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

Executive Pay and the High Cost of Healthcare

Two recent articles examined hospital executive pay. One was “Bitter Pill: Why Medical Bills Are Killing Us” from Time magazine (1). We reviewed this article in our “March 2013 Critical Care Journal Club” (2). The other is a more recent article from Kaiser Health News (3). The later is particularly intriguing since it discusses healthcare executive compensation. We thought it might be of interest to examine executive compensation from selected nonprofit hospital tax returns from Arizona, New Mexico and Arizona. (Table 1). [Editor's note: It may be necessary to enlarge the view on your browswer to adquately visualize the tables.]

Table 1. Financial information from Southwest hospitals latest year tax return as listed by GuideStar (4).

*Includes Scottsdale Healthcare Corporation

These Southwest hospitals appear to be doing quite well. Overall they had combined incomes of $19,831,088,546, assets of $ 10,228,640,923 and profits of $1,145,888,944. None lost money. Although the data from organizations such as Dignity, Banner, Scottsdale Healthcare, Exempla, and Presbyterian Healthcare include several hospitals, they are doing well, especially for “nonprofit” hospitals.

The CEOs were also doing well (Table 2).

Table 2. CEO and executive compensation from Southwest hospitals latest year tax return as listed by GuideStar (4).

*Includes employees listed on Form 990.

**Includes Scottsdale Healthcare Corporation

The CEOs were paid an average of $1,718,484 and the average executive made $591,618. Not bad for being paid by a “nonprofit” organization. The CEO pay is nearly 8 times and the executive pay is nearly 3 times the slightly over $200,000 average Southwest pulmonary and critical care physician received in 2011 (5).

The Kaiser Healthcare News article went on to point out that boards at nonprofit hospitals are often paying hospital administrators much more for boosting volume than delivering healthcare value (3). Hospital administrators agreed but were quick to point out that compensation is increasingly being determined by healthcare performance incentives. However, James Guthrie, a hospital compensation consultant for Integrated Healthcare Strategies stated about administrative compensation, "What you're seeing is incentive plans that look pretty similar to what they looked like five years ago or ten years ago…they're changing, but they're changing fairly slowly."

Two of the local executives mentioned in the Kaiser Healthcare News article were Lloyd Dean and Peter Fine, heads of Dignity Health and Banner Health respectively. Incentive goals for Dean included unspecified "annual and long-term financial performance” (4). Dean's bonus for 2011 was $2.1 million. Fine speaks of "an unwavering commitment to improve clinical quality and efficiency" but Fine's long-term incentive goals included profits and revenue growth (4).

"Boards of trustees in health care are oriented around top-line, revenue goals," said Dr. Donald Berwick, who was CEO of the Institute of Healthcare Improvement (IHI) and later the Administrator for the Centers for Medicare and Medicaid Services (CMS) (Figure 1).

Figure 1. Dr. Donald Berwick

"They celebrate the CEO when the hospital is full instead of rewarding business models that improve patients' care." Such deals undermine measures in the 2010 health law that aim to cut unnecessary treatment and control costs, say economists and policy authorities (3).

An explosion of medical regulatory groups have arisen to improve quality, including Berwick’s IHI. These regulatory groups have often produced guidelines embraced by hospital administrators as improving healthcare. However, the administrators are often self-servingly paid bonuses for guideline compliance. Because nearly all the regulatory organizations are “nonprofit” like the hospitals, surely they would have more modest profits (Table 3).

Table 3. Financial information of healthcare regulatory organizations from latest year tax return as listed by GuideStar (4).

We are happy to report that the regulatory organizations had much more humble finances compared to the Southwest hospitals. Overall the four we examined totaled incomes of $589,724,293, assets of $563,032,211 and profits of $30,489,739. Only the American Board of Internal Medicine lost money with a loss of $-1,733,146 on income of nearly $50 million. For comparison, we added the Phoenix Pulmonary and Critical Care Research and Education Foundation to Table 3. It is the financial source behind the Southwest Journal of Pulmonary and Critical Care.

Executive pay was also more modest than Southwest hospital administrators (Table 4).

Table 4. CEO and executive compensation from healthcare regulatory organizations latest year tax return as listed by GuideStar (4).

*Includes employees listed on Form 990.

The CEOs were paid an average of $885,938 and the average executive made $382,009. Although much lower than the average $1,718,484 and the $591,618 paid to Southwest hospital CEO and executives, these salaries are still not bad for a “nonprofit” organization.

The only regulatory organization to lose money was the American Board of Internal Medicine. Either an increase or revenue or a decrease in expenses will eventually be necessary. The major source of income for the American Board is test revenue and increasing the fee for certification or the frequency and/or fees for maintenance of certification may be necessary. Alternatively, they could pay their CEO less than $786,751, eliminate the CEO’s spousal travel benefits, or lower the compensation for general internists such as Eric Holmboe from $417,945 to be more in line with the $161,000 average income of general internists in the mid-Atlantic region (4,5).

Donald Berwick has a good point and is correct. Hospital administrators need to be rewarded more for improving healthcare and less for keeping the hospital full and profits high. However, in 2009 while CEO at IHI Berwick was compensated $920,952 (4). This is almost 7 times the compensation of the average pediatrician in New England (5). Included were $88,200 in bonuses. It is unclear from the tax return what justified these bonuses (4).

Executive pay for both hospital and regulatory administrators is too high and contributes to the high cost of healthcare. We find no evidence that either type of administrator contributes much to improved patient-centered outcomes. Quality care continues to rely on an adequate number of good doctors, nurses and other healthcare providers. If anyone should be paid bonuses for healthcare, it is those providing care, not administrators.

Present bonus systems for healthcare administrators are perverse. As noted above these include bonuses for keeping the hospital full and profits high, neither consistent with what should be the goals of a nonprofit organization. Furthermore, increasing pay for supervising an increased number of administrative personnel will only add to the increasing costs. If administrators must be paid a bonus let them be paid for performance directly under their control. This could include ensuring that adequate numbers of good doctors and nurses are caring for the patients and improving administrative efficiency. These should result in better care but lower numbers of administrators consuming fewer healthcare dollars.

Last Friday, June 14, the Medicare Payment Advisory Commission, or MedPAC released their recommendations to Congress (8). These include recommendations that may be relative to hospital administrative pay. One is for “site-neutral payment”. Currently Medicare pays hospitals more than private physician offices for many services. MedPAC recommended that Congress “move immediately to cut payments to hospitals for many services that can be provided at much lower cost in doctors’ offices.” The commission said that “current payment disparities had created incentives for hospitals to buy physician practices, driving up costs...” This will increase the hospital’s bottom line, and therefore, the administrators’ bonuses. We agree with MedPAC’s recommendation.

MedPAC also told Congress that “the financial penalties that Medicare imposes on hospitals with high rates of patient readmissions are too harsh for hospitals serving the poor and should be changed.” Based on this and data that higher mortality is associated with lower readmission rates, we agree (9). Rewarding hospitals for potentially harmful patient practices that increase the hospital’s bottom line are not appropriate. Financial incentives for reducing readmissions should only be part of a more global assessment of patient outcomes including mortality, length of stay and morbidity. Regulatory administrators need to become more focused on patients and less on an endless array of surrogate markers that have little to do with quality of care.

Richard A. Robbins, M.D.*

Clement U. Singarajah, M.D.*

References

1. Brill S. Bitter Pill: Why Medical Bills Are Killing Us. Time. February 20, 2013. PDF available at: http://livingwithmcl.com/BitterPill.pdf (accessed 6/17/13).
2. Stander P. March 2013 critical care journal club. Southwest J Pulm Crit Care. 2013;6(4):168-9. Available at: http://www.swjpcc.com/critical-care-journal-club/2013/4/2/march-2013-critical-care-journal-club.html (accessed 6-17-13).
3. Hancock J. Hospital CEO Bonuses Reward Volume And Growth. Kaiser Health News. June 16, 2013. Available at: http://www.kaiserhealthnews.org/Stories/2013/June/06/hospital-ceo-compensation-mainbar.aspx (accessed 6-17-13).
4. http://www.guidestar.org/ (accessed 6-17-13).
5. http://www.medscape.com/sites/public/physician-comp/2012 (accessed 6-17-13).
6. Robbins RA, Thomas AR, Raschke RA. Guidelines, recommendations and improvement in healthcare. Southwest J Pulm Crit Care 2011;2:34-37. Available at: http://www.swjpcc.com/editorial/2011/2/25/guidelines-recommendations-and-improvement-in-healthcare.html
7. Robbins RA. Why is it so difficult to get rid of bad guidelines? Southwest J Pulm Crit Care 2011;3:141-3. Available at: http://www.swjpcc.com/editorial/2011/11/1/why-is-it-so-difficult-to-get-rid-of-bad-guidelines.html
8. http://www.medpac.gov/documents/Jun13_EntireReport.pdf (accessed 6-17-13).
9. Robbins RA, Gerkin RD. Comparisons between Medicare mortality, morbidity, readmission and complications. Southwest J Pulm Crit Care. 2013;6(6):278-86. Available at: http://www.swjpcc.com/general-medicine/2013/6/13/comparisons-between-medicare-mortality-readmission-and-compl.html

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

Reference as: Robbins RA, Singarajah CU. Executive pay and the high cost of healthcare. Southwest J Pulm Crit Care. 2013;6(6):299-304. doi: http://dx.doi.org/10.13175/swjpcc080-13 PDF

Choosing Wisely-Where Is the Choice?

A little over a year ago an editorial was posted in the Southwest Journal about the Choosing Wisely campaign from the American Board of Internal Medicine and Consumer Reports (1). You may remember that Choosing Wisely announced a list of procedures or treatments that patients should question (2). In the editorial we wondered why pulmonary organizations such as the American Thoracic Society (ATS) and the American College of Chest Physicians authored none of the recommendations and offered 10 suggestions. We also openly questioned if the recommendations were intended to improve patient care or reduce costs, and thus improve the profits of third party carriers.

We can now report that recommendations were announced at the recent ATS meeting in Philadelphia. Seven recommendations were made for critical care and seven for pulmonary disease. Five from the critical care list and five from the pulmonary list will eventually be chosen for inclusion in Choosing Wisely. The recommendations are listed below:

Critical Care

1. Thou shalt not order diagnostic tests at regular intervals (e.g., daily) but instead order tests based on needs.
2. Thou shalt not use parenteral nutrition in the first 7 days of an ICU admission in patients adequately nourished.
3. Thou shalt not transfuse red blood cells in hemodynamically stable patients with a hemoglobin > 7 gm/dL.
4. Thou shalt not sedate mechanically ventilated patients without an indication.
5. Thou shalt not continue life support for at patients at high risk for death.
6. Thou shalt not initiate or continue antimicrobials without an indication.
7. Thou shalt not place or maintain an arterial or central venous catheter without an indication.

Pulmonary

1. Thou shall not perform thoracic CT scans for follow up of pulmonary nodules more frequently than the guidelines (Fleishner Society) suggest.
2. Thou shalt not discontinue oxygen from recently discharged patient prescribed oxygen without checking for hypoxemia.
3. Thou shalt not routinely administer intravenous corticosteroids for exacerbations of asthma or chronic obstructive pulmonary disease when the patient is able to take oral steroids.
4. Thou shalt not do thoracic CT scan screening for patients at low risk for lung cancer.
5. Thou shalt not do chest x-rays on asymptomatic patients routinely.
6. Thou shalt not offer vasoactive agents for groups 2 (left heart disease) and 3 (hypoxia) pulmonary artery hypertension (PAH).
7. Thou shalt not perform thoracic CT angiography for pulmonary embolism on patients with low probability and a negative d-dimer.

In the question and answer session after the recommendations were presented, a member of the audience noted that most of the recommendations were negative, directing physicians what not to do. We confess that we added the “Thou shalt not …” to emphasize this point but cannot overlook the fact that these recommendations look suspiciously like commandments. The negativity implicit in the ATS recommendations is consistent with the recommendations by other subspecialties listed on the Choosing Wisely website (2).  While the recommendations are reputedly about reducing the use of unnecessary or potentially dangerous testing, both worthy goals, the tone suggests there will be consequences for failure to comply.

What we find offensive is the Choosing Wisely and ultimately the ABIM foundation assertion that this is an initiative “focused on encouraging physicians, patients and other health care stakeholders to think and talk about medical tests and procedures that may be unnecessary” (2). Where is the encouragement and where is the choice in a series of DO NOT commandments?  It seems an even-handed approach of an objective statement would be much more appropriate and yet carry the same information, e.g. Chest CT scans are rarely required for screening patients at low risk for lung cancer rather than “Do not do thoracic CT scan screening for patients at low risk for lung cancer”.  It seems that rather than encouraging conversation the Choosing Wisely statement puts doctor and patient in an adversarial relationship especially if the doctor feels something is needed which is expressly stated with a “Do not”.

Rather than a laundry list of no-no’s a guiding principle might be better. The American College of Physicians (ACP) has offered, “The physician should always act in the best interests of the patient” (3). Despite objections to the profession of the author of the ACP statement, a lawyer, the overall sentiment is a good one (4). It removes the adversarial relationship the Choosing Wisely campaign encourages and places physicians where they belong-on the side of the patient.

In our view the present Choosing Wisely campaign has fundamental flaws-not because it is medically wrong but because it attempts to replace choice and good judgment with a rigid set of rules that undoubtedly will have many exceptions. Based on what we have seen so far, we suspect that Choosing Wisely is much more about saving money than improving patient care. We also predict it will be used by the unknowing or unscrupulous to further interfere with the doctor-patient relationship.  When the recommendations of an authoritarian body take the form of commandments and preempt clinical decision making, then it seems the wise choice of a wary clinician is to tacitly comply - in other words there is no choice.

Richard A. Robbins, M.D.*

Allen R. Thomas, M.D.*

References

1. Robbins RA, Thomas AR. Will fewer tests improve healthcare or profits? Southwest J Pulm Crit Care 2012;4:111-3.
2. http://www.choosingwisely.org/ (accessed 6/3/13).
3. Snyder L.  American College of Physicians Ethics Manual.  Sixth Edition.  Ann Intern Med. 2012:156;1:suppl 73-101.
4. Raschke RA. February 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:51-2.

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

Reference as: Robbins RA, Thomas AR. Choosing wisely-where is the choice? Southwest J Pulm Crit Care. 2013;6(6):272-4. PDF

The State of Pulmonary and Critical Care in the Southwest

Sunday afternoon at the American Thoracic Society International Conference has two sessions we usually attend – the Great Cases Conference and the Awards Session. These are fun sessions. The Great Cases Conference is a chance to test your diagnostic acumen against master clinicians. The awards session is when leaders in pulmonary, critical care and sleep are acknowledged for their accomplishments and/or public service.

The Great Cases Conference was co-chaired by Dona Upson from New Mexico. The master clinicians included Marvin Schwarz from Colorado, Tom Colby from Arizona, and John Newell, who until recently was from Colorado. Sharon Rounds from Brown was another of the master clinicians and did her pulmonary/critical care training in Colorado.

The awards session was chaired by Monica Kraft, who was a pulmonary fellow and later faculty member at the University of Colorado and National Jewish Health (NJH). Jonathan Samet, a former resident, faculty member and division chief at the University of New Mexico, was presented the Edward Livingston Trudeau Medal. The Amberson Lecturer was David Schwartz from the University of Colorado. Polly Parsons, a graduate of the University of Arizona College of Medicine, who did her residency and pulmonary fellowship at Colorado, and later was a faculty member at Colorado, was presented the ATS distinguished service award. Allen Thomas was a resident and pulmonary fellow in Phoenix and practices at the Phoenix VA, and was presented the ATS Clinician of the Year. Abderrahmane E. Amine Temmar from Albuquerque was one of the other two finalists for clinician of the year. Kay Kreiss, the recipient of the Public Health Service award, was on faculty at NJH /University of Colorado for more than 14 years.  Paul Noble, a former University of Colorado fellow, was presented with a recognition award for scientific accomplishments. Although not presented until the Women’s Forum on Monday, the list is not complete without acknowledging the Elizabeth A. Rich, MD Award to Suzanne Lareau of the University of Colorado, having moved there from the Albuquerque VA.

Arizona, New Mexico and Colorado’s 13.9 million residents represent only 4.4% of the United States’ 313.9 million inhabitants. Why so many good physicians, and other clinicians, trained or reside in the Southwest is unclear. Perhaps it was pioneers in the field such as Tom Petty in Denver, Benjamin Burrows in Tucson and William and Randy Lovelace in Albuquerque who inspired so many young physicians. Regardless, the Southwest seems to be overly blessed with great pulmonary, critical care and sleep physicians. We at the Southwest Journal of Pulmonary and Critical Care wish to recognize their accomplishments and note that the state of pulmonary, critical care and sleep in the Southwest appears very good indeed.

Richard A. Robbins, M.D.

Dona J. Upson, M.D.

Carolyn H. Welsh, M.D.

Reference as: Robbins RA, Upson DJ, Welsh CH. The state of pulmonary and critical care in the Southwest. Southwest J Pulm Crit Care. 2013;6(5): 246. 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