but would be penalized under CMS' HRRP.

Causes for Readmission after a COPD Exacerbation

Most patients readmitted after a COPD exacerbation are not readmitted for COPD. Shah et al. (9) recently examined nearly 200,000 COPD exacerbation hospital readmissions in the Medicare population. Only 27.6% were classified as being readmitted for COPD. There were a variety of readmission diagnosis with respiratory failure, pneumonia, CHF, asthma, septicemia, cardiac dysrhythmias, fluid and electrolyte disorders, intestinal infection, and non-specific chest pain and other accounting for the rest. This data is consistent with previous studies by Jencks et al. (12) who found 36.2% of exacerbation patients were readmitted for COPD. Not surprisingly, the sickest patients (as defined by the Charlson sum) are more likely to be readmitted (9). This would also be consistent with causes of readmission being diverse rather than limited to COPD.

Importantly, two observations were made which may have major implications for care after COPD exacerbations (9). First, patients dually enrolled in Medicare and Medicaid had higher readmission rates. These patients tend to be poorer and seek care at "safety net" hospitals. A penalty for readmissions would be largest at these hospitals which may most in need of financial help. Second, patients discharged home without home care were more likely to be readmitted. This will likely influence more discharges to either an extended care facility or with home care which may actually increase costs rather than result in the cost savings that CMS hopes to collect.

Interventions that Reduce COPD Readmissions

Jennings et al. (13) used a "bundle" for patients with COPD exacerbations in hopes of reducing readmissions and emergency department visits. The bundle consisted of smoking cessation counseling, screening for gastroesophageal reflux disease and depression or anxiety, standardized inhaler education, and a 48 hour postdischarge telephone call. It is easy to criticize these interventions. A single session of smoking cessation counseling is usually inadequate (14). Although gastroesophageal reflux disease has been associated with COPD, there is only a single trial with lansoprazole demonstrating a reduction in COPD exacerbations (15). To our knowledge there is no data on screening for depression or anxiety, standardized inhaler education and a single phone call in preventing COPD readmissions. Not surprisingly, the bundle did not work. However, it underscores that interventions to prevent COPD readmissions are unknown. Until these are defined, it seems unlikely that any program will be successful in reducing COPD readmissions.

Potential COPD Readmission Reduction Strategies

Discharge and Follow-Up

Discharge to an extended care facility or with home care reduces readmissions (9). Approximately one third of readmissions after hospitalization for COPD occur within 7 days of discharge and 60% occur within 15 days (9). Therefore, even close outpatient followup within 2 weeks of discharge from the hospital, may not prevent a majority of readmissions. However, we would recommend that close follow-up of patients be liberal which seems likely to have some impact on readmissions. Follow-up telephone calls may be reasonable but probably need to be more than a single call at 48 hours (13). We offer some additional suggestions below that have not been subjected to randomized trials, but seem reasonable based on the current state of knowledge.

Pharmacologic Therapy

1. Bronchodilators. Many of the therapies that treat COPD exacerbations have been tested to determine if chronic use might prevent exacerbations. The best evidence is for the long-acting bronchodilators. Two large randomized controlled trials have confirmed that a combination of a long-acting beta agonist (salmeterol) with an inhaled corticosteroid (fluticasone) or a long-acting anticholinergic (tiotropium) reduce exacerbations (16,17). Given that only about one-third of readmissions are due to COPD, the impact, if any, with addition of long-acting bronchodilators after a COPD exacerbation would likely be small. The newer long-acting beta agonists and anticholinergics would also be expected to reduce exacerbations and might prevent readmissions.
2. Inhaled corticosteroids. Addition of inhaled corticosteroids to long-acting bronchodilators in COPD remains controversial. A meta-analysis by Spencer et al. (18) recommended regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent exacerbations. However, the data supporting this recommendation is unclear. It is also unclear if their addition would prevent readmissions.
3. Antibiotics. Continuous or intermittent treatment with some antibiotics, particularly macrolides, reduces exacerbations. Treatment with azithromycin for one year lowered exacerbations by 27% (19). Although the mechanism(s) accounting for the reduction in exacerbations is unknown, current concepts suggest the reduction is likely secondary to the macrolides’ anti-inflammatory properties. However, concern has been raised about a very small, but significant, increase in QT prolongation and cardiovascular deaths with azithromycin (20). In addition, the recent trial with azithromycin raised the concern of hearing loss which occurred in 25% of patients treated with azithromycin compared to 20% of control (19). An alternative to the macrolides may be tetracyclines such as doxycycline, which also possess anti-inflammatory properties but do not lengthen QT intervals nor cause hearing loss (21). Similar to the long-acting bronchodilators, antibiotics might reduce readmissions, but since most readmissions are not due to COPD, the effect would likely be small.
4. Medication Compliance. Poor compliance with inhaled therapies has been implicated as a factor contributing to COPD exacerbations (22). The role of COPD medication noncompliance has not been specifically assessed in hospital readmissions, although it seems likely to be a contributing factor. Socioeconomic factors influence medication compliance and could lead to greater readmission rates in hospitals caring for patients with limited financial and social resources. Poor compliance with COPD medications as well as medications for comorbid conditions may both be important as most readmissions are not due to COPD.

Conclusions

Prevention of COPD readmissions after a COPD exacerbation represents a challenge with no straight-forward strategies to reduce readmissions other than discharge to an extended care facility or home with home health. Readmissions come from heterogeneous causes but most are not due to COPD suggesting that comprehensive care for disorders other than just COPD is likely important.

References

1. Centers for Medicare and Medicaid Services. Readmissions reduction program. Available at: http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/Readmissions-Reduction-Program.html (accessed 6/4/15).
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13. Jennings JH, Thavarajah K, Mendez MP, Eichenhorn M, Kvale P, Yessayan L. Predischarge bundle for patients with acute exacerbations of COPD to reduce readmissions and ed visits: a randomized controlled trial. Chest. 2015;147(5):1227-34. [CrossRef] [PubMed]
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17. Tashkin DP, Celli B, Senn S, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-54. [CrossRef] [PubMed]
18. Spencer S, Karner C, Cates CJ, Evans DJ. Inhaled corticosteroids versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 Dec 7;(12):CD007033. [PubMed]
19. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365:689-98. [CrossRef] [PubMed]
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Reference as: Robbins RA, Wesselius LJ. Reducing readmissions after a COPD exacerbation: a brief review. Southwest J Pulm Crit Care. 2015;11(1):19-24. doi: http://dx.doi.org/10.13175/swjpcc089-15 PDF

Acetylcholine Stimulation of Human Neutrophil Chemotactic Activity Is Directly Inhibited by Tiotropium Involving Gq Protein and ERK-1/2 Regulation

Makoto Kurai^1,2,3

Richard A. Robbins^1,2

Sekiya Koyama⁴

Jun Amano³

John M. Hayden¹

¹Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona 85012, ²Arizona Respiratory Center, University of Arizona, Tucson, Arizona 85724, ³Second Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan, ⁴Department of Pulmonary Internal Medicine, National Hospital Organization Chushin Matsumoto Hospital, Matsumoto 399-0021, Japan

Abstract

Tiotropium, a long-acting anticholinergic, may improve chronic obstructive pulmonary disease (COPD) by mechanisms beyond bronchodilatation. We tested the hypothesis that tiotropium may act as an anti-inflammatory mediator by directly acting on and inhibiting human neutrophil chemotactic activity (NCA) that is promoted by acetylcholine (ACh) exposure.  ACh treatment increased NCA in a dose dependent manner (p < 0.001) and tiotropium pretreatment reduced ACh stimulation (dose effect; 0 to 1000 nM; p < 0.001).  Selective muscarinic receptor inhibitors demonstrated that subtype-3 (M3) receptor plays a role in NCA regulation.  In addition, NCA that was stimulated by cevimeline (M3 agonist) and pasteurella multocida toxin (PMT, M3 coupled Gq agonist). However, the increased NCA to cevimeline and PMT was reduced by tiotropium pretreatment (p < 0.001).  ACh treatment stimulated ERK-1/2 activation by promoting protein phosphorylation and tiotropium reduced this effect (p < 0.01). In addition, pretreatment of the cells with a specific MEK-1/2 kinase inhibitor reduced ACh stimulated NCA (p < 0.01). Together these results demonstrated that cholinergic stimulation of NCA is effectively inhibited by tiotropium and is governed by a mechanism involving M3 coupled Gq signaling and downstream ERK signaling. This study further demonstrates that tiotropium may act as an anti-inflammatory agent in lung disease.

Abbreviation List

• Ach – acetylcholine
• ANOVA – analysis of variance
• AS - complement activated serum
• BCA - bicinchoninic acid
• ChAT - choline acetyltranferase
• COPD – chronic obstructive pulmonary disease
• ERK - extracellular-signal-regulated kinases
• GAPDH - glyceraldehyde-3-phosphate dehydrogenase
• LPS – lipopolysaccharide
• M3 – muscarinic subtype 3 receptor
• MEK - mitogen-activated protein/extracellular signal-regulated kinase
• NCA – neutrophil chemotactic activity
• PMT - pasteurella multocida toxin
• rhIL-8 - recombinant human interleukin-8
• RIPA - radioimmunoprecipitaion assay
• SEM – standard error of mean
• TBST - tris-buffered saline and tween 20

Introduction

Anticholinergic therapy has been regarded as a first choice bronchodilator in the management of stable chronic obstructive pulmonary disease (COPD) (1).  The agents included within this class of therapeutics effectively reverse the stimulation of parasympathetic produced acetylcholine (ACh) on smooth muscle airway contraction. Parasympathetic activity is increased with airway inflammation, and in regards to COPD, is an important mechanism because vagal tone appears to be one of the only reversible components of airflow restriction (2).  Besides bronchoconstriction, ACh may also be involved in airway remodeling and other pathophysiogical mechanisms that are important in the propagation of lung disease (1,3-8). Recently it has been suggested that ACh may be expressed in the lung independent of a parasympathetic mechanism. In support of this notion, ACh synthesizing enzyme (choline acetyl transferase) has been found to be ubiquitously expressed in the airways, pulmonary epithelial cells, and immune cells such as neutrophils and monocytes (9-12). In addition, these cells also appear to express functional muscarinic receptors (9-11).  Interestingly, the expression and function of certain muscarinic receptors in neutrophils may be increased in COPD (13), thus suggesting increase bioactivity associated with enhanced lung inflammation. We and others have previously demonstrated that ACh may also stimulate resident lung cells to release chemotactic factors and subsequently these factors can induce pro-inflammatory chemotaxis indirectly in vitro (3,4,8,9). 

It has been recently reported that outcomes of COPD are improved by inhalation of cholinergic inhibitors, and tiotropium (tiotropium bromide, Spiriva®; Boehringer Ingelheim, Ingelheim, Germany) demonstrates the greatest improvements in COPD because of its long-acting, once daily administered, anticholinergic capability (1).  Although tiotropium predominantly functions as a bronchodilator, it has also been shown to inhibit ACh-induced proliferation of fibroblasts and myofibroblasts (16), and inhibit the release of chemotactic factors from cultured lung epithelial cells, fibroblasts and alveolar macrophages in vitro (3,4). Taken together these results suggest a plausible beneficial role of tiotropium on airway remodeling and action as an anti-inflammatory agent in chronic airway disease.

We have previously reported that supernatants from macrophages that were treated with tiotropium prior to a challenge with lipopolysaccharide (LPS) greatly reduced the subsequent stimulation of NCA and this result did not occur by inhibited release of chemotactic factors (17). Based on these results, we postulated that tiotropium from the test media may actually passively diffuse through the pores of the filter that separates the chambers of the microchemotaxis unit and possibly interact directly with the neutrophils. In this study, we tested the hypothesis that tiotropium may act as an anti-inflammatory agent by directly interacting on neutrophils and inhibiting their chemotactic capability.

It has been well established that infiltration of neutrophils and the modulation of their activity play an important role in propagating and governing inflammation in a variety of lung diseases such as COPD (18).  In addition, muscarinic receptor G-protein coupled signal transduction (19) and downstream ERK-1/2 activity (20-22) may also play an important regulatory role in controlling the migration of neutrophils.  In this study, we further demonstrate that tiotropium may inhibit NCA, in part, through the regulation of muscarinic receptor coupled Gq-protein and ERK-1/2 mediated signal transduction (Figure 1).

Figure 1. Putative mechanism of tiotropium effect on neutrophil chemotaxis. Acetylcholine (ACh) either exogenously released or acting in a paracrine fashion stimulates the muscarinic type 3 (M3) receptor. This subsequently activates Gq protein which activates extracellular-signal-regulated kinases (ERK) 1/2. ERK 1/2 translocates into the nucleus activating various transcription factors which result in cell migration. Tiotropium decreases chemotaxis by inhibiting the binding of ACh to the M3 receptor.

Methods

This study was conducted with the approval from the Research and Development and Institutional Review Board Committees of the Carl T. Hayden Veteran’s Affairs Medical Center, Phoenix, Arizona.

Purification of Human Blood Neutrophils and Experimental Models

Human primary neutrophils were isolated and purified from heparinized plasma obtained from normal healthy individuals by the method of Böyum (23). The purified neutrophils were exposed to ACh (sodium acetylcholine, Sigma-Aldrich) up to 60 min prior to chemotaxis.  For most experiments, cells were also pretreated with the various factors listed below for 30 min prior before selected agonist treatment. Inclusive of these agents are tiotropium bromide (Boehringer-Ingelheim); muscarinic (M) receptor antagonists including  pirenzepine dihydrochloride  (M₁; Sigma-Aldrich); gallamine trithiodide M₂ (M₂; Sigma-Aldrich); 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; M₃; Sigma-Aldrich); M₃ receptor agonist cevimeline HCl (EVOXAC^®, Daiichi Sankyo, Inc., Parsippany, NJ); selective G-protein agonists(G_q, Pasteurella multocida toxin [PMT], EMD Biosciences Inc., San Diego, CA, G_o, mastoparan, Biomol International, Plymouth Meeting, PA) and a specific mitogen-activated protein/extracellular signal-regulated kinase (MEK)-1/2 inhibitor (U0126; Sigma-Aldrich). 

Neutrophil Chemotaxis Analysis

The chemotaxis assay was performed in a 48-well microchemotaxis chamber (NeuroProbe Inc., Cabin John, MD) using previously described methods (14).   Either recombinant human interleukin-8 (rhIL-8, Sigma-Aldrich) or complement activated serum (AS) were used as the chemoattractants. Neutrophil viability was assessed and not altered by tiotropium.

Western Blot Analysis

The examination of corresponding regulation of extracellular signal-regulated kinase (ERK)-1/2 proteins by ACh and tiotropium in neutrophils was performed by Western Blot analyses. Both phosphorylated (p) and total (t) ERK-1/2 proteins were examined. Rabbit monoclonal antibodies directed against human pERK-1/2, tERK-1/2, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proteins were purchased from Cell Signaling Technology (Beverly, MA).

For the ACh time-course experiment, neutrophils (1 x 10⁷) were treated with 100 μM ACh for period ranging from 0 to 60 min of exposure. After establishing the maximal time effect (~15-20 min), subsequent experiments were conducted examining the effect of a 30 min tiotropium (100 nM) pretreatment on ACh challenged ERK-1/2 protein expression.

Neutrophils were lysed with ice-cold radioimmunoprecipitaion assay (RIPA) buffer including a proteolytic inhibitor cocktail (Santa Cruz Biotechnology, Santa Cruz, CA) as per the manufacturer’s instructions. Total protein concentration of the lysates was determined by the bicinchoninic acid (BCA) protein assay (Thermo Fisher Scientific, Rockford IL). Protein concentrations were then adjusted to 40 µg in a standardized volume before addition of 2x sample buffer (Invitrogen, Grand Island, NY) and heating for 5 min at 85˚C.  Cell proteins were then separated by electrophoresis on 4-20% tris-glycine acrylamide gels (Invitrogen, Grand Island, NY) and transferred to membranes (HCL-hybond, GE Healthcare, Piscataway, NJ) by electroblotting at 25 volts overnight at 4^oC.  The membranes were then pretreated with 1x tris-buffered saline and tween 20 (TBS-T) plus 5% non-fat dried milk for at least 2 hours at room temperature before exposure to the primary antibodies (1:2000) as per manufacturer’s suggestion overnight at 4^oC. After subsequent washing with TBS-T a horseradish peroxidase-conjugated goat anti-rabbit secondary antibody (1:2000) was added for at least 1 h at room temperature.  

After multiple washings, the membranes were exposed to peroxidase substrate for enhanced chemiluminescence (Pierce ECL Western Blotting Substrate, Thermo Fisher Scientific, Rockford, IL) for 5 min. Membranes were wrapped and placed against autoradiograph film (Hyperfilm ECL; GE Healthcare, Piscataway, NJ) and developed (up to 30 min). The resulting protein bands were quantified by densitometry (Personal Densitometer SI, Image Quant ver. 5, Molecular Dynamics, GE Healthcare Biosciences Corp.).

Statistical Analyses

Unless stated otherwise data are means ± SEM resulting from at least 3 individual experiments. Data were analyzed by one-way ANOVA followed by selected post-hoc Neuman-Keuls tests. p < 0.05 was considered significant.

Results

Stimulation of neutrophil chemotactic activity by cholinergic challenge

Neutrophils were pretreated with varied concentrations of ACh ranging between 1-100 µM prior to exposure to two different chemotactic agents including rhIL-8 (500 ng/ml) and AS.  As demonstrated in Figure 2, ACh treatment stimulated NCA in a dose dependent manner for both IL-8 and AS (p < 0.001). Similarly, at the 1 or 10 µM level ACh stimulated NCA when exposed to either IL-8 or AS, respectively. Moreover, the maximal level of stimulation by ACh was attained when the cells were treated with 100 µM ACh (Figure 2).  As reported previously, this concentration of ACh provided maximal effects in other cell types (13,15).  Beyond the dose effect studies, we also tested the effect of duration of ACh exposure (15 to 60 min) on NCA and found a significant stimulatory effect to occur within 60 min of exposure (data not shown).

Figure 2.  The effect of acetylchoine (ACh) stimulation on neutrophil chemotaxis. Neutrophils were treated with varied concentrations of ACh for 60 min prior to exposure to rhIL-8 (closed diamond) or complement activated serum (open diamond).  Neutrophil chemotactic activity (NCA) is on the ordinate and the concentration of ACh is on the abscissa. Values are expressed as means ± SEM.  For each experiment a significant dose effect was demonstrated (ANOVA, p < 0.0001; 15 observations per experiment). *p < 0.05, **p < 0.001 means differed as compared with those from non-treated controls.

Tiotropium pretreatment inhibited cholinergic stimulation of neutrophils

Neutrophils were pretreated for 30 min with varied concentrations of tiotropium ranging between 0.1 to 1000 nM prior to exposure to ACh.  Tiotropium pretreatment significantly reversed the stimulatory effect of effect of ACh on NCA at concentrations ranging greater than 1 nM. A dose dependent was observed with the maximum reduction approaching 45% (p<0.001) at levels beyond 10 nM (Figure 3).

Figure 3.  The effect of tiotropium on ACh-stimulated neutrophil chemotaxis.  Neutrophils were treated with tiotropium at various concentrations (0.1 to 1000 nM) for 30 min prior to treatment to ACh for an additional 60 min and exposure to rhIL-8 as the chemoattractant. Values are expressed as means ± SEM.  A treatment effect was demonstrated by one-way ANOVA (p < 0.0001) for three independent experiments.  ^#p < 0.01 means differed compared with non-treated controls; *p < 0.05, **p < 0.001 means differed compared with those from ACh-stimulated neutrophils.

The effect of selective muscarinic receptor antagonists on cholinergic stimulation of neutrophil chemotaxis.

It has been recently demonstrated that neutrophils express muscarinic receptors sub-types 1 through 3 (10,11) and tiotropium can interact amongst these receptors as an antagonist with varying affinities (M₃>M₁>M₂) (1).  Thus, we examined the effect of a variety of muscarinic receptor antagonists with specificity to the varied receptors including pirenzepine dihydrochloride (M₁), gallamine trithiodide (M₂) and 4-DAMP (M₃). Neutrophils were pretreated with these muscarinic antagonists at the varied concentrations (0.1 – 1000 nM) for 30 min prior to exposure to 100 µM ACh.

As demonstrated in Figure 4C, 4-DAMP significantly inhibited the increase of NCA that resulted from ACh treatment (32% decrease; p<0.05) although this effect was not as robust as those of tiotropium demonstrated in Figure 3.  In contrast to 4-DAMP, gallamine pretreatment did not alter NCA that was stimulated by ACh treatment.  Although not significant, an inhibitory trend was observed by pirenzepine pretreatment on cholinergic stimulation of NCA (Figure 4A).

Figure 4.  The effect of various muscarinic (M) receptor antagonists on ACh-stimulated neutrophil chemotaxis.  Neutrophils were treated with pirenzepine (M₁ inhibitor; figure 3A), gallamine (M₂ inhibitor; figure 3B) and 4-DAMP (M₃ inhibitor; figure 3C) at various concentrations (0.1 – 1000 nM) for 30 min prior to treatment with ACh and exposure to rhIL-8.  Values are expressed as means ± SEM.  Treatment effects were displayed by ANOVA for pirenzepine (p < 0.03; n = 5), gallamine (p < 0.02; n = 3) and 4-DAMP (p < 0.01; n = 3) experiments. ^#p < 0.05 means differed as compared with non-treated controls.  *p< 0.05 means differed compared with those from ACh-stimulated cells.

Tiotropium bromide effects NCA by altering M₃ receptor G_q-protein coupling

As suggested by results of the muscarinic receptor antagonists above, the M₃ receptor seems to play a prominent role in the regulation of cholinergic induction of NCA. To confirm this role, we examined the effect of the specific M₃ receptor agonist cevimeline on NCA.  Neutrophils were pretreated with tiotropium (30 min) prior to exposure to 300 µM cevimeline for an additional 30 min.  As seen in Figure 4A, NCA was promoted by cevimeline treatment when exposed to rhIL-8 (~41% increase as compared to controls; p < 0.001).  Similar to the response demonstrated in the ACh series of experiments, tiotropium pre-treatment significantly reversed the stimulatory effect of cevimeline (~40% decrease, p < 0.001) on NCA to a level that was similar to non-treated control neutrophils (Figure 5A). 

  

Figure 5. Tiotropium inhibited the stimulatory effect of cevimeline (M₃ receptor agonist) and pasteurella multocida toxin (PMT; G_q signaling stimulator) on NCA. Neutrophils were pre-treated with tiotropium for 30 min before the addition of cevimeline (Figure 4A) or PMT (Figure 4B) for an additional 30 min and exposure to rhIL-8. Values are expressed as means ± SEM. Treatment effects were displayed for both series of experiments (ANOVA; p < 0.0001, n=3). ^#p < 0.001 means differed as compared with non-treated neutrophils. *p < 0.001 means differed as compared with those from cevimeline- and PMT- stimulated cells.

G-proteins are important regulators in chemokine and complement mediated chemotaxis, and are early-stage regulatory components coupled to muscarinic receptor function (19,24,25). To test whether M₃ receptor coupled G-protein pathway is involved in the regulation of cholinergic stimulation of NCA, we treated neutrophils with a potent G_q agonist (Pasteurella multocida toxin; PMT) (26). As demonstrated in Figure 5B, PMT treatment effectively stimulated NCA (~32% increase; p < 0.001) when compared to non-treated controls. In addition, when the neutrophils were pretreated with tiotropium for 30 min prior to PMT stimulation, NCA was markedly reduced by 38% (p < 0.001) as compared to PMT treatment alone (Figure 5B). To further examine the specificity of this event we treated neutrophils with mastoparan, an agonist of the G_o proteins coupled to the M₂ and M₄ receptor function. In contrast to PMT, mastoparan treatment did not influence NCA (data not shown).

 Cholinergic activation of ERK-1/2 in neutrophils is inhibited by tiotropium treatment.

It has been previously established that ERK-1/2 protein activation provides a pivotal regulatory role on neutrophil chemotaxis (22,27,28) and it is a downstream signaling pathway that is influenced by G-proteins (29-31). Thus, we examined the effect of ACh activation (100 µM) on ERK-1/2 signaling in neutrophils and began with examining the effect of time of cholinergic exposure (0 to 60 min) on ERK-1/2 protein expression. As seen in Figure 5, ACh treatment activated pERK-1/2 expression but did not alter the level of tERK-1/2 proteins in the cells. The stimulation of pERK-1/2 reached the maximal effect within 15-30 min of exposure to ACh, and began to decrease after 45 min of exposure (Fig 6). Similar reductions on pERK-1/2 expression were demonstrated in experiments where neutrophils were treated with ACh for longer periods (>60 min; data not shown).

Figure 6. The effect of time of exposure of ACh on ERK-1/2 protein activation in neutrophils. Cells were treated with 100 μM ACh for various times from 0 through 45 min of exposure. Total cell proteins were isolated and examined for phosphorylated (p) and total (t) ERK-1/2 expression assessed by Western-blot (Figure 5A). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was assessed as a loading control. The corresponding mean ratio of pERK-1/2: tERK-1/2 resulting from densitometric scans is demonstrated in figure 6B.

A further series of experiments (n=4) were conducted to examine the effect of tiotropium on the inhibition of cholinergic stimulation of ERK-1/2. Neutrophils were pretreated with 100 nM tiotropium for 30 min prior to exposure to 100 µM ACh for 15 min. As seen in Figure 7, ACh treatment increased the activation of ERK proteins (pERK/tERK ratio = 0.85 for ACh vs. 0.52 in non-treated control cells; p < 0.01) and tiotropium pretreatment markedly reversed this effect and where expression was reduced to control cell levels (Figure 7).

Figure 7. The effect of tiotropium on ACh stimulated ERK-1/2 protein activation in neutrophils. Cells were treated with 100 nM of tiotropium prior to expose to 100 μM of ACh for 15 min. Total cell proteins were isolated and pERK-1/2, tERK-1/2 and GAPDH expression was determined by Western-blot. A representative experiment is shown in Figure 6A and ERK-1/2 activation expressed as pERK1/2: tERK-1/2 is demonstrated in Figure 6B. Values are expressed as means ± SEM. A treatment effect was demonstrated by ANOVA (p < 0.005; n=4 experiments). ^#p < 0.01 means differ as compared with non-treated neutrophils; * p < 0.01 means differ as compared to those from ACh stimulated cells.

Cholinergic stimulation of NCA is reduced by an inhibitor of ERK-1/2 phosphorylation

Based of the aforementioned results on pERK-1/2 expression activation of ERK-1/2 by phosphorylation may govern NCA. Neutrophils were pretreated with U0126 (a specific MEK-1/2 kinase inhibitor) for 30 min prior to exposure to ACh (100µM) for an additional 60 min. As seen in Figure 8, U0126 pretreatment strongly inhibited (p < 0.01) the increase of NCA by ACh treatment to levels similar to non-treated control cells.

Figure 8. Neutrophil chemotactic activity that is stimulated by ACh is inhibited by an antagonist of ERK-1/2 phosphorylation. Cells were pretreated with a specific inhibitor of MEK-1 and -2 (U0126; 10 µM) for 30 min prior to the addition of 100 µM ACh for an additional 30 min before assessing NCA as described above. Values are expressed as means ± SEM. A treatment effect was demonstrated by ANOVA (p < 0.001) resulting from three independent experiments. ^#p < 0.001 means differed as compared with non-treated neutrophils. *p< 0.01 means differed compared with those from ACh stimulated cells.

Discussion

Previous clinical results have suggested that tiotropium inhalation provides beneficial clinical outcomes in COPD that may result from modulating mechanisms beyond bronchodilatation (1,10). An intriguing suggestion has been that anticholinergic therapy may act as an anti-inflammatory. The mechanism(s) by which this action occurs has not been fully elucidated; however, recent in vitro studies have suggested that tiotropium may indirectly influence neutrophil chemotaxis by inhibiting the release of chemotactic factors by resident lung cells that would subsequently promote NCA (3,4). In a model using U937 macrophages, we previously reported that NCA was decreased from supernatants that were obtained from LPS-challenged cells treated with tiotropium and that this result did not occur from a reduction in corresponding chemotactic factor expression measured in the supernatants (17). Specifically, we found that heightened levels of IL-8 did not correlate (r = 0.38; p > 0.13) with the reduction in NCA upon tiotropium treatment (0.1 to 1000 nM). Similar effects were also shown regarding LTB₄ analyses (17). Based on these results, we formulated the hypothesis that tiotropium contained in the supernatants may actually interact with the neutrophils and influence their activity directly.

Current concepts suggest that an influx of neutrophils is important in the pathogenesis of COPD (18). These neutrophils release proteases and toxic oxygen radicals that contribute to the inflammation seen in COPD. It is this inflammation that results in the emphysema and airway remodeling that causes the structural changes in COPD that lead to the clinical symptoms of breathlessness and/or cough. Previous studies in animal models of COPD have shown that tiotropium is anti-inflammatory (5,32). More recent studies in humans suggest that tiotropium reduces neutrophil chemotaxis (33). Migration of neutrophils from COPD patients are also decreased by tiotropium similarly to the normal human neutrophils used in this study (34). The present studies are consistent with these results and support an anti-inflammatory role for tiotropium in COPD.

It has not been established to date that cholinergic stimulation may directly affect NCA in vitro. In the present study, we report that exogenous ACh pretreatment enhanced NCA when the cells were exposed to differing chemotactic agents. In addition, we found that tiotropium treatment prior to ACh exposure very effectively reduced stimulated NCA. The bioactive concentrations of tiotropium that were used in this study initially ranged from 10 -1000 nM and the lower bioactive responsive doses were similar to those previously reported to affect human lung fibroblast proliferation (35), fibroblast differentiation (16), and the release of chemotactic factors from epithelial cells, fibroblasts and alveolar macrophages in vitro (3,4). In order to elicit a robust effect on NCA, we opted to use a dose of 100 nM of tiotropium throughout the study. At this level, tiotropium was non-toxic and remained below the estimated maximum concentration of ~2000 nM to be present in the lung epithelial lining fluid after inhalation of the drug (36).

There is increasing evidence that signaling from extraneuronally produced ACh may play an important role in regulation of lung inflammation (1,9). ACh may enhance proinflammatory cell chemotaxis indirectly by stimulating resident lung cells to release chemotactic factors (3,4,14,15). Recently, choline acetyltranferase (ChAT) has been localized in human blood and skin derived neutrophils; however, to date there have been no studies establishing ChAT expression in pulmonary neutrophils (10). However, a recent report by Neumann et al. (37) demonstrated that mononuclear cells (T cells and monocytes) expressed ~0.36 pmol ACh/10⁶ cells, whereas granulocytes (containing predominantly neutrophils) expressed considerably less concentration of ACh although their synthetic capacity was greater than CD3⁺ cells. Thus, it remains to be established whether pulmonary neutrophils may produce Ach, especially under conditions of inflammation. It also remains to be established whether neutrophils produce sufficient ACh to regulate a cholinergic response in an autocrine manner.

It has also been reported that neutrophils express muscarinic receptors (9.10,13,38). Interestingly, the expression of muscarinic receptors is modulated in neutrophils in COPD, particularly the M₃ receptors which are more highly expressed under this condition (13). In this study we demonstrated that neutrophils may react to exogenous cholinergic stimulation thus suggesting that paracrine cholinergic stimulation may be a viable mechanism of control of neutrophil activity associated with inflammation.

In an early attempt to characterize the muscarinic receptor(s) involved in cholinergic regulation of NCA we used a panel of selective antagonists and tested their reactivity against ACh stimulation. To accomplish this objective we pretreated neutrophils with pirenzepine, gallamine and 4-DAMP prior to cholinergic treatment. Our results demonstrated that only the inhibitor 4-DAMP significantly reversed the effect of ACh on NCA. These results further confirm that anti-inflammatory control may entail the antagonism of the muscarinic type-3 receptor. This is comparable to our previous studies that have demonstrated that ACh may promote chemotactic factor release from resident lung cells by influencing M₃ receptors (4,14,15).

We further treated neutrophils with cevimeline, a M₃ receptor agonist (39), and found that this compound markedly increased NCA. When neutrophils were treated with PMT, a G_q agonist (27,40), it stimulated their activity and to a level comparable to those of cevimeline. Moreover, tiotropium pretreatment dramatically inhibited PMT stimulated NCA. Taken together, these results suggest that tiotropium may interact with the M₃ receptor and possibly modulate early G_q mediated signaling cues affecting NCA by cholinergic treatment.

The M₃ receptors have the capacity to activate multiple signaling pathways in various cell types. For example, it has been established that the M₃ receptor and G_q protein pathway is involved in airway smooth muscle contraction and may function by regulating PLC, inositol 1,4,5-triphosphate (IP₃) and intracellular Ca²⁺ signaling (41). In addition, it has been shown that G_q-deficient neutrophils possess deficient calcium signaling and defective chemotactic responsiveness (42). Furthermore it has been reported that ERK activation is associated with G_q-protein stimulation (29,30) and ERK signaling is an important integral regulator of NCA (22,27,28). In this study, we find that ACh treatment enhanced neutrophil ERK-1/2 protein phosphorylation but not total ERK1/2 expression. In addition, the pretreatment of the cells with tiotropium reversed this activity. Similarly, Profita et al. (4) demonstrated that ACh mediated release of IL-8 in human bronchial epithelial cells may be regulated in part by an ERK-dependent mechanism.

In summary, these data support the role of cholinergic stimulation on NCA an important inflammatory process contributing to pulmonary disease. This study also demonstrated an alternative anti-inflammatory role of tiotropium on directly reducing chemotactic activity by inhibiting, in part, G_q protein and ERK activation in neutrophils. Furthermore, this action was independent of type or concentration of chemotactic factor. This present study may provide some insight into the recently reported discordance between significant reductions in total exacerbation compared with no reduction in proinflammatory marker (including IL-8) concentration in sputa from COPD patients treated with tiotropium (43). The inhibition of neutrophil migration is one effect which may contribute to the anti-inflammatory effects of anticholinergics and may explain, at least in part, the reduction in exacerbations of COPD seen with tiotropium.

Acknowledgements

This study was funded by Boehringer Ingelheim and the Phoenix Pulmonary and Critical Care Research and Education Foundation and the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government..

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Reference as: Kurai M, Robbins RA, Koyama S, Amano J, Hayden JM. Acetylcholine stimulation of human neutrophil chemotactic activity is directly inhibited by tiotropium involving Gq and ERK-1/2 regulation. Southwest J Pulm Crit Care 2012:5:152-68. (Click here for a PDF version)

Meta-Analysis of Self-Management Education for Patients with Chronic Obstructive Pulmonary Disease

Jessica Hurley, MD¹

Richard D. Gerkin, MD¹

Bonnie Fahy, RN, MN²

Richard A. Robbins, MD^2* 

Good Samaritan Regional Medical Center¹ and the Phoenix Pulmonary and Critical Care Research and Education Foundation², Phoenix, AZ

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a common disease frequently associated with high use of health services. Self-management education is a term applied to programs aimed at teaching patients skills that promote the self-efficacy needed to carry out medical regimens specific to control their disease. In COPD, the value of self-management education is not yet clear and a recent trial was terminated early because of excess mortality in the intervention group.

Objectives

The objective of this meta-analysis was to assess the settings, methods and efficacy of COPD self-management education programs on patient outcomes and healthcare utilization.

Selection criteria

Randomized controlled trials of self-management education in patients with COPD were identified. Studies focusing primarily on comprehensive pulmonary rehabilitation (education and exercise) and studies without usual care as a control group were excluded.

Search strategy

We searched PubMed (January 1985 to May 2012) as well as other meta-analysis and reviews.

Data collection and analysis

Two reviewers (JH and RAR) independently assessed study quality and extracted data. Investigators were contacted for additional information.

Main results

The reviewers included 3 group comparisons drawn from 12 trials. The studies showed no significant change in mortality, with one study being an outlier compared to the others.  However, the meta-analysis revealed a reduction in the probability of hospital admission among patients receiving self-management education compared to those receiving usual care.

Conclusions

It is likely that self-management education is associated with a reduction in hospital admissions with no change in mortality. However, because of heterogeneity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the preferred curriculum and delivery method of self-management education programs in COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and the only one of the top 5 causes of death that is increasing (1).  The economic and social burden of the disease is immense. The patient usually suffers progressive disability with frequent hospitalizations and emergency room visits. Hospitalizations and emergency room visits account for much of the health care costs from COPD, and therefore, strategies to decrease the these outcomes have received considerable attention (2,3). 

One strategy to improve COPD care has been self-management education, a term applied to any formalized patient education program aimed at increasing knowledge and teaching skills that increase self-efficacy, thus improving collaboration with their healthcare provider to optimally manage patient care. Similar strategies have been successful in other chronic diseases (4-6). However, the effects of self-management programs in COPD, although encouraging, are still unclear (7). Furthermore, a recent trial was terminated prior to enrollment of the planned number of subjects because of excess mortality in the intervention group receiving self-management education (8).

Prompted by the surprising result of an increase in mortality, we reexamined health care outcomes for COPD self-management education by meta-analysis. We found no significant change in mortality but significant reductions in hospitalizations.

Methods

Criteria for considering studies for this review

Types of Studies: Only randomized controlled trials evaluating the effect of self-management education on patients with COPD were used.  Every study included some form of patient education that addressed COPD disease self-management. For inclusion, the study must also include a control group that received usual care and were excluded from the interventional self-management education.  Studies prior to 1985 were not included since medical management for COPD differed from current practice guidelines. 

Types of study participants: Only patients with a clinical diagnosis with COPD were included.  Spirometry was not required to be reported in the study to determine the diagnosis of COPD if the patients admitted had previously been diagnosed with COPD by the referring physician. Patients with a sole diagnosis of asthma or reactive airway disease were excluded from this review.

Types of interventions: In order to qualify as an intervention, the primary goal of the study had to center on improving the patient’s fundamental knowledge and understanding of the disease process and self-management of COPD. The methods of information delivery were highly variable and included written, verbal, visual, and/or audio communication.

Types of outcomes measured: The outcomes identified in studies that were included in this review include mortality, hospital admissions, and emergency room visits.

Search methods

Two separate reviewers (JH, RAR) used systematic searches via the information databases including PubMed.  The terms used to search included “COPD” in addition to one of the following words or phrases: “educat*” or “education” or “patient-educat*” or “patient-education” or “patient educat*” or “patient-education” or “self-manag*” or “self-management” or “self manag*” or “self management” or “disease manag*” or “disease management”.  The searches are current through May of 2012. 

Data collection and analysis

Selection of studies: The two reviewers placed successfully retrieved articles using the above search criteria into 3 categories:

1. Include: RCT evaluating COPD patients and self-management education versus usual care
2. Possibly Include: RCT evaluating COPD patients and disease education but more information needed beyond what is available in the abstract
3. Exclude: not an RCT, not focused on self-management of COPD or did not include usual care comparison or primary outcome focused solely on pulmonary rehabilitation

Data extraction: Information from the accepted studies was collected and included: number of patients in the control and interventional groups, type of intervention used (i.e. disease education, medication instructions, pharmacy action plans), length of study until primary outcome, mortality of each group, respiratory-related hospital admissions, and respiratory-related ED visits.

Data analysis:

Publication bias:  Funnel plots were constructed to examine the pattern of study effects by study size.  Outliers on the plot with respect to a 95% confidence interval were also determined.

Assessment of heterogeneity: The I square statistic was used to examine variability in study results.  If I square was greater than 20%, sensitivity analysis was conducted to determine, if possible, the source of heterogeneity.

Data synthesis:  Continuous outcomes were analyzed using weighted mean difference with 95% confidence intervals.  For dichotomous outcomes, a pooled odds ratio was used.  A fixed effects model was used if I square was less than 20%.  A random effects model, using the technique of DerSimonian and Laird (20), was used if I square was greater than 20 %.

RevMan 5.1. (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011) was used for the analysis.

Results

Results of the search: Searches identified 1904 titles and abstracts that were screened to identify 71 potentially relevant articles about self-management education in COPD. Full-text versions of these papers were obtained, and independently assessed by two reviewers (JH and RAR). These were searched for data on mortality, hospitalizations and emergency room (ER) visits.  A total of 12 trials were identified which met the review entry criteria (8-19).

Subjects: A total of 2476 patients were randomized in the 12 studies. The studies were heterogenous with some recruiting patients from outpatient clinics, some from general practice, some from inpatient hospital admissions for COPD exacerbations and some from several sources.

Interventions: All 12 studies described COPD self-management education compared with usual care. The educational delivery mode consisted of group education or individual education. Educational topics varied, as did the discipline of the provider. The follow-up time was variable ranging from 2-12 months.

Comparisons: Twelve studies that compared self-management education with usual care have been included in this review. In one study two intervention groups and one usual care group were used (11). The intervention groups were considered sufficiently similar to be combined.

Outcomes: Reported outcome categories were variable. Studies included in the review identified mortality (10 studies), respiratory-related hospital admissions (9 studies) and emergency room (ER) visits (4 studies).

Missing data: Additional data was requested from the two most recent studies (8,9). A reply was received from one author and is listed in the acknowledgement section.

Mortality: Ten studies reporting mortality were included in the meta-analysis (8-15,18,19). There was no significant difference in mortality between the usual care and intervention groups (OR 0.76; 95% CI (0.44 to 1.30); Figure 1; p=0.31).

Figure 1.  Forest plot of mortality

The level of statistical heterogeneity for this outcome (I square = 54%) may be related to the outlying effect from the report by Fan et al. (8), since its removal led to a lower I square statistic (0%). Also removal of the study resulted in a statistically significant improvement in mortality rate (OR 0.64; 95% CI 0.46 to 0.90)

Respiratory-related Hospital admissions: Nine studies reporting COPD-related hospital admissions were included in the meta-analysis (8-11,13-16,18). There was little heterogeneity present (I square = 0%).  There was a clinically and statistically significant reduction of the probability of at least one hospital admission among patients receiving self-management education compared to those receiving usual care (OR 0.76; 95% CI (0.65 to 0.88); p< 0.001; Figure 2).

 

Figure 2. Forest plot of pulmonary hospitalization

Emergency room visits: Four trials that reported the effect of self-management education on Emergency Room (ER) visits related to COPD were included in the meta-analysis (9,11,12,17). Although the level of heterogeneity was high (I square = 83%), removal of any one study had little effect on this variability.  There was no significant difference between patients receiving self-management education compared to those receiving usual care in the average number of respiratory-related emergency room visits (Mean difference 0.12/pt-yr; 95% CI (-0.21 to 0.46): p=0.47; Figure 3).

Figure 3. Forest plot of pulmonary emergency room visits/pt-yr.

Discussion

This meta-analysis systematically evaluated comparisons of self-management education for patients with COPD compared to usual care. The review was prompted by a recent report of increased mortality in patients receiving COPD education (8). Meta-analysis did not confirm an increase in mortality and determined the recent study had significant heterogeneity compared to the other studies.  We confirm a previous meta-analysis which demonstrated a significant decrease in COPD-related hospitalizations in the intervention groups (7). 

Self-management education has been successfully utilized in a number of chronic diseases (4-6). Education including the use of pre-defined action plans may lead to faster and more frequent treatment of COPD exacerbations, thus resulting in the reduction in hospitalizations. Although we did not review cost-effectiveness, hospitalizations represent the major cost of COPD care (2,3). Therefore, self-management education is likely cost-effective. In support of this concept, a recent cost-effective analysis of one successful self-management education program revealed an average cost savings of $593 per patient (21).

This review has a number of limitations. First, there was variation in the intervention content and delivery. Some studies included action plans in the self-management curriculum and others incorporated additional components of pulmonary rehabilitation including exercise. The type and intensity of education delivery varied from one-on-one instruction, group interaction and the distribution of written material.

Second, the COPD-population was defined in varying detail, with studies using very diverse inclusion criteria. As a result, heterogeneity in disease severity was present. This may explain some of the differing results, including the increase in mortality observed in the recently published study (8).

Third, the studies assessed a broad spectrum of outcome measures and length of follow-up. Often meta-analyses could not be performed because of different outcome measures utilized or different methodology used to calculate the same outcome (e.g. ER visits). This lack of data consistency hampered statistical combination and therefore may have biased the estimates in the review.  Since self-management programs are intended to achieve behavioral changes, follow-up should ideally be long term and this was not the case in all studies.

The final limitation was that knowledge of one’s disease does not necessarily lead to behavioral change. It is unclear at this point if the educational programs lead to an increase in healthy behaviors.

The results of the study by Fan et al. (8) showing an increase in mortality is not confirmed by this meta-analysis. Fan’s manuscript describes the BREATH trial which was a randomized, controlled, multi-center trial performed at 20 VA medical centers comparing an educational comprehensive care management program to guideline-based usual care for patients with chronic obstructive pulmonary disease. The intervention included COPD education during 4 individual and 1 group sessions, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. It is unclear why this education and self-management which is not very dissimilar from other studies would increase mortality. Although the patients were recruited after they were hospitalized, and therefore, likely had more advanced COPD than in some other studies, this alone should not explain excess mortality in the intervention group. An accompanying editorial by Pocock in the same issue of the Annals of Internal Medicine identified no apparent reason for the increase in mortality and points out that education seems an unlikely cause (22). We also have been unable to identify an explanation for the increase and agree with Pocock that the reason seems most likely secondary to statistical chance. The present meta-analysis is consistent with this concept.

For future research of the efficacy of self-management education of COPD patients in improving patient outcomes and decreasing health care utilization, it is important to create more homogeneity in the design of the studies (educational curriculum, demographics, outcome measures and follow-up period). The effectiveness of the individual components of self-management education programs (i.e., action plans, exercise programs) should also be evaluated.

From this meta-analysis, we have shown that self-management education is associated with a reduction in hospital admissions, with no indication for detrimental effects in other outcome parameters. This would seem sufficient to justify a recommendation of self-management education in COPD. However, due to diversity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the form and content of self-management education programs in COPD.

Acknowledgements

We are grateful to Kathryn Rice for her assistance in obtaining additional data from her study (9).

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Reference as: Hurley J, Gerkin RD, Fahy B, Robbins RA. Meta-analysis of self-management education for patients with chronic obstructive pulmonary disease. Southwest J Pulm Crit Care 2012;4:194-202. (Click here for a PDF version of the manuscript)

For the accompanying editorial "A Little Knowledge is a Dangerous Thing" click here.