Adherence to Prescribed Medication and Its Association with Quality of Life Among COPD Patients Treated at a Tertiary Care Hospital in Puducherry – A Cross Sectional Study

S Keerti kumar S

B Maharani, MD

R Venkateswara Babu, MD

M Prakash, MD 

Departments of Pharmacology, Respiratory Medicine and Community Medicine

Indira Gandhi Medical College and Research Institute

Puducherry, India

Abstract

Introduction: Medication adherence is a major determinant for the success of therapy among chronic obstructive pulmonary disease (COPD) patients. The research objectives of the present study were to assess the adherence to prescribed medications and its association with quality of life among COPD patients, to determine the major factors that influence the medication adherence and to assess patient’s knowledge on COPD and its relation to medication adherence.

Methods: It was a hospital based cross-sectional study. Patient demographic characteristics, smoking and alcoholic status, severity grading of COPD, concomitant disease, affordability of patients to medication, patient knowledge on COPD (Knowledge Questionnaire), adherence to medication and inhaler, major factors influencing adherence, disease control and quality of life (COPD Assessment Test) were recorded.

Results: Most of the patients were non-smokers and patients exposed to occupational air pollutants was high. Complete adherence to prescribed medication was found among 47% (MAS Score 6) of the participants and 81% of the participants were partially adherent (MAS score, range of 1-6). Highly adherent group was found to have high CAT score which was statistically significant. (P=0.020). Major factors for medication non-adherence were forgetfulness (82.5%) and symptomatic relief of illness (12.5%). There was no statistically significant association between individual knowledge questions and medication adherence except the question “COPD medicines prevent the disease from getting worse” (P=0.021).

Conclusion: There was a statistically significant association between medication adherence and quality of life. Appropriate health education should be implemented for improving patient awareness and medication adherence.

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases (1). In industrialized and developed countries, it is one of the leading causes of morbidity and mortality (2). The World Health Organization predicts that COPD will become the third leading cause of death by 2030 (3). Currently, various drugs like β2 agonist (long and short acting), inhalational anticholinergics, inhalational corticosteroids and methyl xanthines are utilized to prevent, control the symptoms and also to minimize the occurrence of COPD exacerbations (4,5).

The main factor that determines the success of therapy appears to be medication adherence. The medication adherence rates among COPD patients in clinical trials has been found to be 70 to 90% but in clinical practice it was very low accounting for only 10 to 40% (6-11). Non-adherence to therapy may lead to poor health and increased morbidity and health care cost, which in turn alters the quality of life (12). There appear to be few studies in India on medication adherence among COPD patients. This study is novel in assessing the adherence to drug therapy and its relation to quality of life, patients’ knowledge on COPD and its relationship to medication adherence and major factors influencing the medication adherence among COPD patients attending the tertiary care Institute in one of the Union Territory in India. 

Methods

Study design and setting: A cross-sectional study was conducted in a tertiary care hospital. The study center was a referral hospital for nearby primary and secondary care hospitals and a separate COPD clinic was run every week for treating COPD patients. The study was conducted for a period of 6 months after obtaining Institutional Ethics Committee clearance.

Study Population: Eligible patients were those referred and diagnosed with COPD by FEV1 and categorized according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging and were receiving medications (with no alterations in treatment regimen during the past 3 months). Since the study was on medication adherence, all the COPD patients attending the outpatient department during the study period were considered. Patients with a history of asthma, allergic rhinitis, hospitalization for COPD exacerbation in last 3 months, heart failure or serious liver disease or renal failure or acute coronary syndrome patients and mental illness patients were excluded.

Data Collection: The patients satisfying the inclusion criteria were interviewed after obtaining their written informed consent. Patient demographic details, smoking and alcoholic status, occupational exposure to air pollutants, age at diagnosis of COPD, duration of COPD, concomitant disease, affordability of patients to medication were recorded. Post-bronchodilator FEV1 was measured with spirometry and grading of COPD was done following Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (13).  

Questionnaires used: Patient knowledge on COPD was assessed using COPD Knowledge Questionnaire (COPD-Q) (14). It is a valid, reliable and low-literacy tool to assess COPD related knowledge in patients. Adherence to medication and inhaler was evaluated by using Medication Adherence Scale (MAS) and Medication adherence report scale (MARS) (15,16). Reasons for non-adherence (missing or discontinuing the dose) were also obtained from the patients.  Disease control and quality of life was assessed by using COPD assessment Test (CAT) (17). CAT score varies with changes in treatment and exacerbations of disease due to poor adherence. CAT scoring ranges between 0 and 40. Score of

> 30                - very high impact of COPD on patients

>20                 - high impact of COPD on patients

10 to 20         - medium impact of COPD on patients

<10                - low impact of COPD on patients

5                   - very low impact of COPD on patients

Statistical Analysis: Data entry was done in MS Excel 2010.  Data was analyzed using professional statistics package EPI Info 7.0 version for windows. Descriptive data was represented as mean ± SD, median and interquartile range for numeric variables, percentages and proportions for categorical variables. Appropriate tests of significance were used depending on nature & distribution of variables like Chi square test, student’s t test for categorical variables. Values of p<0.05 were considered statistically significant. Spearman’s correlation test was used to find out the relationship between medication adherence and quality of life.

Results

During the six months study period, 157 COPD patients were contacted. Out of the 157 patients, 19 patients refused to participate in the study, 5 patients were not able to answer appropriately and 42 patients had not satisfied the inclusion criteria. A total of 91 patients completed the study and gave complete responses to the questionnaire. 

Sociodemographic characteristics of the patients were summarized in Table 1.

Table 1. Sociodemographic characteristics of the study participants.

Most of the patients were non-smokers and patients exposed to occupational air pollutants was high. Based on GOLD staging of severity of COPD, 14% were graded as mild, 63% were graded as moderate, 20% were graded as severe and 3% of patients had very severe form of COPD. Concomitant diseases like diabetes, hypertension and hyperthyroidism was found in 74.7% of the participants. Nearly 50% of the participants belong to very low socioeconomic status as per Modified Prasad Classification and medication cost was affordable only by 24.2%.  

Patient responses to COPD – Knowledge Questionnaire (COPD-Q) and its relation to medication adherence were summarized in Table 2.

Table 2. COPD Knowledge Questionnaire responses and its relation to medication adherence among study participants.

*p<0.05 - statistically significant.

There was no statistically significant association between individual knowledge questions and medication adherence except the question “COPD medicines prevent the disease from getting worse” (P=0.021). Average COPD-knowledge score was 6.23 ± 1.57.

Responses to medication adherence scale were summarized in Table 3.

Table 3. Responses to COPD medication adherence.

The adherent sum score ranged between 1-6, 43 (47%) participants who had a sum score of 6 were fully adherent to prescribed medications, 27 (30%) participants had a sum score of 5 and others had a sum score of 1-4 were partially adherent to prescribed medications. The overall medication adherence (range 1-6) among the participants was 81%.

Inhalational medications were used only by 43 (47.3%) patients. Responses to adherence to inhaled medications were summarized in Table 4.

Table 4. Responses to inhalational medication adherence.

MARS sum score was 23.55±3.95. Higher score indicates higher self-reported adherence. MARS sum score ranged between 5-25. Out of 43 patients, 39 (91%) had the sum score in the range of 21-25.

The common reasons for medication non-adherence were forgetfulness (82.5%), symptomatic relief of illness (12.5%), 10% responded that medicines got exhausted and 2.5% reported that it was socially inconvenient to take the medications.

CAT score of the patients and grading were summarized in Tables 5 and 6.

Table 5. COPD Assessment Test (CAT) – Individual item responses.

Table 6. Categorization of study participants based on CAT Score.

There was a statistically significant difference between adherent and partially adherent groups with respect to CAT score of the participants (Student’s t test; p value=0.020).

Highly adherent group was found to have high CAT score. (Table 7).

Table 7. Association between medication adherence score and CAT score.

Student’s t test; p value=0.020.

There was a statistically significant weak positive correlation (r=0.246) between medication adherence sum and CAT score.

Discussion

The patients in the present study had adherence to the medication at 47%. The percentage of adherence was less than the studies conducted in Hungary (58.2%) and Nepal (65%) (18,19). Although complete adherence was less than 50%, majority of the participants were partially adherent to the medications which was at 81% (Table-3). The most common cause for non-adherence was forgetfulness (82.5%). The percentage was very high when compared to other studies in which forgetfulness accounted for about 50% (15,19). 

There was a statistically significant association between medication adherence score and the CAT score similar to the study done by Kocakaya et.al. (20). The study had revealed better the adherence, better the quality of life. Though there is weak positive spearman’s correlation which was statistically significant, it may not be clinically significant. This can be overcome by increasing the sample size. Only 43 participants used inhalational medications and there was higher self-reported adherence to inhalational medications. That data is similar to a study done by Tommelein et al. (16).

In the tertiary care Institute where the study was conducted, patients with moderate and severe symptoms alone were advised to purchase inhaler and during inhaler introduction they were properly trained on how to use the inhaler. Further, compliance to the inhalational medications were checked during each follow-up. Since moderate to severe symptomatic patients were comfortable with inhalational medications, there was high degree of adherence to inhalational medications.

The patient’s COPD knowledge score was 6.23 ± 1.57. It was less when compared to the study done by Ray SM., et al. (7.6 ± 2.1) (14). Awareness of the patients on smoking and its association with COPD, reversal of COPD with quitting of smoking was only around 50% but comparable to prior studies (14). The percentage of COPD patients with smoking was only 22%. The results were similar to the study done by Mahmood T et.al., in which the percentage of nonsmokers with COPD was higher when compared to smokers with COPD (21). It was interesting to note that 100% of the participants were not aware about the importance of flu and pneumonia vaccination. It may be because of poor literacy rate and lack of awareness among the participants.

The results of our study are not surprising and consistent with prior studies. However, sociodemographic factors affect compliance. To our knowledge this is the first study to show the association between adherence and quality of life in COPD in a unique Indian population.

Conclusion

The study showed a statistically significant association between medication adherence and quality of life. Further studies evaluating the impact of education on medication adherence and quality of life are needed.  

References

1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. Am J Respir Crit Care Med. 2017;195(5):557–82. [CrossRef] [PubMed]
2. Viegi G, Scognamiglio A, Baldacci S, Pistelli F, Carrozzi L. Epidemiology of chronic obstructive pulmonary disease (COPD). Respiration. 2001;68:4–19. [CrossRef] [PubMed]
3. World Health Organisation. Chronic obstructive pulmonary disease (COPD) [Internet]. WHO. [cited 2017 Dec 28]. Available from: http://www.who.int/respiratory/copd/en/ (accessed 6/18/19)
4. Toy EL, Beaulieu NU, McHale JM, et al. Treatment of COPD: Relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105(3):435–41. [CrossRef] [PubMed]
5. Cazzola M, Dahl R. Inhaled Combination Therapy with Long-Acting β2-Agonists and Corticosteroids in Stable COPD. Chest. 2004;126(1):220–37. [CrossRef] [PubMed]
6. Rand CS, Nides M, Cowles MK, Wise RA, Connett J. Long-term metered-dose inhaler adherence in a clinical trial. The Lung Health Study Research Group. Am J Respir Crit Care Med. 1995;152:580–8. [CrossRef] [PubMed]
7. Kesten S, Flanders J, Serby CW, Witek TJ. Compliance with tiotropium, a once daily dry powder inhaled bronchodilator, in one-year COPD trials. Chest. 2000;118:191s– 192s.
8. Van Grunsven PM, Van Schayck CP, Van Deuveren M, Van Herwaarden CL, Akkermans RP, Van Weel C. Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (COPD): results of the Detection, Intervention and Monitoring Program of COPD and Asthma (DIMCA) Study. J Asthma. 2000;37:225–34. [PubMed]
9. Krigsman K, Nilsson JL, Ring L. Refill adherence for patients with asthma and COPD: comparison of a pharmacy record database with manually collected repeat prescriptions. Pharmacoepidemiol Drug Saf. 2007;16:441–8. [CrossRef] [PubMed]
10. Bender BG, Pedan A, Varasteh LT. Adherence and persistence with fluticasone propionate/salmeterol combination therapy. J Allergy Clin Immunol. 2006;118:899-904. [CrossRef] [PubMed]
11. Breekveldt-Postma NS, Gerrits CMJM, Lammers JWJ, Raaijmakers J a. M, Herings RMC. Persistence with inhaled corticosteroid therapy in daily practice. Respir Med. 2004;98(8):752–9. [PubMed]
12. Montes de Oca M, Menezes A, Wehrmeister FC, et al. Adherence to inhaled therapies of COPD patients from seven Latin American countries: The LASSYC study. PLoS ONE. 2017;12(11):e0186777. [CrossRef] [PubMed]
13. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: 2019 report. Available at: https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-v1.7-FINAL-14Nov2018-WMS.pdf (accessed 6/18/19).
14. Ray SM, Helmer RS, Stevens AB, Franks AS, Wallace LS. Clinical utility of the chronic obstructive pulmonary disease knowledge questionnaire. Fam Med. 2013;45(3):197–200. [PubMed]
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16. Tommelein E, Mehuys E, Van Tongelen I, Brusselle G, Boussery K. Accuracy of the Medication Adherence Report Scale (MARS-5) as a quantitative measure of adherence to inhalation medication in patients with COPD. Ann Pharmacother. 2014;48(5):589–95. [CrossRef] [PubMed]
17. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34:648-654. [CrossRef] [PubMed]
18. Agh T, Inotai A, Meszaros A. Factors Associated with Medication Adherence in Patients with Chronic Obstructive Pulmonary Disease. Respiration. 2011;82(4):328–34. [CrossRef] [PubMed]
19. Shrestha R, Pant A, Shakya Shrestha S, Shrestha B, Gurung RB, Karmacharya BM. A Cross-Sectional Study of Medication Adherence Pattern and Factors Affecting the Adherence in Chronic Obstructive Pulmonary Disease. Kathmandu Univ Med J. 2015;13(49):64–70. [PubMed]
20. Kocakaya D, Yıldızeli ŞO, Arıkan H, et al. The relationship between symptom scores and medication adherence in stable COPD patients. Eur Respir J. 2017;50(61):PA1062.
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Cite as: kumar S KS, Maharni B, Babu RV, Prakash M. Adherence to prescribed medication and its association with quality of life among COPD patients treated at a tertiary care hospital in Puducherry – a cross sectional study. Southwest J Pulm Crit Care. 2019;18(6):157-66. doi: https://doi.org/10.13175/swjpcc021-19 PDF 

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

Antibiotics as Anti-inflammatories in Pulmonary Diseases

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

Abstract

The currently available evidence for the use of chronic antibiotic therapy, principally macrolides and tetracyclines, as anti-inflammatory therapy in pulmonary disorders is reviewed. Historically, treatment of a number of chronic diseases with tetracyclines showed modest benefits but reports of the successful treatment of diffuse panbronchiolitis with erythromycin stimulated research in other lung diseases as well as shifting the focus from tetracyclines to macrolides. Chronic macrolide therapy is now recommended for patients with frequent exacerbations of cystic fibrosis and COPD and considerable evidence exists for potential benefits in asthma. There is also evidence of macrolide efficacy in the prevention of obliterative bronchiolitis after lung transplantation. Small trials have suggested possible benefit of macrolides in IPF. Taken together these suggest a potential for antibiotics, particularly macrolides, in some pulmonary inflammatory disorders.

History

Based on responses to antibiotics the concept arose over 70 years ago that several common diseases might have an infectious origin. In 1949, Thomas McPherson Brown reported favorable results of tetracycline treatment for rheumatoid arthritis patients at the 7th International Congress on Rheumatic Diseases (1). It was hypothesized these effects were due to a mycoplasma infection. However, the beneficial effects of cortisone in the treatment of arthritis were described at the same meeting. The effect of tetracycline paled beside that of steroids, and the salutary effects of antibiotics on rheumatoid arthritis were largely ignored.

Acne rosacea is a common, chronic dermatologic condition, whose cause remains unknown. Tetracyclines were the first systemic drugs used in the treatment of rosacea, and have been the mainstay therapy for more than 50 years (2). More recently, sub-antimicrobial doses of tetracyclines have been shown to be effective in rosacea presumably through an anti-inflammatory effect (3). Dermatitis herpetiformis is a disease now thought to be secondary to gluten sensitivity. However, this disorder has been treated with dapsone for over 60 years despite its non-infectious origin (4).

Tetracyclines have long been used for periodontal disease with clinical benefit presumed to be from their antimicrobial properties. However, as early as 1983, Golub (5) proposed that tetracyclines might have a beneficial effect by modifying inflammation. Now the tetracyclines are thought to exert their beneficial effects by anti-inflammatory effects, anti-collagenase effects, and a reduction in bone loss (6).

In 1959 the late Neil Cherniack published a double-blind study of 67 patients with chronic bronchitis or bronchiectasis treated with tetracycline, penicillin, a combination of oleandomycin and penicillin, or placebo for 3 to 22 months (7). Patients who received tetracycline had significantly fewer lower respiratory illnesses than those treated with placebos or penicillin. The average duration of these illnesses was also shorter in patients treated with tetracycline.

The anti-inflammatory effects of the macrolides were brought to light because of their effects on an uncommon pulmonary disease, diffuse panbronchiolitis (DPB). DPB is a rare disease seen in Japan and characterized by a chronic inflammatory neutrophilic inflammation of the airways, DPB has a 5-year survival rate of just 63% but only 8% when patients’ airways became colonized with Pseudomonas aeruginosa (8). However, in the early 1980s it was discovered that chronic treatment with erythromycin resulted in dramatically improved 5-year survival to 92% (8). This improvement occurred despite a failure to eliminate the bacterial colonization and was associated with a dramatic decrease in the accumulation of airway neutrophils (8,9). Interestingly, the effect on neutrophilic inflammation was found to be a nonspecific effect of the macrolides. Other macrolides (clarithromycin, roxithromycin and azithromycin) produced a similar suppression of the neutrophilic inflammation (10).

Gradually, with a better understanding of the pathogenesis of these common disease and basic studies examining anti-inflammatory effects, the macrolides and tetracyclines were recognized as anti-inflammatories. Inflammation is proposed to play a role in the pathogenesis of a number of pulmonary disorders. The encouraging results of the above suggested that macrolides and tetracyclines might be beneficial in pulmonary inflammatory conditions. Studies have examined a number of disorders including cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, and asthma.

Anti-inflammatory Mechanisms of Action

Macrolides and tetracyclines exert their antibacterial effects by inhibiting bacterial protein synthesis. Although the anti-inflammatory mechanisms of action of the tetracyclines and macrolides are likely multiple, one important mechanism by both is a reduction in production of a multitude of pro-inflammatory cytokines. Most of these cytokines are regulated at the transcriptional level through proteins such as nuclear factor-κβ (NF- κβ), activator protein-1 (AP-1) and/or p38 mitogen-activated protein kinases (p38 MAPK). Although the studies have varied depending on the in vitro systems examined, most have described a shortening of the half-life of pro-inflammatory cytokine mRNA usually through effect on one or more of the transcriptional control proteins (10-13).

Cystic Fibrosis

A major step in the use of antibiotics as anti-inflammatories occurred with the introduction of macrolides as adjunctive therapy in cystic fibrosis in 2003. Like diffuse panbronchiolitis, airways of cystic fibrosis patients show chronic inflammation with neutrophils which are often infected with Pseudomonas aeruginosa. Saiman et al. (14) conducted a multicenter, randomized, double-blind, placebo-controlled trial of azithromycin in cystic fibrosis patients infected with Pseudomonas. They found a reduction in exacerbations and greater weight gain in those treated with azithromycin compared to control. Following several confirming studies, cystic fibrosis patients are now commonly treated with macrolide antibiotics, especially when infected with Pseudomonas (15).

Tetracyclines have been less commonly used probably because of the staining of teeth and bone in younger, growing children. However, a recent small trial of 19 adult cystic fibrosis treated with chronic doxycycline showed an improvement in FEV1 and an increase in time to the next exacerbation compared to 20 placebo-treated controls (16). This might suggest an alternative in older patients or those at high risk for side effects from macrolides.

Non-CF Bronchiectasis

Long-term treatment with antibiotics has been recommended in patients with bronchiectasis and frequent exacerbations (17). This is based on studies showing decreased rates of exacerbations and some improvement in quality of life. It is not clear whether this effect is due to the antibacterial or anti-inflammatory properties of macrolides. In addition to Cherniak’s tetracycline trial which included bronchiectatics (7), an early MRC trial in 1957 showed that long-term twice weekly oxytetracycline over 1 year led to reduced sputum purulence, fewer days confined to bed and fewer days off work (18). Later trials in non-CF bronchiectasis have been done primarily with azithromycin and it is noted that there is an increased risk of macrolide-resistant organisms developing in these patients, as well as other risks associated with macrolide therapy including ototoxicity and QT prolongation (19).

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is one of the most expensive diseases to treat (20). A number of studies examining costs of COPD have shown that exacerbations, especially those resulting in hospitalization, account for the majority of costs (21,22). Although treatment with glucocorticoids, long-acting beta2-agonists, and long-acting muscarinic antagonists reduce the frequency of acute exacerbations, COPD patients receiving all three of these medications still average 1.4 acute exacerbations per year (23). Beginning in the early 2000’s there were a number of studies that reported an improvement in COPD exacerbations with macrolides (24-27). This culminated in a large, NIH-sponsored, randomized, placebo-controlled, multi-center trial demonstrating that azithromycin decreased COPD exacerbations by about 20% (28).

However, despite overwhelming data that macrolides modestly reduce COPD exacerbations and professional society recommendations for macrolide use in COPD patients at high risk for COPD exacerbations, adoption of chronic therapy with macrolides in COPD has been slow (29). The major reason appears to be concerns over side effects (29). Although azithromycin is well tolerated in the majority of patients, the drug can have serious adverse effects as noted in the trials in non-CF bronchiectasis including hearing loss and QT prolongation (29). The latter is especially concerning given that within less than one year of publication of the azithromycin NIH trial in the New England Journal of Medicine, a large trial the same reported a near 3-fold increase in mortality in patients receiving macrolides (30).

Despite early trials demonstrating efficacy in decreasing COPD exacerbations, tetracyclines have received little attention compared to macrolides. In addition to Cherniak’s study (7) there is a confirming report by Norman in 1962 (31). Tetracyclines might represent an alternative to macrolides in patients at high risk for complications from the macrolides.

Asthma

Asthma, like cystic fibrosis and COPD, is an inflammatory airway disease although usually characterized by eosinophilic inflammation. Studies suggesting macrolides might be useful as anti-inflammatories in asthma go back as far as 1970 (32). After the initial study by Itkin and Menzel (32), few studies were performed until the 2000’s. However, a 1993 study from National Jewish suggested troleandomycin might be useful as a steroid-sparing agent in children with asthma and two Japanese studies published in 1999 and 2000 with roxithromycin and clarithromycin both gave positive results in small numbers of patients (33-35).

In studies whose logic is reminiscent of Thomas McPherson Brown’s concept of mycoplasma infection in rheumatoid arthritis, Kraft et al. (36) investigated chronic chlamydia and mycoplasma infection in asthma and the response to macrolide therapy. In 2002 they reported that clarithromycin treatment increased FEV1 in asthmatics but only in those with evidence of C. pneumoniae or M. pneumoniae infection by PCR in upper and lower airway samples. Sutherland and co-workers (37) also showed improvement in airway hyper-responsiveness with clarithromycin therapy but in both PCR-positive and negative groups. The difference likely resides in identifying and chronic chlamydia and mycoplasma infection. A positive PCR does not necessarily equate to chronic infection and the serologic results from different assays are variable complicating these studies (38,39).

A number of studies have been conducted since Kraft’s investigation examining clarithromycin or azithromycin and assessing various clinical responses and inflammatory parameters in asthma (40-47). These studies have been inconsistent with some showing benefits while others did not. A Cochrane review in 2005 by Richeldi et al. (48) and a review article in 2014 by Wong et al. (49) both concluded that insufficient data existed to recommend chronic macrolide therapy in asthma.

The inconsistency in these results might be explained by the small patient numbers and because various phenotypes of asthma were included. Brusselle et al. (47) reported that azithromycin treatment significantly reduced exacerbation rates only in patients with severe neutrophilic asthma compared with placebo. However, neutrophilic asthma has been associated with increased bacterial load confusing whether benefits are due to an anti-inflammatory or an antibiotic effect (50). Furthermore, clarithromycin reduces neutrophil numbers in patients with severe asthma and it has been suggested that those patients with a neutrophilic phenotype might respond better to the anti-inflammatory effects of macrolide therapy (44,51).

A recent well-done recent study from Australia might tip the balance in favor of chronic macrolide therapy in difficult-to-control asthma. Gibson et al. (52) performed a randomized, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in 420 adults with symptomatic asthma despite current use of inhaled corticosteroid and a long-acting bronchodilator. Patients were randomly assigned to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Azithromycin reduced asthma exacerbations by nearly half and significantly improved asthma-related quality of life.

Tetracyclines as anti-inflammatories in asthma have received much less attention than the macrolides. In 2008 Daoud et al. (53) reported that minocycline allowed for a reduction in steroid dose in asthmatics who were steroid-dependent. A study from India demonstrated an improvement in post bronchodilator FEV1, the FVC, and the FEF (25-75) in asthmatics treated with doxycycline (54).

Obliterative Bronchiolitis

Obliterative bronchiolitis (OB) has historically gone by a variety of terms including bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia (BOOP) and, more recently, cryptogenic organizing pneumonia (COP) although some now separate OB as a separate entity (55). Histologically OB is very similar to diffuse panbronchiolitis, and in fact, panbronchiolitis has been grouped with OB (55). The OB histological pattern is now most commonly seen after lung transplantation or hematopoietic stem-cell transplantation (HSCT). However, OB can be seen with autoimmune disease, particularly rheumatoid arthritis; exposure to inhalational toxins such as sulfur dioxide, hydrogen sulfide, nitrogen oxides, and fly ash; and as an unusual complication following infection with adenovirus, measles virus, or mycoplasma (55).

The treatment of OB is usually corticosteroids or other immunosuppressants (55). However, since OB can result in death or decreased respiratory function, studies with adjunctive therapy or prevention of OB have been of interest. Azithromycin has resulted in improved pulmonary function in approximately 50% of lung-transplant recipients with obliterative bronchiolitis (56,57). A retrospective analysis indicated that the administration of azithromycin in patients with obliterative bronchiolitis after lung transplantation is associated with improved survival (58). Studies examining azithromycin after HSCT were done given the beneficial effects after lung transplantation. Surprisingly, the results were completely different. In a randomized clinical trial that included 465 patients, 2-year airflow decline-free survival was significantly worse for the azithromycin group than for the placebo group (59). The trial was terminated early for a significant increased risk in the azithromycin group of hematological relapses. The FDA recently issued a warning against using chronic azithromycin therapy in HSCT.

There is a paucity of data on treatment of OB with macrolides in non-transplant conditions. In 1993, Ichikawa et al. (60) used erythromycin for 3-4 months in six patients with a diagnosis of bronchiolitis obliterans OP confirmed on histological examination. All improved by the completion of therapy. However, a recent trial of azithromycin in eight patients with post-infectious OB did not produce an improvement in pulmonary function parameters (61). No studies were identified using tetracyclines as therapy in OB.

Cryptogenic Organizing Pneumonia

This entity, which was formerly known as bronchiolitis with organizing pneumonia (BOOP) can involve small airways, but also involves alveolar ducts and alveoli and can present as patchy peripheral opacities (62). It is considered an inflammatory disease which is usually very responsive to corticosteroid therapy, but may relapse when steroid therapy is withdrawn (63). There are several reports now that cryptogenic organizing pneumonia responds to treatment with macrolide and suggest that long term suppression with macrolides can avoid side effects associated with long term steroid therapy (63).

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a condition that has also been associated with neutrophils but with inflammation in the alveoli rather than the airways. With the introduction of nintedanib and pirfenidone and the realization that corticosteroids are of no benefit, the management of IPF has dramatically changed over the past decade (64). A recent publication done during the course of the shift in IPF therapy suggests that azithromycin added to conventional reduced the incidence of acute exacerbations (65). However, these retrospective results need to be interpreted with caution, since as noted above “conventional therapy” for IPF has changed profoundly. For example, many of the patients included in this study were subjected to corticosteroid therapy or other immunosuppressive agents, both of which are no longer recommended in IPF treatment (65). A similar study was performed by Kawamura et al. (66) performed from 2005-16. This single-center retrospective study of patients with IPF demonstrated that treatment of 38 consecutive patients with azithromycin (500 mg/day) for 5 days led to increased survival compared to 47 historical controls treated with a fluoroquinolone-based regimen.

A trial with minocycline in IPF was registered at clinicaltrials.gov but results were apparently never published (67). A small trial in 6 IPF patients treated with doxycycline for 24 weeks showed significant improvement in 6-minute walk time, St. George’s Respiratory Questionnaire, FVC, and quality of life compared to 6 controls (68).

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease that lead to progressive cystic destruction of the lungs. A recent study with doxycycline in LAM patients produced no effect upon vital capacity, gas transfer, shuttle walk distance or quality of life (69). The authors concluded that it is unlikely that doxycycline has a useful effect in LAM.

Summary

Macrolides are clinically useful in reducing exacerbations of cystic fibrosis, chronic obstructive pulmonary disease, bronchiolitis obliterans after lung transplantation, and possibly asthma. Tetracyclines might be considered as a substitute in some situations.

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Cite as: Robbins RA. Antibiotics as anti-inflammatories in pulmonary diseases. Southwest J Pulm Crit Care. 2018;17(3):97-107. doi: https://doi.org/10.13175/swjpcc104-18 PDF 

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.

References

1. Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 2007;29:1224-38. [CrossRef] [PubMed]
2. Steer J, Gibson GJ, Bourke SC. Predicting outcomes following hospitalization for acute exacerbations of COPD. QJM. 2010;103:817-29. [CrossRef[ [PubMed]
3. Johannesdottir SA. Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study. J Med Econ. 2013;16:897-906. [CrossRef] [PubMed]
4. Tan WC. Factors associated with outcomes of acute exacerbations of chronic obstructive pulmonary disease. COPD. 2004;1(2):225-47. [CrossRef] [PubMed]
5. Sharif R, Parekh TM, Pierson KS, Kuo YF, Sharma G. Predictors of early readmission among patients 40 to 64 years of age hospitalized for chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11:685-94. [CrossRef] [PubMed]
6. Guerrero M, Crisafulli E, Liapikou A, Huerta A, Gabarrus A, Chette A, Soler N, Torres A. Readmission for acute exacerbation within 30 days of discharge is associated with a subsequent increase in mortality risk in COPD patients: A long-term observational study. PLoS ONE. 2016;11:e0150737. [CrossRef] [PubMed]
7. Jones PW, Harding G, Berry P, Wiklunf I, Chen WH, Kline Leady N. Development and first validation of the COPD assessment test. Eur Respir J. 2009;34:648-54. [CrossRef] [PubMed]
8. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994:47:1245-51. [CrossRef] [PubMed]
9. Walraven C, Dhalla IA, Bell C, Etchells E, Stiel IG, Zarnke K, Austin PC, Foster AJ. Derivation and validation of an Index to predict early death or unplanned readmission after discharge from hospital to community. CMAJ. 2010; 182: 551-7. [CrossRef] [PubMed]
10. Garcia-Aymerich J, Monso E, Marrades RM, Escarrabill J, Felez MA, Sunyer J, Anto JM. Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation. EFRAM study. Am J Respir Crit Care Med. 2001;164:1002-7. [CrossRef] [PubMed]
11. Garcia-Aymerich J, Farrero E, Félez MA, Izquierdo J, Marrades RM, Antó JM. Risk factors of readmission to hospital for a COPD exacerbation: a prospective study. Thorax. 2003;58:100-5. [CrossRef] [PubMed]
12. Gudmundsson G, Gislason T, Janson C, et al. Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression. Eur Respir J. 2005;26:414–19. [CrossRef] [PubMed]
13. Cao Z, Ong KC, Eng P, Tan WC, Ng TP. Frequent hospital readmissions for acute exacerbation of COPD and their associated factors. Respirology. 2006;11(2):188-95. [CrossRef] [PubMed]
14. Lau AC, Yam LY, Poon E. Hospital re-admission in patients with acute exacerbation of chronic obstructive pulmonary disease. Respir Med. 2001;95:876-84. [CrossRef] [PubMed]
15. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;159:158-64. [CrossRef] [PubMed]
16. Wang Q, Bourbeau J. Outcomes and health-related quality of life following hospitalization for an acute exacerbation of COPD. Respirology. 2005;10:334-40. [CrossRef] [PubMed]
17. Almargo P, Barriero B, DeEchaguen AO, Quintana S, Rodriguez CM, Heredia JL, Garau J. Risk factors for hospital re-admission in patients with chronic obstructive pulmonary disease. Respiration. 2006;73:311-7. [CrossRef] [PubMed]
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]
19. Ngyuen HQ, Chu L, Liu ILA, Lee JS, Suh D, Korotzer B, Yuen G, Desai S, Coleman KJ, Gould MK. Associations between physical activity and 30-day readmission risk in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11(5): 695-705. [CrossRef] [PubMed]
20. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 1999;159:158–164. [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

April 2018 Pulmonary Case of the Month

Ashely L. Garrett, MD

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 74-year-old woman with known chronic obstructive pulmonary disease (COPD) presented to emergency department on 2/4/18 with dyspnea. She had been hospitalized at another hospital from 12/29/17 - 1/30/18 for a COPD exacerbation and health care associated pneumonia described as a cavitary pneumonia. She was treated with various doses of systemic steroids and antibiotics. Her course was complicated by atrial fibrillation with a rapid ventricular response. She eventually was discharged to a skilled nursing facility.

Past Medical History, Social History and Family History

She has a known history of COPD with an FEV1 of 22% of predicted and is on 2L/min of O2 by nasal cannula. There is also a history of:

• Hypertension.
• Hypercholesterolemia.
• Paroxysmal atrial fibrillation, not on anticoagulation.
• Right 4 mm PICA aneurysm

She lives in rural Kingman, AZ with some dust and outdoor bird exposure.

Family history is noncontributory.

Medications

• Alprazolam 0.25 mg p.o. b.i.d.
• Symbicort two puffs inhaled b.i.d.
• Diltiazem 120 mg p.o. q.12h
• Disopyramide 150 mg p.o. q.6h
• Furosemide 20 mg p.o. daily
• Levalbuterol 0.31 mg q.6 days p.r.n.
• Meperidine 50 mg p.r.n. pain
• Metoprolol succinate 12.5 mg p.o. b.i.d
• Prednisone 10 mg p.o. daily

Physical Examination

• Vitals: BP 110/65 mm Hg, P 130 irregular beats/min, T 37° C, Respirations 20 breaths/min
• General: Appears in mild respiratory distress
• Lungs: Distant breath sounds
• Heart: Irregular rhythm with distant tones
• Abdomen: no organomegaly, masses or tendernesses
• Extremities:  No edema

Which of the following should be done at this time? (Click on the correct answer to proceed to the second of six pages)

1. Arterial blood gases (ABGs)
2. Chest x-ray
3. Electrocardiogram
4. 1 and 3
5. All of the above

Cite as: Garrett AL. April 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(4):174-82. doi: https://doi.org/10.13175/swjpcc050-18 PDF

Correlation between the Severity of Chronic Inflammatory Respiratory Disorders and the Frequency of Venous Thromboembolism: Meta-Analysis

Stella C. Pak, MD

Andrew Kobalka, BS

Yaseen Alastal, MD

Scott Varga, MD 

Department of Medicine

University of Toledo Medical Center

Toledo, OH, USA 43614

Abstract

The present study aims to integrate the growing body of evidence on the possible association between the severity of chronic inflammatory respiratory disorders (CIRDs) and the frequency of venous thromboembolism (VTE). Eight studies were analyzed to assess the correlation between the severity of CIRDs and the incidence of VTE. Our results suggest that there is no significant increased risk of VTE in patients with severe CIRD compared to mild or moderate CIRD, OR=0.92 (95% CI 0.59 – 1.43; I² = 74%). Further studies are indicated to explore this possible association. Gaining a better understanding of the VTE risk for patients with CIRDs will enable clinicians to provide better individualized risk management and preventive care.

Introduction

In this age of rapid developments in health care, pioneering attempts are being made to improve the management of chronic inflammatory respiratory disorders (CIRDs). Despite significant public health efforts over the past few decades, the prevalence of CIRDs continues to rise. Common types of CIRDs include asthma, chronic obstructive pulmonary disorder (COPD), and bronchiectasis. Bronchiectasis, a pathologic description of lung damage characterized by inflamed and dilated thick-walled bronchi (1), is most commonly caused by respiratory infections or other pro-inflammatory events such as toxin inhalation (2). Patients with recurrent airway damage due to impaired mucociliary clearance secondary to genetic alterations commonly develop bronchiectasis (2); the overall percentage of bronchiectasis patients with cystic fibrosis is approximately 5-6% (3,4).

There is a growing body of evidence suggesting that individuals with CIRDs are at increased risk for developing venous thromboembolism (5-7). Multiple studies indicate one tenth of patients with acute COPD exacerbation develop VTE (5). Despite this, the possible correlation between CIRD severity and VTE risk has not been sufficiently explored in the literature.

Two plausible mechanisms for VTE in CIRDs are inflammation-induced thrombosis and steroid-induced thrombosis. Inflammation-induced thrombosis involves interaction among activated platelets, leukocytes, and endothelial cells promoting excessive procoagulant activity of endothelium (8). Steroids are also postulated to induce prothrombotic state by increasing the serum concentration of von Willebrand factor and plasminogen activator inhibitor-1 (9).

Subtypes of VTE including PE and DVT can lead to significant chronic complications. Nearly 50% of patients who have DVT develop post-thrombotic syndrome within 2 years despite being on anticoagulant therapy (10). Chronic thromboembolic pulmonary hypertension, which is reported to occur in 0.5 to 4% of patients with history of PE, can lead to right-sided heart failure, exercise intolerance, and dyspnea (11). A recent study showed that pulmonary embolism led to higher mortality in patients with severe COPD compared to general population (12). Episodes of VTE and their sequelae complicate the management of patients with CIRDs. Considering this burden from VTE, preventive measures with risk stratification are needed.

Assessing the correlation between the severity of CIRDs and the risk for VTE would improve the quality of care by allowing accurate risk assessment and proper risk management. Furthermore, demystifying this association would give patients agency in their own care. A recent study showed that 84% of activated protein C-resistant women on combined oral contraceptives changed their method of contraception after finding out that they had increased risk for VTE, and a majority were pleased to learn of their APC resistance status (13). Understanding the correlation between the severity of CIRDs and VTE would help clinicians provide better education and lifestyle advice to patients with CIRDs.

The goal of this study is to assess the correlation between the severity of CIRDs (including COPD, asthma, and cystic fibrosis) and the frequency of VTE. Gaining a better understanding of these correlations will offer significant clinical benefits and facilitate better individualized care for patients with varying severity of CIRDs.

Methods

Search Strategy

English language studies published up to March, 10^th 2017 were located via a search of MEDLINE, EMBASE, Cochrane Library, CINAHL, and Web of Science. Key search terms included the following: “CIRD,” “COPD,” “Asthma,” “CF,” “DVT,” “PE,” and “VTE.” Appendix 1 describes specific search terms used in each database.

Inclusion Criteria

The criteria for inclusion required studies: 1) to include adult patients with CIRDs with different severity based on objective index or score system 2) to include the frequency of VTE among participants 3) to be prospective or retrospective observational studies, and 4) to report raw number of patients found to have VTE in different severity group.

Exclusion Criteria

The following criteria were used to exclude studies from this review: 1) Use of subjective measure in severity determination 2) Case study 3) Pediatrics population 4) Non-English literature.

Meta-Analysis

A random effects meta-analysis was performed to determine the association between the severity of CIRDs and VTE risk. The random model was applied to derive the summary estimate. Proportions were calculated using logit transformation (log-odds). Heterogeneity was assessed using the I² value. The funnel plot was constructed to detect and adjust for potential publication bias.  All statistical tests were two-sided and p-values of less than 0.05 were statistically significant. All statistical analyses were performed using the Review Manager 5.3.5 program (Cochrane, London, UK).

Results

A total of 8 trials (23,899 patients) were included for analysis (14-21). Table 1 describes the characteristics of included studies.

Table 1. Characteristics of included studies.

HCT: hematocrit, ATS: American Thoracic Society, GOLD: Global Initiative for Chronic Obstructive Lung Disease, PE: pulmonary embolism, DVT: deep venous thromboembolism, GINA: Global Initiative for Asthma Classification.

The odds ratio of DVT frequency for people with severe COPD compared to those with moderate or mild COPD was 0.92 (95% CI 0.59 – 1.43; I² = 74%) (Figure 1).

Figure 1. Forest plot of studies on chronic inflammatory respiratory disorders and venous thromboembolism with study-type subanalysis.

 In subgroup analysis, the odds ratio for prospective studies was 0.67 (95% CI 0.46 – 0.96; I² = 0%). On the other hand, subgroup analysis from retrospective studies showed odds ratio of 1.34 (95% CI 0.88 – 2.03; I² = 53%). Funnel plot suggests that publication bias minimally influenced retrospective studies (Figure 2). However, the plot suggests that mild publication bias exists among the included prospective studies.

Figure 2. Funnel plot of studies on chronic inflammatory respiratory disorders and venous thromboembolism with study-type subanalysis.

Discussion

Our results indicate no significant association between the severity of CIRDs and VTE risk. Several limiting factors, including substantial variation in the measures of disease severity, may have influenced the final result. Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system, American Thoracic Society (ATS) grading system, and the presence of polycythemia were used as disease severity measures in patients with COPD. Global Initiative for Asthma Classification (GINA) system measured severity of asthma, and ATS grading system measured severity of cystic fibrosis. We tried to use the random effect model to compensate for this heterogeneity. Confounding factors such as smoking status, exercise level, BMI, quality of health care, and ethnicity could also have contributed to the development of VTE in the studied population. Finally, a wide variation in cohort size across studies could have confounded the results.

The outcome of subanalysis on prospective studies was contradictory to those of retrospective studies. The retrospective study design, the researchers tend to have limited control over consistency and accuracy. Major limitation for prospective studies is the loss to follow-up associated with relatively long follow-up period (22). These limitations may have contributed to these contradictory outcomes from subanalyses.

The presence of polycythemia was used as a severity indicator for COPD in three of the studies, while GOLD stages II-IV was used in two of the studies. The decision to use polycythemia as an indicator of COPD severity was based upon the finding that more than 70% of COPD patients with polycythemia are in GOLD stage III or IV (21). However, as not every patient with polycythemia is in GOLD stage III or IV, this novel measure might not be strongly correlated enough with disease severity.

While large-scale prospective and retrospective studies assessing COPD severity and VTE risk have been undertaken, the multiple systems for grading COPD severity limits our ability to compare studies. A uniform disease severity grading system is needed to compare studies in this way.

In summary, our results indicate no significant association between the severity of CIRDs and VTE risk. Further exploration of the relationship between disease severity in patients with CIRDs and risk of VTE is necessary to improve risk stratification system and preventive care for this patient population. We hope the present work helps foster subsequent research on this possible association.

References

1. Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JE, Coulden RA, Flower CD, Bilton D, Keogan MT. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med. 2000 Oct, 162(4 Pt 1): 1277-84. [CrossRef] [PubMed]
2. Athanazio R. Airway disease: similarities and differences between asthma, COPD and bronchiectasis. Clinics (Sao Paulo). 2012;67:1335-43. [CrossRef] [PubMed]
3. Verra F, Escudier E, Bignon J, Pinchon MC, Boucherat M, Bernaudin JF, de Cremoux H. Inherited factors in diffuse bronchiectasis in the adult: a prospective study. Eur. Respir. J. 1991 Sep; 4(8)937-44. [PubMed]
4. Girodon E, Cazeneuve C, Lebargy F, Chinet T, Costes B, Ghanem N, Martin J, Lemay S, Scheid P, Housset B, Bignon J, Goossens M. CFTR gene mutations in adults with disseminated bronchiectasis. Eur. J. Hum. Genet. 1997 May-Jun; 5(3):149-55. [PubMed]
5. Ambrosetti M, Ageno W, Spanevello A, Salerno M, Pedretti RF. Prevalence and prevention of venous thromboembolism in patients with acute exacerbations of COPD. Thromb Res. 2003;112: 203-7. [CrossRef] [PubMed]
6. Lippi G, Favaloro EJ. Allergy and venous thromboembolism: a casual or causative association. Semin Thromb Hemost. 2016;42: 63-8. [CrossRef] [PubMed]
7. Takemoto CM. Venous thromboembolism in cystic fibrosis. Pediatr Pulmonol. 2012;47: 105-12. [CrossRef] [PubMed]
8. Aksu K, Donmez A, Keser G. Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des. 2012;18: 1478-93. [CrossRef] [PubMed]
9. Stuijver DJ, Majoor CJ, van Zaane B, Souverein PC, de Boer A, Dekkers OM, Büller HR, Gerdes VEA. Use of oral glucocorticoids and the risk of pulmonary embolism: a population-based case-control study. Chest. 2013;143: 1337-42. [CrossRef] [PubMed]
10. Baldwin MJ, Moore HM, Rudarakanchana N, Gohel M, Davies AH. Post-thrombotic syndrome: a clinical review. J Thromb Haemost. 2013;11: 795-805. [CrossRef] [PubMed]
11. Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev. 2014;28: 221-6. [CrossRef] [PubMed]
12. Bahloul M, Chaari A, Tounsi A, et al. Incidence and impact outcome of pulmonary embolism in critically ill patients with severe exacerbation of chronic obstructive pulmonary diseases. Clin Respir J. 2015;9: 270-7. [CrossRef] [PubMed]
13. Lindqvist PG, Dahlback B. Reactions to awareness of activated protein C resistance carriership: a descriptive study of 270 women. Acta Obstet Gynecol Scand. 2003;82: 467-70. [CrossRef] [PubMed]
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15. Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C, Tonnel AB, Remy-Jardin M. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144: 390-6. [CrossRef] [PubMed]
16. Majoor CJ, Kamphuisen PW, Zwinderman AH, Ten Brinke A, Amelink M, Rijssenbeek-Nouwens L, et al. Risk of deep vein thrombosis and pulmonary embolism in asthma. Eur Respir J. 2013;42(3):655-61. [CrossRef] [PubMed]
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21. Guo L, Chughtai AR, Jiang H, Gao L, Yang Y, Yang Y, Liu Y, Xie Z, Li W. Relationship between polycythemia and in-hospital mortality in chronic obstructive pulmonary disease patients with low-risk pulmonary embolism. J Thorac Dis. 2016;8: 3119-31. [CrossRef] [PubMed]
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Cite as: Pak SC, Kobalka A, Alastal Y, Varga S. Correlation between the severity of chronic inflammatory respiratory disorders and the frequency of venous thromboembolism: meta-analysis. Southwest J Pulm Crit Care. 2017;14(6):285-91. doi: https://doi.org/10.13175/swjpcc035-17 PDF

April 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Pulmonary Department

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 63-year-old woman with a prior diagnosis of possible rheumatoid arthritis was referred for dyspnea with more vigorous activities in Prescott where she now lives (elevation 5367 ft.). She is receiving hydroxychloroquine 400 mg/day.

Past Medical History, Social History and Family History

She has a past medical history of hypertension. She smoked about a pack per day from age 20 to 40. There is a history of colon cancer in her mother and  lung cancer in a sister.

Physical Examination

• Vitals: BP 155/102, SpO2 93% on room air
• Chest: slightly decreased breath sounds but clear
• Cardiovascular:  regular rhythm without murmur
• Extremities:  no cyanosis, clubbing or edema
• The remainder of the physical examination is normal

What testing would you perform at this time? (Click on the correct answer to proceed to the second of five pages)

1. Chest X-ray
2. Pulmonary function testing
3. Rheumatoid factor
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. April 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(4):129-33. doi: https://doi.org/10.13175/swjpcc040-17 PDF

Inhaler Device Preferences in Older Adults with Chronic Lung Disease

Laith Ghazala, MD¹

Christian Bime, MD MSc^1,2

Felipe Cortopassi, PT RPFT MBA³

Todd Golden, MS¹

Cristine E. Berry, MD MHS^1,2

¹Department of Medicine and the ²Asthma and Airway Disease Research Center

University of Arizona College of Medicine

Tucson, AZ USA

³ Pulmonary Department

State University of Rio de Janeiro

Rio de Janeiro, RJ, Brazil

Abstract

Introduction: Patient preferences are important for medication adherence and patient satisfaction, but little is known about older adult preferences for inhaler devices.

Methods: We developed a 25-item written self-administered questionnaire assessing experience with inhalers, prior inhaler education, and preferences with respect to inhaler device features and inhaler device teaching. We then conducted a cross-sectional survey of patients at least 65 years of age with chronic lung disease who had experience using inhaler devices for at least six months in the ambulatory setting.

Results: Fifty participants completed the questionnaire. The majority of participants (80%) reported prior experience with a metered dose inhaler (MDI), but only 26% used an MDI with a spacer. Most patients (76%) had received formal instruction regarding proper use of the inhaler, but only 34% had ever been asked to demonstrate their inhaler technique. Physician recommendation for an inhaler, cost of the inhaler device, and inhaler features related to convenience were important with respect to patient preferences. With regard to inhaler education, participants prefer verbal instruction and/or hands-on demonstration at the time a new inhaler is prescribed in the setting of the prescribing provider’s office.

Conclusion:  Patient preferences for inhaler devices and inhaler education among older adults indicate physician recommendation, cost, and convenience are important. The impact of patient preferences on inhaler adherence and clinical outcomes remains unknown.

Introduction

Inhalers represent the mainstay of treatment for most patients with chronic lung disease, especially obstructive lung diseases  (1,2). There are several different inhaler devices, including pressurized metered-dose inhalers, dry powder inhalers, soft mist inhalers, and nebulizers. Evidence suggests that different inhaler devices are equivalent with respect to drug delivery when the technique for appropriate utilization has been mastered (3,4). However, several factors may influence the ability to use an inhaler device properly, such as cognitive function, inspiratory flow rate, or hand strength and dexterity. These issues are particularly relevant to consider when prescribing inhaler devices for older adults (5-7).

The multitude of inhaler devices on the market is growing every day, and while this may allow providers to better tailor therapy to individual patient needs, it also increases the complexity of selecting an inhaler device (3,5). For prescribing providers, it is ever more challenging to consider all the potential factors that may influence both proper use of and adherence to inhaler therapy. Ideally, a provider would assess patient-level factors that impact proper device use and cost of the device to an individual patient, as well as patient preferences. Individual preferences may be shaped by prior experience with inhalers, exposure to advertising, advice from family and friends, lifestyle factors, comorbidities, recommendations from other healthcare providers, and a variety of other factors. Therefore, in selecting an inhaler device for a patient, it is important that providers consider factors beyond those that influence proper inhaler use, as patient preferences may impact adherence to therapy (3,5).

After providers identify an appropriate inhaler device that their patient is capable of using properly (considering physical and/or cognitive limitations) and that is selected based on patient preferences, the next obstacle to achieving maximal inhaler efficacy is ensuring the patient has been properly instructed on the multiple steps required for optimal medication administration from their inhaler device. While the importance of teaching patients about proper inhaler technique has been emphasized in international guidelines for the care of patients with asthma and chronic obstructive pulmonary disease (COPD) (1,2), there is limited information available about patient preferences for device instruction, especially in older adults, including timing, setting, and format of education.

The elderly represent an important population in which inhalers are frequently prescribed but the challenges of inhaler device selection are magnified (6-8). Accordingly, we conducted a single-center cross-sectional study to identify patient preferences for inhaler device features and inhaler device education among older adults in the ambulatory setting. The results of this study have been previously reported in the form of an abstract (9).

Methods

In order to assess patient preferences regarding inhalers, we developed a 25-item written questionnaire survey (see online supplement). In addition to patient preferences about inhaler device features and inhaler device education, the survey also assessed demographic information, medical history, patient experience with inhaler devices and prior device education, and perceived challenges to proper device use.

Participants were recruited from the ambulatory clinics (pulmonary and internal medicine) and pulmonary function laboratory at Banner University Medical Center in Tucson, Arizona between May 2014 and February 2015. Individuals were included if they were at least 65 years of age and had a history of chronic lung disease for which they were prescribed an inhaler device for at least six months. Those who were hospitalized, who did not speak English, or who were unable to read or write were excluded. Surveys were self-administered.

All participants provided written informed consent. This study was approved by the local institutional review board and was conducted according to the ethical principals of the Declaration of Helsinki.

Survey responses were subsequently recorded and tabulated in REDCap (https://projectredcap.org/). Categorical data was described using proportions (N(%)) and continuous data was described using mean with standard deviation (SD) or median with interquartile ratio (IQR).

Results

Fifty participants of mean age 74 (range 65-89) years completed the survey, including 22 men and 28 women (Table 1).

Table 1. Study Participant Demographic and Clinical Characteristics

N=50; continuous variables are described using mean (standard deviation) and categorical variables are described as n (%). *Physician diagnosis of respiratory disease; categories are not mutually exclusive and patients may report multiple diagnoses. COPD=chronic obstructive pulmonary disease.

The vast majority (96%) of participants were living at home, and most participants (78%) reported being independent with respect to activities of daily living. The participants were mostly well-educated, with 26% having completed college and 38% with a graduate degree. Comorbid conditions were common, including factors that may influence inhaler use and education, such as visual impairment (37%), hearing impairment (33%), and hand arthritis (22%). Almost all participants reported a physician diagnosis of chronic obstructive pulmonary disease (COPD) or asthma. In addition five patients also reported a history of interstitial lung disease; two of those had mixed history of asthma and ILD.

The majority of participants (80%) reported prior experience with a metered dose inhaler (MDI), but only 26% used an MDI with a spacer (Table 2).

Table 2. Prior Inhaler Devices Used and Prior Education Regarding Inhalers

N=50; categorical variables are described as n (%). *Categories are not mutually exclusive as patients may have been prescribed multiple inhaler devices by multiple providers and received formal instruction from multiple providers using multiple educational formats. MDI=metered dose inhaler, DPI=dry powder inhaler, Neb=nebulizer.

Most patients (76%) had received formal instruction regarding proper use of the inhaler, but only 34% had ever been asked to demonstrate their inhaler technique (Table 2). The majority of participants (66%) also reported no challenges to using their prescribed inhaler device properly (Table 3).

Table 3. Perceived Challenges Influencing Proper Use of Prescribed Inhaler

N=50; survey respondents could select more than one answer.

When asked to rate how well they understood the purpose of their inhaled medication (1=no understanding, 10=complete understanding), participants reported good understanding with a median rating of 8 (IQR 6-9). When asked to rate their confidence regarding how well they understood the proper use and handling of their inhaler device (1=no confidence, 10=very confident), participants reported a high level of confidence with a median rating of 9 (IQR 8-10).

When asked about the importance of various inhaler features with respect to their own individual preferences, participants provided a rating score ranging from 1 (not important) to 10 (very important) (Table 4).

Table 4. Patient Preferences Regarding Inhaler Features

N= 50; patient ratings are presented as median (IQR) scores and are based on a scale from 1 (not important) to 10 (very important).

Nearly all patients identified physician recommendation of an inhaler device as being very important with a median rating of 10 (IQR 10-10). Other inhaler features that were deemed important by most patients include device portability and short medication administration time. Some factors, such as whether or not an inhaler device required regular cleaning, afforded multiple doses, or was used once daily, received high median scores but demonstrated broader variability in overall response range. Cost of the inhaler was important to many patients as well with a median rating of 10 (IQR 4-10) (Table 4). Although the survey did not ask participants to compare devices, no significant difference was noted in the analysis regarding preferences between those taking nebulizers and those using DPI or MDI.

When asked about their preference for inhaler education format, participants indicated that they preferred hands-on demonstration and/or verbal instructions (Table 5).

Table 5. Patient Preferences Regarding Inhaler Device Education

*Some participants did not respond to all questions and thus denominator reflects total n that responded. Preferences are not mutually exclusive because participants could select multiple options.

The majority (70%) would like to receive this teaching at their prescribing doctor’s office, and most (71%) indicated they would like the education to occur at the time a new inhaler is prescribed (Table 5).

Discussion

In our cross-sectional survey of patient preferences in older adults with respiratory disease and prior inhaler experience, we determined that physician recommendation for a given inhaler and the cost of the inhaler were very important to patients. Moreover, patient preferences for inhaler features related to convenience were common, including device portability, once daily dosing, short medication administration time, and multiple-dose devices. The majority of patients also preferred an inhaler device that did not require routine cleaning, such as a nebulizer device. Providers may need to educate patients beyond the purpose of an inhaler by taking time to describe the reasons for selection of a particular inhaler, especially in cases where patient preferences are not aligned with provider objectives in selecting an appropriate inhaler device when there are patient-specific limitations to proper inhaler technique.

This is particularly important for older adults, as we demonstrated in our study that comorbidities that influence proper inhaler use are common among elder patients who have been prescribed inhalers (e.g. hand arthritis, sensory impairment, and stroke). However, in spite of this, we found in our study that spacers remain underutilized, with only a minority of patients who had experience with MDI also reporting prior use with a spacer. Using a spacer in conjunction with a MDI has been recommended for all patients because it minimizes the need for hand-breath coordination and facilitates better drug delivery ², but spacers are thought to be especially important for older adults who may experience additional challenges to proper inhaler technique (7,10). Arthritis that limits flexibility and coordination in the absence of weakness could also impact proper device administration.

Overall, study participants reported being quite confident that they understood how to properly use their inhaler, yet only a minority of patients had ever been asked to demonstrate how they use their inhaler. This is in contrast to international guidelines for obstructive lung disease that recommend checking inhaler technique at each visit. ^{1, 2} Participants also reported very few perceived challenges to proper inhaler use, and several individuals reported no challenges at all, even when they were permitted to provide their own free response in the survey. These findings suggest that patients may underestimate the complexity of inhaler delivery systems and may therefore underappreciate the importance of inhaler education. There are limited data to compare different devices in patients with chronic lung diseases and this was not addressed in our study; however, Komase et al. (11) found that DPI is a preferred device due to its ease of use and association with fewer errors.

Of note, study participants strongly preferred to receive inhaler education at the time a new inhaler is prescribed in the prescribing provider’s office. However, this may be challenging to implement in practice, given the vast number of inhaler devices on the market. Not all clinic staff may be familiar with the features of the different classes of inhaler devices, comparing MDI to DPI to nebulizer, much less feel comfortable teaching about the various features of different DPI devices that are now available. Moreover, placebo devices for patient teaching are not always readily available for each device, which makes it difficult to teach proper use at the time a new device is prescribed. Our study findings indicate participants preferred an educational format of verbal instruction and/or hands-on demonstration, but it may be more feasible for clinic staff to use a web-based video format for initial instruction while patients are still in the office setting and can ask questions as needed and they can then watch the video again at home. This should be followed by another clinic visit to assess proper inhaler technique using the patient’s own device shortly after the prescription is filled. Of course, this is particularly important for older adults because they are more likely to demonstrate errors in inhaler technique than younger patients (12).

To date, there is little evidence that taking into account patient preferences regarding inhaler devices results in improved clinical outcomes. However, preferences may influence multiple factors that are important for disease impact, including inhaler device adherence, health-related quality of life, and patient satisfaction with the selected device (13,14). Further research is needed to establish the relationship between patient preferences with inhaler devices and clinical outcomes in patients with obstructive lung disease. The limited evidence to date regarding patient preferences for inhalers suggests that patients find factors related to convenience very important, similar to our findings. For example, Molimard and colleagues (15) showed that dose recording, multiple-dose carrying, and daily dosing were important to patients with COPD and that delivery device features were more critical to patients than the medication compound that was delivered. Ease of use and ability to use the inhaler device during episodes of dyspnea were also found to be important DPI features in a European study of patients with asthma and COPD (16).

The major strengths of this study include that it is patient-centered with an emphasis on patient preferences for inhaler devices and inhaler education. Moreover, we focused on older adults because this special subpopulation often receives inadequate attention, especially in the study of patient preferences, and the physical and cognitive factors that influence proper inhaler use are particularly relevant among elders. We acknowledge that this study is limited in that we did not directly assess proper inhaler use among the participants but instead queried their understanding of proper inhaler use, and therefore we cannot definitively conclude if participants were overly confident or appropriately confident. It is also important to note that our study participants were predominantly Caucasian and also well educated, and therefore the patient preferences we observed may not be representative of all adults with chronic lung disease. Of note, we did not assess use of soft-mist inhalers (SMI) or preferences related to SMI in our survey because they were not widely available in our region at the start of this study.

Conclusion

In summary, patient preferences for inhaler devices and inhaler education among older adults indicate physician recommendation, cost, and convenience are important. Prescribing providers should explain their rationale for inhaler device selection and the importance of inhaler education because patient preferences may not always align with provider priorities or the individual patient-level physical and cognitive factors a provider may consider when selecting an inhaler device.

References

1. Global Initiative for Obstructive Lung Disease (GOLD). The Global Strategy for Diagnosis, Management and Prevention of COPD (updated 2016). Accessed July 18, 2016 at www.goldcopd.org.
2. Global Initiative for Asthma (GINA). The Global Strategy for Asthma Management and Prevention (updated 2016). Accessed July 19, 2016 at www.ginasthma.org.
3. Yawn BP, Colice GL, Hodder R. Practical aspects of inhaler use in the management of chronic obstructive pulmonary disease in the primary care setting. Int J Chron Obstruct Pulmon Dis. 2012;7:495-502. [CrossRef] [PubMed]
4. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005 Jan;127(1):335-71. [CrossRef] [PubMed]
5. Geller DE. Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler. Respir Care. 2005 Oct;50(10):1313-21; discussion 1321-2. [PubMed]
6. Taffet GE, Donohue JF, Altman PR. Considerations for managing chronic obstructive pulmonary disease in the elderly. Clin Interv Aging. 2014;9:23-30. [CrossRef] [PubMed]
7. Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2011 Jul 1;68(13):1221-32. [CrossRef] [PubMed]
8. Jarvis S, Ind PW, Shiner RJ. Inhaled therapy in elderly COPD patients; time for re-evaluation? Age Ageing. 2007 Mar;36(2):213-8. [CrossRef] [PubMed]
9. Ghazala L, Bime C, Cortopassi F, Baalachandran R, Oren E, Berry CE. Inhaler device preferences in older adults with chronic lung disease. Am J Resp Crit Care Med. 2015;191(A5797) [Abstract].
10. Lavorini F, Mannini C, Chellini E, Fontana GA. Optimising Inhaled Pharmacotherapy for Elderly Patients with Chronic Obstructive Pulmonary Disease: The Importance of Delivery Devices. Drugs Aging. 2016 Jul;33(7):461-73. [CrossRef] [PubMed]
11. Komase Y, Asako A, Kobayashi A, Sharma R. Ease-of-use preference for the ELLIPTA® dry powder inhaler over a commonly used single-dose capsule dry powder inhaler by inhalation device-naïve Japanese volunteers aged 40 years or older. Int J Chron Obstruct Pulmon Dis. 2014 Dec 11;9:1365-75. [CrossRef] [PubMed]
12. Chorao P, Pereira AM, Fonseca JA. Inhaler devices in asthma and COPD--an assessment of inhaler technique and patient preferences. Respir Med. 2014 Jul;108(7):968-75. [CrossRef] [PubMed]
13. Anderson P. Patient preference for and satisfaction with inhaler devices. Eur Respir Rev. 2005;14(96):109-116. [CrossRef]
14. Shikiar R, Rentz AM. Satisfaction with medication: an overview of conceptual, methodologic, and regulatory issues. Value Health. 2004 Mar-Apr;7(2):204-15. [CrossRef] [PubMed]
15. Molimard M, Colthorpe P. Inhaler devices for chronic obstructive pulmonary disease: insights from patients and healthcare practitioners. J Aerosol Med Pulm Drug Deliv. 2015 Jun;28(3):219-28. [CrossRef] [PubMed]
16. Hawken NA, Amri I, Elmoctar Neine M, Aballea S, Torvinen S, Plich A. Preferences for Dry Powder Inhaler Attributes Among Patients With Asthma and Chronic Obstructive Pulmonary Disease From Five European Countries. Value Health. 2015 Nov;18(7):A364. [CrossRef] [PubMed]

Quick Look

Current Knowledge:

Inhalers are the mainstay of therapy for obstructive lung disease, but selection of a particular inhaler for an individual can be challenging, particularly in the elderly because of factors related to aging that may influence proper inhaler technique. Providers should also consider patient preferences, but little is known about preferences for inhaler devices among older adults.

What this paper contributes to our knowledge:

Patient preferences for inhaler devices and inhaler education among older adults indicate physician recommendation, cost, and convenience are important. Providers should consider individual patient factors that influence proper inhaler use along with patient preferences when selecting an inhaler.

Cite as: Ghazala L, Bime C, Cortopassi F, Golden T, Berry CE. Inhaler device preferences in older adults with chronic lung disease. Southwest J Pulm Crit Care. 2016;13(5):225-34. doi: https://doi.org/10.13175/swjpcc097-16 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).
2. Wier LM, Elixhauser A, Pfuntner A, Au DH. . Overview of hospitalizations among patients with COPD, 2008: Statistical Brief #106. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville, MD: Agency for Health Care Policy and Research (US); 2006–2011 Feb. Available from: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb106.pdf (accessed 5/4/15)
3. Elixhauser A, Au DH, Podulka J. . Readmissions for chronic obstructive pulmonary disease, 2008: Statistical Brief #121. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville, MD: Agency for Health Care Policy and Research (US); 2006–2011 Sep. Available from: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb121.pdf (accessed 6/4/15).
4. Medicare Payment Advisory Commission (MEDPAC). Report to the Congress: promoting greater efficiency in Medicare, 2007.
5. Robbins RA, Gerkin RD. Comparisons between Medicare mortality, morbidity, readmission and complications. Southwest J Pulm Crit Care. 2013;6(6):278-86.
6. Stein BD, Bautista A, Schumock GT, Lee TA, Charbeneau JT, Lauderdale DS, Naureckas ET, Meltzer DO, Krishnan JA. The validity of International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for identifying patients hospitalized for COPD exacerbations. Chest. 2012;141(1):87-93. [CrossRef] [PubMed]
7. Skull SA, Andrews RM, Byrnes GB, et al. ICD-10 codes are a valid tool for identification of pneumonia in hospitalized patients aged ≥ 65 years. Epidemiol Infect. 2008;136(2):232-40. [CrossRef] [PubMed]
8. Kiyota Y, Schneeweiss S, Glynn RJ, Cannuscio CC, Avorn J, Solomon DH. Accuracy of Medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records. Am Heart J. 2004;148(1):99-104. [CrossRef] [PubMed]
9. Shah T, Churpek MM, Coca Perraillon M, Konetzka RT. Understanding why patients with COPD get readmitted: a large national study to delineate the medicare population for the readmissions penalty expansion. Chest. 2015;147(5):1219-26. [CrossRef] [PubMed]
10. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-13. [CrossRef] [PubMed]
11. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-38. [CrossRef] [PubMed]
12. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-28. [CrossRef] [PubMed]
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]
14. Rigotti NA, Munafo MR, Stead LF. Smoking cessation interventions for hospitalized smokers: A systematic review. Arch Intern Med. 2008;168:1950-60. [CrossRef] [PubMed]
15. Sasaki T, Nakayama K, Yasuda H, Yoshida M, Asamura T, Ohrui T, Arai H, Araya J, Kuwano K, Yamaya M. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57(8):1453-7. [CrossRef] [PubMed]
16. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89. [CrossRef] [PubMed]
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]
20. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-90. [CrossRef] [PubMed]
21. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007;7:232-6. [CrossRef] [PubMed]
22. Ismaila A, Corriveau D, Vaillancort J, Parsons D, Dalal A, Su Z, Sampalis JS. Impact of adherence to treatment with tiotropium and fluticasone propionate/salmeterol in chronic obstructive pulmonary disease patients. Curr Med Res Opin. 30(7);1427-36, 2014. [CrossRef] [PubMed] 

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

COPD Exacerbations: An Evidence-Based Review

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ

Abstract

COPD exacerbations are a major source of COPD morbidity, mortality and cost. Exacerbations tend to become more frequent as COPD progresses with the cause assumed to be infectious in about 80% of patients. The mainstay of management is inhaled bronchodilators with judicious use of oxygen, antibiotics, corticosteroids and assisted ventilation. Recent studies have examined strategies to prevent exacerbations of COPD including use of macrolide antibiotics and self-management education.

Definition of COPD Exacerbations

There is no standard definition of COPD exacerbations. However, the workshop, “COPD: Working Towards a Greater Understanding”, proposed the following working definition in 2000: “A sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD” (1). This seems to be the mostly commonly used definition today. Others have defined exacerbations specifically in terms of increased dyspnea, sputum production, or sputum purulence (2,3).  However, exacerbations of COPD comprise a range of symptoms making specific medical complaints difficult to include in a comprehensive definition (1).

Epidemiology of COPD Exacerbations

Exacerbations reduce quality of life, speed disease progression, and increase the risk of death (4,5). Furthermore, exacerbations resulting in hospitalization account for the major cost of COPD (6). The best predictor of future exacerbations is a history of frequent exacerbations (7). As many as 50% of exacerbations are not reported to physicians and 3-16% require hospitalization (8). Hospital mortality is 3-10% and mortality of ICU admission is 15-24%.  Half of the patients hospitalized will require readmission in the next 6 months (8).

Frequency of exacerbations increase with increasing severity of COPD. In a systematic review, patients with mild COPD had a mean of 0.82 exacerbations per year (9). The rates increased to 1.17, 1.61, and 2.01 in patients with moderate, severe, and very severe disease, respectively.

COPD is a lung disease that is frequently associated with other comorbid conditions. These comorbidities affect health outcomes, increase the risks of hospital admission, increase the risk of death, and account for more than 50% of use of health-care resources for COPD (10,11). The relationship of certain comorbidities with COPD is not surprising because of COPD’s connection with cigarette smoking and aging. Cigarette smoking is not only a major risk factor for COPD, but also for cardiovascular disease, osteoporosis, and lung cancer and all are more frequently seen in COPD patients (12). Aging is a major risk factor for most chronic diseases including COPD. Almost half of all COPD patients aged 65 years or over have at least three chronic medical disorders (13). Consistent with this concept, a cluster analysis indicated that age rather than FEV₁ accounted for most of the comorbidities and symptoms (14). Furthermore physical inactivity, which is frequently observed in COPD, has been linked to aging and to major comorbidities (15-17). The presence of comorbidities likely explains why clinical outcomes in COPD only weakly correlate with the FEV1 (18).

Another common denominator between COPD and its major comorbidities is systemic inflammation. Increased concentrations of circulating cytokines (tumor necrosis factor α and interleukins 6 and 8), adipokines (leptin, ghrelin), and acute-phase proteins (C-reactive protein, fibrinogen) are seen in COPD and its comorbid diseases (19). In several studies biomarkers of systemic inflammation have been observed in patients with COPD, particularly when disease is severe and during acute exacerbations (19,20).  Whether these systemic markers spill over from the lungs into the systemic circulation or merely reflect the proinflammatory state is unclear (21). However, none of these systemic inflammatory markers have received generalized acceptance in predicting or diagnosing exacerbations.

Etiology of COPD Exacerbations

Several causes of exacerbations have been suggested for patients with COPD, including heart failure, pneumonia, pulmonary embolism, non-adherence to inhaled medication, or inhalation of irritants, such as tobacco smoke or particles (19). However, the most frequent cause cited by most is viral or bacterial infection (19). In patients admitted to hospital with COPD exacerbations, viruses, bacteria or both, were detected in 78% of cases (22). The exacerbations associated with infection were more severe than those in patients with non-infectious causes (22). However, the 80% frequency of infectious causes may be an overestimation.  The accepted gold standard for the diagnosis of bacterial causes is the isolation of a potentially pathogenic bacterium by sputum culture. However, sputum cultures are neither sensitive nor specific. An additional difficulty is that a substantial proportion of patients with stable COPD have bacterial colonization (23). These include the organisms most commonly associated with exacerbations: H. influenzae, S. pneumoniae, and M. catarrhalis.

Viruses are thought to account for 15–25% of all infective exacerbations, particularly human rhinovirus, influenza, parainfluenza, and adenoviruses (19). Infection with both viruses and bacteria are seen in 25% of patients with exacerbations who are admitted to hospital (22).  Viral exacerbations are strongly correlated with colds at presentation, high frequency of exacerbations, and severe respiratory symptoms during exacerbations. Experimental evidence suggests that upper respiratory tract infections can lead to lower respiratory tract inflammation and symptoms. COPD patients experimentally infected in the upper respiratory tract with rhinovirus developed lower respiratory symptoms, airflow obstruction, systemic inflammation, and inflammation in their airways (24). In addition to inducing lower respiratory inflammation and symptoms, viral infections may facilitate subsequent bacterial infection. Although viral infections are usually self-limiting, secondary bacterial infection may prolong exacerbations (24).

Gastroesophageal reflux has been suggested to play an important role in a number of respiratory diseases and has been independently associated with increased frequency of COPD exacerbations (7). Similarly, sleep-apnea has also been shown to be an independent predictor of COPD exacerbations (25).

No serum marker of bacterial or viral infection in COPD exacerbations has gained general acceptance. However, measurements of procalcitonin and C-reactive protein have been suggested as predictors of bacterial infection since both have been shown to predict results to antibiotic therapy (26,27). Increased concentrations of serum interferon-γ-inducible protein10 were useful in identifying rhinovirus infection in one study (28).

A recent publication by Bafadhel et al. (29) measured biomarkers in sputum and serum from a total of 145 COPD patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, serum CXCL10, and percentage peripheral eosinophils. Future research may establish the usefulness of these as well as other biomarkers in predicting and diagnosing infectious causes of COPD exacerbations.

Diagnostic Interventions in COPD

Clinical judgment is necessary in evaluating the need for hospital admission and which diagnostic tests need to be performed. Patients with mild exacerbations may be managed as outpatients with no diagnostic testing. Patients with more severe exacerbations may need diagnostic testing and hospitalization when appropriate.

Chest x-rays have been found to be useful in evaluation of COPD exacerbations. Data from observational studies show that in 16% to 21% of the chest radiographs change patient management (30-32). Arterial blood gases are helpful in assessing the severity of an exacerbation and the degree of hypoxemia and hypercarbia. The later is particularly important in identifying patients that are likely to require hospitalization and additional ventilatory support (33). Although spirometry and peak flows may be useful in identifying an exacerbation, available evidence does not support their routine measurement to guide therapy during an exacerbation (33).

Treatment of COPD Exacerbations

Therapies for treatment of COPD exacerbations and their evidence basis are summarized in Table 1.  

Table 1. Therapies for COPD exacerbations.

Oxygen. In my practice inappropriate empiric use of high doses of oxygen was becoming increasingly problematic. High doses of oxygen can result in absorption atelectasis, increased ventilation-perfusion mismatch and increased hypercarbia. The British Thoracic Society (BTS) has published guidelines that oxygen is a treatment for hypoxemia, not breathlessness or dyspnea (34). Oxygen has not been shown to affect breathlessness in nonhypoxemic patients, and therefore, empirically increasing oxygen administration for breathlessness when the oxygen saturation is satisfactory is ineffective and potentially harmful. BTS suggests oxygen should be prescribed to achieve a target saturation of 94-98% for most acutely ill patients or 88-92% for those at risk for hypercapnic respiratory failure. Hypercapnic patients at high risk for respiratory failure may usually be safely managed with oxygen saturations as low as 85-88%.

In support of the concept that empiric use of high flow oxygen may do more harm than good, Austin et al. (35) compared nontitrated high flow oxygen with titrated oxygen in the prehospital setting in COPD patients with an acute exacerbation. Those administered oxygen to a titrated oxygen saturation of 88-92% had reduced mortality, hypercapnia and respiratory acidosis compared to those treated with nontitrated oxygen at 8-10 L/min.

It appears to make little difference if oxygen is administered by nasal cannula or Venturi mask. In a study comparing patients assigned to receive oxygen through a Venturi mask or nasal prongs oxygen saturation improved to the same extent without any significant effect upon arterial carbon dioxide tension or pH (36).

Bronchodilators. The first line of treatment for a COPD exacerbation is to increase the frequency of short-acting inhaled beta 2-agonists and/or anticholinergics. However, there are only four randomized, controlled trials comparing beta 2-agonists with anticholinergics and all analyzed short-term effects (37). Overall, the available data show similar FEV1 improvement with either bronchodilator. Although use of both in combination is common, there does not appear to be strong evidence to support this approach (37,38). There is very limited data on use of long-acting beta 2-agonists (formoterol and salmeterol) or long-acting anticholinergics (tiotropium) in treatment of exacerbations of COPD.  

Metered-dose inhaler (MDI) and small volume nebulizers appear to be equivalent in the acute treatment of adults with airflow obstruction (39). It is assumed that the cost of delivery is lower with MDIs due to decreased nursing or respiratory therapist time needed to administer the drugs. Spacer devices have been used with an MDI in most studies.

Thirty years ago methylxanthines, such as aminophylline, were the mainstay therapy for COPD exacerbations. However, these drugs have largely fallen out of favor. A meta-analysis on use of methylxanthines in acute COPD exacerbation did not find any evidence to support their use (40). Methylxanthines do not significantly improve FEV1 during COPD exacerbations and have a narrow therapeutic window with numerous potential side effects including nausea, vomiting, headache, arrhythmias, and seizures.

Corticosteroids. Corticosteroids significantly reduce the risk of treatment failure and length of hospital stay (41). Although the optimal dosage and length of therapy are unknown, the largest trial used methylprednisolone 125 mg intravenously every 6 hours for 72 hours (42). Two weeks of oral prednisone after intravenous therapy was as efficacious as 8 weeks (40). In a retrospective review among patients hospitalized with COPD exacerbations, oral therapy was not associated with worse outcomes compared to high-dose intravenous therapy (43).  

Antibiotics. As previously mentioned, infectious etiologies may account for as many as 80% of the acute COPD exacerbations (19,22). Therefore, it is reasonable to expect that antibiotics would be efficacious. Studies going back to the 1980’s show a significant benefit of antibiotic treatment, with a success rate of 68% for the antibiotic group compared to 55% for the placebo group (2). Subsequent meta-analyses have confirmed these findings (33,44,45). Patients with more severe exacerbations are more likely to benefit from antibiotics than those with milder exacerbations. The presence of purulent sputum may be predictive of the presence of active infection and identify those patients most likely to benefit from antibiotic therapy (46).       

Controversy exists regarding the choice of the newer, broad-spectrum antibiotics compared to the older, traditional antibiotics. Some studies have found significantly higher persistence or worsening of symptoms in patients treated with first-line agents (amoxicillin, cotrimoxazole, tetracyclines, or erythromycin) compared to second or third-line agents (amoxicillin/clavulanate, azithromycin, or ciprofloxacin) (47,48). On the other hand, other studies suggest that host factors rather than antibiotic choice are the primary determinants of treatment failure (49). It may be that the anti-inflammatory effects of certain antibiotics such as the macrolides or tetracyclines account for some of the variability (50,51). Recently a concern has been raised regarding macrolides causing QT prolongation and a very small, but significant, increase in cardiovascular death (52). Tetracyclines such as doxycycline may represent an alternative to the macrolides since they do not cause QT prolongation

The duration of antibiotic therapy is also controversial. However, a recent meta-analysis by El Moussaoui et al. (53) suggests that 5 days of therapy is as effective as longer durations of therapy.

Other Pharmacologic Agents. A variety of mucolytics, mucokinetics, expectorants, antiproteases, antioxidants and immunostimulants have been proposed to treat COPD exacerbations but do not have well established clinical efficacy (54). A review of mucolytic agents in acute exacerbations of COPD suggested there was no evidence that they shortened the duration of the exacerbations or improved the FEV1 (55). However, the analysis did suggest that mucolytics might improve symptoms compared to controls. In the nonacute COPD setting, a meta-analysis has found a small reduction in the number of acute exacerbations and days of illness when mucolytics were routinely used (55).

Chest Physiotherapy. During acute COPD exacerbations mechanical percussion of the chest as applied by physical/respiratory therapists is ineffective in improving symptoms or lung function, although it may increase the amount of sputum expectorated (38,56). Furthermore, there may be a transient worsening in FEV1 after chest percussion (38).

Noninvasive Positive-Pressure Ventilation (NIPPV). Noninvasive positive pressure ventilation (NIPPV) is probably the largest therapeutic advance in treating COPD exacerbations in the past 20 years. Meta-analysis has found not only a reduction in the need for intubation and mechanical ventilation with NIPPV, but also a reduction in the risk of death (57). Patients hospitalized for exacerbations of COPD with rapid clinical deterioration should be considered candidates for NIPPV. However, there are no standardized criteria to predict which patients will benefit. Therefore, careful observation, usually in the intensive care unit, is necessary should NIPPV fail.

Heliox. Helium is a low density inert gas that in combination with oxygen (heliox) has been used as an additive treatment in upper airway obstructions and other causes of respiratory failure. The rationale for its use during COPD exacerbations is to diminish respiratory effort, peak pressure, and intrinsic positive end expiratory pressure. A meta-analysis in 2002 evaluated the limited literature on the use of heliox in acute COPD exacerbations and concluded that there is insufficient data to support its use (58). A recent randomized trial failed to show heliox reduced intubation rates, duration of noninvasive ventilation, length of stay, complications or 28-day mortality (59). Furthermore, heliox has the disadvantage of coming in fixed concentrations of oxygen sometimes making its use problematic especially in hypercarbic patients.

Reduction of COPD Exacerbations

Continuous therapies for reduction of COPD exacerbations are shown in Table 2.

Table 2. Continuous therapies for reduction of COPD exacerbations.

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 (60,61). Both appear to appear to be similarly efficacious in exacerbation reduction (62).

Research is being done with several new bronchodilators to treat COPD. Roflumilast, an oral specific phosphodiesterase 4 inhibitor, reduced the frequency of exacerbations by 17% in patients with severe or very severe COPD (63). Reductions are also seen with the addition of roflumilast to salmeterol or tiotropium (64). Several new, once-daily, long-acting beta-agonists and anticholinergics are under development and being tested alone or in combination. Indacaterol, a once daily beta-agonist, is the first of these once daily beta-agonists to become clinically available. It is anticipated that these will also reduce exacerbations similar to salmeterol/fluticasone or tiotropium.

Since both long-acting anticholinergics and long-acting beta-agonists/inhaled corticosteroids reduce exacerbations, it is logical that a combination might be additive in reducing exacerbations of COPD. However, a recent study suggests that addition of salmeterol/fluticasone to tiotropium was ineffective compared to tiotropium alone in reducing exacerbations although FEV1 and albuterol use were improved (65).

Inhaled corticosteroids. Addition of inhaled corticosteroids to long-acting bronchodilators in COPD is controversial. A recent meta-analysis by Spencer et al. (66) suggests that there was no reduction in exacerbations with addition of an inhaled corticosteroid to a long-acting beta-agonist. Furthermore, addition of corticosteroids was associated with a higher incidence of pneumonia. On the other hand, a retrospective, observational study suggested that the use of inhaled corticosteroids prior to a COPD exacerbation resulted in reduced mortality (67). In elderly COPD patients without a history of an exacerbation addition of inhaled corticosteroids was not associated with improved outcomes (68). This suggests that if inhaled corticosteroids are efficacious, they may only be efficacious in patients with a history of exacerbations.

Antibiotics. Continuous treatment with some antibiotics, particularly macrolides, reduces exacerbations. A randomized controlled trial with erythromycin reduced exacerbations by 35% compared to placebo (69). In a more recent study, treatment with azithromycin for one year lowered exacerbations by 27% (70). 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 (52). 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 (70). 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 (50).

Immunizations. Until recently, the only pneumococcal vaccine approved for use in adults in the United States and Europe was the 23-valent pneumococcal polysaccharide vaccine (PPSV23). This is despite no randomized, controlled trial of the vaccine showing a reduction in clinical outcomes (71). Recently a 7-valent diphtheria-conjugated pneumococcal vaccine has been approved for use in adults. This conjugated vaccine induces greater serotype-specific immunoglobulin G (IgG) and functional antibody than does PPSV23 for up to 2 years after vaccination (72). Whether these increases in surrogate markers will translate into lower rates of COPD exacerbations is unknown.

It appears, from the limited number of studies performed, that influenza vaccine reduces exacerbations in COPD patients (73). The effect appears to be due to a reduction in exacerbations occurring three or more weeks after vaccination due to influenza. There is a mild increase in transient local adverse effects with influenza vaccination, but no evidence that vaccination increases exacerbations immediately after administration.

Other approaches. Pulmonary rehabilitation and self-management education programs reduce hospitalization for COPD exacerbations (74, 75).  A recent study found increased mortality with COPD self-management education (76) but this was not confirmed by meta-analysis (75). Lung volume reduction surgery, an approach to severe COPD, was surprisingly found to reduce exacerbation frequency (77). The cause of the reduction is unknown but may reflect the benefits of reducing hyperinflation. A specific effect of long-term oxygen in appropriate patients on reducing exacerbations has not been demonstrated. However, there is evidence that underuse of long-term oxygen therapy results in increased hospital admissions (78).  Vitamin D levels have been found to be reduced in some patients with COPD. However, treatment with vitamin D did not improve exacerbation rates except those with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) (79).

Clinical Approaches

Outpatient. Based on the available evidence, my approach was to prescribe antibiotics and prednisone for home use during an exacerbation to most patients with severe or very severe COPD (FEV1 < 50% predicted) and patients with moderate COPD who had been hospitalized or had frequent exacerbations. Most severe and very severe COPD patients were also treated with long-acting bronchodilators and an albuterol rescue inhaler. Many were treated with a combination of both a long-acting beta agonist (salmeterol or formoterol) with an inhaled corticosteroid and a long-acting anticholinergic. Patients with mild exacerbations were treated as outpatients with antibiotics (usually doxycycline) and oral prednisone. Prednisone was given as a fixed dose (usually 15 mg/day) for 7-14 days since tapering with short-term use is unnecessary (80). Some patients with frequent exacerbations were prescribed chronic doxycycline therapy in hopes of reducing exacerbations. Most received pulmonary rehabilitation and therapy for smoking cessation if needed.

It is usually appropriate to initiate discussions about end of life planning with a COPD patient as an outpatient (81). Autonomy of the patient is the predominant ethical principle that drives end-of-life care. These discussions should prepare patients with advanced COPD for a life-threatening exacerbation of their chronic disease. Discussions should include ICU admission and intubation and mechanical ventilation using data where appropriate to assist in the decision. Pulmonary rehabilitation provides an important opportunity to assist advance care planning for patients with moderate-to-severe COPD. Patients with COPD sometimes qualify for formal hospice services, especially when they are having repeated exacerbations and poor clinical function. Opportunities for hospice care are frequently neglected for patients coming to the end of life with COPD. Morphine is the drug of choice for the relief of dyspnea and in selected patients chronic positive pressure ventilation may be used (82).

Inpatient. My rationale was that if a patient was sick enough to be in the hospital, he was sick enough to receive bronchodilators, antibiotics, and corticosteroids. Chest x-rays and arterial blood gases were routinely performed on hospitalized patients. Those with hypercarbia and respiratory acidosis were usually admitted to the ICU and especially those with an exacerbation sufficiently severe to require noninvasive positive pressure ventilation. Oxygen was titrated to maintain the SpO2 at 88-92%, and if severe respiratory acidosis was present, oxygen was titrated to a SpO2 of 85-88%.  Albuterol by MDI was used as often as needed to control symptoms, sometimes as often as every 1-2 hours with careful monitoring. Ipratropium by MDI was added if the patients were not receiving tiotropium. If the patients were taking long-acting bronchodilators as outpatients, these were continued during inpatient hospitalization. Doxycycline was used as an antibiotic in the absence of culture evidence or x-ray evidence to choose an alternative. Corticosteroids were given as methylprednisolone 125 mg IV every 6 hours for 3 days and then oral prednisone for another 2 weeks. Rarely, methylxanthines were added in those very severe patients who failed to clinically improve in 1-3 days. Those who were not on long-acting bronchodilators were started on one or both prior to discharge to reduce the number of future exacerbations. Patients were followed up in the outpatient clinic about 2-3 weeks after hospital discharge.

Conclusions

COPD exacerbations are common and can often be managed as outpatients with careful planning and education in self-management. Communication between the patient and physician regarding end of life planning is useful in planning future care during a severe exacerbation. Most patients can be managed with inhaled bronchodilators, antibiotics and corticosteroids. Titration of oxygen or administration of NIPPV usually requires hospitalization, especially in hypercarbic patients.

References

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Reference as: Robbins RA. COPD exacerbations: an evidence-based review. Southwest J Pulm Crit Care 2012;5:36-51. (Click here for a PDF version of the manuscript)

Spirometry Use in Patients Prescribed Albuterol

Kevin Park, M.D.

Che' S. Ornelas, M.D.

Richard A. Robbins, M.D.

Phoenix VA Medical Center, Banner Good Samaritan VA Medical Center and the Phoenix Pulmonary and Critical Care Medicine and Research Foundation, Phoenix, AZ

Address correspondence to:     Richard A. Robbins, M.D.

                                             502 E. Vermont Drive

                                             Gilbert, AZ 85295

                                             E-mail: rickrobbins@cox.net

Conflict of Interest Statement: None of the authors have conflicts of interest pertinent to the subject matter of this manuscript. 

Abstract

Background:  Previous studies have shown that spirometry is obtained in only about a third of patients with chronic obstructive pulmonary disease (COPD) in primary care practice. This study evaluated spirometry use in persons prescribed an albuterol inhaler in the primary care clinics at a Veterans Administration (VA) hospital.

Methods: One hundred ninety-seven patients prescribed albuterol were reviewed for age, education level of the primary care practioners, other respiratory medications and diagnosis.

Results: The average age was 63.2 years (SD, 11.5), and 93% of patients were male. Obtaining spirometry was not age or sex-dependent but became more frequent with the use of tiotropium (72.2%), long-acting beta agonists (71.8%), ipratropium (69.4%)  or inhaled corticosteroids (63.5%) compared to albuterol alone (39.4%, p=0.0007). Eighty of the patients had a diagnosis of COPD (40.6%), 40 a diagnosis of asthma (20.3%), 23 other respiratory diagnoses (11.7%) but 54 (27.4%) had no respiratory diagnosis. Patients diagnosed with COPD were more likely to have spirometry performed (71.2%) than patients diagnosed with asthma (35%), other respiratory diagnosis (34.7%) or no respiratory diagnosis (40.7%) (p=0.00068).

Conclusions: The above data demonstrate that spirometry is more frequently used in patients with COPD than previously reported and increases when additional medications are added to albuterol.

Introduction

Spirometry is recommended for the diagnosis of most adult respiratory disease including chronic obstructive pulmonary disease (COPD) and asthma (1-5). However, previous publications have revealed that in patients with COPD spirometry is performed in only about a third of the patients (6-10). Based on this data, we initiated a quality improvement project to examine compliance with spirometry guidelines in primary care.

Most previous investigations have examined patients’ diagnosis of COPD or asthma and examined the percentage of patients who had spirometry. However, the diagnosis of COPD or asthma is frequently incorrect (11-13). Furthermore, these projects may likely both under- and over-diagnose COPD in patients with no symptoms (14). Since albuterol is recommended as initial treatment for both diseases (1-4), we examined recent prescriptions for albuterol at a single VA medical center. Our rationale was that this should eliminate asymptomatic patients or patients with very mild disease. We found that in patients prescribed albuterol who also had a diagnosis of COPD that spirometry was performed over double (72%) of previous reports.

Methods

This project was approved by the institutional review board of the Carl T. Hayden VA Hospital. Using VA records we identified 200 patients seen in primary care who were prescribed an albuterol inhaler and had a primary care visit between November 1-5, 2010 or November 8-12, 2010. The electronic records were reviewed for each patient. Demographic data (age, sex); education level of provider (MD or DO, nurse practioners); diagnosis (COPD, asthma, other respiratory diagnosis or no diagnosis); other respiratory medications, and the presence of spirometry were recorded. When spirometry was available for COPD patients, spirometric values of FEV1/FVC% or FEV1% predicted were recorded and used to classify COPD severity based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (1,15).

Statistical Analysis

Comparisons between the groups with and without spirometry were made with χ2 tests for categoric variables and t tests for continuous variables. The association between having spirometry performed and patient characteristics was evaluated in unadjusted models.

Results

Chart review

Two hundred charts were examined, but 3 patients were excluded, one because they had not been prescribed albuterol and two because of incomplete data. The remaining 197 patients were evaluated.

Demographics

Age was 63+11 years and 7% of the patients were female. Age and sex were not significantly different between those who had spirometry and those who did not (data not shown, p>0.05 both comparisons).

Education Level of Provider

There were 16 MD or DO physician primary care providers and 8 nurse practioners. The physicians saw 136 patients and the nurse practioners 61. Spirometry was present on 73 of the patients seen by physicians (53.7%) and 29 of the patients seen by nurse practioners (47.5%, p=0.45).

Other Respiratory Medications

Numbers of patients with other respiratory medications are shown in Table 1. Many patients were on multiple medications. Patients on albuterol alone were significantly less likely to have spirometry than those on other medications (p=0.0007). Only two patients were receiving theophylline and one oral prednisone.

Table 1. Spirometry and other respiratory medications prescribed

LABA=Long-acting beta agonist

ICS=Inhaled corticosteroid

*p=0.0007 compared to other medications

Diagnosis

COPD was diagnosed in 80 patients (40.6%), asthma in 40 patients (20.3%), other respiratory diagnosis in 23 patients (11.7%) but no respiratory diagnosis was recorded in 54 patients (27.4%). Other respiratory diagnosis included 10 patients with tobacco dependence, 3 with dyspnea, 2 with lung carcinoma, and 2 with obstructive sleep apnea and one each with allergies, cannabis dependence, sinusitis, coin lesion, pulmonary embolus and respiratory disorder not otherwise specified. Patients with COPD were significantly more likely to have spirometry performed than other diagnosis (Table 2).

Table 2. Spirometry and respiratory diagnosis

*p=0.00068 compared to other diagnosis

Of the 57 patients with COPD and spirometry, 5 had very severe disease (FEV1 <30% predicted), 16 had severe disease (30% < FEV1< 50% predicted), 34 had moderate disease (50% < FEV1 < 80% predicted) and 2 had mild disease (FEV1>80% predicted) by GOLD criteria. Six of the 18 COPD patients without spirometry were receiving albuterol alone compared to 11 of the 57 of the COPD patients with spirometry (p=0.5519).

Discussion

The objective of this study was to examine spirometry use in primary care in patients with prescribed albuterol. Overall, the presence of spirometry in patients was low, with only 51.8% of patients having spirometry performed during the analysis period. Patients diagnosed with COPD or who had additional respiratory medications prescribed in addition to albuterol were more likely to undergo spirometry. In the present study, 71.8% of patients with COPD received spirometry.  This is more than twice the percentage of previous reports where only about a third of COPD patients had spirometry performed (6-10).

Spirometry is performed in some general medicine clinics, but in our hospital spirometry is performed in the pulmonary function laboratories or in the pulmonary clinic, a situation that may differ from many health-care systems. However, a previous report from a VA hospital reported only about a third of newly diagnosed COPD patients received spirometry (7). Our study differs in several aspects which might explain at least part of the variance. First, rather than looking at a diagnosis of COPD, we examined patients who were prescribed albuterol. This includes patients with asthma and other respiratory diagnosis. Second, we included patients with long-standing COPD rather COPD recently diagnosed. Previous reports suggest that as the number of visits increases that the likelihood of spirometry also increases (10). Third, many patients are “co-managed”, that is they received health care elsewhere in addition to the VA. It is entirely possible that they may have had spirometry performed elsewhere which is not available in our medical record. However, in contrast to previous studies, chart reviews were performed on each patient. If the patient had a previous spirometry recorded in the chart from another institution this should have been noted in our study. Fourth, the VA pharmacy placed restrictions on primary care physicians prescribing long-acting bronchodilators, especially tiotropium. These patients were usually referred to our pulmonary clinic where spirometry was usually required prior to referral.

Several factors have been previously identified that are related to lower rates of spirometry. Age had been reported as the factor with the most pronounced impact on decreasing the likelihood of undergoing spirometry in a VA population (6). However, we found no influence of age on the likelihood of spirometry performance. COPD diagnosis has also been reported to have a decreased likelihood of spirometry performance (8), but in contrast, we found that COPD actually increased the likelihood of spirometry performance. The use of theophylline has also been associated with decreased levels of spirometry performance. However, only about 1% of our patients were prescribed theophylline.

There are several limitations to our study. First, it is a single site study. It is possible that our primary care physicians are more likely to order spirometry because of increased awareness or restrictions in prescribing long-acting bronchodilators or referral to a pulmonary clinic. Previous reports from the VA have demonstrated that there is a large geographic variation in the use of spirometry to diagnose COPD (8). The location of the present study was in Veterans Integrated Service Network 18 (Arizona, New Mexico and West Texas) where spirometry use (36.9%) approximated the National mean (36.7%). It is unclear whether the results from the present study can be generalized to the VA as a whole or non-VA institutions is unclear. Second, we examined patients prescribed an albuterol inhaler rather than those with a diagnosis of COPD or asthma. This likely eliminates many patients with mild or no symptoms which differs from previous studies. The US Preventive Services Task Forces has recommended against screening asymptomatic patients with spirometry (16).

The patients with no diagnosis given albuterol were a heterogenous group and the indications for the use of albuterol were often absent or unclear. Although albuterol can be empirically prescribed for asthma, cough or COPD, the indications for albuterol were absent in the majority of charts.

This study suggests that in contrast to previous reports, much of the current COPD diagnosis and management is based on spirometric evidence of airway obstruction in addition to symptoms. Although the role of spirometry in routine clinical practice remains unclear, primary care providers at our VA hospital appear to frequently use spirometry in patients with COPD.

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Reference as: Park K, Ornelas CS, Robbins RA. Spirometry use in patients prescribed albuterol. Southwest J Pulm Crit Care 2011;4:25-9. (Click here for a PDF version of the manuscript)