December 2012 Pulmonary Case of the Month: Applying Genetics

Lewis J. Wesselius, MD¹

Thomas D. Kummet, MD²

¹Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

²Olympic Medical Cancer Center

Sequim, WA

History of Present Illness

A 65 year old woman presented to her physician in with upper abdominal pain in August, 2007.  A CT scan of the abdomen demonstrated no abnormalities in her abdomen, but a 3.7 x 2.4 cm mass in the left lower lobe was noted.

PMH, FH and SH

She has no significant prior medical history. She is a life-long nonsmoker. There is no significant family history

Physical Examination

Her physical examination is unremarkable.

Which of the following is true?

1. Lung cancer does not occur in nonsmokers
2. The lesion is likely a rounded pneumonia based on its size
3. A family history of lung cancer is not associated with an increase in lung cancer
4. Calcification of the mass usually indicates lung cancer
5. Adenocarcinoma is the most common lung cancer seen in nonsmokers

Reference as: Wesselius LJ, Kummet TD. December 2012 pulmonary case of the month: applying genetics. Southwest J Pulm Crit Care 2012;5:272-8. PDF

November 2012 Pulmonary Case of the Month: The Wolves Are at the Door

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 49 year old female was admitted for hypoxia, lethargy, and an abnormal chest x-ray. She was recently discharged after a 10 day outside hospital stay for a diagnosis of pneumonia treated initially with azithromycin, then clindamycin and discharged on levofloxacin. Corticosteroids given during that hospitalization and she was discharged on taper. As the steroids were tapered, she had increasing dyspnea, confusion, and lethargy. She presented to the emergency room with an abnormal CT chest x-ray and was started on meropenem, vancomycin and azithromycin, and was also given IV methylprednisolone (125 mg initial dose).

PMH, FH and SH

She had her first stroke at age 18 and walks with a cane and has some expressive aphasia. There were multiple prior episodes of pneumonia (25 in 5 years). She was diagnosed with systemic lupus erythematosis (SLE) with lupus pneumonitis (based on surgical lung biopsy) about 3-4 years prior to admission. She had a St. Jude mitral valve replacement 12 years ago and had suffered a hemorrhagic stroke presumed secondary to anticoagulation. There is also a history of nephrolithiasis and recurrent urinary tract infections and anemia with multiple prior transfusions.

Her mother died at 49 reportedly due to complications of SLE.

Physical Examination

• Temperature 37.1° C;  Blood Pressure127/75 mm Hg;  Pulse 80 beats/min; SaO2 96% on 3 LPM
• HEENT: no significant abnormalities identified
• Chest: clear to auscultation and percussion
• Cardiovascular: mechanical click, no murmur
• Extremities: trace edema

Laboratory Evaluation

• Hemoglobin 10.1 g/dL   WBC  11,900  cells/μL   Platelets 137,000 cells/μL  
• INR 2.62
• Creatinine 0.9 mg/dL  BUN 15 mmol/L
• N-terminal pro-brain natriuretic peptide (NT pro-BNP) 1,294 pg/ml
• C-reactive protein (CRP) 74.7 mg/L 
• Erythrocyte sedimentation rate (ESR) 14 mm/hr
• Drug Screen:  negative

Chest X-ray

Her chest x-ray is shown below (Figure 1).

Figure 1. Portable chest radiography at the time of admission.

Which of the following are pulmonary complications of SLE?

1. Pleuritis
2. Chronic interstitial pneumonitis
3. Acute lupus pneumonitis
4. Pulmonary hypertension
5. All of the above

Reference as: Wesselius LJ. November 2012 pulmonary case of the month: the wolves are at the door. Southwest J Pulm Crit Care 2012;5: 223-8. PDF 

October 2012 Pulmonary Case of the Month: Hemoptysis from an Uncommon Cause

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 39 year old woman is seen with a history of cough intermittently productive of small amounts of blood or blood-tinged sputum for 4 months. She reports no other respiratory symptoms and has otherwise felt well.

PMH, FH and SH

There was no significant PMH and no prior history of lung disease. Her father has a history of Parkinson’s disease and osteosarcoma. She is a nonsmoker, does not drink alcohol, and has never abused drugs. She has 2 children and is engaged to be remarried.

Physical Examination

Her physical examination is normal.

Chest X-ray

Her chest x-ray is below (Figure 1).

Figure 1. Panel A: Frontal chest radiography. Panel B: Lateral chest radiography.

Laboratory Evaluation

Hemoglobin was 13.2 g/dL and WBC was 8400 cells/μL with a normal differential. Urinanalysis was unremarkable.

Which of the following statements regarding hemoptysis is or are true?

1. A normal chest x-ray makes a benign cause of the hemoptysis more likely
2. Most patients with lung cancer are asymptomatic
3. Hemoptysis in children is usually associated with an infection or a foreign body
4. 1 + 3
5. All of the above

Reference as: Wesselius LJ. October 2012 pulmonary case of the month: hempotypsis from an uncommon cause. Southwest J Pulm Crit Care 2012;5:169-75.  PDF

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

Makoto Kurai^1,2,3

Richard A. Robbins^1,2

Sekiya Koyama⁴

Jun Amano³

John M. Hayden¹

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

Abstract

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

Abbreviation List

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

Introduction

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

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

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

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

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

Methods

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

Purification of Human Blood Neutrophils and Experimental Models

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

Neutrophil Chemotaxis Analysis

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

Western Blot Analysis

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

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

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

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

Statistical Analyses

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

Results

Stimulation of neutrophil chemotactic activity by cholinergic challenge

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

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

Tiotropium pretreatment inhibited cholinergic stimulation of neutrophils

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

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

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

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

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

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

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

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

  

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

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

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

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

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

Acknowledgements

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

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

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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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)

Cough and Pleural Disease in a Burmese Immigrant – A Masquerader

George M. Solomon, MD¹

Eric Schmidt, MD^1,2

Randall Reves, MD³

Carolyn Welsh, MD¹

Department of Medicine, Divisions of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver¹

Denver Health Medical Center²

Denver Metro Tuberculosis Control Program, Denver Public Health Department³

Corresponding Author:         George M. Solomon, MD

                                          Research Building 2

                                          9th Floor12700 E. 19th Ave

                                          Aurora, Colorado 80045

                                          Phone 303-398-1392

                                          George.solomon@ucdenver.edu

Financial Disclosures: No authors report any financial conflicts to disclose

Abstract

We present a case of a 58 year old Burmese male who presented to our center with progressive pulmonary and constitutional symptoms after treatment for pulmonary tuberculosis. Our investigation revealed peripheral and bronchogenic eosinophilia and clinical features consistent with progressive pulmonary paragonimiasis. After serological confirmation of the diagnosis, the patient had resolution of symptoms with praziaquantel therapy for the condition.  This case highlights the importance of considering this diagnosis when there is a possibility of undercooked shellfish exposure especially in immigrants from endemic areas for paragonimiasis where raw shellfish is more commonly ingested.

Case Presentation 

A 58 year old Burmese male was referred for evaluation of cough and pleural abnormalities on a chest radiograph.  The patient had arrived in Boston as a Burmese refugee the previous year.  Upon arrival in the United States, he was found to have a right middle lobe infiltrate, multiple cavitary nodules on chest CT, three negative sputum AFB smears and 10 mm induration on Mantoux tuberculin skin testing.  He was treated with rifampin, isoniazid, pyrazinamide, and ethambutol for 2 months with resolution of the cavitary nodules but developed an increasing right pleural opacity. Sputum cultures were negative for mycobacteria.

He moved to Denver, Colorado where an additional four months of isoniazid and rifampin were completed for presumed culture negative pulmonary tuberculosis. At the end of treatment he noted an increase in his persistent cough and fatigue associated with low grade fevers.  A repeat chest radiograph now revealed a small right-sided pleural effusion (Figure 1).

Figure 1. Chest radiograph demonstrating right-sided small pleural effusion

Assessment at the pulmonary clinic revealed persistent cough and a 6.8 kg weight loss.  Physical examination was pertinent for a temperature of 99.0 ºF, dullness to percussion and crackles in the right lung.  The patient reported occasional tobacco use and reported occasional raw seafood consumption in Burma.  He denied other medical history at this time except for untreated hypertension. 

Laboratory investigation was pertinent for a white blood cell count of 10,000 per µl with a differential of 22% eosinophils and normal platelet and hemoglobin levels. Anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), and rheumatoid factor levels as well as a comprehensive metabolic profile and coagulation labs were all normal. 

Computed tomography of the chest at the time of presentation to the pulmonary clinic compared to the one a year earlier in Boston are shown in Figure 2.

Figure 2. A. Computed Tomography image of the chest demonstrating right middle lobe opacification and pleural effusion at presentation to the pulmonary clinic. B. Computed Tomography image of the chest at time of initial treatment in Boston demonstrating right-sided cavitary disease and pleural process.

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) revealed 960 nucleated cells, 68% of which were eosinophils.  Routine cultures grew normal oral flora and were negative for actinomyces, fungi and mycobacteria.  Wet prep for oocysts and larvae was negative. 

Ultrasound revealed only a small loculated pleural effusion, precluding thoracentesis.

Because of suspicion for parasitic illness, a filarial antibody panel was also sent and was negative. Paragonimus antibody immunoblot assay was positive.

Case Follow-up

The patient was treated with praziquantel 25 mg/kg orally three times daily for 3 days with improvement in symptoms and radiographic abnormalities as show in Figure 3. 

Figure 3. Chest radiograph following treatment with praziquantel demonstrating resolution of resolving right-sided pleural effusion and right-sided infiltrates.

Discussion

Paragonimiasis results from infection by one of the more than fifty species of the genus paragonimus (most commonly P. westermanii).  There are approximately 2.5 million cases annually reported in endemic areas, mostly in Indo-China and sub-Saharan Africa.  In the western world, most cases are reported in immigrants from endemic regions where undercooked shellfish are culturally consumed.  Approximately 50-70% of infections are initially diagnosed as tuberculosis in the U.S. (1), as demonstrated in this case.  

The lifecycle of the organism begins with early ingestion and early disease characterized by cough, fever, and pleuritic chest pain resulting from a transdiaphragmatic spread of larvae into the pleural space from the abdomen.  Prominent features of this “early” disease are pneumothorax or pleural effusion and peripheral eosinophilia (2).  Additionally, transient pulmonary infiltrates may be observed. This presentation may help to explain the response of parenchymal abnormalities in response to the anti-tuberculosis treatments.  In fact, the “response” to treatment may have been a consequence of the natural history of early stage paragonimiasis. 

The failure of resolution of pleural disease in this case to anti-tuberculosis drugs should have alerted clinicians to consider alternative diagnoses.  The progressive pleural disease in this case while on anti-tuberculosis drugs highlights progression of paragonimiasis pulmonary disease.  “Late” stage lung disease results from mature fluke inhabitation in the lung parenchyma. During this phase, patients typically resolve their peripheral eosinophilia and fever but may have persistent dark brown hemoptysis.   Radiographic features in this stage are varied and include parenchymal mass-like lesions or chronic pleural lesions (2).

If paragonimiasis is suspected, diagnosis is most readily made by serological evaluation. Heretofore, microscopic evaluation of oocysts and larvae from sputum or BAL yielded a diagnosis in only 50-75% of cases (3).  Serological evaluations including immunoblot assays for P. Westermanii antibodies have a reported sensitivity of 96% and specificity of 99% (4) and ELISA-based assays have a reported sensitivity of 92% and specificity of 90% (5); thereby, these assays have therefore largely supplanted other microscopic evaluation given the superior diagnostic performance

Treatment regimens are nearly 100% effective in cure for pulmonary disease. Typical regimens include three days of praziquantel therapy at 25mg/kg given three times daily. It is additionally important to counsel patients and their families on avoidance of raw seafood as well as contact prophylaxis, as cross-contamination from soiled utensils can result in illness to others (6).  A recent case series of locally-acquired paragonimiasis from undercooked river shellfish in the U.S. acquired from undercooked shellfish in restaurants (7) further highlights the importance of considering this diagnosis especially if the history of potential exposure is substantiated, thus raising awareness of paragonimiasis infection as a potential public health hazard in food/beverage establishments. 

In summary, paragonimiasis is a relatively common infection in endemic areas of the world. Infection is often mistaken as tuberculosis in immigrants to the western world. However, knowledge of the clinicopathologic features of the disease should lead to appropriate consideration and treatment for at-risk patients. 

References

1. Kagawa FT. Pulmonary paragonimiasis. Seminars in Respiratory Infections 1997;12:149-158.
2. Mukae H, Taniguchi H, Matsumoto N, Iiboshi H, Ashitani J, Matsukura S, Nawa Y. Clinicoradiologic features of pleuropulmonary paragonimus westermani on Kyusyu Island, Japan. Chest 2001;120:514-520.
3. Khan R, Sharma OP. Bronchial lavage in tropical pneumonias. Curr Opin Pulm Med 2007;13:225-229.
4. Slemenda SB, Maddison SE, Jong EC, Moore DD. Diagnosis of paragonimiasis by immunoblot. Am J Trop Med Hyg 1988;39:469-471.
5. Imai J. Evaluation of elisa for the diagnosis of paragonimiasis westermani. Trans R Soc Trop Med Hyg 1987;81:3-6.
6. Johnson RJ, Jong EC, Dunning SB, Carberry WL, Minshew BH. Paragonimiasis: Diagnosis and the use of praziquantel in treatment. Reviews of infectious diseases 1985;7:200-206.
7. Human paragonimiasis after eating raw or undercooked crayfish --- Missouri, July 2006-September 2010. MMWR 2010;59:1573-1576.

Reference as: Solomon GM, Schmidt E, Reves R, Welsh C. Cough and pleural disease in a Burmese immigrant-a masquerader. Southwest J Pulm Crit Care 2012;4:205-10. (Click here for a PDF version of the manuscript)

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

Jessica Hurley, MD¹

Richard D. Gerkin, MD¹

Bonnie Fahy, RN, MN²

Richard A. Robbins, MD^2* 

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

Abstract

Background

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

Objectives

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

Selection criteria

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

Search strategy

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

Data collection and analysis

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

Main results

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

Conclusions

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

Introduction

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

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

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

Methods

Criteria for considering studies for this review

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

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

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

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

Search methods

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

Data collection and analysis

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

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

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

Data analysis:

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

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

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

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

Results

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

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

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

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

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

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

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

Figure 1.  Forest plot of mortality

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

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

 

Figure 2. Forest plot of pulmonary hospitalization

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

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

Discussion

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

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

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

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

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

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

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

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

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

Acknowledgements

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

References

1. Akinbami LJ, Liu X. Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998-2009. NCHS Data Brief 2011;63:1-8.
2. Toy EL, Gallagher KF, Stanley EL, Swensen AR, Duh MS. The economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review. COPD 2010;7:214-28.
3. Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic evaluation of COPD. Chest 2000;118:1278-85.
4. Ofman JJ, Badamgarav E, Henning JM, Knight K, Gano AD, Jr., Levan RK, et al. Does disease management improve clinical and economic outcomes in patients with chronic diseases? A systematic review. Am J Med 2004;117:182-92.
5. Gwadry-Sridhar FH, Flintoft V, Lee DS, Lee H, Guyatt GH. A systematic review and meta-analysis of studies comparing readmission rates and mortality rates in patients with heart failure. Arch Intern Med 2004;164:2315-20.
6. Jovicic A, Holroyd-Leduc JM, Straus SE. Effects of self-management intervention on health outcomes of patients with heart failure: a systematic review of randomized controlled trials. BMC Cardiovasc Disord 2006;6:43.
7. Effing T, Monninkhof EM, van der Valk PD, van der Palen J, van Herwaarden CL, Partidge MR, Walters EH, Zielhuis GA. Self-management education for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007;17:CD002990.
8. Fan VS, Gaziano JM, Lew R, et al. A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial. Ann Intern Med 2012;156:673-83.
9. Rice KL, Dewan N, Bloomfield HE, Grill J, Schult TM, Nelson DB, Kumari S, Thomas M, Geist LJ, Beaner C, Caldwell M, Niewoehner DE. Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med. 2010;182:890-6.
10. Boxall A, Barclay L, Sayers A, Caplan GA. Managing chronic obstructive pulmonary disease in the community. A randomized controlled trial of home-based pulmonary rehabilitation for elderly housebound patients. J Cardiopulm Rehabil 2005;25:378–85.
11. Coultas D, Frederick J, Barnett B, Singh G, Wludyka P. A randomized trial of two types of nurse-assisted home care for patients with COPD. Chest 2005;128:2017–24.
12. Martin IR, McNamara D, Sutherland FR, Tilyard MW, Taylor DR. Care plans for acutely deteriorating COPD: a randomized controlled trial. Chronic Respiratory Disease 2004;1:191–5.
13. Rea H, McAuley S, Stewart A, Lamont C, Roseman P, Didsbury P. A chronic disease management programme can reduce days in hospital for patients with chronic obstructive pulmonary disease. Intern Med J 2004;34:608–14.
14. Bourbeau J, Julien M, Maltais F, et al. Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease specific self-management intervention. Arch Intern Med 2003;163:585–91.
15. Monninkhof E, van der Valk P, van der Palen J, van Herwaarden C, Zielhuis G. Effects of a comprehensive self-management programme in patients with chronic obstructive pulmonary disease. Eur Respir J 2003;22:815–20.
16. Gallefoss F, Bakke PS, Rsgaard PK. Quality of life assessment after patient education in a randomized controlled study on asthma and chronic obstructive pulmonary disease. Am J Respir Critical Care Med 1999;159:812–7.
17. Gourley GA, Portner TS, Gourley DR, et al. Humanistic outcomes in the hypertension and COPD arms of a multicenter outcomes study. J Am Pharm Assoc 1998;38:586–597.
18. Littlejohns P, Baveystock CM, Parnell H, Jones P. Randomised controlled trial of the effectiveness of a respiratory health worker in reducing impairment, disability, and handicap due to chronic airflow limitation.  Thorax 1991;46:559–64.
19. Cockcroft A, Bagnall P, Heslop A, et al.Controlled trial of respiratory health worker visiting patients with chronic respiratory disability. BMJ (Clin Res Ed) 1987;294:225–8.
20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
21. Dewan NA, Rice KL, Caldwell M, Hilleman DE. Economic evaluation of a disease management program for chronic obstructive pulmonary disease. COPD 2011;8:153-9.
22. Pocock SJ. Ethical dilemmas and malfunctions in clinical trials research. Ann Intern Med 2012;156:746-747.

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

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

June 2012 Pulmonary Case of the Month: What’s a Millet Seed Look Like?

Alexis Christie, MD

Robert Viggiano, MD

Lewis J. Wesselius, MD

Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 32 year old woman presents with a week long history of dyspnea, cough, fatigue, tiredness and pruritis. She has a past medical history (PMH) of Stage IIB, nodular sclerosing Hodgkin’s disease diagnosed in January, 2011. She underwent several cycles of chemotherapy and eventually an autologous stem cell transplant in January, 2012. Her current medications include:

• Acyclovir 800mg bid
• Ativan 0.5mg q4h/ prn
• Hydromorphone 8mg q4h/ prn
• Atarax 100mg q6h/ prn
• Compazine 10mg q6h/ prn

She had just finished a course of levofloxacin.

PMH, SH and FH

As above. She is a life-long nonsmoker and has no history of lung disease.

Physical Examination

Her physical examination was normal.

Chest X-ray

Her chest x-ray was interpreted as unchanged from previous examinations. 

Which of the following are indicated?

1. Thoracic CT scanning
2. PET scanning
3. Empiric treatment with broad spectrum antibiotics
4. All of the above

Reference as: Christie A, Viggiano R, Wesselius LJ. June 2012 pulmonary case of the month: what's a millet seed look like? Southwest J Pulm Crit Care 2012;4:182-8. (Click here for a PDF version of the case)

May 2012 Pulmonary Case of the Month: Things Are Not Always as They Seem

Lewis J. Wesselius, MD

Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 69 year old woman was seen for side effects of corticosteroids. She is a winter visitor to Arizona. She was hospitalized in March 2008 with increased dyspnea and cough and had an abnormal CT chest. A VATS lung biopsy was performed. The pathology of the lung biopsy interpreted as bronchiolitis obliterans. She was started on prednisone 60 mg/day.

Subsequently, she returned to Minnesota and was seen by rheumatologist with a diagnosis made of possible rheumatoid arthritis. She was treated with methotrexate (12.5 mg weekly) and continued prednisone at 20 mg/day from 2008 to 2011.  At that time a question was raised of methotrexate lung toxicity and it was stopped but she continued on prednisone 20 to 40 mg/day.  She is currently having issues with steroid side effects and seen for a second opinion.

PMH, SH and FH

She has a history of knee and other joint pains.  She had knee replacement surgery in Jan 2008 with worsening of her dyspnea and cough.  She has a history of diabetes which was apparently induced by the corticosteroids. Her current medications include prednisone 20 mg/day, insulin, metformin, lovastatin. She is a former smoker with 25 pack-years but quit 25 years ago. She has no family history of lung disease.

Physical Examination

She was an obese woman appearing somewhat Cushingoid in no acute distress. On chest auscultation she had diminished breath sounds but no crackles or wheezes. Examination of her joints revealed no abnormalities. The remainder of her physical examination was normal.

Chest X-ray

Her chest x-ray was interpreted as normal.

Which of the following are indicated?

1. Pulmonary function testing
2. Pulmonary CT scanning
3. Rheumatologic evaluation
4. Repeat of open lung biopsy
5. All of the above

Reference as: Wesselius LJ. May 2012 pulmonary case of the month: things are not always as they seem. Southwest J Pulm Crit Care 2012;4:142-8. (Click here for a PDF version of the case)

April 2012 Pulmonary Case of the Month: Could Have Fooled Me!

Bridgett A. Ronan, MD

Robert Viggiano, MD

Lewis J. Wesselius, MD

Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 60 year old man was seen by his primary care physician with cough for 2 weeks which was dry and worse with deep breathing. He had been exposed to smoke from industrial storage fire just prior to the onset of his cough. He had developed fever for the past 3 days.

PMH, SH and FH

He has a history of osteopenia and was found to have a +PPD in high school for which he was never treated with isoniazid. Originally from New York he has lived in Arizona for 14 years. He was a former smoker having a 45 pack-year history having quit in 2007. He drives a delivery truck. His sister had tuberculosis which was treated and his father has emphysema.

Physical Examination

He had mild rhonchi in the right upper lung field. Otherwise, the physical exam was unremarkable.

Laboratory and Chest X-ray

A CBC was performed which revealed a hemoglobin of 11.7 g/dL, white blood cell (WBC) count of 11.9 X 1000 cells/ml with 79% neutrophils, and a platelet count of 337 X 1000/mL. Coccidioidomycosis serologies were drawn. A chest x-ray was taken (Figure 1).

Figure 1. Chest x-ray taken by the patient’s primary care physician which shows bilateral lung consolidations with multiple poorly defined bilateral lung nodules.

Considerations at this point include:

1. Community acquired pneumonia
2. Coccidioidomycosis
3. Tuberculosis
4. Pneumonitis from smoke inhalation
5. Pulmonary embolism
6. All of the above

Reference as: Ronan BA, Vigianno R, Wesselius LJ. April 2012 pulmonary case of the month: could have fooled me! Southwest J Pulm Crit Care 2012;4:122-9. (Click here for a PDF version of the case)

Pulmonary Nodules with Cutaneous Manifestations: A Case Report and Discussion

Christopher Strawter, MD

Pedro Quiroga, MD

Syed Zaidi, MD

Thomas Ardiles, MD

Maricopa Medical Center

Phoenix, Arizona

Abstract

The differential diagnosis of multiple pulmonary nodules is large and includes congenital and inherited disorders, malignancy, infectious etiologies, noninfectious granulomatous and inflammatory conditions,among many others. Diagnostic evaluation is aided by attention to extrapulmonary symptoms and features. We herein describe an unusual case of multiple pulmonary nodules attributed to cysticercosis and present a discussion of pathophysiologic changes related to medications and highlight the diagnostic value of extrapulmonary cutaneous features.

Case Report

History of Present Illness

A 31-year-old incarcerated Hispanic male presented with a nonproductive cough for several months and one episode of blood tinged sputum.  He admitted to weight loss and night sweats, headaches, and visual disturbances.  He was an immigrant from Honduras and lived in Arizona for the past 15 years.  He had chronic hepatitis C infection and was receiving treatment with pegylated interferon-alfa-2a (IFN-α) and ribavirin. His symptoms began one month after initiating antiviral therapy.

Physical Exam

On admission, his vital signs were stable.  Several mobile one cm cutaneous and subcutaneous nodules were palpable on the trunk and neck. Lymphadenopathy was not present.  The neurological exam revealed diplopia upon lateral gaze. The cardiopulmonary exam was unremarkable. 

Laboratory Data

Routine hematology work-up revealed leukopenia (2.3 x 10³/µL), neutropenia (1.4 x 10³/µL) without eosinophilia.  AST and ALT were 239 U/L and 265 U/L respectively. Quantiferon TB and coccidioidomycosis tests were negative.

Radiology

Plain radiograph of the chest was unremarkable.   Computed Tomography (CT) of the chest demonstrated multiple bilateral well defined nodules ranging in size from 7.2 mm to 11mm in diameter involving lung parenchyma and chest wall soft tissue structures (Figure 1). 

Figure 1. Computed tomography (CT) chest lung window.  Seen here are multiple, bilateral, well defined nodules involving the lung parenchyma and subcutaneous tissue.

MRI of the brain showed extensive bilateral T2 hyperintense and peripherally enhancing foci within the cerebrum, cerebellum and extraocular muscles consistent with the vesicular stage of neurocysticercosis (Figure 2). 

Figure 2. MRI brain.  Extensive bilateral T2 hyperintense and peripherally enhancing foci within the brain parenchyma and extraocular muscles consistent with the vesicular stage of neurocysticercosis (A). The scolex can be visualized within the cyst as a high intensity nodule giving the lesion a pathognomonic ‘hole-with-dot’ appearance (B).

Histopathology

Bronchoscopy revealed normal airways with negative bronchoalveolar lavage.  Histopathology from a needle core biopsy of a chest wall nodule revealed a cystic wall structure, consistent with cysticercosis (Figure 3).

 

Figure 3. Stained microsection of a chest wall needle core biopsy showing the cystic wall structure of cysticercosis. The wall consists of 3 layers: an outer or cuticular layer, a middle cellular layer and an inner fibrillary layer.

Percutaneous lung nodule biopsy demonstrated nonspecific necrotic granulomatous tissue. 

Hospital Course

On the basis of neuroimaging and subcutaneous biopsy findings, a diagnosis of disseminated cysticercosis with pulmonary involvement was made and the patient was started on a 28-day course of albendazole therapy.  One month follow-up revealed resolution of respiratory symptoms. Repeat CT chest, 53 days post-hospitalization revealed a regression in the magnitude of the pulmonary nodules, the largest now measuring 6mm in diameter (Figure 4). 

Figure 4. CT scans of the chest, lung windows. Comparing Panel A with Panel B performed 53 days later reveals a reduction in the size of the bilateral pulmonary nodules (arrows) after a 28-day course of anti-parasitic therapy with albendazole.

Regression of the pulmonary nodules was consistent with the diagnosis of pulmonary cysticercosis, in line with previous reports (1).

Discussion

The differential diagnosis of multiple pulmonary nodules is large. A variety of pulmonary disorders may affect both cutaneous and subcutaneous tissues and the lung (Table 1).

The findings of extrapulmonary nodules in other organ systems and biopsy of nodules can help establish the diagnosis or limit the differential diagnosis of multiple pulmonary nodules when thoracic image findings are nonspecific.

Cysticercosis refers to infection by the larval stage of the pork tapeworm, Taenia solium.  Cysticercosis has emerged as a cause of severe neurologic disease in the United States that primarily affects immigrants from endemic regions.  Within the US cases of cysticercosis are mostly reported in CA, IL, OR, TX, and NY.  Disseminated cysticercosis is an uncommon manifestation of the disease with fewer than 50 cases described worldwide, most occurring in India.  Even more unusual is involvement of the lung parenchyma (1), with less than 10 cases described in literature.  To our knowledge, this is only the second case of disseminated cysticercosis with pulmonary involvement described in North America (2). 

Cysticercosis most commonly affects the central nervous system (neurocysticercosis). However, when disseminated, it frequently involves the skin and subcutaneous tissue.  Cutaneous cysticerci are often a clue to the involvement of internal organs.  In one case series of thirty-three patients with disseminated cysticercosis, sixteen (48%) presented with cutaneous lesions (3).  Detection of the parasite in a biopsy specimen of skin nodules will aid in the diagnosis of disseminated cysticercosis and may prevent further, unnecessary diagnostic tests from being performed.

Sarcoidosis is a common cause of pulmonary nodules with extrapulmonary manifestations.  Recent reports have characterized the development of sarcoidosis in patients receiving pegylated interferon alfa and ribavirin for the treatment of Hepatitis C (4).  In sarcoidosis, there is a predominance of Th1 type immune response, while Th2 lymphocytes are relatively inactivated in granuloma formation (5).  Both IFN-α and ribavirin stimulate the differentiation of Th1-type lymphocytes while inhibiting the activation of Th2-type lymphocytes (6).  Together, this combination therapy works in favor of granuloma formation and the activation/re-activation of sarcoidosis. The temporal association between the initiation of therapy for hepatitis C and the onset of symptoms in the above case raised concern for drug induced sarcoidosis.  However, sarcoidosis is a diagnosis of exclusion and the specific identification of the parasite in the subcutaneous nodule biopsy makes sarcoidosis unlikely. 

The skin is the most common site for disseminated coccidioidomycosis.  Multiple pulmonary nodules with cutaneous lesions in an individual living in Arizona should raise suspicion for coccidioidomycosis. The above patient had a negative coccidioidomycosis work-up and biopsies were not consistent with that of coccidioidomycosis.

Conclusion

Pulmonary cysticercosis is an uncommon manifestation of cysticercosis.  The differential diagnosis of multiple pulmonary nodules is large. However, the diagnosis may be aided by recognizing extrapulmonary lesions that are often associated with lung diseases.  Disseminated cysticercosis with pulmonary involvement should be suspected in any patient presenting with multiple pulmonary nodules who is an immigrant from an endemic region or an individual who has resided in one of the States where cysticercosis is most commonly encountered.

References

1. Mamere AE, Muglia VF. Disseminated Cysticercosis With Pulmonary Involvement. J Thorac Imaging 2004;19:109-111.
2. Walts AE, Nivatpumin T, Epstein A. Pulmonary cysticercus. Mod Pathol 1995;8:299-302
3. Arora PN, Sanchetee PC, Ramakrishnan KR, Venkataram S. Cutaneous, mucocutaneous and neurocutaneous cysticercosis. Indian J Dermatol Venereol Leprol 1990;56:115-8
4. Ramos-Casals M, Mana J, Nardi N et al. Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases. Medicine 2000;84:69-80.
5. Rodríguez-Lojo, M. Almagro, J. M. Barja, et al., “Subcutaneous Sarcoidosis during Pegylated Interferon Alfa and Ribavirin Treatment for Chronic Hepatitis C,” Dermatology Research and Practice, vol. 2010, Article ID 230417, 2010. doi:10.1155/2010/230417
6. Tam RC, Pai B, Bard J, et al. Ribavirin polarizes human T cell responses towards a type 1 cytokine profile. J Hepatol 1999;30:376-382.

Address inquires to: Christopher.Strawter@mihs.org

Reference as: Strawter C,  Quiroga P, Zaidi S, Ardiles T. Pulmonary nodules with cutaneous manifestations: A  case report and discussion. Southwest J Pulm Crit Care 2012;4:116-21. (Click here for a PDF version of the manuscript)

March 2012 Pulmonary Case of the Month: There’s Air in There

Alexis Christie, MBBS

Lewis J. Wesselius, MD

History of Present Illness

A 40 year old male was seen with a one week history of dyspnea, dry cough, weakness and abdominal pain. He has a history of acute myelogenous leukemia (AML) diagnosed in December, 2010. He underwent consolidation chemotherapy but had a complication of acute lung injury following chemotherapy thought either to be due to infection or ara-C lung toxicity. Bronchoalveolar lavage was negative and video-assisted thoracotomy revealed only organizing pneumonia.

He underwent stem cell transplantation in May 2011 from a hepatitis C +, allogenic bone marrow transplant and received lamivudine post transplant because of the hepatitis C. Unfortunately, bone marrow biopsy in June 2011 revealed recurrent AML He received two cycles of decitabine.

He had further complications of severe graft versus host disease affecting his eyes, mouth and liver and severe, recurrent C. difficile sepsis. Present medications included: co-trimoxazole (Bactrim), lamivudine, acyclovir, posaconazole, tacrolimus, and prednisone.

Physical exam

Physical exam revealed a thin, moderately short of breath man but was otherwise unremarkable.

Radiology

His chest X-ray (Figure 1) and selected images from his CT scan (Figure 2) are shown below:

Figure 1. Chest x-ray.

Figure 2. Thoracic CT scan. Lung windows.

In addition to the confluent areas of airspace and ground glass opacities throughout both lungs what other finding is present?

1. Enlarged mediastinal lymph nodes
2. Pneumothorax
3. Atelectasis of the left lower lobe
4. Pneumomediastinum
5. Large RLL lung mass

Reference as: Christie A, Wesselius LJ. March 2012 pulmonary case of the month: there's air in there. Southwest J Pulm Crit Care 2012;4:88-93. (Click here for a PDF version of the case presentation)

Treatment of Coccidioidomycosis-associated Eosinophilic Pneumonia with Corticosteroids

Joshua Malo, MD

Yuval Raz, MD 

Linda Snyder, MD

Kenneth Knox, MD

University of Arizona Medical Center

Department of Medicine

Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine

Tucson, AZ 85724

Abstract

Pulmonary coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. The clinical spectrum of this disease ranges from an asymptomatic presentation to severe disease with ARDS and hypoxemic respiratory failure. Despite evidence supporting the use of corticosteroids for severe pulmonary disease in other fungal infections, there is currently no established role for this therapy in coccidioidomycosis infections. Peripheral eosinophilia is a common feature of coccidioidomycosis; however, pulmonary eosinophilia is rarely reported. In the setting of pulmonary eosinophilia of other etiologies, corticosteroid therapy has been demonstrated to have a role in reducing the inflammatory response and leading to a more rapid resolution of hypoxemic respiratory failure. We report a case of a patient with primary pulmonary coccidioidomycosis complicated by severe pulmonary eosinophilia that demonstrated rapid improvement after the initiation of corticosteroid therapy.

Case Report

A 71-year-old man presented to the emergency room in Tucson, Arizona with a one-week history of fever, cough, and malaise. The patient’s symptoms began while returning from a trip to northern California. A chest radiograph ordered by the primary care physician demonstrated a right upper lobe consolidation (Figure 1) and azithromycin was prescribed. Fevers persisted along with worsening cough over the next three days, and the patient presented for further evaluation.

Figure 1. Admission radiograph demonstrating right upper lobe airspace disease

Medical history was remarkable for viral cardiomyopathy requiring placement of an ICD after an episode of sudden cardiac death in 2006. An episode of S. bovis bacteremia occurred 4 months prior to the current presentation and was treated with a course of cefazolin. There is no known personal or family history of atopic disease. There is no history of tobacco use or significant occupational exposures. The patient had been living in Arizona during the preceding year and had no other recent travel history, dust, or environmental exposures.

On physical exam, temperature was 38.8°C and pulse oximetry saturation was 90 percent on room air. The patient was in moderate respiratory distress with rales auscultated in the right upper lung zone. Subsequent laboratory examination revealed a PaO2 of 69 mmHg on 4 liters-per-minute of oxygen via nasal cannula. A metabolic panel showed elevated transaminases and his initial leukocyte count was 11.8 x 10³/mL with differential including 5% eosinophils.

The patient was admitted to the medical ward and treated with vancomycin, cefepime, and moxifloxacin for pneumonia caused by a potentially resistant organism. Fluconazole was started on the third hospital day for empiric treatment of primary pulmonary coccidioidomycosis. A CT angiogram of the chest showed bilateral multilobar pneumonia (Figure 2).

Figure 2. CT angiogram of the chest demonstrating multilobar consolidation of the right lung

The patient deteriorated and required intubation for severe hypoxemia two days later. A bronchoalveolar lavage revealed Coccidioides spherules on cytological examination. Liposomal amphotericin B was initiated, which led to the development of oliguric renal failure necessitating hemodialysis. Initial Coccidioides serology was negative, however sputum and BAL cultures demonstrated C. immitis. Despite antifungal therapy his pulmonary status worsened with progressive bilateral pulmonary infiltrates and worsening hypoxemic respiratory failure (Figure 3).

Figure 3. CXR demonstrating progressive bilateral alveolar opacities consistent with ARDS.

In addition, he had a steadily increasing peripheral eosinophilia reaching a maximum of 40 percent with a leukocyte count of 14.8 x 10³/mL despite the absence of any signs of disseminated coccidioidomycosis. A repeat BAL again showed Coccidioides spherules and eosinophils of 40 and 56 percent from the right middle lobe and lingula, respectively. Methylprednisolone 40mg IV three times daily was started with a decline in blood eosinophils to one percent within 24 hours. Chest radiographs and A-a gradient rapidly improved over the next 3 days leading to successful extubation. The patient was transitioned to oral fluconazole and prednisone and discharged from the hospital in good condition two weeks later.

At the follow-up six weeks after initial presentation, he remains on fluconazole and prednisone 15mg daily with no signs of disseminated coccidioidomycosis and is continuing a gradual reduction of prednisone dosage.

Discussion

Coccidioidomycosis is caused by either of 2 species of the dimorphic fungus Coccidioides. Endemic regions are present in North and South America, with the majority of cases within the United States arising in Arizona and California. Although peripheral eosinophilia is a commonly reported finding (1), pulmonary eosinophilia has rarely been described.

Acute eosinophilic pneumonias may be idiopathic or a secondary inflammatory response to various infections or environmental exposures. In regions where endemic fungal infections are common, differentiating between eosinophilic pneumonias of idiopathic versus infectious etiology is vital in order to avoid inappropriate therapy and its adverse consequences. A review of the literature concerning pulmonary coccidioidomycosis and concurrent pulmonary eosinophilia demonstrates only 9 prior case reports. Corticosteroid therapy was used for treatment of the pulmonary eosinophilia in only 3 of these cases, 2 of which resulted in death from disseminated coccidioidal infection (1-3). One case ended in spontaneous resolution of disease without antifungals or corticosteroids leading the authors to suggest a conservative approach with corticosteroids due to the risk for dissemination (4).

In our case, there was progressive clinical deterioration despite ten days of treatment with appropriate antifungal regimen, leading to our decision to treat with corticosteroids. The immediate decrease in peripheral eosinophilia in conjunction with the rapid clinical improvement leads us to the conclusion that corticosteroids were beneficial in the resolution of his acute respiratory failure. The clinical response observed is similar to that expected in idiopathic acute eosinophilic pneumonia which supports the notion that the eosinophilic response, as opposed to the primary infection, was primarily responsible for our patient’s severe hypoxemia.

There remains a risk for disseminated disease. In the cases cited in which patients died of dissemination, antifungal therapy preceding corticosteroid therapy was not described. Due to the risk of underlying pulmonary coccidioidomycosis in endemic regions, corticosteroid therapy for eosinophilic pneumonia should only be considered in the setting of severe hypoxemic respiratory failure and once adequate antifungal therapy has been initiated.

According to recent guidelines there is no role for corticosteroid therapy in the treatment of coccidioidomycosis due to a lack of convincing data for efficacy and safety (5). There is precedent for treating severe pulmonary disease caused by other fungal infections, such as histoplasmosis and blastomycosis, with corticosteroids. We suggest that there is a role for the use of corticosteroid therapy in the setting of progressive respiratory failure due to coccidioidomycosis with associated pulmonary eosinophilia that has failed conventional antifungal therapy.

References

1. Echols RM, Palmer DL, Long GW. Tissue eosinophilia in human coccidioidomycosis. Rev Infect Dis 1982;4:656–664.
2. Lombard CM, Tazelaar HD, Krasne DL. Pulmonary eosinophilia in coccidioidal infections. Chest 1987;5:734–736
3. Swartz J, Stoller JK. Acute Eosinophilic Pneumonia Complicating Coccidioides immitis Pneumonia: A Case Report and Literature Review. Respiration 2009;77:102–106
4. Whitlock WL, Dietrich RA, Tenholder MF. Acute eosinophilic pneumonia (letter). N Engl J Med 1990;322:635
5. Limper AH, Knox KS, Sarosi GA, et al. Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96–128

The authors report no conflicts of interest

Address correspondence to:     Joshua Malo, MD

                                             University of Arizona Medical Center

                                             Department of Medicine    

                                             Section of Pulmonary, Allergy, Critical

                                             Care and Sleep Medicine

                                             Tucson, AZ 85724

                                             E-mail: jmalo@deptofmed.arizona.edu

Reference as: Malo J, Raz Y, Snyder L, Knox K. Treatment of coccidioidomycosis-associated eosinophilic pneumonia with corticosteroids. Southwest J Pulm Crit Care 2012;4:61-66. (Click here for a PDF version of the manuscript) 

Sympathetic Empyema Arising from Streptococcus anginosus Splenic Abscess

Emad Wissa, MD

Robert A. Raschke, M.D.

Manoj Mathew, MD, FCCP, MCCM 

Good Samaritan Regional Medical Center

1111 E. McDowell Road

Phoenix, AZ 85006

Abstract

We report a 52 year old male with a history splenic infarction, abdominal pain and shortness of breath. CT scanning revealed a splenic abcess and empyema. Cultures from both sites grew Streptococcus anginosus. These resolved with drainage and antibiotics. Physicians should consider Streptococcus species when confronted with a patient with splenic infarction.

Introduction

Sympathetic Empyema Thoracis or sympathetic empyema is a rare entity. The mechanism by which this occurs is via penetration by a subdiaphragmatic abscess into the pleural space. Most reported cases have occurred in the right hemithorax secondary to the presence of a liver abscess or ascites. Splenic abscess are rare and are often seen in the setting of embolic endocarditis, infections from Salmonella or other bacterial invade the infarcted spleen (1,2). To our knowledge, this is the first reported case of sympathetic empyema likely secondary to a Streptococcus splenic abscess.

Case Report

A 52 year old male presented with a 2 day history of shortness of breath and 2 a month history of left upper quadrant pain. His medical history included hepatitis C, drug abuse and splenic infarction. On examination his breathing was labored. His chest X-ray was remarkable for a left lower lobe opacification (Figure 1).

Figure 1. Chest x-ray showing left lower lobe opacification.

He was endotracheally intubated and started on broad spectrum antibiotics. A computed tomography (CT) of the chest and abdomen demonstrated a moderate left side pleural effusion, compressive atelectasis, a small amount of ascites and a splenic abscess (Figure 2).

Figure 2. Coronal CT of chest and upper abdomen.

A chest tube was placed into the left hemithorax, and a pigtail catheter was placed into the splenic abscess. Cultures from both sites yielded Streptococcus anginosus. The empyema was treated with antibiotics, and chest tube fibrinolytic therapy with tissue plasminogen activator (TPA) and dornase alpha. Blood cultures were sterile and echocardiogram revealed no vegetations. The patient was extubated on hospital day 4. The left pleural empyema responded well to fibrinolytic therapy with chest tube removal on day 10. The splenic abscess required long term drainage with pigtail remaining in place for 3 weeks before the abscess resolved. The patient was discharged home on hospital day 24 on amoxicillin.

Discussion

Sympathetic empyema is an infection in the pleural space caused by translocation of a bacterial infection from the liver, ascitic fluid or from a splenic abscess. This patient had a known history of splenic infarction predisposing him to bacterial invasion and splenic abscess formation. The absence of cough, sputum production, and lobar consolidation argues against an empyema arising from and underlying pneumonia, although we can not exclude that possibility. Our review of the medical literature demonstrates no known cases of sympathetic empyema from Streptococcus anginosus. Physicians should also consider this organism in a patient with a splenic abscess.

References

1. Buscaglia A. Empyema due to splenic abscess with Salmonella newport. JAMA1978;240:1990.
2. Tornos M.P, Mayor G, Nadal A, Soler A. Empyema and splenic abscess in infective endocarditis. Int J Cardio 1984;6:746-8.

Reference as: Wissa E, Raschke RA, Mathew M. Sympathetic empyema arising from streptococcus anginosus splenic abscess. Southwest J Pulm Crit Care 2012;4:48-50. (Click here for a PDF version of the case presentation)

February 2012 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Associate Editor Pulmonary

History of Present Illness

A 49 year old female was seen for fever and shortness of breath in December 2011. She has a history of right infiltrating ductal breast cancer diagnosed in 2001 at age 38. Treatment included mastectomy with negative lymph nodes, followed by 4 courses of doxarubicin and cytoxan. She did well until March 2010 when erythema was noted over her right chest.  Biopsy showed adenocarcinoma consistent with  breast carcinoma. The biopsy was “triple negative”, i.e., negative for estrogen receptors, progesterone receptors and Her2. PET scan demonstrated multiple positive lymph nodes in the mediastinum, supraclavicular area and bone metastases. She received radiation to her chest wall and chemotherapy most recently gemcitabine, carboplatin and iniparib. In October 2011 brain metastases were noted and she was started on stereotactic brain radiation and dexamethasone.

Past Medical, Family and Social Histories

• She had a prothrombin mutation noted and was begun prophylactically on warfarin in 2010.
• There was a family history of breast carcinoma.
• She was a non-smoker with no unusual exposures.
• Current medications include omeprazole, metoprolol, and warfarin.

Physical Examination

She was receiving oxygen at 3 L/min by nasal cannula. Temperature was to 37.9°C. She had bilateral crackles on chest auscultation, most prominent at bases. Physical Examination was otherwise noncontributory.

Initial Laboratory Evaluation

• Hemoglobin/Hematocrit 11.8 g/dL/33.9%
• White blood count 5.1 X10⁹/L
• Platelets 64 X 10⁹/L
• INR 1.58 

Chest CT scan

Chest CT scan is in figure 1.

Figure 1. Selected images from the admission CT scan. The CT scan was interpreted as showing diffuse groundglass opacities and scattered centrilobular nodules. 

Which of the following diagnosis are consistent with the patient’s presentation and CT scan?

1. Pulmonary edema
2. Bacterial pneumonia
3. Fungal pneumonia
4. Drug reaction
5. All of the above

Reference as: Wesselius LJ. February 2012 pulmonary case of the month. Southwest J Pulm Crit Care 2012;4:42-7.

(Click here for a PDF version of the case presentation)

(Click here for a Powerpoint slide presentation of the case)

Spirometry Use in Patients Prescribed Albuterol

Kevin Park, M.D.

Che' S. Ornelas, M.D.

Richard A. Robbins, M.D.

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

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

                                             502 E. Vermont Drive

                                             Gilbert, AZ 85295

                                             E-mail: rickrobbins@cox.net

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

Abstract

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

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

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

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

Introduction

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

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

Methods

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

Statistical Analysis

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

Results

Chart review

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

Demographics

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

Education Level of Provider

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

Other Respiratory Medications

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

Table 1. Spirometry and other respiratory medications prescribed

LABA=Long-acting beta agonist

ICS=Inhaled corticosteroid

*p=0.0007 compared to other medications

Diagnosis

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

Table 2. Spirometry and respiratory diagnosis

*p=0.00068 compared to other diagnosis

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

Discussion

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

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

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

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

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

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

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