Long-Term Low-Dose Erythromycin in Patients With Unexplained Chronic Cough: A Double-Blind Placebo Controlled Trial

http://thorax.bmj.com/content/early/2010/10/21/thx.2010.142711.
abstract
Thorax doi:10.1136/thx.2010.142711
• Chronic cough
Long-term low-dose erythromycin in patients with

unexplained chronic cough: a double-blind placebo
controlled trial
1. Nadia Yousaf , 1
2. William Monteiro , 1
3. Debbie Parker , 1
4. Sergio Matos , 2
5. Surinder Birring , 3
6. Ian D Pavord 1
+ Author Affiliations
1. Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust,
1
Leicester, UK
2. Institute of Electronics and Telematics Engineering (IEETA), University of Aveiro, Aveiro, Portugal
2
3. Kings College Hospital, Denmark Hill, London, UK

3
1. Correspondence to
Professor Ian D Pavord, Institute for Lung Health, Glenfield Hospital, University Hospitals of
Leicester NHS Trust, Groby Road, Leicester LE3 9QP, UK; ian.pavord@uhl-tr.nhs.uk
• Received 14 May 2010
• Accepted 5 August 2010
• Published Online First 21 October 2010
Abstract
Aims Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has
suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-
term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with
unexplained chronic cough.
Methods 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take
250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough
frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary
outcome measure was change in 24 h cough frequency at 12 weeks.
Results There was no difference in the change in cough frequency between the erythromycin and placebo groups at
12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically
significant between-treatment difference in the change in sputum neutrophils at 12 weeks (−10.2% vs +6.6% with
erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no
difference in the change in other measures of cough between treatments.
Conclusions Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but
not cough frequency or severity in patients with unexplained chronic cough.
Macrolides
• 14-member (clarithromycin,
erythromycin, roxithromycin)
• 15-member (azithromycin)
Macrolides
• Immunomodulatory effects
• Decreases length of stay and
mortality
G. W. Amsden. Anti-inflammatory effects of macrolides—an
underappreciated benefit in the
treatment of community-acquired respiratory tract infections and chronic
inflammatory
pulmonary conditions? J Antimicrob Chemother 2005 55(1):10-21
Macrolides
• Decrease sputum/mucus
production
• suppress the overabundance
of neutrophils (PMNs)
• eosinopenic effect
• break down and prevent
further development of
biofilms of P. aeruginosa
G. W. Amsden. Anti-inflammatory effects of macrolides—an
underappreciated benefit in the
treatment of community-acquired respiratory tract infections and
chronic inflammatory
pulmonary conditions? J Antimicrob Chemother 2005 55(1):10-21
Pharmacological Treatment Options for Bronchiectasis:

Focus on Antimicrobial and Anti-Inflammatory Agents
Ilowite, Jonathan; Spiegler, Peter; Kessler, Heather
Abstract
Patients with bronchiectasis experience tenacious mucus, recurrent infectious exacerbations, and
progressive worsening of symptoms and obstruction over time. Treatment is aimed at trying to
break the cycle of infection and progressive airway destruction. Antibacterial treatment is
targeted towards likely organisms or tailored to the results of sputum culture. Inhaled
antibacterial therapy may offer the advantage of increased local concentration of medication,
while minimizing systemic adverse effects; however, to date, studies have been equivocal in this
disorder. Macrolides, in addition to their antibacterial properties, have unique anti-inflammatory
properties, which may make them useful in this disorder. Other mucoactive and anti-
inflammatory agents, such as inhaled corticosteroids, mannitol and hypertonic saline, may also
prove useful in this disease, but further studies are needed.
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Azithromycin as a Treatment for COPD

After 12 weeks of low-dose azithromycin, COPD patients showed increased alveolar
macrophage expression of mannose receptors and increased phagocytosis of apoptotic
bronchial epithelium cells.
Chronic obstructive pulmonary disease (COPD) is associated with inflammation and loss of lung
integrity. Some investigators have hypothesized that these changes result from dysregulated
apoptosis of bronchial epithelial cells and reduced phagocytosis by alveolar macrophages (AMs).
Low-dose macrolide antibiotics have been shown to have anti-inflammatory properties, and
azithromycin may be particularly useful because of its ability to reach high levels in AMs. One
proposed mechanism for these macrolide effects involves enhanced expression of collectins and
their receptors. Mannose-binding lectin (MBL) — a lung collectin — binds to mannose receptors
(MRs) on the surface of AMs and augments phagocytosis.
In a partially industry-funded study involving 11 patients with COPD, researchers in Australia
investigated azithromycin’s effectiveness and mechanism of action. In vitro, azithromycin
significantly enhanced the percentage of AMs expressing MRs on their surface. Moreover, MBL
levels and surface MR expression on AMs in bronchoalveolar lavage (BAL) samples from
COPD patients were significantly lower than those in samples from nonsmoking healthy controls
(P<0.05). However, after 12 weeks of low-dose azithromycin (250 mg orally for 5 days, then
twice weekly), the expression of MRs and the phagocytotic ability of AMs were significantly
increased. In addition, the percentage of apoptotic bronchial epithelial cells in BAL samples
from COPD patients was significantly decreased.
Comment: The findings from in vitro and ex vivo analyses suggest that low-dose azithromycin
can reduce inflammation in patients with COPD by increasing AM phagocytosis of apoptotic
bronchial epithelial cells. This effect is not antibacterial but rather is modulated through the
innate immune response.
— Neil M. Ampel, MD
Published in Journal Watch Infectious Diseases July 23, 2008
10.1378/chest.123.1.261 CHEST January 2003 vol. 123 no. 1 261-265
Tissue Reparative Effects of Macrolide Antibiotics in

Chronic Inflammatory Sinopulmonary Diseases*
1. Kevin W. Garey, PharmD,
2. Anita Alwani, MD,
3. Larry H. Danziger, PharmD and
4. Israel Rubinstein, MD, FCCP
1. From the Department of Clinical Sciences and Administration (Dr. Garey), University of
*
Houston College of Pharmacy, Houston, TX; the Departments of Medicine (Drs. Alwani and
Rubinstein) and Pharmacy Practice (Dr. Danziger), Colleges of Medicine and Pharmacy,
University of Illinois at Chicago, Chicago, and Chicago VA Health Care System, West Side
Division, Chicago, IL.
1. Correspondence to: Israel Rubinstein, MD, FCCP, Professor of Medicine, Section of
Respiratory and Critical Care Medicine, Department of Medicine (M/C 787), University of
Illinois at Chicago, 840 S Wood St, Chicago, IL 60612-7323; e-mail: Irubinst@uic.edu
Next Section
Abstract
It is well established that macrolide antibiotics are efficacious in treating sinopulmonary
infections in humans. However, a growing body of experimental and clinical evidence indicates
that they also express distinct salutary effects that promote and sustain the reparative process in
the chronically inflamed upper and lower respiratory tract. Unlike the anti-infective properties,
these distinct effects are manifested at lower doses, usually after a relatively prolonged period
(weeks) of treatment, and in the absence of an identifiable, viable pathogen. Long-term, low-dose
administration of macrolide antibiotics has been used most commonly for sinusitis, diffuse
panbronchiolitis, asthma, bronchiectasis, and cystic fibrosis. It is associated with down-
regulation of nonspecific host inflammatory response to injury and promotion of tissue repair.
Although large-scale trials are lacking, the prolonged use of these drugs has not been associated
with emergence of clinically significant bacterial resistance or immunosuppression. Long-term,
low-dose administration of 14- and 15-membered ring macrolide antibiotics may represent an
important adjunct in the treatment of chronic inflammatory sinopulmonary diseases in humans.
• anti-inflammatory
• immunomodulatory
• macrolide antibiotics
It is well established that macrolide antibiotics, including the semisynthetic derivatives of

erythromycin, are clinically useful in treating sinopulmonary infections in humans.123 However, a
growing body of experimental and clinical evidence emanating predominantly from Japan
indicates that the 14- and 15-membered ring macrolide antibiotics also possess distinct
salutary properties that promote and sustain the reparative process in the chronically inflamed
upper and lower respiratory tract.45 Unlike the anti-infective properties, these distinct effects are
expressed at lower doses, usually after a relatively prolonged period (weeks) of treatment, and in
the absence of an identifiable, viable pathogen. 4678 Importantly, long-term, low-dose
administration of macrolide antibiotics is not associated with increased incidence of adverse
events, emergence of clinically relevant bacterial resistance, or immunosuppression.8910
Although the mechanisms underlying the pleiotropic tissue reparative effects of macrolide
antibiotics in chronically inflamed sinopulmonary tissues in humans are uncertain, they may be
related, in part, to the highly hydrophobic nature of the 14- and 15-membered lactone ring
coupled with the hydrophilic nature of both sugar moieties of the cell. 3111213 This distinct
biophysical feature may form drug micelles and promote avid and preferential interaction of
macrolide antibiotics with phospholipids in the plasma and intracellular organellar membranes,
including the nucleus, in activated effector cells that sustain uncontrolled, self-perpetuating
inflammation in the chronically inflamed sinopulmonary tissue, such as leukocytes,
macrophages, epithelial cells, goblet cells, and fibroblasts.3111213 This process may, in turn, alter
the biophysical state of the membrane bilayer in effector cells, including fluidity and charge,
thereby disrupting the functional integrity of key membrane-associated proteins that regulate
key intracellular metabolic and transcriptional pathways involved in the inflammatory cascade,
such as reactive oxygen species, nitric oxide, and cytokines.131415
The purpose of this review is to provide a concise account of the tissue reparative effects of
macrolide antibiotics in chronic inflammatory sinopulmonary diseases in humans based on
published English-language literature. Articles were identified by a MEDLINE search from 1966 to
present using the search terms macrolides, anti-inflammatory, and immunomodulatory, and a
review of identified bibliographies. A detailed account of the putative cellular and molecular
mechanisms underlying these effects is beyond the scope of this article.
Previous SectionNext Section

Chronic Inflammatory Sinopulmonary Diseases
Chronic Rhinosinusitis and Nasal Polyps
Chronic sinusitis, a common disease of the paranasal sinuses, is characterized by purulent sinus
effusion and nasal discharge.16 Neutrophils play an important role in regulating the inflammatory
process by secreting various pro-inflammatory cytokines, such as interleukin (IL)-8.17 Fourteen-
membered ring macrolide antibiotics, such as erythromycin and clarithromycin, are efficacious
in chronic sinusitis.8181920 Patients administered low-dose clarithromycin8 or roxithromycin (not
available in the United States)19 displayed improved aeration, and decreased neutrophil and IL-8
levels in the nasal discharge. Suzuki et al21 determined the prognostic factors that influence the
efficacy of low-dose macrolide antibiotic therapy. They found that patients without atopy or
eosinophilia were more likely to respond to either clarithromycin or roxithromycin. Importantly,
maximal effects were not seen until at least 12 weeks of continuous therapy, and the authors
hypothesized that even longer treatment may be necessary for maximal effect. In further in vitro
studies, cultured nasal epithelial cells from patients with chronic sinusitis secreted less IL-8 in the
presence of low concentrations of 14-membered ring macrolides.1920222324
Asthma
Macrolide antibiotics, especially troleandomycin and erythromycin, have been studied since the
1950s and have been shown to decrease corticosteroid requirement in patients with
corticosteroid-dependent asthma.252627 For instance, Spector et al28 reported a double-blind,
crossover trial comparing troleandomycin to placebo in 74 corticosteroid-dependent patients with
severe asthma and chronic bronchitis. Sixty-seven percent of patients had a marked
improvement in sputum production, pulmonary function measurements, need for
bronchodilators, and subjective evaluations. Much of this effect, however, was attributed to
troleandomycin-induced inhibition of methylprednisolone and theophylline metabolism by the
hepatic cytochrome P450 complex.29303132
In vitro studies have suggested that macrolide antibiotics have beneficial anti-inflammatory
and immunomodulatory effects in patients with asthma who are independent of the
corticosteroid metabolism.33 Macrolide antibiotics inhibit lymphocyte proliferation in response to
phytohemagglutinin, decrease neutrophil accumulation through decrease chemotactic activity,
decreased mucus secretion, and decrease contraction of isolated bronchial tissue.33
Open-label studies with troleandomycin in methyprednisolone-dependent patients with asthma

(adults and children) have demonstrated greater reduction in corticosteroid doses than would be
predicted by hepatic inhibition of corticosteroid metabolism.273435 Gotfried et al36 showed a
significant improvement in pulmonary function test results and quality of life measures in
prednisone-dependent patients with asthma administered a 6-week course of clarithromycin
without any change in prednisone requirements. In a small case series of patients administered
clarithromycin for 1 year, two of three prednisone-dependent patients were able to discontinue
prednisone entirely.10
Macrolide antibiotics are efficacious measures in asthmatic patients without corticosteroid

dependency by reducing airway hyperreactivity.313738394041 A 10-week course of low-dose
erythromycin was associated with a significant decrease in bronchial hyperresponsiveness in
asthmatic patients tested by histamine challenge.3839 Similar effects were observed when 12
hospitalized children were treated with roxithromycin.42 Tamaoki et al43 showed that
erythromycin, roxithromycin, and clarithromycin attenuated the contractile response of human
isolated bronchial strips to electrical field stimulation. They hypothesized that macrolide
antibiotics inhibit the cholinergic neuroeffector transmission in human airway smooth muscle.
Another possible explanation for the efficacy of macrolide antibiotics in patients with asthma is
the role of chronic infectious diseases, particularly Chlamydia pneumoniae.44 These infectious
agents may underlie acute asthma exacerbations and the initiation and maintenance of asthma
in previously asymptomatic patients.45 The anti-infective vs tissue reparatory effects of
macrolide antibiotics in asthma will require further controlled studies to unravel these
pathways.
Diffuse Panbronchiolitis
Diffuse panbronchiolitis, a noninfectious, inflammatory disease prevalent in Japan, is
characterized by chronic inflammation of the respiratory bronchioles, and parabronchial and
luminal accumulation of mononuclear inflammatory cells.464748 Persistent accumulation of
neutrophils evokes airway damage through the effects of oxidative and proteolytic products.495051
In addition, there is a significant correlation between neutrophil accumulation and augmented
neutrophil chemotactic activity in the BAL fluid of these patients.51
Diffuse panbronchiolitis presents with chronic cough, mucopurulent expectoration, and dyspnea,
and is associated with chronic sinusitis in 75% of cases. The chest radiograph and high-
resolution CT findings reveal diffuse ill-defined centrilobular nodules with hyperinflated lungs.
Bronchiectasis is observed in the most advanced cases.46 Infections with Haemophilus influenzae,
Streptococcus pneumoniae, Klebsiella pneumonia, and Staphylococcus aureus are common and
are ultimately superceded by infections with Pseudomonas aeruginosa.52 Untreated, the 5-year
mortality rate is 50% and the 10-year survival rate is 25%.74648 Kudoh47 reported that long-term,
low-dose oral administration of erythromycin was effective in the treatment of diffuse
panbronchiolitis. Eighteen patients with diffuse panbronchiolitis were treated for 19 months with
significant increases in lung function along with decreased signs and symptoms of disease.
Similar effects were observed with roxithromycin, clarithromycin, and azithromycin.4567
Clindamycin, piperacillin, and ampicillin, administered as comparator agents in these trials, were
ineffective. Since the initiation of macrolide antibiotic therapy in patients with diffuse
panbronchiolitis, the 10-year survival rate has improved > 90%.6752 However, the mechanisms
underlying these salutary effects have not yet been elucidated.
Non-Cystic Fibrosis Bronchiectasis and Chronic Bronchitis

Bronchiectasis and chronic bronchitis are characterized by excessive mucus production. 535455 An 8-
week pilot study of low-dose erythromycin showed an improvement in lung function and a
decrease in sputum volume in patients with bronchiectasis.56 Koh et al57 treated 25 children with
bronchiectasis with 12 weeks of low-dose roxithromycin and found an improvement in sputum
purulence by 6 weeks and a decrease in airway hyperresponsiveness by inhaled methacholine
challenge. In another study, low-dose roxithromycin treatment improved symptoms, pulmonary
functions, and radiographic findings of patients with chronic lower respiratory tract
inflammation. This was associated with a decrease in IL-8, neutrophil elastase, and
complement 5a concentrations in the epithelial lining fluid and resulted in attenuation of
neutrophil infiltration.58
Cystic Fibrosis and P aeruginosa Colonization

Nonmucoid P aeruginosa initially invades the airway of patients with cystic fibrosis and
subsequently transforms into mucoid strains producing alginate, a major component of the
mucoid material.596061 These mucoid strains form a bacterial biofilm by encasing the alginate
around them as they adhere to the airway mucosa, thereby enhancing their resistance to the
host’s phagocytic activity.626364 Alginate also increases sputum viscosity thus promoting bacterial
colonization.
The minimum inhibitory concentration of macrolide antibiotics for most pseudomonal infections
is higher than the peak serum concentration achieved after the IV administration of these drugs. 65
Thus, by conventional criteria, P aeruginosa is resistant to macrolide antibiotics. However, Kita
et al66 showed that erythromycin exhibited an inhibitory effect on the virulence factors produced
by P aeruginosa, such as protease, elastase, and leucocidin. Likewise, 14- and 15-membered
ring macrolide antibiotics inhibit alginate production by mucoid P aeruginosa strains, an effect
not seen with 16-membered ring macrolide antibiotics.61626364 It is also notable that 14- and 15-
membered ring macrolide antibiotics can facilitate the penetration of bacterial biofilm by
ciprofloxacin thus eliminating bacteria inside the biofilm.67
Cryptogenic Organizing Pneumonia

Hotta68 showed that in a small number of patients with cryptogenic organizing pneumonia, daily,
low-dose, oral erythromycin for 2 to 3 months is associated with a favorable clinical response
along with a significant decrease in IL-8 and neutrophil chemotactic activity in the BAL fluid.
These preliminary observations should be corroborated by large-scale studies using well-defined
patient populations with idiopathic pulmonary fibrosis.

Conclusion
Long-term, low-dose administration of 14- and 15-membered ring macrolide antibiotics is
associated with salutary tissue reparative effects in patients with chronic inflammatory
sinopulmonary diseases such as chronic sinusitis, asthma, bronchiectasis, cystic fibrosis, and
diffuse panbronchiolitis that are distinct from their anti-infective properties. Overall, these
responses are associated with down-regulation of the nonspecific host inflammatory response to
injury in these tissues. Importantly, the prolonged use of these drugs is not associated with
emergence of clinically significant bacterial resistance or immunosuppression. Large-scale,
double-blind, randomized studies are warranted to establish the merit of long-term, low-dose
macrolide antibiotic therapy in chronic inflammatory sinopulmonary conditions.

Footnotes
• Abbreviation: IL = interleukin
• Dr. Garey is on the Speakers’ Bureau for Abbott Laboratories and Aventis Pharmaceuticals.
Dr. Danziger is on the Speakers’ Bureau and has received research grants from Abbott
Laboratories, Ortho-McNeil Pharmaceuticals, AstraZeneca Pharmaceuticals, and Merck &
Co.
• Dr. Rubinstein is on the Speakers’ Bureau and has received research grants from Abbott
Laboratories, Aventis Pharmaceuticals, GlaxoSmithKline, and Chiron. Financial support for
this review was provided by the University of Illinois at Chicago and Abbott Laboratories.
•
○ Received October 16, 2001.
○ Accepted June 27, 2002.
Previous Section
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Kolbe, J, Wells, AU Bronchiectasis: a neglected cause of respiratory morbidity and
mortality. Respirology 1996;1,221-225
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Tsang, KW, Ho, PI, Chan, KN, et al A pilot study of low-dose erythromycin in
bronchiectasis. Eur Respir J 1999;13,361-364
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Koh, YY, Lee, MH, Sun, YH, et al Effect of roxithromycin on airway responsiveness in
children with bronchiectasis: a double-blind, placebo-controlled study. Eur Respir J
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Nakamura, H, Fujishima, S, Inoue, T, et al Clinical and immunoregulatory effects of
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Medline
Macrolides for the Treatment of Chronic Sinusitis,
Asthma, and COPD*
1. Mark H. Gotfried, MD, FCCP
1. *
From the University of Arizona, Phoenix, AZ.
Next Section
Abstract
In addition to their well-known antimicrobial activity, macrolides possess immunomodulatory
properties that may confer beneficial effects to patients with respiratory diseases associated
with chronic inflammation. These properties include attenuation of inflammatory responses in
the lung, mucoregulatory properties, and effects on bronchial responsiveness. Macrolides
increase mucociliary clearance, improve sinusitis symptoms, and decrease nasal secretions and
polyp size in patients with sinusitis. They also have been shown to modify the inflammatory
response associated with chronic sinusitis. In patients with asthma, macrolides have been
reported to reduce airway hyperresponsiveness and improve pulmonary function, and have
historically been selected for their “steroid-sparing” effect. Preliminary data from studies of
patients with COPD have shown improvements in symptom scores and FEV1 after macrolide
treatment. As biological response modifiers, macrolides have the potential to improve the
outcomes of patients with inflammatory airway diseases. Large scale, placebo-controlled clinical
trials designed to assess long-term efficacy and safety in these diseases are warranted.
• anti-inflammatory activity
• asthma
• clarithromycin
• COPD
• erythromycin
• macrolides
• roxithromycin
• sinusitis
The role of macrolide antibiotics for the treatment of upper and lower respiratory tract
infections is well-established. Based on a consistent record of efficacy, the newer macrolides,
clarithromycin (Biaxin; Abbott Pharmaceuticals; Abbott Park, IL) and azithromycin (Zithromax;
Pfizer Pharmaceuticals; New York, NY), are currently recommended by several agencies/medical
societies for first-line (or alternative) treatment of community-acquired pneumonia, acute
exacerbations of chronic bronchitis, acute bacterial sinusitis, and streptococcal pharyngitis.
Perhaps less appreciated is a long-standing and relatively consistent body of literature that
suggests that macrolides act as biological response modifiers, attenuating respiratory tract
inflammation.
Independent of their potent antimicrobial activity, 14-membered and 15-membered macrolides
possess anti-inflammatory properties that may contribute to clinical benefits observed in
patients with airway inflammation (Table 1 ).12345 Macrolides can normalize bronchial and nasal
mucus secretion and/or properties, and may reduce bronchial hyperresponsiveness and sputum
purulence. Macrolides also affect neutrophil migration, the oxidative burst in phagocytes, the
production of proinflammatory cytokines, and eosinophilic inflammation. The clinical impact of
these effects in patients with chronic sinusitis, asthma, and COPD is the focus of this article. The
results of studies in which patients with chronic sinusitis, asthma, or COPD received a macrolide
are summarized.

Chronic Sinusitis
Chronic sinusitis is one of the most common diseases in the United States, affecting 14% of the
population.6 It is a burdensome clinical illness, significantly diminishing quality of life. 78 Between
1990 and 1992, sinusitis-associated symptoms resulted in > 70 million days of restricted
activity.9 The economic impact of the disease is also staggering, with health-care expenditures in
the United States attributable to sinusitis estimated to be about $5.8 billion annually.10
Nasal congestion, increased quantity and tenacity of secretions, facial pain, and fatigue are
common among patients with chronic sinusitis. Hyperplastic changes in the mucosa,
hypertrophy, and hypersecretion of the nasal and paranasal sinus mucosa are typical, as is an
inflammatory infiltrate containing lymphocytes, plasma cells, neutrophils, and eosinophils.11
Hyperplastic and hypertrophic changes of the nasal mucosa cause narrowing of the drainage
route from the paranasal sinuses and sinus cavities, leading to mucosal congestion and edema.
Hypersecretion disturbs mucociliary clearance. Obstruction of the sinus ostia creates an
increasingly hypoxic environment within the sinus, and leads to inflammation and an ideal
culture medium within the sinus cavity.12 Maintaining ostia patency is critical to reversing the
cycle of sinusitis.13 As summarized below, there is accumulating evidence that macrolides may
alter the natural history of chronic sinusitis, which is characterized by elevated levels of
inflammatory mediators (eg, granulocyte macrophage colony-stimulating factor, interleukin [IL]-
3, and IL-8).141516 Macrolides may inhibit the vicious cycle of cytokine production, neutrophil
recruitment, and impaired mucociliary function at the site of inflammation, thereby interrupting
the prolonged inflammation of chronic sinusitis.
Clinical Experience
Clinical reports of macrolide use in patients with chronic sinusitis come primarily from small,
open-label case series. Consistent across the studies have been improvements in sinusitis
symptoms, shrinkage in the size of nasal polyps, and a decrease in levels of proinflammatory
cytokines in nasal secretions. Most of the clinical experiences demonstrating the favorable anti-
inflammatory effects of macrolides on patients with chronic sinusitis have been published in the
Japanese literature. A summary of articles describing the clinical experience with macrolides in
patients with chronic sinusitis is presented in Table 2 .1718192021222324252627
Data from the beginning of the last decade from Kikuchi and coworkers17 from Japan documented
improvement of sinusitis signs and symptoms in 50 to 100% of patients who were given
macrolide therapy. The investigators treated 26 postoperative patients with persistent sinus
symptoms following sinus surgery using erythromycin, 600 mg per day for an average of 7.9
months. Also published in the Japanese literature were the results of studies by Nishi et al22 and
Suzuki et al.27 Following treatment with clarithromycin, 400 mg daily for 4 weeks, significant
improvements in mucociliary clearance, volume of secretions, cough frequency, and dyspnea-on-
exertion were documented in 32 patients with sinobronchial syndrome.22 Low-dose roxithromycin
(Rulid; Albert-Roussel Pharma GmbH; Wiesbaden, Germany) was shown to significantly improve
the aeration of all four sinuses and to significantly reduce neutrophil and IL-8 levels in the nasal
discharge of 12 patients with chronic sinusitis.27
The first article describing the use of macrolides in patients with chronic sinusitis appeared in
the English literature in 1996. Hashiba and Baba20 treated 45 chronic sinusitis patients with
clarithromycin, 400 mg daily for 8 to 12 weeks. Improvements in symptoms and rhinoscopic
findings were directly related to the duration of macrolide therapy. The investigators noted
improvement rates of 5%, 48%, 63%, and 71%, respectively, after 2, 4, 8, and 12 weeks of
therapy. After 12 weeks of therapy, 64% of patients had reduced viscosity of nasal secretions,
56% had reduced quantity of nasal secretions, 62% had reduced postnasal drip, and 51% had
reduced nasal obstruction. Clinical benefit in patients with chronic sinusitis also was observed
following long-term administration of roxithromycin, 150 mg daily.26
The following year, Rubin and associates21 reported on the results of a study in which the nasal
mucus properties in 10 healthy volunteers were compared to those in 10 patients with purulent
rhinitis before and after treatment with clarithromycin, 500 mg twice daily for 2 weeks. Before
the initiation of therapy with the macrolide, secretions from those patients with rhinitis had
statistically significantly decreased wetability and sneeze clearability, and had statistically
significantly increased the percentage of solids and cohesion, compared to those in secretions
from the healthy subjects. After clarithromycin therapy, the secretions from the healthy adults
without nasal symptoms were similar, based on rheology, hydration, cohesion, and
transportability, to that of rhinitis patients. The secretion volume decreased by > 10-fold (p <
0.01), and mucociliary transportability increased by 30% (p = 0.005). Secretory response to
methacholine was not affected by clarithromycin, suggesting that the effect of the macrolide on
mucus properties was based on the modulation of inflammation.
In a prospective, open-label study conducted at a single center in the United States, 25 patients
(mean age, 45 years) with chronic sinusitis were treated with clarithromycin, 500 mg twice daily
for 14 days.24 The diagnosis of chronic sinusitis was established based on history, physical
examination findings, and the results of an ear-nose-throat evaluation and CT scan. Biopsy
specimens of the maxillary sinus mucosa were obtained prior to the initiation of macrolide
therapy and 7 days after its completion. Statistically significant reductions from baseline were
observed for all major markers of sinus mucosal inflammation, including the levels of
macrophages (CD68), elastase, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and the activity of
eosinophils (EG2). Edema score decreased by 41% (p < 0.001). Improvement in clinical signs and
symptoms (ie, sinus pain, sinus headache severity, nasal congestion, nasal discharge, and
mucopurulent discharge) was observed at the 1-week and 2-week follow-up visits (Fig 1 ).24 The
associated reduction of various markers of sinus inflammation supports the hypothesis that
clarithromycin modulates the immune response.
While endoscopic sinus surgery cures many patients with chronic sinusitis, especially those with
anatomic narrowing of the drainage route from the sinuses, there is a group of patients who
experience persistent symptoms following surgical intervention. Cervin and colleagues19
evaluated the effect of macrolide therapy (erythromycin, 250 mg twice daily, or clarithromycin,
250 mg once daily) on clinical outcome and mucociliary parameters in 17 patients with chronic,
persistent sinusitis after sinus surgery. Twelve of these patients responded to macrolide therapy
at 3 months and were reassessed after 12 months of treatment. Nonresponders abandoned
antibiotic therapy after 3 months. At the 12-month follow-up visit, an improvement in the
mucociliary transit time was observed (p < 0.05), without a statistically significant change in
ciliary beat frequency. Statistically significant improvements also were seen in endoscopic nasal
examination scoring (p < 0.01) as well as in nasal congestion, sticky secretions, and runny nose
at both 3 and 12 months based on visual analog scale scoring (p < 0.01 each). Patients also
experienced fewer headaches (p < 0.05).
Patients with chronic sinusitis often develop nasal polyps, which are either neutrophil-dominant
(ie, containing abundant proinflammatory cytokines such as IL-8) or eosinophil-dominant. The 14-
membered macrolides (eg, erythromycin, clarithromycin, and roxithromycin), and less so the
16-membered macrolides (eg, josamycin [Yamanouchi Pharmaceutical Co; Tokyo, Japan]),
inhibited IL-8 secretion from cultures of human nasal epithelial cells harvested from the nasal
polyps of patients with chronic sinusitis.28
Yamada and coworkers23 evaluated the effect of macrolide therapy on the size of nasal polyps
and IL-8 levels in the nasal lavage fluid of 20 patients (age range, 24 to 84 years; mean age, 57
years) with chronic paranasal rhinosinusitis. All patients had experienced > 1 year of congestion,
rhinorrhea, postnasal drip, olfactory disturbance, and/or discomfort in the regions of the sinuses.
During macrolide treatment (clarithromycin, 400 mg daily for 8 to 12 weeks), patients had a
significant decrease in levels of IL-8, a critical cytokine in the pathogenesis of chronic
rhinosinusitis. Clinical response correlated significantly with decreased IL-8 levels. In the group of
patients in whom polyps were reduced in size during macrolide therapy, IL-8 levels were
significantly higher at baseline (231.2 vs 88.1 pg/mL, respectively [among those whose polyps
showed no change in size; p < 0.005]) and decreased by more than fivefold (p < 0.05). In
contrast, there was no difference in IL-8 levels before and after macrolide therapy in the
patients in whom polyps did not change in size.
Similar findings were reported by Ichimura et al, 25 who treated 20 patients with nasal polyps
associated with chronic sinusitis with roxithromycin, 150 mg once a day for 8 weeks. At the
completion of macrolide treatment, a reduction in the size of nasal polyps was observed in
more than half of the treated patients. The investigators theorized that the shrinkage of nasal
polyps by macrolides is related to the suppression of cytokine production by inflammatory cells
in the paranasal sinus epithelium.

Asthma
Affecting about 5% of the population, 29 asthma is associated with increased risks of long-term
morbidity and mortality. Exposure to allergens and airway irritants (eg, tobacco smoke and air
pollutants) has been proposed as causes for increased prevalence and morbidity of asthma.29 In
1999, asthma accounted for about 9.5 million physician office visits and 500,000 hospitalizations
in the United States.30 While death due to asthma is relatively uncommon, the age-adjusted
annual mortality rate is significantly higher among African Americans than among whites, and
was higher among women than men for each ethnic group.30 The annual economic burden of
asthma in the United States, including direct and indirect costs, has been estimated at $14
billion.30
Asthma is the prototypical inflammatory disease of the lower airways. Persistent airway
inflammation, a cardinal feature of asthma, produces airway hyperresponsiveness and
recurrent episodes of airway obstruction. Given the role of airway inflammation, the prompt
initiation of an anti-inflammatory agent (ie, inhaled or oral corticosteroids) is the mainstay of
therapy.29 According to data published over the last several years, macrolide therapy improves
the signs and symptoms of asthma, likely as a result of their anti-inflammatory properties.
Clinical Experience
The initial experience with macrolides in treating asthma dates back > 40 years.31 Since then,
reductions in steroid use by > 50% in steroid-dependent asthmatic patients,3233343536 airway
hyperresponsiveness,34 and hospital admissions,353738 as well as improved spirometry test results
(eg, FEV1 and FVC)323338 and asthma control3738 have been documented in numerous trials
subsequent to treatment with troleandomycin. Similar benefits to patients with asthma have
been observed with the newer macrolides.
Evaluating 23 asthmatic patients who were not receiving steroid therapy, Miyatake et al39
documented a decrease in bronchial hyperresponsiveness to a histamine challenge following 10
weeks of treatment with low-dose erythromycin. Similar results have been observed with
clarithromycin and roxithromycin. In a double-blind, placebo-controlled, crossover study,
Amayasu and coworkers40 measured bronchoconstriction caused by the inhalation of
methacholine in 17 adults with bronchial asthma who received clarithromycin, 200 mg, or
placebo twice daily for 8 weeks. The investigators reported a statistically significant decrease (vs
placebo and the baseline values of clarithromycin) in symptoms, blood and sputum eosinophil
counts, and sputum eosinophilic cationic protein, as well as in the suppression of bronchial
hyperresponsiveness after 8 weeks of treatment.40 Shimizu and associates41 documented a
significant decrease in airway hyperresponsiveness to a histamine challenge in 12 hospitalized
asthmatic children after 4 weeks (p < 0.05) and 8 weeks (p < 0.01) of therapy with
roxithromycin, 150 mg daily.
We conducted a double-blind, randomized, placebo-controlled, pilot study42 to evaluate the
efficacy of therapy with clarithromycin, 500 mg twice daily for 6 weeks, in 21 patients with
corticosteroid-dependent asthma (ie, patients had been receiving ≥ 5 mg prednisone for ≥ 6
months prior to study enrollment). Compared with baseline values, increases in FVC (p = 0.038)
and FEV1 (p = 0.07), as well as decreases in nocturnal dyspnea (p = 0.05), social concerns (p =
0.048), and chest discomfort (p = 0.02) were found posttreatment (Table 3 ).42 The decrease in
nighttime symptoms, a surrogate marker for inflammation, is suggestive of a clinical benefit
based on the anti-inflammatory effects of macrolides. No increase in steroid dosage was
required during the study. In fact, during the study, the majority of the patients were able to
reduce their prednisone dosage, and two elderly patients discontinued prednisone therapy
altogether.43
An anti-inflammatory bronchial effect also has been reported with roxithromycin. In a double-
blind, placebo-controlled, crossover study44 of 14 patients with aspirin-intolerant asthma,
patients’ symptoms, serum eosinophil counts, sputum eosinophil levels, and serum and sputum
eosinophilic cationic protein levels were statistically significantly decreased after 8 weeks of
therapy with roxithromycin, 150 mg twice daily. Kamoi and collaborators45 reported significantly
reduced (p < 0.01) bronchial hyperreactivity and synthesis of free radicals (ie, superoxide anion)
in 10 asthmatic patients who had been treated with roxithromycin, 150 mg daily for 3 months,
compared to 10 healthy control subjects. Most patients required at least 2 months of macrolide
therapy for demonstrable clinical improvement.
The efficacy of macrolide therapy in patients with asthma may not be based exclusively on
their antiinflammatory effects. Atypical intracellular pathogens (Chlamydia pneumoniae and
Mycoplasma pneumoniae) may play a role in the pathogenesis of reactive airway diseases,46474849
and macrolides possess antimicrobial activity against these pathogens.5051525354 In one study, 55 M
pneumoniae or C pneumoniae was present in the airways (detected by polymerase chain
reaction [PCR]) in more than half of stable patients with chronic asthma. Thus, it is difficult to
distinguish between the anti-inflammatory and antimicrobial effects of macrolides compared
with the beneficial responses in some patients with asthma.
Macrolide therapy improves lung function in patients with asthma associated with the presence
of atypical pathogens. Hahn and Golubjatnikov 56 treated 46 asthmatic patients with doxycycline
(Vibramycin; Pfizer Pharmaceuticals; New York, NY), 100 mg twice daily, azithromycin, 1 g once
weekly, or erythromycin, 1 g daily for a median of 4 weeks. The mean FEV1 (67.8% of predicted at
baseline) increased by 12.5% after treatment (p = 0.003). Subsequently, Kraft and associates55
conducted a double-blind study in which 52 stable patients with chronic asthma were
randomized to therapy with clarithromycin, 500 mg, or placebo twice daily for 6 weeks.
Macrolide therapy resulted in significantly increased mean (± SD) FEV1 levels in asthmatic
patients who were PCR-positive for Chlamydia or Mycoplasma (baseline, 2.50 ± 0.16 L;
posttreatment, 2.69 ± 0.19 L; p = 0.05). In contrast, there was no improvement in FEV1 in
patients who were PCR-negative (baseline, 2.59 ± 0.24 L; posttreatment, 2.54 ± 0.18 L; p =
0.85). A statistically significant reduction in inflammatory mediators (ie, IL-5, IL-12, and TNF-α),55
and in eosinophil and neutrophil levels in bronchoalveolar lavage fluid57 also was observed with
clarithromycin, suggesting immunomodulatory activity.
Black et al58 randomized 232 asthmatic patients who were antibody-positive for C pneumoniae to
roxithromycin, 150 mg, or placebo twice daily. After 6 weeks of therapy, patients treated with the
macrolide had significantly increased nighttime peak expiratory flow (increase from baseline:
roxithromycin, 15 L/min; placebo, 3 L/min; p = 0.02), but a nonsignificant change in the daytime
peak expiratory flow (increase from baseline: roxithromycin, 14 L/min; placebo, 8 L/min). These
benefits disappeared within 3 months of stopping the medication. The authors speculated that
macrolide therapy might have temporarily mitigated the effects of chlamydial infection on the
patient’s airways, with infection and its sequelae persisting after the discontinuation of
treatment.

COPD
COPD is a common and costly disease, with substantial morbidity and mortality. Approximately
16 million individuals in the United States have COPD.59 During 1999, COPD accounted for > 12
million physician visits and 713,000 hospitalizations.30 COPD ranks fourth among all causes of
death in the United States.30 Annual expenditures for health care and lost productivity due to
COPD were estimated30 at $32 billion, including $18 billion in direct health-care expenditures,
$6.8 billion in indirect morbidity costs, and $7.3 billion in indirect mortality costs.
COPD is characterized by progressive airflow limitation caused by an abnormal inflammatory

response of the lungs to noxious particles or gases. An increasing appreciation for the role that
inflammation plays in the pathophysiology of COPD has led to the use of inhaled corticosteroids
in the treatment of this disease.606162 As summarized below, preliminary data document
improvements in clinical end points as well as in pulmonary function test results with the
administration of macrolides in patients with COPD, another line of evidence for the beneficial
role of macrolides in treating respiratory tract diseases with an inflammatory component.
Banerjee and coworkers636465 randomized patients with moderate-to-severe COPD (ie, FEV1, <
60%) to 3 months of therapy, with either clarithromycin, 500 mg daily (24 patients), or matching
placebo (33 patients). The study measured numerous parameters of airway inflammation,
bacterial colonization, pulmonary function, exercise tolerance, and overall health status. At the
conclusion of the treatment interval, clarithromycin had not altered the sputum total cell count, 63
inflammatory cytokine levels,63 or pathogen count64 in the sputum of stable COPD patients. While
sputum total cell count and absolute neutrophil count did not correspond to measurements of
pulmonary function or to the results from the shuttle walk test, findings did indicate a significant
correlation between both total cell count and absolute neutrophil count with total health status
impact, respiratory symptoms, and activity scores among clarithromycin-treated COPD patients
(p < 0.03).65
In contrast, Nixon and coworkers66 documented improvements in spirometry findings as well as

clinical benefits with macrolide therapy of COPD. In their study, 25 patients with COPD
experiencing an exacerbation received clarithromycin, 500 mg twice daily for 2 weeks. The
absolute FEV1 increased from 1.12 L at baseline to 1.34 L posttreatment (p = 0.003), and the
mean total scores for signs and symptoms of COPD decreased from 11.12 (95% confidence
interval, 10.46 to 11.78) to 5.40 (95% confidence interval, 4.08 to 6.73). The most profound
improvement in symptoms occurred after the first week of treatment and was sustained during
the second week. When treatment was prolonged to 4 weeks, improvement continued but did
not show significant change after the second week of treatment.67

Discussion
Macrolides possess immunomodulatory properties that may be of therapeutic benefit in patients
with chronic airway inflammation. Prolonged treatment is likely to be beneficial in at least some
patients with inflammatory disease, such as sinusitis and asthma. The role of macrolides for
patients with COPD remains to be determined, although the preliminary data are encouraging.
There is debate with respect to the contribution of anti-inflammatory benefits vs antimicrobial

action as they relate to the efficacy of macrolides in treating respiratory tract diseases.
Evidence exists that suggests that the response to macrolides may be a consequence of anti-
inflammatory effects. For example, pharmacokinetic studies show that the minimum inhibitory
concentrations of clinically relevant pathogens in certain disease states are substantially higher
than the maximum levels of erythromycin achieved in serum and sputum during long-term
macrolide therapy. This suggests that a positive clinical outcome in a disease such as diffuse
panbronchiolitis may be attributed to something other than an antibacterial effect.68 The relative
ineffectiveness of 16-membered ring macrolides compared to that of 14-membered ring
macrolides, despite the relatively comparable antimicrobial activity,69 also suggests a
mechanism that is unrelated to antimicrobial activity.
In summary, as biological response modifiers, macrolides may improve both symptoms and
function in patients with inflammatory respiratory diseases such as chronic sinusitis, asthma, or
COPD. Large-scale, placebo-controlled studies are warranted to confirm the efficacy and safety of
long-term treatment with macrolides for these diseases.

CME Questions
The American College of Chest Physicians designates this continuing medical education activity
for 1 credit hour in category 1 of the Physician’s Recognition Award of the American Medical
Association. To obtain credit, please complete the question form at http://www.chestnet.org.
Credit can be obtained ONLY through our online process.
1. Which of the following is not true of the effects of macrolides on neutrophils?

1. Decrease neutrophil oxidative burst
2. Inhibit phagocytosis
3. Inhibit neutrophil migration to inflammatory sites
4. Stimulate neutrophil adhesion
5. Increase neutrophil degranulation

2. All of the following are effects of macrolides relevant to airway inflammation except:
1. Inhibit synthesis and/or secretion of proinflammatory cytokines
2. Decrease eosinophilic inflammation

3. Increase mucociliary transport
4. Reduce goblet cell secretions
5. Increase bronchoconstriction
3. Clinical trials of the efficacy of macrolides for the treatment of asthma show all of the
following except:
1. Increase in FVC and FEV1

2. Decrease in nocturnal dyspnea
3. Decrease in chest discomfort
4. Increase in dosage of prednisone
5. Decrease social concerns
4. Clinical experience with macrolide therapy for the treatment of chronic sinusitis shows all
of the following except
1. Improvement in sinus symptoms such as sinus pain, headache, nasal congestion,

nasal discharge, and mucopurulent discharge
2. Reduced mucociliary transport
3. Reduction in rhinorrhea, postnasal drip, nasal obstruction, and sense of dullness in

the head
4. Reduced volume of secretions

5. Reduction of size of nasal polyps
5. Which of the following is not true of the efficacy of macrolides for the treatment of COPD?
1. Decreased sputum cell count
2. Increased FEV1
3. No correlation between neutrophil count or sputum total cell count and pulmonary
function
4. Significant correlation between neutrophil count and respiratory symptoms
5. Significant correlation between total cell count and total health status

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Table 1.
Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation12345

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Table 2.
Clinical Experience with Macrolide Therapy for Chronic Sinusitis
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Figure 1.
Effect of clarithromycin in patients with chronic sinusitis.24

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Table 3.
Effect of Clarithromycin in Asthma*
Footnotes
• Abbreviations: IL = interleukin; PCR = polymerase chain reaction; TNF = tumor necrosis
factor
• Learning objectives:
1. To understand the clinical data on the efficacy of macrolides for the treatment of
chronic sinusitis, asthma, and COPD.
2. To realize that large-scale, placebo-controlled studies determining the efficacy and

safety of macrolides for the treatment of chronic sinusitis, asthma, or COPD are
warranted.
3. To be aware of the prevalence and the significant economic burden that chronic
sinusitis, asthma, and COPD have on society.
4. To understand the effects of macrolides on neutrophils.

5. To understand the effects of macrolides on airway inflammation.
• Dr. Gotfried has received research grants from and is a member of the Speakers’ Bureau
of Abbott Laboratories. He also received financial remuneration from Abbott Laboratories
for his participation at the Roundtable Meeting.
• This manuscript is derived from the proceedings of the Symposium on Macrolide Effects
presented at the 2002 American College of Chest Physicians Annual Meeting.
Previous Section
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Med 1995;34,469-474
Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation12345
Inhibit synthesis and/or secretion of proinflammatory cytokines
Effects on neutrophils
Decrease neutrophil oxidative burst
Inhibit neutrophil migration (chemotaxis) to inflammatory sites
Increase apoptosis of neutrophils (?)
Neutrophil degranulation (?)
Inhibit neutrophil adhesion
Inhibit phagocytosis
Decrease eosinophilic inflammation
Increase mucociliary transport
Reduce goblet cell secretion
Decrease bronchoconstriction (decrease endothelin-1 release, inhibit cholinergic

responses of airway smooth muscle)
Table 3.
Effect of Clarithromycin in Asthma*
Pretreatm Posttreatm p
ent ent Value
1.85 ±
FEV1 1.6 ± 0.58 0.76 0.07
0.003
FVC 2.7 ± 0.9L 3.0 ± 1L 8
Chest
discomfort 0.7 ± 0.8 0.5 ± 0.7 0.02
Nighttime 3.20 ±2.51 ±

SOB 2.15 2.16 0.051
Social 3.6 ± 2.6 3.0 ± 2.6 0.048

Pretreatm Posttreatm p
ent ent Value
concerns
• * Values given as mean ± SD, unless otherwise indicated. SOB = shortness of breath.
Table used with permission of Gotfried et al.42
Chronic Macrolide Therapy in Inflammatory Airways Diseases Chest

November 2010 138:1202-1212; doi:10.1378/chest.10-0196
• Abstract
• Full Text
• Full Text (PDF)
• doi: 10.1378/chest.10-0196 CHEST November 2010 vol. 138 no.

5 1202-1212
Chronic Macrolide Therapy in Inflammatory Airways Diseases

1. Adam L. Friedlander, MD and
2. Richard K. Albert, MD, FCCP
1. From the Division of Pulmonary Sciences and Critical Care Medicine (Drs
Friedlander and Albert), and the Department of Medicine, Denver
Health (Dr Albert), Department of Medicine, University of Colorado
Denver Health Sciences Center; and the Department of Medicine (Dr
Friedlander), National Jewish Health, Denver, CO.
1. Correspondence to:
Adam L. Friedlander, MD, National Jewish Health, 1400 Jackson St,
Denver, CO 80206; e-mail: Adam.Friedlander@UCDenver.edu
Abstract
Long-term therapy with the macrolide antibiotic erythromycin was shown to
alter the clinical course of diffuse panbronchiolitis in the late 1980s. Since
that time, macrolides have been found to have a large number of
antiinflammatory properties in addition to being antimicrobials. These
observations provided the rationale for many studies performed over the last
decade to assess the usefulness of macrolides in other inflammatory airways
diseases, such as cystic fibrosis, asthma, COPD, and bronchiolitis obliterans
syndrome. This review summarizes the immunomodulatory properties of
macrolides and the results of these recent studies demonstrating their
potential for being disease-modifying agents.
Footnotes
• Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians
(http://www.chestpubs.org/site/misc/reprints.xhtml).
 Abbreviations
AECOPD
acute exacerbation of COPD
BALF
BAL fluid
BOOP
bronchiolitis obliterans organizing pneumonia
BOS
bronchiolitis obliterans syndrome
CF
cystic fibrosis
DPB
diffuse panbronchiolitis
TNF-α
tumor necrosis factor α
• Received January 22, 2010.

• Accepted May 27, 2010.
• © 2010 American College
Long-term Clarithromycin Decreases Prednisone

Requirements in Elderly Patients With Prednisone-
Dependent Asthma*
1. Kevin W. Garey, PharmD,
2. Israel Rubinstein, MD, FCCP,
3. Mark H. Gotfried, MD, FCCP,
4. Ishrat J. Khan, MBBS,
5. Suchitra Varma, MBBS and
6. Larry H. Danziger, PharmD
1. *
From the University of Illinois at Chicago (Drs. Garey, Rubinstein, Gotfried, and Danziger;
Mssrs. Varma and Khan), Chicago, IL; and The Good Samaritan Regional Medical Center
(Dr. Gotfried), Phoenix, AZ.
1. Correspondence to: Israel Rubinstein, MD, FCCP, Section of Respiratory and Critical Care
Medicine, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St (M/C
787), Chicago, IL 60612-7323; e-mail: IRubinst@uic.edu
Next Section
Abstract
Prolonged use of prednisone is associated with serious side effects, such as osteoporosis,
particularly among elderly individuals. Macrolide antibiotics exhibit anti-inflammatory effects
that are distinct from their antimicrobial properties. Thus, the purpose of this case report is to
describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing
prednisone requirements in three elderly patients with prednisone-dependent asthma. Three
patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg
prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid. They
were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and
adverse events. The prednisone dose was tapered in a stepwise fashion at each clinic visit.
Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month
follow-up, two of three patients discontinued prednisone therapy, while the third patient
displayed increased spirometry readings and noted an increasingly better quality of life.
Pulmonary function tests were stable or improved over this time period, with no reported adverse
events, including increased rate of infections. One patient relapsed upon discontinuation of
clarithromycin therapy but has since responded to re-initiation of treatment. Long-term oral
clarithromycin may have a role in reducing prednisone requirements in elderly patients with
prednisone-dependent asthma.
• anti-inflammatory
• clarithromycin
• macrolides
• prednisone-dependent asthma
Several studies have suggested that macrolide antibiotics have salutary effects in patients with
asthma, including a corticosteroid-sparing effect.123 The mechanisms underlying this response are
thought to be related, in part, to anti-inflammatory effects of the drugs, which are distinct from
their antimicrobial effects.4 Elderly patients with prednisone-dependent asthma are at high risk
for developing devastating side effects from prolonged use of the drug, particularly
osteoporosis.5 Hence, the use of macrolides in these patients in an attempt to reduce
prednisone dependency would be advantageous.

Case Report
This case report begins to address the issue by describing three elderly patients with prednisone-
dependent asthma who reduced or discontinued oral prednisone therapy after long-term
treatment with clarithromycin, a 14-membered ring macrolide.
Patient 1
A 63-year-old white man received a diagnosis of severe asthma in 1995 and had been
prednisone-dependent since that time. He had received a diagnosis of asthma as a child, and
that condition had resolved as he reached the age of 18 years. He had quit smoking
approximately 20 years before this study (14 pack-year history). Skin allergy tests were positive
for mold dust. Physical examination was significant for a cushingoid appearance. Baseline FVC
and FEV1 were 1.72 L and 1.12 L/s, respectively (44% and 36% predicted, respectively). His
current asthma treatment consisted of inhaled triamcinolone, 1,600 μg daily; inhaled albuterol,
810 μg daily; oral theophylline, 400 mg daily; and prednisone, 10 mg daily. His symptoms were
aggravated by attempts to taper his prednisone dose. In August 1998, he was given
clarithromycin, 500 mg bid. Five months later, he discontinued prednisone entirely with no
significant change in spirometry. Due to unexplained ecchymoses while receiving clarithromycin
alone for 2 months, the drug was discontinued. The patient experienced an acute exacerbation of
asthma 1 month later and was given oral prednisone and clarithromycin, 500 mg bid. Within 2
months, the patient discontinued prednisone. He has remained on clarithromycin through 12
months of follow-up. No other changes were made to his medications. Clarithromycin was well
tolerated, and he has remained asymptomatic.
Patient 2
A 65-year-old white woman received a diagnosis of severe asthma in 1986. Her symptoms were
frequently exacerbated by attempts to taper her prednisone dose. Her medical history was
significant for a 22-year history of allergic rhinitis and infrequent symptoms of gastroesophageal
reflux. The patient had quit smoking at the age of 27 years (5 pack-year history). Baseline FVC
and FEV1 were 3.25 L and 2.26 L/s, respectively (115% and 100% predicted, respectively).
Current asthma treatment regimen consisted of inhaled triamcinolone, 1,000 μg qd; inhaled
metaproterenol, 7.8 mg qd; inhaled cromolyn sodium, 6,400 μg qd; and prednisone, 10 mg qd.
In February 1997, the patient was given clarithromycin, 500 mg bid. Within 3 months, she
tapered her prednisone to 5 mg qd, with a concomitant increase in FVC and FEV1 to 3.54 L and
2.69 L/s, respectively (127% and 120% predicted, respectively). Three months later, she
discontinued prednisone entirely. No changes in spirometry or adverse events were noted
through 12 months of follow-up.
Patient 3
A 67-year-old white man had received a diagnosis of asthma in 1984 and had been dependent on
prednisone for the past 1.5 years. He experienced four to five acute exacerbations of asthma per
year. His medical history was significant for gastroesophageal reflux. He had no smoking history.
Baseline FVC and FEV1 were 4.12 L and 2.57 L/s, respectively (97% and 76% predicted,
respectively). He was treated with ipratropium, 144 μg qd; salmeterol, 84 μg qd; flunisolide,
2,000 μg qd; beclomethasone, 168 μg qd; theophylline, 600 mg qd; and prednisone, 5 mg qd. He
was given clarithromycin, 500 mg bid, and within 3 months, FVC increased to 5.3 L (125%
predicted) with no change in FEV1. Plasma theophylline concentrations were unchanged
throughout the observation period. The patient noted a significant improvement in quality of life,
manifested by increased energy levels and enthusiasm. Several attempts to taper oral
prednisone to 5 mg qd failed. Nonetheless, the patient did not experience an acute exacerbation
of asthma throughout the 12 months of clarithromycin therapy. No adverse events were noted.

Discussion
The new finding from these case reports is that long-term (12 months) treatment with oral
clarithromycin, 500 mg bid, is associated with a significant reduction in prednisone dependency
in elderly patients with prednisone-dependent asthma. Importantly, this phenomenon was
associated with a significant improvement in asthma coupled with no reported adverse events,
including an increased rate of infection. The salutary effects of clarithromycin were observed
only after several weeks of continuous therapy while the prednisone dose was being tapered.
Previous studies from Japan have shown that relatively short-term (< 3 months) therapy with oral
erythromycin and roxithromycin, two macrolide antibiotics, was associated with significant
improvement in bronchial hyperreactivity in patients with asthma.678 However, the mechanisms
underlying this response were not determined. Moreover, these patients were either children or
adults. The results of our case studies support and extend these observations by showing that
long-term treatment with clarithromycin may be beneficial in elderly patients with prednisone-
dependent asthma. Whether the corticosteroid-sparing effects of this drug are related, in part, to
downregulation of the inflammatory cascade in the airway of patients with asthma remains to be
determined.491011
Prolonged use of prednisone in patients with asthma, particularly elderly patients, is associated
with devastating side effects, including osteoporosis.5 Hence, therapeutic measures to reduce or
eliminate prednisone dependency in these patients are desirable. The results of this case report
suggest that long-term administration of oral clarithromycin may be a useful approach to
accomplish this goal. However, the mechanisms underlying the corticosteroid-sparing effect of
clarithromycin were not elucidated in this study. Earlier studies had suggested possible
interactions between macrolides and corticosteroids, causing increased concentrations of the
steroid.12 This is unlikely in the cases reported here, as two patients were able to discontinue
prednisone entirely for a sustained period while remaining in remission. Also, Fost et al13 recently
demonstrated that clarithromycin did not affect the pharmacokinetics of prednisone. Clearly,
additional prospective studies are indicated to investigate the role of long-term clarithromycin
therapy in elderly patients with prednisone-dependent asthma.
In summary, long-term oral clarithromycin therapy may have a role in the treatment of elderly
patients with prednisone-dependent asthma. Future research will be necessary to further
elucidate their effects.

Footnotes
• This study was supported in part by a grant from Abbott Laboratories.
•
○ Received January 13, 2000.
○ Accepted April 13, 2000.
Previous Section
References
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Immunomodulatory Activity and Effectiveness of

Macrolides in Chronic Airway Disease*
1. Bruce K. Rubin, MEngr, MD, FCCP and
2. Markus O. Henke, MD
1. From the Department of Pediatrics (Dr. Rubin), Wake Forest University School of Medicine,
*
Winston-Salem, NC; and Department of Pulmonary Medicine (Dr. Henke), Philipps-

University Marburg, Marburg, Germany.
Next Section
Abstract
The use of troleandomycin as adjunctive therapy for the treatment of patients with
corticosteroid-dependent asthma first suggested an immunomodulatory effect of the macrolide
antibiotics. This led to studies of the macrolides in other chronic airway diseases, such as
diffuse panbronchiolitis (DPB), a disease occurring primarily in East Asia. The use of macrolides
for the therapy of patients with DPB has led to dramatic improvements in pulmonary function
and prolonged survival. Similar benefits have been documented in Japanese studies of
bronchiectasis, chronic bronchitis, and sinobronchial syndrome. Clinical and pathologic
similarities between DPB and cystic fibrosis (CF) led to the investigation of macrolides for the
treatment of CF. Data now suggest that persons with CF will benefit from macrolide therapy. In
vitro and in vivo studies suggest that macrolides may inhibit the pulmonary influx of
neutrophils, inhibit the release of proinflammatory cytokines, protect the epithelium from
bioactive phospholipids, and improve the transportability of airway secretions. The
immunomodulatory effects of the macrolides also may be beneficial for the treatment of other
chronic inflammatory conditions.
• azithromycin
• clarithromycin
• cystic fibrosis
• cytokines
• diffuse panbronchiolitis
• erythromycin
• macrolide antibiotics
• neutrophil
• troleandomycin
Interest in the immunomodulatory effects of macrolide antibiotics began with the observation
that patients with severe asthma required lower doses of steroids if they also had received
troleandomycin (TAO).1 Subsequently, macrolides have been studied for other airway diseases
including diffuse panbronchiolitis (DPB) and cystic fibrosis (CF). The most convincing
demonstration of the immunomodulatory effects of macrolides has been in the treatment of
DPB, a pulmonary disease of unknown etiology that is found primarily in Japan. In 1984, the 5-
year survival rate for DPB was only 26%, but treatment with macrolides has dramatically
increased the 10-year survival rate of these patients to 94%. 2 The effectiveness of these drugs
appears to be limited to the 14-membered and 15-membered macrolides, such as
erythromycin, clarithromycin, and azithromycin. These drugs improve pulmonary function, and
decrease morbidity and mortality in patients with DPB.2345 These macrolides decrease
proinflammatory cytokines in serum and BAL fluid (BALF), decrease mucus hypersecretion, and
may protect the airway epithelium from damage.678
CF is similar to DPB in many ways including symptoms and pulmonary pathology. Both diseases
are characterized by cough, persistent sinus disease, neutrophilic airway inflammation,
susceptibility to persistent endobronchial infection with opportunistic pathogens, and progressive
deterioration in pulmonary function, and both diseases are responsive to the immunomodulatory
effects of macrolides. This article reviews the immunomodulatory effects of macrolides, and
the evidence for their clinical efficacy for the treatment of DPB and CF.

The Steroid-Sparing Effects of Macrolides
A number of studies91011121314 have shown an improvement in the clinical symptoms of
corticosteroid-dependent patients with asthma and a reduction in corticosteroid dosage with
concomitant TAO therapy. Pharmacokinetic studies1516 have suggested that the beneficial effects
of TAO therapy may be due, in part, to the inhibition of steroid metabolism. TAO was shown to
significantly prolong the serum half-life of methylprednisolone. However, in reported studies,
some steroid-dependent patients were able to completely discontinue concomitant oral steroid
therapy without worsening asthma severity, suggesting that TAO had direct anti-inflammatory
activities. Studies1417 also have shown that low-dose TAO directly attenuates bronchial
hyperresponsiveness in children with severe asthma and that the effects were independent of its
action on glucocorticoid metabolism. In another study, TAO appeared to inhibit T-cell proliferation
in peripheral blood mononuclear cells from patients with steroid-resistant asthma.18 In this
supplement to CHEST, Gotfried describes more recent studies designed to assess the direct
effects of clarithromycin in adults with severe persistent asthma (see page 52S).

The Effects of Macrolides on Mucus Secretion
Macrolide antibiotics also appear to be mucoregulatory, that is, they are able to decrease
mucus hypersecretion in persons with airway disease without suppressing baseline physiologic
secretion. In a double-blind, placebo-controlled, 8-week trial of 31 patients with chronic
bronchitis, bronchiectasis, or DPB, low-dose clarithromycin (100 mg twice daily) profoundly
decreased the expectorated sputum volume from 51 to 24 g per day (p < 0.001). 19 Treatment
with clarithromycin also increased the percentage of solid composition and the elastic modulus
of the sputum (p < 0.05) but did not alter its dynamic viscosity. Based on these data, the
investigators suggested that clarithromycin reduces both mucus and water secretion.
Clarithromycin also significantly reduced the volume of nasal mucus secretion, both at baseline
and with methacholine stimulation, and improved the sneeze (airflow) transportability in 10
patients with purulent rhinitis.20 Roxithromycin therapy for 12 weeks significantly decreased
sputum volume and “purulence” in 25 children with bronchiectasis.21 The mechanism by which
macrolides inhibit mucus hypersecretion is thought to involve decreasing the inflammatory
stimulus for hypersecretion.2223

The Effects of Macrolides on DPB
DPB is a chronic inflammatory pulmonary disease that is well-recognized in Japan and Korea, and
is less commonly diagnosed in the West.242526 Although upper airway symptoms, including chronic
sinusitis, usually begin in late childhood, DPB is usually diagnosed between the second and fifth
decades of life, and is characterized by chronic, progressive, obstructive, and inflammatory
sinobronchial disease. The clinical diagnostic criteria of DPB are given in Table 1 .2 These criteria
include airflow limitation, sinusitis, sputum expectoration, dyspnea, and chronic airway infection,
often with mucoid Pseudomonas aeruginosa. The results of pulmonary function tests typically
show a mixed obstructive/restrictive picture similar to that for CF. Radiographic findings include
reticular or nodular shadows, and CT scans show the characteristic central nodules with a tree-in-
bud appearance.2627

Clinical Studies
Kudoh and colleagues27 were the first to demonstrate that low-dose erythromycin ameliorated the
signs and symptoms of DPB. Therapy often will improve the appearance of chest radiographs and
normalize pulmonary function. A large number of studies352728 have confirmed the effectiveness of
long-term macrolide therapy for the treatment of DPB. These are summarized here.
In a retrospective analysis of 498 Japanese patients with DPB,2 a significant improvement in

survival was associated with treatment using 400 to 600 mg daily of erythromycin. Subjects
were categorized into one of three groups based on the date of the initial diagnosis. Group A
included 190 subjects who had received diagnoses between 1970 and 1979, group B included
221 subjects who had received diagnoses between 1980 and 1984, and group C included 87
subjects who had received diagnoses between 1985 and 1990. A comparison of Kaplan-Meier
survival curves of subjects in each group (Fig 1 ) showed significantly improved survival for the
63 patients in group C who had been treated with erythromycin compared with those in group A
(p < 0.0001), group B (p < 0.0001), and 24 patients from group C who had not been treated with
erythromycin (p < 0.0056). The 5-year survival rates of subjects not treated with erythromycin in
groups A and C did not differ significantly.
The long-term efficacy and safety of clarithromycin was evaluated in 10 subjects with DPB who
were treated for 4 years with clarithromycin, 200 mg per day. 3 Pulmonary function improved in
most subjects within 6 months of initiating treatment with clarithromycin. The FEV1 increased
from 1.74 L at baseline to 2.31 L at 6 months (p < 0.01), and the FVC increased from 2.67 L at
baseline to 3.16 L at 6 months (p < 0.005) [Fig 2 ]. The resting PaO2 significantly increased within
3 months after beginning macrolide therapy (p < 0.05). Sputum cultures were positive for
Haemophilus influenzae, Haemophilus parahaemolyticus, Streptococcus pneumoniae, and P
aeruginosa at baseline but were negative within 6 months after beginning therapy. The
treatment was well-tolerated, and clarithromycin provided a sustained clinical benefit.
Data from 28 subjects with DPB treated with erythromycin, 600 mg per day for 1 month, showed
that the drug produced significant clinical improvement, and decreased the number of
neutrophils and the concentration of interleukin (IL)-8 in BALF.29 These observations were
independent of P aeruginosa infection in these subjects, suggesting a systemic, anti-
inflammatory effect of erythromycin in patients with this disease.
The mechanism by which macrolides improve the symptoms of DPB probably includes inhibiting
the pulmonary influx of neutrophils.630 In chronic inflammation of the airways, neutrophils
accumulate in the airway secreting elastase, myeloperoxidase, and inflammatory mediators that
can produce epithelial dysfunction. Many studies have evaluated the effects of macrolides on
neutrophils. BALF from patients with DPB contains many neutrophils. Macrolides may inhibit the
production or secretion of proinflammatory cytokines, which results in the reduced accumulation
of neutrophils in the airway.31 In vitro studies32 have shown that macrolides inhibit the production
of proinflammatory cytokines through the inhibition of transcription factors, nuclear factor κB,
and activator protein-1. In vitro data also suggest that macrolides may protect the epithelium
from bioactive phospholipids and may improve the transportability of airway secretions.619203334
Treatment with erythromycin, 600 mg daily for 6 to 12 months, was associated with a reduction
in both neutrophil number (p < 0.01) and neutrophil- derived elastolytic activity (p < 0.001) in
the BALF of 11 subjects with DPB. 35 This was associated with improved pulmonary function. In 19
subjects with DPB, treatment with erythromycin, 600 mg per day, or roxithromycin, 150 mg per
day for 1 to 24 months, improved the FVC and FEV1 (p < 0.01), and reduced the percentage of
neutrophils in BALF by 63.8% compared with baseline (p = 0.0001). A higher percentage of
neutrophils and the concentration of IL-1β are associated with increasing levels of IL-8 in the
BALF of patients with DPB. 3637 IL-1β, tumor necrosis factor (TNF)-α, and IL-8 were measured in the
BALF of 19 subjects with DPB, and were compared with 7 healthy subjects and 17 subjects with
pulmonary sarcoidosis, who served as disease controls.31 The pretreatment concentrations of IL-
1β and IL-8 in patients in the DPB group were higher than those of healthy subjects (p < 0.05) or
of those with sarcoidosis (p < 0.01), and BALF concentrations of IL-1β (p < 0.015) and IL-8 (p <
0.05) were significantly reduced following macrolide therapy (Fig 3 , left). In subjects with DPB,
there was a significant correlation between the percentage of neutrophils and the concentration
of IL-8, and the concentrations of IL-1β and IL-8 (Fig 3, right).
In another study,39 macrolide therapy reduced neutrophil numbers, and the concentration of IL-8
in BALF in 14 subjects with DPB. It also improved the FVC percent predicted (p < 0.01), the FEV 1
percent predicted (p < 0.02), and the PaO2 (p < 0.01) over pretreatment values.38 Macrolide
therapy also significantly decreased the concentration of β-defensin-2 but not β-defensin-1 in
BALF, or concentrations of β-defensin-1 or β-defensin-2 in the plasma of these subjects.39 β-
defensins are endogenous antimicrobial peptides, but they also may cause pulmonary injury.38
Similarly, 2 to 6 months treatment with clarithromycin, 200 mg per day, erythromycin, 600 mg
per day, or roxithromycin, 150 mg per day, reduced the absolute number of lymphocytes and
activated CD8+ cells in the BALF of subjects with DPB, with a corresponding increase in the
CD4+/CD8+ ratio.40

The Effects of Macrolides in CF
Based on the similarities between DPB and CF, macrolide antibiotics have now been studied as
immunomodulatory medications for the treatment of CF.4142 In a pilot study,43 daily azithromycin
was given for > 3 months (and up to a year) to 7 children aged 6 to 17 years with CF and P
aeruginosa infection. During the study, no concomitant therapy with steroids, dornase alfa, or IV
Ig was administered to these subjects. Excluding the first 2 months of treatment from their
analysis, the authors compared mean FVC and FEV1 percent predicted values in the 6 months
before starting azithromycin with those after therapy in the final month of the trial. The FVC rose
from 62.8 to 70.3% predicted, with a median improvement of 11.3% (p < 0.03), and FEV1 percent
predicted increased by 11.0% (p < 0.03).
This group at the Royal Brompton Hospital then conducted a 15-month randomized, double-blind,
placebo-controlled, crossover trial44 of orally administered azithromycin therapy in 41 children
(age range, 8 to 18 years) with CF. Subjects received either azithromycin or placebo for 6 months
followed by a 2-month washout period, and then were crossed over to the other treatment group.
The primary outcome measure was a change in FEV1. They also measured FVC, concentrations of
IL-8 and neutrophil elastase (NE) in sputum, exercise tolerance using a 3-min step test, change
in antibiotic usage, frequency of respiratory exacerbations, Pseudomonas colony counts, and
quality of life. Subjects who weighed ≤ 40 kg received either a single azithromycin tablet, 250
mg, daily or matching placebo, while subjects weighing > 40 kg received either two azithromycin
tablets, 250 mg (total, 500 mg), or two matching placebo tablets daily. Fifteen of the 41 subjects
(36.6%) continued the established treatment with dornase alfa.
The primary end point was FEV1, which improved by 5.4% (95% confidence interval [CI], 0.8 to
0.5%) with azithromycin compared with placebo in the fourth and sixth month treatment period
visits (Fig 4 ). Fifty percent of the children had an improvement in the primary end point of at
least 10%. There was a suggestion that children who were homozygous for the deltaF 508 mutation
did better than the rest of the group. The mechanism of benefit could not be determined, in that
there was no difference in sputum bacteriology results, sputum NE levels, or IL-8 levels. The
authors did not assay NE activity, which could have been inhibited by azithromycin.
A post hoc comparison of the results in the groups of subjects either taking or not taking dornase
alfa was conducted on the basis of an in vitro study,45 which suggested that azithromycin inhibits
this enzyme. In this subgroup analysis, the children not inhaling dornase alfa (26 patients) had
an increase in FEV1 of 11.5% (95% CI, 5.3 to 16.5), whereas those who also inhaled dornase alfa
had a decrease of 3.6% (95% CI, −22 to 3.9). However, before recommending that patients
taking azithromycin discontinue therapy with dornase alfa, it should be remembered that this
may be a chance finding in a study not adequately powered for subgroup analysis, and so needs
confirmation by other studies.
Wolter et al46 conducted a 3-month, prospective, randomized, double-blind trial of azithromycin,

250 mg daily, in 60 adults with CF. Clinically stable subjects ranging in age from 18 to 44 years
were randomized to receive either azithromycin or placebo. Statistical analysis was adjusted for
differences between the two groups in gender, weight, and baseline pulmonary function, but
subjects were not stratified by disease severity. Monthly assessments included spirometry, body
weight, sputum cultures with quantitative bacterial counts, serum C-reactive protein (CRP), and
erythrocyte sedimentation rate as markers of systemic inflammation, and quality of life
domains measured by the chronic respiratory disease questionnaire. The mean FEV1 and FVC
were 56.6% predicted and 72.4% predicted, respectively, at the start of the study. Significant
differences were measured between the azithromycin-treated and placebo-treated groups in
change in FEV1 percent predicted (p = 0.047) and change in FVC percent predicted (p = 0.001).
Subjects randomized to azithromycin maintained pulmonary function over the 3 months of the
study, whereas patients receiving placebo had a deterioration of FEV1 percent predicted and FVC
percent predicted. The azithromycin group also required fewer days of therapy with IV antibiotics
(p = 0.009), fewer days at home receiving IV antibiotics (p = 0.037), and fewer courses of IV
antibiotics (p = 0.016). Subjects randomized to azithromycin scored higher on improvements in
dyspnea (p = 0.042), fatigue (p = 0.003), emotional (p = 0.012) and mastery domains (p =
0.035), and total scores (p = 0.035) of the chronic respiratory disease questionnaire compared
with those in the placebo arm.
In the azithromycin group, the median CRP declined steadily over time, while serum levels
remained relatively constant in the placebo group. In subjects who received azithromycin, the
reduction in CRP strongly correlated with baseline CRP, which negatively correlated with the FEV1
percent predicted (p < 0.001). No significant between-group differences were reported in
erythrocyte sedimentation rate, body mass index, bacterial types, or density. The subjects in this
study represented an older CF population with more severe respiratory disease who received a
relatively short course of azithromycin compared with those reported by Equi et al.44 Despite the
differences in demographics and study design, both young and older subjects with CF responded
to therapy with azithromycin, as reflected in the improved pulmonary function and quality of life.
In contrast to these studies, Ordonez et al47 failed to show a therapeutic benefit of macrolide
therapy in a small pilot study of 10 adults (age range, 19 to 26 years) with CF and P aeruginosa
infection. Subjects were treated with placebo for 3 weeks followed by 6 weeks of therapy with
clarithromycin, 500 mg twice daily. Clarithromycin had no significant effect on pulmonary
function, the number of neutrophils, or the concentrations of IL-8, NE, TNF-α, and
myeloperoxidase in induced sputum samples. The authors suggested that the lack of effect may
have been due to there being too few subjects or too short of a treatment period, leading to a
type 2 error.47
The Cystic Fibrosis Foundation sponsored a large trial that was presented at the North American
Cystic Fibrosis Meeting in New Orleans in 2002. The design was parallel group, with a 2-week
run-in period, a 168-day treatment period, and a 28-day washout period. The dose was 500 mg if
the patient’s weight was ≥ 40 kg, 250 mg if the patient’s weight was < 40 kg, and was given on
3 days in the week, with provision for stepdown to a lower dose if that dose was not tolerated.
One hundred eighty-five patients were randomized, of whom 87 received azithromycin and 98
received placebo. Only one subject (in the placebo limb) did not complete the follow-up. The
groups were well-matched. The mean age was 20 years, just over half were men, and the
starting FEV1 was approximately 70% predicted. The results showed a treatment benefit of 0.093
L or 6.21% predicted for FEV1, and 4.95% for FVC (highly statistically significant). There was
marked variation in the individual response. Approximately 12% of patients increased FEV1 by ≥
15% while receiving azithromycin (none receiving placebo), but the conditions of some patients
actually deteriorated. Any benefit was lost within 28 days of discontinuing therapy. The
investigators reported a 40% reduction in infective exacerbations, but only the percentage of
subjects hospitalized (patients receiving azithromycin, 16%; patients receiving placebo, 30%)
reached statistical significance. The azithromycin group gained 800 g in weight compared with
the placebo group at the end of the treatment period. This is important, because some
macrolides are thought to be anorexigenic. Physical functioning on a quality-of-life score
improved significantly while patients received azithromycin. There were no problems with the
emergence of resistant microorganisms, with more new isolates of Staphylococcus aureus
appearing in the placebo group. In terms of adverse events, nausea and diarrhea were common
in the azithromycin group, which was not a surprise. What was surprising is that there was more
wheezing reported in the azithromycin group despite improved lung function. One might
speculate that this was due to secretions mobilizing in the major airways. There was no drug
toxicity, and dose reduction or study drug discontinuation was rare and equally distributed
between the two groups.

Conclusion
In nearly all reports, patients with DPB or CF who have received macrolide antibiotics have
responded with dramatic improvements in pulmonary function. The treatment of DPB is the most
striking example of the benefits of macrolides. Before the introduction of macrolide therapy,
the 10-year survival rate was reported to be 12 to 50%,2 but since the introduction of macrolide
therapy the 10-year survival rate is now > 90%. It is probable that patients with CF may realize
similar benefits with long-term macrolide therapy. This is the focus for ongoing research. There
is also strong clinical evidence for the effectiveness of macrolides in the treatment of
bronchiectasis, chronic bronchitis, and sinusitis, as described in the review by Gotfried in this
supplement.
Both in vivo and in vitro studies strongly support the immunomodulatory effects of macrolides.
Further studies will determine which of the macrolides are the most effective, the duration of
the effect, the long-term consequences of the long-term use of these antibiotics, and their
mechanisms of action. This information may lead to the development of more specific
therapeutic agents. Based on the effectiveness of macrolides for the treatment of DPB and CF,
these drugs may be beneficial for the treatment of other chronic inflammatory respiratory
conditions, as well as other nonrespiratory diseases such as chronic arthritis, inflammatory
bowel disease, and chronic inflammatory skin conditions.

CME Questions
The American College of Chest Physicians designates this continuing medical education activity
for 1 credit hour in category 1 of the Physician’s Recognition Award of the American Medical
Association. To obtain credit, please complete the question form at http://www.chestnet.org.
Credit can be obtained ONLY through our online process.
1. Diagnostic criteria for DPB include all of the following except:
1. FEV1 < 70% and PaO2 < 80 mm Hg

2. Elevated titers of cold hemagglutinin × ≥ 64
3. Bilateral fine nodular shadow
4. Decreased sputum secretion

5. History of parasinusitis
2. Macrolides may inhibit the production of proinflammatory cytokines, which results in
which of the following?
1. Reduced accumulation of neutrophils in the airway
2. Increased accumulation of neutrophils in the airway

3. Inhibition of nuclear factor-κB and activator protein-1
4. Stimulation of nuclear factor-κB and activator protein-1 production
5. Stimulation of the CF transmembrane receptor function
3. Which of the following in not a potential mechanism by which macrolides exert their
effect for the treatment of DPB and CF?
1. Supression of the CF transmembrane receptor function
2. Protection from bioactive phospholipids
3. Improvement in the mucociliary and cough transportability of airway secretions
4. Expression of the ▵508 CF transmembrane receptor mutation
5. Inhibition of proinflammatory cytokines
4. Which of the following is not affected by macrolides?

1. IL-8
2. IL-1β
3. TNF-α
4. β-defensins
5. IL-2
5. Which of the following has not been shown in clinical trials of macrolides for the
treatment of DPB and CF?
1. Increased sputum production

2. Increased FEV1
3. FVC
4. Increased PaO2
5. Increased quality of life
View this table:
• In this window
• In a new window
Table 1.
Diagnostic Criteria for DPB
• In this page
• In a new window
Figure 1.
The survival rate of patients treated with erythromycin (group c EM+) was significantly greater
than that of untreated patients (group c EM-) [p < 0.0056]. Untreated patients were not different
from historical control subjects (group a) [p < 0.2475]. This figure was adapted with permission
from Kudoh et al.2
• In this page
• In a new window
Figure 2.
Top, A: Mean FEV1 increased within 3 months of beginning clarithromycin therapy in 10 subjects
with DPB. A maximal value was reached at 6 months and was sustained for 4 years. Bottom, B:
The FVC increased to a maximal level within 6 months of beginning clarithromycin and was
sustained for 4 years. * = p < 0.01 compared to baseline; ** = p < 0.05 compared to baseline;
## = p < 0.005 compared to baseline. This figure was adapted with permission from Kadota et
al.3
• In this page
• In a new window
Figure 3.
Left: The level of IL-8 (mean ± SE) in the BALF of subjects with DPB was compared before and
after macrolide therapy, and was compared to subjects with sarcoidosis (SAR) or healthy
volunteers. Right: Correlation between the percentage of neutrophils and the levels of IL-8 in the
BALF of 19 subjects with DPB (r = 0.509; p < 0.05). This figure was adapted with permission from
Sakito et al.31
• In this page
• In a new window
Figure 4.
Left, A: Mean (95% CI) change from baseline of FEV1 in 41 children with CF who were treated with
azithromycin and placebo in a crossover trial. The mean FEV1 was greater during the
azithromycin arm of the trial (p = 0.031). The median relative difference between azithromycin
and placebo was 5.4% (95% CI, 0.8 to 10.5). Right, B: Mean (95% CI) change from baseline visit
of FVC percent predicted for each treatment period. This figure was adapted with permission
from Equi et al.44
Footnotes
• Abbreviations: BALF = BAL fluid; CF = cystic fibrosis; CI = confidence interval; CRP = C-
reactive protein; DPB = diffuse panbronchiolitis; IL = interleukin; NE = neutrophil elastase;
TAO = troleandomycin; TNF = tumor necrosis factor
• Learning objectives:
1. To be aware of the diagnostic criteria for DPB.
2. To understand the clinical evidence for the efficacy of macrolides for the treatment
of DPB and CF.
3. To understand the potential immunomodulatory effects of macrolides for the

treatment of chronic diseases of the airways.
4. To understand the effects of macrolides on mucus secretion.

5. To realize the immunomodulatory effects of macrolides are independent of their
antimicrobial effects.
6. To realize the clinical utility of these drugs for the treatment of chronic inflammatory
conditions.
• Neither Dr. Rubin, nor the department(s) with which he is affiliated, has received
something of value (ie, any item, payment, or service valued in excess of $750.00) from a
commercial or other party related directly or indirectly to the subject of this submission. He
has received research grants and honoraria, and is a consultant for Abbott Laboratories.
He has also received research grants from Zambon Pharmaceuticals. Neither Dr. Henke,
nor the department(s) with which he is affiliated, has received something of value (ie, any
item, payment, or service valued in excess of $750.00) from a commercial or other party
related directly or indirectly to the subject of this submission. This article will be presenting
information about immunomodulatory uses of macrolide antibiotics that is considered
research and is not yet approved for any purpose.
Previous Section
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Long-Term Low-Dose Erythromycin in Patients With Unexplained Chronic Cough: A Double-Blind Placebo Controlled Trial

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Long-Term Low-Dose Erythromycin in Patients With Unexplained Chronic Cough: A Double-Blind Placebo Controlled Trial

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http://thorax.bmj.com/content/early/2010/10/21/thx.2010.142711.

Long-term low-dose erythromycin in patients with

3. Kings College Hospital, Denmark Hill, London, UK

• Received 14 May 2010

• Accepted 5 August 2010

• Published Online First 21 October 2010

Pharmacological Treatment Options for Bronchiectasis:

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Azithromycin as a Treatment for COPD

Tissue Reparative Effects of Macrolide Antibiotics in

It is well established that macrolide antibiotics, including the semisynthetic derivatives of

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Open-label studies with troleandomycin in methyprednisolone-dependent patients with asthma

Macrolide antibiotics are efficacious measures in asthmatic patients without corticosteroid

Non-Cystic Fibrosis Bronchiectasis and Chronic Bronchitis

Cystic Fibrosis and P aeruginosa Colonization

Cryptogenic Organizing Pneumonia

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COPD is characterized by progressive airflow limitation caused by an abnormal inflammatory

In contrast, Nixon and coworkers66 documented improvements in spirometry findings as well as

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There is debate with respect to the contribution of anti-inflammatory benefits vs antimicrobial

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1. Which of the following is not true of the effects of macrolides on neutrophils?

3. Inhibit neutrophil migration to inflammatory sites

4. Stimulate neutrophil adhesion

5. Increase neutrophil degranulation

2. Decrease eosinophilic inflammation

1. Increase in FVC and FEV1

1. Improvement in sinus symptoms such as sinus pain, headache, nasal congestion,

2. Reduced mucociliary transport

3. Reduction in rhinorrhea, postnasal drip, nasal obstruction, and sense of dullness in

4. Reduced volume of secretions

4. Significant correlation between neutrophil count and respiratory symptoms

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Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation12345

Clinical Experience with Macrolide Therapy for Chronic Sinusitis

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Effect of clarithromycin in patients with chronic sinusitis.24

Effect of Clarithromycin in Asthma*

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2. To realize that large-scale, placebo-controlled studies determining the efficacy and

4. To understand the effects of macrolides on neutrophils.

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