September 2012 Pulmonary Case of the Month: The War on Drugs

Sudheer Penupolu, MD

Philip J. Lyng, MD

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 69 year old woman was seen with a three day history of nonproductive cough and shortness of breath.

PMH, SH and FH

She has a past history of atrial fibrillation and hypothyroidism.

Her present medications include:

• Diltiazem
• Amiodarone
• Aspirin
• Levothyroxine
• Multi vitamins

There is a 20 pack-year smoking history but she quit in 1998. She is employed as a law school professor.

Physical Examination

Her physical examination is normal.

Chest X-ray

Her admission chest x-ray is shown in Figure 1.

An electrocardiogram showed normal sinus rhythm.

Which of the following is the most likely cause of the patient’s clinical picture?

1. Viral bronchitis
2. Exacerbation of COPD
3. Pneumonia
4. Congestive heart failure
5. Drug reaction

Reference as: Penupolu S, Lyng PJ, Wesselius LJ. September 2012 pulmonary case of the month: the war on drugs. Southwest J Pulm Crit Care 2012;5:107-14. (Click here for a PDF version of the article)

Tiotropium Bromide Inhibits Human Monocyte Chemotaxis

Makoto Kurai MD (mkurai08@shinshu-u.ac.jp)^{1, 2, 3}

Richard A. Robbins MD (rickrobbins@cox.net)^{1, 2, 5}

Sekiya Koyama MD (syjskoyama@go.tvm.ne.jp) ⁴

Jun Amano MD, PhD (junamano@shinshu-u.ac.jp) ³

John M. Hayden PhD (John.Hayden2@va.gov)¹

¹Carl T. Hayden VA Medical Center, Phoenix, AZ, 85012, USA

²Arizona Respiratory Center, University of Arizona, Tucson, AZ, 85724, USA

³The Second Department of Surgery,

Shinshu University School of Medicine, Matsumoto 390-8621, Japan

⁴The Department of Pulmonary Internal Medicine,

National Hospital Organization Chushin Matsumoto Hospital, Matsumoto 390-0021, Japan

⁵Phoenix Pulmonary and Critical Care Research and Education Foundation, Gilbert, AZ 85295, USA

Abstract

Tiotropium bromide (Spiriva®) is used as a bronchodilator in chronic obstructive pulmonary disease (COPD).  However, clinical evidence suggests that tiotropium bromide may improve COPD by mechanisms beyond bronchodilation.  We hypothesized that tiotropium bromide may act as an anti-inflammatory agent by inhibiting monocyte chemotaxis, a process that plays an important role in the lung inflammation of COPD.  To test this hypothesis monocytes were pretreated with tiotropium bromide prior to exposure to chemotactic agents and monocyte chemotactic activity (MCA) was evaluated with a blind chamber technique.  Tiotropium bromide inhibited MCA in a dose- and time- dependent manner (respectively, p< 0.01) by directly acting on the monocyte. Acetylcholine (ACh) challenge increased MCA (p< 0.01), and tiotropium bromide effectively reduced (p< 0.01) the increase in MCA by ACh. The inhibition of MCA by tiotropium bromide was reversed by a muscarinic type 3 (M₃)-muscarinic receptor antagonist (p< 0.01), and was not effected by an M₂ receptor antagonist.  Furthermore, a selective M₃ receptor agonist, cevimeline, and G_q protein stimulator, Pasteurella multocida toxin, significantly increased MCA (P < 0.01), and tiotropium bromide pretreatment reduced (p< 0.01) the increase in MCA induced by these agents. These results suggest that tiotropium might regulate monocyte chemotaxis, in part, by interfering with M₃-muscarinic receptor coupled G_q protein signal transduction. These results provide new insight that an anti-cholinergic therapeutic may provide anti-inflammatory action in the pulmonary system.  

Introduction

Tiotropium bromide is a novel long-acting, inhaled, anticholinergic agent that is used as a treatment for chronic obstructive pulmonary disease (COPD). It has reported to have beneficial effects on the pulmonary function compared to other anticholinergic (short-acting) and beta-2 adrenergic agents. Although tiotropium predominantly functions as a bronchodilator, it reduces the development of acute exacerbations in COPD (1,2). These effects suggest that tiotropium might possess some function as an anti-inflammatory agent in addition to a bronchodilator (3-6). Tiotropium also has the potential to inhibit acetylcholine-induced proliferation of fibroblasts and myofibroblasts (7), further suggesting plausible beneficial influences on airway remodeling in COPD patients.

Acetylcholine (ACh) participates in the control of airway tone, which is an important factor contributing to the airway obstruction in the airway diseases (8). Anticholinergic agents effectively reverse the parasympathetic nerve stimulation and attenuate the smooth muscle contraction in the airway. This effect is especially important in regard to COPD because the  parasympathetic nerve stimulation is augmented in the airway inflammation (9). Recent studies have demonstrated that ACh participates in the inflammatory processes through the release of chemotactic factors from alveolar macrophages and bronchial epithelial cells which subsequently promote inflammatory cell infiltration (10,11). Moreover, ACh treatment induces the proliferation of fibroblasts and myofibroblasts (7).  Recently, it has also been reported that ACh synthesizing enzyme, choline acetyltransferase, is ubiquitously expressed in the airway cells (12), and that lung epithelial cells and pulmonary inflammatory cells can produce ACh and express functional muscarinic receptors (13). Thus, ACh may be involved in the airway inflammation, remodeling, and other pathophysiological phenomena acting in an autocrine and paracrine fashion (13,14).

In the present study, we evaluated tiotropium as an anti-inflammatory agent in monocyte chemotaxis. Moreover, we assessed key intracellular mechanisms that may regulate the inhibition of tiotropium-induced monocyte chemotaxis. We found that muscarinic receptor coupled G-protein signal transduction plays a role in the migration of monocyte. The results demonstrated that tiotropium inhibited the capability of monocytes to migrate to the chemotactic factor MCP-1, at least partly, by modulating muscarinic type 3 (M₃) receptor coupled G_q protein signal transduction. These data suggest that tiotropium may play an anti-inflammatory role by inhibiting monocyte chemotaxis.

Materials and Methods

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

Purification of peripheral blood monocytes and the monocyte chemotaxis assay.  Mononuclear cells for the chemotaxis assay were obtained from normal human volunteers by Ficoll-Hypaque density centrifugation to separate red blood cells and neutrophils from mononuclear cells (15). The enriched population of monocytes isolated by this method routinely display >98% viability as assessed by trypan blue exclusion (Sigma-Aldrich, St. Louis, MO). The cells were suspended in HBSS (Invitrogen, Carlsbad, CA) containing 2% bovine serum albumin (BSA, Sigma-Aldrich) at pH 7.5 to give a final concentration of 5 x 10⁶ cells/ml. The suspension was then used for the monocyte chemotaxis assay.              

The monocyte chemotaxis assay was performed by a 48-well microchemotaxis chamber (NeuroProbe, Cabin John, MD) as described previously (16). Briefly, 25 μL of a solution containing 100 ng/ml of recombinant human monocyte chemoattractant protein (MCP-1; Sigma-Aldrich) was placed into the lower wells, and a 10 μm thick polyvinylpyrrolidone-free polycarbonate filter (Nucleopore, Pleasanton, CA) with a pore size of 5 μm was placed over the bottom chamber. The concentration of MCP-1 used in this study was established previously (17). The silicon gasket and top pieces of the chamber were applied, and 50 μL of the cell suspension described above was placed into the top wells above the filter. The chambers were incubated in humidified air in 5% CO2 at 37° C for 90 min. After incubation, the chamber was disassembled, and non-migrated cells were wiped away from the filter. The filter was then immersed in methanol for 5 min, stained with Diff-Quik (American Scientific Product, McGraw Park, IL), and mounted on a glass slide. Cells that completely migrated through the filter were counted by using light microscopy (1000x) in at least 10 random high-power fields (HPF) per well.

Effects of tiotropium on MCP-1 - induced MCA. To evaluate the dose-dependent effects of tiotropium, monocytes were treated with 0, 0.01, 0.1, 1.0, 10, 100, 1000 nM for 30 min at 37º C in a humidified 5% CO2 atmosphere prior to MCA assay. After this interim, the cells were transferred to the chemotaxis chamber and exposed to the chemotactic agent for an additional 90 min in the environment described above.

To assess the time-dependent effects of tiotropium, monocytes were treated with 1000 nM tiotropium (maximal responsive dose) for varying times (0, 15, 30, 60, 90, 120 min) prior to MCA assay, and then they were transferred to the chemotaxis chamber and exposed to MCP-1 for additional 90 min.

The viability of monocytes after tiotropium exposure was evaluated by examining cell morphology and measuring lactate dehydrogenase (LDH) activity in the supernatant fluids. LDH activity was assessed by use of a commercially available kit (Tox-7; Sigma-Aldrich) according to the manufacture’s instructions. Dose- (up to 1000 nM) and time- (up to 3 hours) effects of tiotropium exposure on LDH activity in the supernatant fluids were not significant in these experiments (p > 0.3; data not shown).  Based on observations of cellular morphology and LDH activity, no toxicity was observed with the concentration or time of exposure of tiotropium used in this study.

Effects of ACh on MCP-1 induced MCA and reversal by tiotropium. Since tiotropium inhibited MCP-1 induced MCA, we determined whether ACh directly interacted with the monocytes and increased their activity in vitro. Monocytes were treated with 100 μM ACh (Sigma-Aldrich) for 60 min at 37° C prior to transfer to the chemotaxis chamber and exposure to MCP-1 for an additional 90 min. The concentration of ACh used in this study was based on a dose that was established previously (8).  Furthermore, to test the effects of tiotropium on MCA that was augmented by ACh, monocytes were treated with 1000 nM of tiotropium for 30 min at 37° C prior to ACh challenge. After this interim of exposure, the chemotaxis assays were performed as described above.

Effects of muscarinic receptor antagonists on MCP-1 induced MCA and abolishment of   tiotropium effects. To determine which muscarinic receptor is involved with the regulation of MCA by tiotropium, gallamine (Sigma-Aldrich) an M₂-receptor antagonist and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (Sigma-Aldrich) an M₃-receptor antagonist were used at the concentration of 300 µM, respectively, according to previous reports (10,11). Monocytes were exposed to these agents for 30 min before treatment with 1000 nM tiotropium for an additional 30 min. At this time the cells were transferred to the chemotaxis chamber as described above.

Effects of M₃-receptor agonists on MCP-1 induced MCA. Because M₃-receptor seemed to be involved with the ACh modulation, we evaluated   whether tiotropium affected the reaction which was mediated through the M₃-receptor agonist. A selective M₃-receptor agonist, cevimeline HCl (EVOXAC^®, Daiichi Sankyo, Inc., Parsippany, NJ), was used at the concentration of 300 μM. Monocytes were pretreated with 1000 nM tiotropium for 30 min at 37° C before the addition of cevimeline for an additional 30 min at 37° C prior to conducting the MCA assay.

Role of muscarinic receptor coupled Gq protein in MCA. Because M₃ receptors are reported to couple with G_q proteins, we evaluated the effects of G_q protein stimulation on MCA.  Pasteurella multocida toxin (PMT) was used as a G_q protein stimulator at the concentration of 100 ng/ml as previously reported (18,19). Monocytes were pretreated with 1000 nM tiotropium for 30 min before exposure to PMT for an addition 30 min at 37º C. The cells then were transferred to the microwell chambers and exposed to MCP-1 as described above.

Statistical Analyses. Unless stated otherwise all the results presented are expressed as means ± SEM from at least 3 individual experiments. Data were analyzed by one-way ANOVA, followed by selected post-hoc Neuman-Keuls multiple comparison tests. In selected experiments, Dunnett’s test was used to examine treatment effects compared to non-treated controls. In all cases, p < 0.05 was considered significant.

Results

Tiotropium inhibition of MCP-1 induced MCA.  Tiotropium significantly inhibited MCP-1-induced MCA in a dose-dependent manner (Figure 1A, p< 0.005). The lowest dose to inhibit MCA was 10 nM (p< 0.05) and the greatest inhibition (~40%; p< 0.01) occurred with a dose of 1000 nM tiotropium. Tiotropium also significantly inhibited MCP-1-induced MCA in a time-dependent manner (Figure 1B, p< 0.001). MCA was inhibited significantly after 60 min (p< 0.01) and reached a plateau after 90 min of exposure to 1000 nM tiotropium.

Figure 1. Panel A: A dose-dependent inhibition of monocyte chemoattractant protein (MCP-1) induced MCA by tiotropium. Monocytes were treated with tiotropium for 30 min before the MCA assay (n = 3). Chemotactic activity is on the ordinate and the concentration of tiotropium is on the abscissa. Values are expressed as means ± SEM. Dose effect by ANOVA (p < 0.005). *p< 0.05, **p< 0.01 means differ compared with non-tiotropium treated controls.  Panel B:  A time-dependent inhibition of MCP-1 induced MCA by tiotropium. Monocytes were treated with 1000 nM tiotropium under all conditions (n = 3). Chemotactic activity is on the ordinate and the duration of tiotropium exposure is on the abscissa. Values are expressed as means ± SEM. Time effect by ANOVA (p< 0.001). *p< 0.01 means differ compared to non-treated controls.

ACh augmentation of MCP-1 induced MCA. ACh challenge of the monocytes increased their MCA ~1.2-fold (Figure 2; p< 0.01).  In addition, pretreatment of the monocytes with tiotropium inhibited (p< 0.01) MCA that was stimulated by ACh to a level that was lower than non-treated controls (Figure 2).

Figure 2. ACh augments MCA induced by MCP-1 exposure. Monocytes were treated with 1000 nM tiotropium for 30 min prior to exposure of 100 μM Ach (n = 3). Chemotactic activity is on the ordinate and the experimental groups are on the abscissa. Values are expressed as means ± SEM. a vs. b; a vs. c means differ (p< 0.01); c vs. d means differ (p < 0.001).

Muscaric receptor type 3 inhibitor reversed the effects of tiotropium.  4-DAMP pretreatment of the monocytes reversed the inhibitory effect of tiotropium on MCP-1 induced MCA (Figure 3). In contrast to 4-DAMP, the pretreatment of gallamine did not alter the reduction of MCA caused by anticholinergic treatment. As shown the figure 3, both gallamine and 4-DAMP that was administered individually did not affect the chemotaxis of monocytes when exposed to MCP-1.

Figure 3. Muscarinic receptor type-3 inhibitor reversed the effects of tiotropium.  Monocytes were pre-exposed to gallamine (M₂ receptor inhibitor) and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; M₃ receptor inhibitor) at the concentration of 300 µM for 30 min before treatment with 1000 nM tiotropium for an additional 30 min (n = 5). Chemotactic activity is on the ordinate and the experimental groups are on the abscissa. Values are expressed as means ± SEM. a vs. b means differ (p<0.01).

Tiotropium inhibition of a specific muscarinic type 3 receptor agonist induced MCA. Cevimeline (300 µM) treatment increased MCP-1 induced MCA as compared to nontreated controls (Figure 4, ~1.4-fold; p < 0.01). This effect was greater than that displayed by individual ACh treatment (Figure 2). In addition, tiotropium abolished the increase in MCA that was augmented by cevimeline treatment (Figure 4, p< 0.01).

Figure 4. Tiotropium inhibited MCA induced by muscarinic type-3 receptor agonist treatment. Monocytes were treated with 1000 nM tiotropium for 30 minutes prior to exposure of 300 µM cevimeline for an additional 30 minutes (n = 4). Chemotactic activity is on the ordinate and the experimental groups are on the abscissa. Values are expressed as means ± SEM. a vs.b; a vs. c; c vs. d means differ (p< 0.01).

Tiotropium inhibition of G_q protein agonist induced MCA.  MCA was significantly increased (1.3-fold; p< 0.01) in response to 100 ng/ml PMT as compared to non-treated controls (Figure 5). Similar to cevimeline, this effect was higher than that of ACh administered alone.  In combination with PMT, tiotropium abolished the increase in MCA to a level that was similar to tiotropium treatment alone (Figure 5, p< 0.01). 

Figure 5. Tiotropium inhibited MCA induced by G_q protein agonist treatment. Monocytes were treated with 1000 nM tiotropium for 30 min prior to exposure of 100 ng/ml Pasteurella multocida toxin (PMT) for an additional 30 min (n = 6).  Chemotactic activity is on the ordinate and the both experimental groups are on the abscissa. Values are expressed as means ± SEM. a vs.b; a vs.c; c vs.d means differ (p< 0.001).

Discussion

In the present study, we demonstrated that tiotropium directly interacted with the monocyte and inhibited MCP-1 induced MCA.  The exogenous addition of ACh increased MCP-1-induced MCA, and tiotropium reversed the increase in MCP-1 induced MCA by ACh.  Interestingly, 4-DAMP, a M₃-receptor antagonist, abolished the effect of tiotropium. Furthermore, cevimeline, a M₃-receptor agonist, and PMT, a G_q protein stimulator, increased MCP-1 induced MCA, and tiotropium pretreatment reversed the increase in MCA by these agents.  These data may suggest that tiotropium directly interacts with monocytes and inhibits their capability to migrate to chemotactic agents by interfering with M₃ receptor coupled G_q protein signal transduction.

The initial concentrations used in this study demonstrated a reduction in MCA from tiotropium ranging from 10 through 1000 nM. The lower doses of tiotropium demonstrating a response in this study are within range to those affecting human lung fibroblast proliferation (7) and fibroblast differentiation (20).  In order to elicit a robust effect on MCA, we opted to use the highest responsive dose (1000 nM) of tiotropium bromide throughout the study. At this level, tiotropium bromide was non-toxic and remained below the estimated maximum concentration of ~2 μM to be present at the lung epithelial lining fluid after inhalation of the drug (21).

Tiotropium has been shown to possess anti-inflammatory effects (1,2,9,13).  Although the recruitment of peripheral blood monocytes to the lung is essential for innate lung immunity, it is also involved in the generation and propagation of an inflammatory response. The excessive migration of blood monocytes to the lung tissue can lead to increased number of alveolar macrophages (22,23), leading to the lung tissue injury via excessive elaboration of inflammatory cytokines, eicosanoids, proteolytic enzymes, and oxygen radicals (24-26). In this context, it might be important to suppress the excessive migration of monocytes to the site of inflammation during acute and chronic inflammation. In the present study, we demonstrated that tiotropium inhibited MCP-1 induced MCA. This result suggests that tiotropium may provide an anti-inflammatory action by inhibiting the monocytes capability to migrate to chemotactic agents that are produced at heightened levels under inflammatory conditions in the lung.

Recently, accumulating evidence demonstrates that acetylcholine and its synthesizing enzyme choline acetyltransferase (ChAT) are present not only in airway nerves, but also in various cells such as airway epithelial cells, endothelial cells, smooth muscle cells, lymphocytes, macrophages, mast cells, eosinophils and neutrophils (11). Furthermore, most inflammatory cells express functional muscarinic receptors (10,11,27,28). Muscarinic receptor agonists increase cytosolic Ca²⁺ and c-fos mRNA expression both in human T- and B- cell lines in an atropine-sensitive manner (29,30).  These findings may suggest that ACh may regulate inflammatory processes in a paracrine and/or autocrine fashion(s) in inflammatory cells (29, 31-33). In the present study, ACh directly interacted with monocytes and stimulated their chemotactic activity. This observation is consistent with the above concept that ACh can regulate inflammatory processes. We demonstrated that tiotropium inhibited the increase in MCA which was induced by ACh. Moreover, tiotropium attenuated MCP-1 induced MCA in the absence of ACh.  Several reports (12,29) suggest that ACh can be generated by ChAT that is localized in monocytes and regulate inflammatory processes in an autocrine and/or paracrine fashion(s). Based on these reports, we postulated that ACh can be generated within the monocyte in response to exterior stimuli and that tiotropium may modulate MCA that is augmented by intrinsic ACh.

Five different subtypes (M₁-M₅) of muscarinic receptor have been identified (34). Although muscarinic receptors are expressed in various inflammatory cells, the expression of each subtype seemed to be variable within each individual inflammatory cell. Although Fujii et al. (27) reported that all 5 classes of muscarinic receptors have been detected by RT-PCR in mononuclear cells, Bany et al. (35) reported that M₂-M₅ but not M₁ mRNA were detected by RT-PCR. Furthermore, Costa et al. (36,37) and Hellstom-Lindahl et al. (38) reported that only M₃-M₅, but not other subtypes, were detected by RT-PCR. Therefore, the expression profile of muscarinic receptors seemed to be variable upon experimental conditions.  Based on these reports, we investigated whether the effect of gallamine, a M₂-receptor antagonist, and 4-DAMP, a M₃-receptor antagonist, may alter the effect of tiotropium on MCA. We did not investigate other muscarinic antagonists because of the reports suggesting that the other muscarinic receptors were not strongly expressed in monocytes.  Our results indicated that tiotropium may act by binding to M₃ receptor.  Profita et al. (39) also demonstrated that M₃ receptors were observed in human blood monocytes by immunohistochemical detection. In addition, Sato et al. (11) suggested that ACh stimulated the bovine alveolar macrophages via M₃ receptor to release factors promoting monocyte chemotactic activity. Furthermore, Fujii et al. (30) reported that the muscarinic receptor agonist, oxotremorine-M, increased c-fos mRNA expression in human T- and B- cell lines via the M₃ muscarinic receptor because this effect could be blocked by 4-DAMP. Taken together, these reports suggest that ACh might be acting predominantly by M₃ receptor regulation in mononuclear cells. Our results also demonstrate that 4-DAMP inhibited the effect of suppression of MCA by tiotropium. Therefore, it is feasible that ACh can be generated by monocytes themselves and act in an autocrine and paracrine manner via M₃ muscarinic receptor interaction and that tiotropium may inhibit this reaction.

Recently, Han et al. (40) reported that a conformational change of the M₃ receptors may occur in the immediate vicinity of the binding site of a G-protein coupled receptor (GPCR) activated by diffusible ligands such as the muscarinic agonist. Furthermore, several studies suggested that  similar conformation changes occur in GPCR’s activated by diffusible ligands such as the beta 2-adrenergic receptor (41, 42). According to this context, the conformational change within the M₃ receptor might occur by a muscarinic antagonist such as 4-DAMP in monocytes. It may be possible that a conformational change in the M₃ receptor, as produced by 4-DAMP interaction, may alter the original binding site for tiotropium and thus reverse its affect on MCA.

Muscarinic receptors belong to the large family of G-protein coupled receptors (GPCR). The accumulating data has demonstrated that the “odd-numbered” muscarinic receptors (M₁, M₃, M₅) couple preferentially to G-proteins of the G_q family, whereas the “even-numbered” receptors (M₂, M₄) prefer G-proteins belonging to the G_i/o family (10).  Our result and several other reports demonstrate that the most important receptor on monocytes seem to be mediated via the M₃ muscarinic receptor.  Therefore, we examined the effect of a selective M₃ muscarinic receptor agonist, cevimeline, and a selective G_q protein stimulator, PMT, on MCA. The results from these experiments demonstrated that both cevimeline and PMT were directly acting on monocytes and augmented MCP-1 induced MCA.  In addition, tiotropium abolished the increase in MCA that were induced by these agents.  These data may suggest that tiotropium may inhibit MCA via M₃ muscarinic receptor and G_q protein signaling.  Although it has been indicated that tiotropium may inhibit MCA via M₃ receptor coupled G_q protein signaling, it remains unknown as to which intracellular signaling pathways beyond G-protein induction may be important in the regulation of MCA. The effects of tiotropium in the regulation of these intracellular mechanisms in monocytes remain as an important issue to be elucidated with future research. 

In conclusion, tiotropium directly interacts with monocytes and inhibits their capability to migrate to chemotactic agents. The results in the present study provide new insight into mechanisms by which tiotropium may act as an anti-inflammatory agent in the pulmonary system. The reduction in monocyte migration may be one mechanism explaining the reduction in COPD exacerbations seen with tiotropium treatment in COPD.

Acknowledgements

Supported by a grant from Boehringer Ingelheim and the Phoenix Pulmonary and Critical Care Research and Education Foundation and the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government..

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36. Costa P, Auger CB, Traver DJ, Costa LG. Identification of m3, m4 and m5 subtypes of muscarinic receptor mRNA in human blood mononuclear cells. J Neuroimmunol 1995;60:45-51.
37. Costa P, Traver DJ, Auger CB, Costa LG. Expression of cholinergic muscarinic receptor subtypes mRNA in rat blood mononuclear cells. Immunopharmacology 1994;28:113-123.
38. Hellstrom-Lindahl E, Nordberg A. Muscarinic receptor subtypes in subpopulations of human blood mononuclear cells as analyzed by RT-PCR technique. J Neuroimmunol 1996;68:139-144.
39. Profita M, Giorgi RD, Sala A, Bonanno A, Riccobono L, Mirabella F, Gjomarkaj M, Bonsignore G, Bousquet J,Vignola AM. Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients. Allergy 2005;60:1361-1369.
40. Han SJ, Hamdan FF, Kim SK, Jacobson KA, Bloodworth LM, Li B, Wess J. Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M(3) muscarinic acetylcholine receptor. J Biol Chem 2005;280:34849-34858.
41. Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK. Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor. Proc Natl Acad Sci U S A 2001;98:5997-6002.
42. Jensen AD, Guarnieri F, Rasmussen SG, Asmar F, Ballesteros JA, Gether U. Agonist-induced conformational changes at the cytoplasmic side of transmembrane segment 6 in the beta 2 adrenergic receptor mapped by site-selective fluorescent labeling. J Biol Chem 2001;276:9279-9290.

Conflict of Interest Statement: M.K., S.R., R.A.R., S.K., and J.A.H. do not have any financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.A.H. received a research grant ($49,900) from Boehringer-Ingelheim (2006-7) to conduct this study.

Reference as: Kurai M, Robbins RA, Koyama S, Amano J, Hayden JM. Tiotropium bromide inhibits human monocyte chemotaxis. Southwest J Pulm Crit Care 2012;5:86-99. (Click here for a PDF version of the manuscript).

August 2012 Pulmonary Case of the Month

All Eosinophilia Is Not Asthma

Lewis J. Wesselius, MD

Departments of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 73 year old man was seen with a one month history of shortness of breath. He dated this to an emergency room visit for an arm injury for which he had a DPT vaccination. Previously, he had been able to swim regularly, but he is now unable to swim due to worsening dyspnea. He also had some cough that was nonproductive.

PMH, SH and FH

He has a past medical history of coronary artery disease with prior stenting of his right and left anterior descending artery in 2010. He also has a history of hypertension, dysplipidemia, a carotid endarterectomy and a single seizure after a corneal transplant.

His present medications include:

• Atorvastatin
• Lisinopril
• Metoprolol
• Warfarin

He has a minimal smoking history and denied use of alcohol, drugs or unusual exposures. 

Physical Examination

His vitals signs were normal and he was afebrile but he was receiving supplemental oxygen at 3 lpm.

Chest examination revealed bilateral crackles but no wheezes.

Cardiovascular examination showed a regular rhythm with a Grade 2/6 systolic ejection murmur.

He had no clubbing or edema.

The remainder of the physical examination was either normal or noncontributory.

Chest X-ray

His admission chest x-ray is shown in Figure 1.

 Figure 1. Admission chest x-ray showing the PA (Panel A) and lateral (Panel B).

Which of the following are possible causes of the patient’s clinical picture?

1. Coccidioidomycosis (Valley Fever)
2. Allergic reaction to the DPT vaccination
3. Pulmonary edema
4. A + C
5. All of the above

Reference as: Wesselius LJ. August 2012 pulmonary case of the month: all eosinophilia is not asthma. Southwest J Pulm Crit Care 2012;5:58-64. (Click here for a PDF version of the case presentation)

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.

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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)

July 2012 Pulmonary Case of the Month: Pulmonary Infiltrates - Getting to the Heart of the Problem

Bridgett Ronan, MD

Robert Viggiano, MD

Lewis J. Wesselius, MD

Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 63 year old man was transferred from outside facility with ventricular tachycardia. He has a past history of ventricular tachycardia and had an intracardiac defibrillator (ICD) placed due to a low ejection fraction. The ICD had administered several shocks to the patient prior to admission.

His present medications included:

• Lisinopril 10 mg bid
• Diazepam 10 mg bid
• Amiodarone 400 mg daily
• Dutasteride 0.5 mg daily
• Tamsulosin 0.4 mg daily
• Dexlansoprazole 60 mg daily
• Levothyroxine 100 mcg daily

The patient underwent and electrophysiology (EP) procedure. He was intubated prior to the procedure. He developed sustained ventricular tachycardia when the ICD was turned off. Eleven cardioversions were required with an accumulated 108 seconds of ventricular tachycardia. He became hypotensive and received 6.2 L boluses of fluids and 5, 400 mg boluses of amiodarone and was placed on an amiodarone drip.

He remained intubated receiving mechanical ventilator after the EP procedure.

He was extubated after 2 days and was initially on oxygen at 6L/min nasal cannula. Over the next several days he developed increasing oxygen requirements and was treated with BiPAP and increasing oxygen.

PMH, SH and FH

As noted above he had a history of recurrent ventricular tachycardia and a dilated cardiomyopathy with an ejection fraction of 30-35%. In addition he had a history of paroxysmal atrial fibrillation, obstructive sleep apnea which resolved with weight loss, hypothyroidism and mild restriction on pulmonary function testing, possibly related to amiodarone or to kyphosis. He is a life-long nonsmoker.

Physical Examination

His vital signs included a Tmax of 38.8 C, heart rate of  79 beats/min, blood pressure of  113/67 mm Hg, respiratory rate of 38 breaths/min, and oxygen saturation of 94% on a 75% high flow mask. His weight had increased to 102 kg from 96.6 kg on admission.

Cardiovascular exam revealed an irregular rhythm but no murmur. There was jugular venous distention present. There was a trace of pedal edema but deeper pitting edema at the hips.

Pulmonary auscultation revealed bilateral rales with diminished breath sounds at the bases.

Chest X-ray

Admission and current chest x-ray are shown in Figure 1.

Figure 1. Admission chest x-ray (panel A) and current chest x-ray (panel B).

Laboratory Evaluation

Arterial blood gases showed a pH of 7.42, a pCO₂ of 39 and a pO₂ of 73 on 70% FiO₂. The white blood cell count (WBC) was elevated at 15.1X10³ cells/mm³.

Which of the following could explain the patient’s increased oxygen requirements?

1. Pulmonary edema
2. Pneumonia
3. Amiodarone lung toxicity
4. A + B
5. A + C
6. All of the above

Reference as: Ronan B, Viggiano R, Wesselius LJ. July 2012 pulmonary case of the month: pulmonary infiltrates - getting to the heart of the problem. Southwest J Pulm Crit Care 2012;5:1-11. (click here for a PDF version of the case)