Treatment after a COPD Exacerbation

A couple of years ago I was consulted about a patient at the Phoenix VA who had been admitted for the third time for a COPD exacerbation in two months. Each time the patient was treated with inhaled short-acting bronchodilators, corticosteroids and an antibiotic; rapidly improved; and was discharged after only one or two days in the hospital.  The discharge medications were albuterol, ipratropium, and rapidly tapering doses of prednisone. Apparently, no consideration was given to adding long-acting beta agonists (LABA), long-acting muscarinic antagonists (LAMA), and/or inhaled corticosteroids (ICS). These later medications have been shown to reduce exacerbations in most studies (1,2).

I was reminded of this incident by a recent article published by Melzer et al. in the Journal of Internal Medicine (3). The authors examined 2760 patients with exacerbations of COPD admitted to hospitals in the VA Northwest Health Network (VISN 20) to determine if a LABA and/or glucocorticoid were prescribed at discharge. These medications reduce exacerbations and the best predictor of a future exacerbation is a history of exacerbations (1,2,4). Of the 2760 patients 93% were not receiving a LABA or an ICS at the time of their exacerbation. Of this 93%, two-thirds of the patients had no change in therapy after their exacerbation. The authors state that “among patients treated for COPD exacerbations, there were missed opportunities to potentially reduce subsequent exacerbations by adding treatments known to modify exacerbation risk”. The authors go on to suggest that the VA could develop a Quality Enhancement Research Initiative (QUERI) program to improve delivery of care for some chronic conditions.

So why did the patient at the Phoenix VA and 2/3 of the patients in VISN 20 not receive a LABA, LAMA and/or inhaled corticosteroid after their exacerbations as recommended by the GOLD and ATS guidelines? Are the doctors in the Pacific Northwest and Phoenix unaware of the guidelines as the article and its accompanying editorial imply (5)? The answer probably lies elsewhere. First, the VA does not use the GOLD or ATS guidelines but has developed their own guidelines (6). These guidelines specifically mention consideration of the addition of inhaled corticosteroids and a LAMA but make no mention of a LABA. Rather than encouraging use of these medications, programs were created at the Phoenix VA which restricted Veterans’ access to these more expensive medications. The VA administration empowered the pharmacy to make unilateral decisions based on fiscal considerations with inadequate expert clinician input. These include a requirement to refer all patients for pulmonary consultation for long-acting bronchodilator therapy. This overloaded the pulmonary clinics with patients that did not necessarily need to be seen. In addition, there was a requirement for a trial of ipratropium before beginning tiotropium which took multiple visits further overloading the clinics.

This is another example of administrators meddling in clinical care only to have it blow up in their face and cause something else to go awry wasting money. In this case, the low use of long-acting bronchodilators likely led to an increase in admissions for exacerbation of COPD which are a major determinant of the costs of COPD care (7). Ignorance of the providers is blamed and another program to correct the harm caused by the initial blunder is created. Another example is the control of blood sugar in the ICU. After pushing for tight control of blood sugar for several years, the VA Inpatient Evaluation Center (IPEC) seamlessly converted their program to one examining hypoglycemia when tight control resulting in hypoglycemia was found to be harmful with the publication of the NICE-SUGAR study (8,9).

A QUERI program examining whether a LABA and/or corticosteroid was prescribed at discharge for a COPD patient does not need to be created. What needs to be done is to allow the physicians in the Pacific Northwest and Phoenix to use their best skills and judgment in caring for the patients without interference. If something must be measured, readmissions for exacerbation of COPD could be considered but should be part of a comprehensive program that measures outcomes such as mortality, length of stay, and morbidity. Otherwise, administrative blunders to correct past mistakes will continue.

Richard A. Robbins, M.D.*

References

1. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available at: http://www.goldcopd.org/Guidelines/guidelines-resources.html  (accessed 7/7/13)
2. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, Marciniuk DD, Denberg T, Schünemann H, Wedzicha W, MacDonald R, Shekelle P; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-91. [CrossRef] [PubMed]
3. Melzer AC, Feemster LM, Uman JE, Ramenofsky DH, Au DH. Missing potential opportunities to reduce repeat COPD exacerbations. J Gen Intern Med. 2013;28(5):652-9. [CrossRef] [PubMed]
4. 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;363:1128-38. [CrossRef] [PubMed]
5. Jubelt LE. Capsule Commentary on Melzer et.al., Missing Potential Opportunities to Reduce Repeat COPD Exacerbations. J Gen Intern Med. 2013;28(5):708. [CrossRef] [PubMed]
6. The Management of COPD Working Group. VA/DOD clinical practice guideline for management of outpatient chronic obstructive pulmonary disease. Available at: http://www.healthquality.va.gov/copd/copd_20.pdf (accessed 7/7/13)
7. Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic evaluation of COPD. Chest. 2000;118(5):1278-85. [PubMed] [PubMed]
8. Falciglia M, Freyberg RW, Almenoff PL, D'Alessio DA, Render ML. Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis. Crit Care Med. 2009;37(12):3001-9. [CrossRef] [PubMed]
9. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97. [CrossRef] [PubMed]

*The opinions expressed are those of the author and not necessarily the Southwest Journal of Pulmonary and Critical Care or the Arizona, New Mexico or Colorado Thoracic Societies.  

Reference as: Robbins RA. Treatment after a COPD exacerbation. Southwest J Pulm Crit Care. 2013;7(1):28-30. doi: http://dx.doi.org/10.13175/swjpcc089-13 PDF

Doxycycline and IL-8 Modulation in a Line of Human Alveolar Epithelium: More Evidence for the Anti-Inflammatory Function of Some Antimicrobials

Beta blockers for severe systolic dysfunction; antibiotics for peptic ulcer disease.  These are just a few examples of the many unpredicted consequences of medication intervention.  Rheumatology has known of the disease modifying anti-rheumatic drug (DMARD) capacity of second generation tetracyclines including doxycycline (1). This has actually led to investigations attempting to identify organisms possibly serving as substrates for inflammatory processes including rheumatoid arthritis and even atherosclerosis. Generally, this has been unsuccessful and the conclusion that doxycycline has intrinsic anti-inflammatory properties has become suspect (2,3).

Experience with higher generation macrolides like azithromycin further lends credence to this concept of antibiotics as intrinsically anti-inflammatory (4). There is a body of data suggesting inhibition of cytokine expression by this drug. In diseases like cystic fibrosis where even very high intracellular concentrations of macrolide have no significant activity against pseudomonas species but the drug therapy does appear to modify disease course further supports this anti-inflammatory contention (5). 

Published work has suggested the beneficial anti-inflammatory effect in COPD relating this broadly to doxycycline’s inhibition of matrix metalloproteinases, MMP(s) (6).  MMP(s) have been postulated to rise as a function of the oxidative stress recurrently demonstrated in chronic obstructive pulmonary disease (COPD).  Additionally, doxycycline has demonstrated the ability to impair neutrophil migration in LPS stimulated alveolar macrophages harvested from bronchoalveolar lavage. Hoyt et al. (7) have now nicely demonstrated ex-vivo that doxycycline is capable of inhibiting IL-8 expression in a line of human lung epithelial cells stimulated by a cytomix, a potent combination of inflammatory stimulators. Importantly, this is a demonstration of measureable inhibition of an inflammatory cytokine by the tetracycline in mammalian cells.

The biologic significance of this still remains to be fully determined. In the large ECLIPSE TRIAL, the major discriminator of inflammatory modulators in COPD with inflammation was IL-6 and not IL-8 which actually decreased in the cohort of individuals with evidence of inflammation (8). Further study may reveal that doxycycline also has a suppressive effect on the former cytokine.

Broadly, MAP kinases are a group of protein kinases that participate in the signaling of stress related mediators like cytokines. A finding reported by Hoyt et al. (7) that will require further investigation concerns the decrease in p38 mitogen-activated protein kinase (p38 MAPK) in response to doxycycline. The data in this regard remains conflicting with reports suggesting p38 MAPK is involved in IL-8 transcription in a human monocyte model with exposure to Clostridium difficile toxin (9). Hoyt et al. (7) found a decrease in p38 MAPK along the absence of change in mRNA by reverse transcription-polymerase chain reaction (RT-PCR) suggesting that effect of doxycycline on IL-8 elaboration is post transcriptional. Others have reported data supporting the concept of post transcription modulation of IL-8 by doxycycline as suggested by Hoyt et al. (10). While validation with repeat studies will be necessary, the finding that IL-8 mRNA by RT-PCR was not affected by levels of doxycycline that inhibited IL-8 is noteworthy. One may conclude that IL-8 assembly at the level of the ribosome could be operative.  While it was previously presumed that the tetracyclines specifically targeted bacterial ribosomes, Robbins et al along with all the other studies support the anti-inflammatory effect of tetracyclines in human disease and demonstrates that mammalian cells are also affected by this moiety.

So Hoyt et al. (7) have added to the knowledge base by definitively demonstrating the non-antimicrobial properties of doxycycline by ex-vivo inhibition of IL-8 production in a line stimulated mammalian alveolar epithelial cells. If the RT-PCR data can be further confirmed, this inhibition of IL-8 by doxycycline appears to be a post-transcriptional mechanism. Whether p38 MAPK is a transcriptional or post-transcriptional cytokine modifier remains to be determined.

Jay E. Blum, M.D.

Chief, Pulmonary and Critical Care

Phoenix VA Medical Center

References

1. Stone M, Fortin PR, Pacheco-Tena C, Inman RD. Should tetracycline treatment be used more extensively for rheumatoid arthritis Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol. 2003;30:2112-22.
2. Anderson JL, Muhlestein JB, Carlquist J, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation.1999;99:1540-7.
3. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007;25:133-5.
4. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23:590-615.
5. Equi AC, Davies JC, Painter H, Hyde S, Bush A, Geddes DM, Alton E. Exploring the mechanisms of macrolides in cystic fibrosis.  Respir Med. 2006;100:687-97.
6. Greenwald RA, Moak SA, Ramamurthy NS, Golub LM. Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. J Rheumatol. 1992;19:927-38.
7. Hoyt JC, Ballering JG, Hayden JM, Robbins RA. Doxycycline decreases production of interleukin-8 in a549 human lung epithelial cells. Southwest J Pulm Crit Care. 2013;6:130-42.
8. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, Lomas DA, Duvoix A, MacNee W, Rennard S, Silverman E, Vestbo J, Wouters E, Agustí A; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065-72.
9. Warny M,  Keates AC, Keates S, Castagliuolo I,  Zacks J,  Aboudola S et al. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest. 2000;105:1147–56.
10. Li J, Kartha S, Iasvovskaia S, Tan A, Bhat RK, Manaligod JM, Page K, Brasier AR and Hershenson MB.  Regulation of human airway epithelial cell IL-8 expression by MAP kinases.  Am J Physiol Lung Cell Mol Physiol. 2002;283:L690-L699.

Reference as: Blum JE. Doxycycline and IL-8 modulation in a line of human alveolar epithelium: more evidence for the anti-inflammatory function of some antimicrobials. Southwest J Pulm Crit Care. 2013;6(4):184-6. PDF 

A Little Knowledge is a Dangerous Thing

An article entitled “A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations: A Randomized, Controlled Trial” from the VA cooperative studies program was recently published in the Annals of Internal Medicine (1).  This article describes the BREATH trial mentioned in a previous editorial (2). BREATH was a randomized, controlled, multi-center trial performed at 20 VA medical centers comparing an educational comprehensive care management program to guideline-based usual care for patients with chronic obstructive pulmonary disease (COPD). The intervention included COPD education during 4 individual and 1 group sessions, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. After enrolling 426 (44%) of the planned total of 960 the trial was stopped because there were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00; 95% CI, 1.46 to 6.17; p = 0.002). Deaths due to COPD accounted for the largest difference (10 deaths in the intervention group versus 3 in usual care; hazard ratio, 3.60; 95% CI, 0.99 to 13.08). This trial led us to perform a meta-analysis of educational interventions in COPD (3). In this meta-analysis of 2476 subjects we found no difference in mortality between intervention and usual care groups and that the recent Annals study was heterogenous compared to the other studies.

Should the recent VA study have been stopped early? Several reports demonstrate that studies stopped early usually overestimate treatment effects (4-7). Some have even suggested that stopping trials early is unethical (7). A number of articles suggest that trials should only be stopped if predetermined statistical parameters are exceeded, with the p value for stopping set at a very low level (4-7).  There was no planned interim analysis for any outcome in the recent VA trial. The rationale for stopping a study for an adverse effect when there is no a priori reasonable link between the intervention and the adverse effect is missing in this instance.  It seems unlikely that education would actually lead to increased deaths in COPD patients.  Any effect should logically have impacted the COPD related mortality, yet there was no significant increase for COPD related deaths in the intervention group. An accompanying editorial by Stuart Pocock makes most of these points and suggests that chance was the most likely cause of the excess deaths (8).

The VA Coop Trials coordinating center told the investigators that the reason for stopping the trial was that there were “significant adverse events” in the intervention group. Inquires regarding what adverse events went unanswered. This would seem to be a breakdown in VA research oversight. The information provided to both investigators and research subjects was incomplete and would seem to be a violation of the informed consent, which states the subject would be notified of any new information that significantly altered their risk.

Lastly, investigators were repeatedly warned by the VA coordinating center that “all communications with the media should occur through your facility Public Affairs office”. It seems very unlikely that personnel in any public affairs office have sufficient research training to answer any medical, statistical or ethical inquiries into the conduct of this study.

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

Richard A. Robbins, M.D.*

Editor, Southwest Journal of Pulmonary

   and Critical Care

References

1. Fan VS, Gaziano JM, Lew R, et al. A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial. Ann Intern Med 2012;156:673-683.
2. Robbins RA. COPD, COOP and BREATH at the VA. Southwest J Pulm Crit Care 2011;2:27-28.
3. Hurley J, Gerkin R, Fahy B, Robbins RA. Meta-analysis of self-management education for patients with chronic obstructive pulmonary disease. Southwest J Pulm Crit Care 2012;4:?-?.
4. Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation.Control Clin Trials 1989;10:209S-221S.
5. Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005;294:2203-9.
6. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010;303:1180-7.
7. Mueller PS, Montori VM, Bassler D, Koenig BA, Guyatt GH. Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med. 2007;146:878-81.
8. Pocock SJ. Ethical dilemmas and malfunctions in clinical trials research. Ann Intern Med 2012;156:746-747.

*Dr. Robbins was an investigator and one of the co-authors of the Annals of Internal Medicine manuscript (reference #1).

Reference as: Robbins RA. A little knowledge is a dangerous thing. Southwest J Pulm Crit Care 2012;4:203-4. (Click here for a PDF version of the editorial)