Am J Otolaryngol 41 (2020) 102315

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Am J Otolaryngol
journal homepage: www.elsevier.com/locate/amjoto

Long-term treatment with clarithromycin and carbocisteine improves lung T

function in chronic cough patients with chronic rhinosinusitis
⁎
Shin Kariyaa, , Mitsuhiro Okanoa,b, Takaya Higakia, Seiichiro Makiharac, Tomoyasu Tachibanad,
Kazunori Nishizakia
a
Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
b
Department of Otorhinolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan
c
Department of Otolaryngology-Head and Neck Surgery, Kagawa Rosai Hospital, Marugame, Japan
d
Department of Otolaryngology, Himeji Red Cross Hospital, Himeji, Japan

A R T I C LE I N FO A B S T R A C T

Keywords: Purpose: Chronic cough is a common complaint. Because the pathophysiology of chronic cough is complicated,
Chronic obstructive pulmonary disease the management of chronic cough is challenging. To the best of our knowledge, no previous study has examined
Sinusitis the effect of macrolide antibiotics in chronic cough patients with chronic rhinosinusitis. The purpose of this
Rhinitis study is to determine the changes in lung function for chronic cough patients with chronic rhinosinusitis who are
Asthma
treated by clarithromycin and carbocisteine.
Paranasal sinus
Materials and methods: Thirty-two chronic cough patients with chronic rhinosinusitis were recruited. Patients
Pulmonary function
Tobacco using inhaled corticosteroids and/or a bronchodilator, asthmatic patients, and patients with abnormal findings
Cigarette on auscultation and/or chest X-ray examination were excluded from this study. The patients received low-dose
Inflammation clarithromycin treatment for 3 months. Both before and after the treatment, a computed tomography (CT) scan
of the paranasal sinuses, lung function test, peripheral blood test, and sino-nasal outcome test (SNOT-20) were
applied.
Results: Both the lung function and Lund-MacKay CT scores were improved by the long-duration therapy with
macrolide antibiotics. The change in obstructive pulmonary function and the improvement of the CT score in
each subject were significantly correlated. SNOT scores also improved after the treatment.
Conclusions: The macrolide antibiotics treatment has beneficial effects on lung function in non-asthmatic chronic
cough patients with normal chest X-ray findings. The improvement of chronic rhinosinusitis may have some role
in the lung condition. Upper respiratory tract examination and treatment may be useful for the management of
chronic cough.

1. Introduction
Chronic cough is a common symptom, usually defined as a persis-
tent cough lasting > 8 weeks. Chronic cough has many possible causes
including internal and external factors. Air pollution is a leading ex-
ternal factor of chronic cough. Smoke- or drug-induced chronic cough
has also been reported. Gastroesophageal disorders such as gastro-
esophageal reflux disease and pulmonary disorders (e.g., asthma and
chronic obstructive pulmonary disease (COPD)) should be the focus of
examinations of chronic cough. Chronic upper respiratory tract diseases
such as rhinitis, rhinosinusitis, and laryngitis are also considered as
possible causes of chronic cough [1]. Post-nasal drip due to sinonasal
diseases is thought to have a harmful effect in the lower airway; how-
ever, definitive mechanisms of association between chronic cough and
rhinosinusitis have not been completely resolved [2].
Chronic rhinosinusitis is a common disease, and patients with
chronic rhinosinusitis often have co-existing lower airway diseases
[3,4]. A recent study examined 1412 chronic cough patients and re-
ported that 73.4% (1036/1412) of the patients were diagnosed with
asthma and/or abnormalities on chest X-ray. In addition, 68.4% (257/
376) had abnormal findings on computed tomography (CT) scans of the
paranasal sinus, and 29.0% (109/376) had rhinosinusitis, based on the
European Position Paper on Rhinosinusitis (EPOS) guidelines [5,6].
Long-term macrolide therapy is useful for the patients with chronic

⁎
Corresponding author at: Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
E-mail address: skariya@cc.okayama-u.ac.jp (S. Kariya).

https://doi.org/10.1016/j.amjoto.2019.102315
Received 25 September 2019
0196-0709/ © 2019 Elsevier Inc. All rights reserved.
S. Kariya, et al. Am J Otolaryngol 41 (2020) 102315

rhinosinusitis [7]. Efficacy of combined treatment with carbocisteine Table 1

and clarithromycin in chronic rhinosinusitis patients has also been re- Pulmonary function in enrolled patients before and after the low-dose, long-
ported [8]. Chronic rhinosinusitis treatment often involves endoscopic term macrolide antibiotics treatment.
sinus surgery as well as medical therapy [9,10]. Before treatment After treatment P
In asthmatic patients, several studies have examined the role of
chronic rhinosinusitis treatment in the management of asthma. A sys- Before bronchodilator inhalation
%VC (%) 95.2 ± 14.1 96.9 ± 14.3 0.153
tematic review showed evidence that surgical treatment (endoscopic
FVC (L) 3.26 ± 0.83 3.26 ± 0.91 0.504
sinus surgery) for chronic rhinosinusitis patients with asthma could FEV1.0/FVC ratio (%) 71.8 ± 8.1 74.2 ± 7.9 0.022
improve clinical asthma outcome measures, including the frequency of %FEV1.0 (%) 81.9 ± 16.0 86.4 ± 12.8 0.001
asthma attacks, the number of hospitalizations, and the use of oral FEV1.0 (L/s) 2.41 ± 0.62 2.53 ± 0.56 0.015
After bronchodilator inhalation
corticosteroids [11]. However, another systematic review concluded
FVC (L) 3.33 ± 0.84 3.35 ± 0.95 0.130
that the effect of medical and/or surgical interventions for chronic FEV1.0/FVC ratio (%) 72.6 ± 9.9 75.1 ± 9.0 0.035
rhinosinusitis remained unclear for lung function in asthmatic patients %FEV1.0 (%) 83.9 ± 16.3 88.3 ± 12.1 0.010
[12]. Although the impact of chronic rhinosinusitis on asthma patients FEV1.0 (L/s) 2.46 ± 0.62 2.60 ± 0.59 0.008
has been extensively examined, the relationship between chronic rhi-
nosinusitis and lower airway diseases other than asthma is under in- The data represent mean ± standard deviation.
%VC, predicted vital capacity.
vestigation.
FVC, forced vital capacity.
To the best of our knowledge, no previous study has reported the
FEV1.0, forced expiratory volume in 1 s.
effect of medical treatment focused on both chronic rhinosinusitis and %FEV1.0, percent predicted FEV1.0.
pulmonary function in patients with chronic cough. The purpose of this
study is to examine the effect of medical treatment on both the severity 2.5. Bronchodilator reversibility test
of chronic rhinosinusitis and lung function in chronic cough patients
without asthma. Inhalation of a short-acting beta-2 agonist bronchodilator (salbu-
tamol, 1.5 mg) was used to test reversibility. The pulmonary function
2. Materials and methods test was performed before and after bronchodilator inhalation.

2.1. Subjects 2.6. Sino-Nasal Outcome Test (SNOT-20)

Retrospective chart review was performed, and 32 patients with a
chief complaint of chronic cough who visited the Department of
Respiratory Medicine were enrolled in this study. The patients were
diagnosed as having chronic rhinosinusitis, based on the European
Position Paper on Rhinosinusitus and Nasal Polyps 2012 [5]. Patients
using inhaled corticosteroids and/or a bronchodilator, asthmatic pa-
tients, and patients with abnormal findings on auscultation and/or
chest X-ray examination were excluded from the study. The patients
who were previously diagnosed with asthma were also excluded. In-
formed consent was obtained from the enrolled subjects. The study was
approved by the Institutional Review Board and performed in com-
pliance with the Declaration of Helsinki.
The patients were treated with low doses of clarithromycin
(200 mg/day) and carbocisteine (1500 mg/day) for > 3 months. Both
before and after the treatment, the patients were examined by periph-
eral blood test, paranasal sinus CT scan, and pulmonary function test. A
Sino-Nasal Outcome Test (SNOT-20) was applied to assess the quality of
life of the patients both before and after the treatment.
2.2. Blood cell counts in peripheral blood
SNOT-20 had five domains ((1) rhinologic domain: need to blow
nose, sneezing, runny nose, postnasal discharge, thick nasal discharge;
(2) ear and facial symptoms domain: ear fullness, dizziness, ear pain,
facial pain/pressure; (3) sleep domain: difficulty falling asleep, waking
up at night, lack of a good night's sleep; (4) psychological domain: fa-
tigue, reduced productivity, reduced concentration, frustration/rest-
lessness/irritability, sadness, and embarrassment; (5) domain of
symptoms not classified into these other domains: waking up tired,
cough). SNOT-20 was used to evaluate the severity of subjective
symptoms.
2.7. Statistical analysis
Values are presented as mean ± standard deviation. The Mann-
Whitney U test was applied to compare two groups. The Wilcoxon
signed-rank test was used for comparisons between pre- and post-
treatment scores. Correlations were analyzed using Spearman's rank
correlation coefficient. P values < 0.05 were considered significant.
Statistical analyses were performed with IBM SPSS Statistic (IBM, New
York, USA).

Blood samples were taken in the outpatient clinic. The white blood
cell counts and eosinophil count in peripheral blood were determined.
2.3. Lund-MacKay CT score
The radiological severity of chronic rhinosinusitis was evaluated
using the Lund-MacKay CT staging system [13].
2.4. Pulmonary function test
Pulmonary function was tested in accordance with the American
Thoracic Society/European Respiratory Society recommendations [14].
The percent predicted vital capacity (%VC), forced vital capacity (FVC),
forced expiratory volume in 1 s (FEV1.0), percent predicted FEV1.0 (%
FEV1.0), and FEV1.0/FVC ratio were measured or calculated.
3. Results
The mean age of the 32 enrolled chronic rhinosinusitis patients with
chronic cough was 59.2 ± 13.2 years. There were 21 males (age:
62.4 ± 10.9 years) and 11 females (age: 53.1 ± 15.5 years), and no
statistically significant difference was found in age between the gen-
ders. Of the 32 patients, 11 patients were never smokers, 16 patients
were past smokers (Brinkman index (number of cigarettes smoked per
day multiplied by number of years of smoking): 290 ± 301), and 5
patients were current smokers (Brinkman index: 848 ± 589). The
Brinkman index in the past smokers was significantly lower than that in
the current smokers (P = 0.021).
The Lund-MacKay CT score before and after the treatment was
10.2 ± 5.6 and 6.0 ± 5.0, respectively. The Lund-MacKay CT score
after the low-dose, long-term macrolide antibiotics treatment was a
significant improvement over the score before the treatment

2
S. Kariya, et al. Am J Otolaryngol 41 (2020) 102315

Fig. 1. The relationship between pulmonary function changes (A, %VC; B, FVC; C, FEV1.0; D, %FEV1.0; E, FEV1.0/FVC ratio) and changes in the Lund-MacKay
computed tomography (CT) score before bronchodilator inhalation. Values on the horizontal axis are calculated by subtracting the CT score before treatment from
the CT score after treatment in each subject. Values on the vertical axis are calculated by subtracting the lung function value before treatment from the lung function
value after treatment in each subject.
(%VC, percent predicted vital capacity; FVC, forced vital capacity; FEV1.0, forced expiratory volume in 1 s; %FEV1.0, percent predicted FEV1.0).

(P < 0.001). The difference between white blood cell (WBC) counts
before (5972 ± 1227/μL) and after (6995 ± 1971/μL) the treatment
was not statistically significant. The eosinophil level in peripheral blood
was not significantly different between before (3.8 ± 1.7%) and after
(4.2 ± 2.7%) the treatment.
The pulmonary function in chronic rhinosinusitis patients with
chronic cough is shown in Table 1 for both before and after the treat-
ment. There was no statistically significant difference in %VC (a para-
meter showing restrictive lung function changes) between before and
after the treatment. In contrast, both before and after bronchodilator
inhalation, FEV1.0, %FEV1.0, and the FEV1.0/FVC ratio (parameters
showing obstructive lung function changes) improved significantly
after the treatment (P < 0.05). The treatment with clarithromycin and
carbocisteine improved both the Lund-MacKay CT score and obstructive
lung function changes in the chronic rhinosinusitis patients with
chronic cough.
Next, we examined the relationship between changes in the Lund-
MacKay CT score and pulmonary function before and after the treat-
ment. Fig. 1A shows the relationship between changes in the Lund-
MacKay CT score and %VC before bronchodilator inhalation. The
horizontal axis shows changes in Lund-MacKay CT score values, sub-
tracting the CT score before treatment from the CT score after treat-
ment. The vertical axis shows changes in %VC values, subtracting pre-
treatment %VC from post-treatment %VC. There was no statistically
significant relationship between the changes in the Lund-MacKay CT
score and %VC. In contrast, the changes in the Lund-MacKay CT score
were significantly correlated to the respective changes in FVC
(r = −0.409, P = 0.023), FEV1.0 (r = −0.392, P = 0.029), %FEV1.0
(r = −0.356, P = 0.047), and the FEV1.0/FVC ratio (r = −0.365,
P = 0.042) before bronchodilator inhalation (Fig. 1B, C, D, and E,

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S. Kariya, et al. Am J Otolaryngol 41 (2020) 102315

Fig. 2. The relationship between pulmonary function changes (A, FVC; B, FEV1.0; C, %FEV1.0; D, FEV1.0/FVC ratio) and changes in the Lund-MacKay computed
tomography (CT) score after bronchodilator inhalation. Values on the horizontal axis are calculated by subtracting the CT score before treatment from the CT score
after treatment in each subject. Values on the vertical axis are calculated by subtracting the lung function value before treatment from the lung function value after
treatment in each subject.
(FVC, forced vital capacity; FEV1.0, forced expiratory volume in 1 s; %FEV1.0, percent predicted FEV1.0).

Table 2 inhalation (Fig. 2B, C, and D, respectively).

SNOT scores before and after the low-dose, long-term macrolide antibiotics The SNOT scores before and after treatment are shown in Table 2.
treatment. The SNOT scores improved after the treatment with clarithromycin and
Before treatment After treatment P carbocisteine. The total SNOT score after the treatment was sig-
nificantly lower than that before the treatment (P = 0.024). The cor-
Rhinologic score 9.1 ± 4.6 8.5 ± 4.1 0.553 relation between the change in each SNOT score before and after the
Ear-facial score 1.9 ± 3.2 1.3 ± 1.8 0.461
treatment and the change in pulmonary function before and after the
Sleep score 5.9 ± 5.1 5.0 ± 5.2 0.357
Psychological score 8.3 ± 4.9 5.0 ± 5.1 0.176 treatment did not reach statistical significance.
Waking-up-tired score 1.6 ± 1.4 1.3 ± 1.1 0.577
Cough score 2.8 ± 1.4 1.6 ± 1.3 0.172 4. Discussion
Total score 29.6 ± 18.5 17.6 ± 10.7 0.024

The data represent mean ± standard deviation.

respectively).
Although patients clinically diagnosed as having asthma were ex-
cluded from this study, subclinical airway obstruction might have some
effect on the findings. To avoid the effect of reversibility of airway
obstruction, bronchodilator inhalation was applied before the pul-
monary function test, and the changes between before and after the
treatment with clarithromycin were calculated. Fig. 2 shows the re-
lationship between changes in the Lund-MacKay CT score and pul-
monary function after bronchodilator inhalation. No significant corre-
lation was found between the changes in the Lund-MacKay CT score
and FVC (Fig. 2A). The changes in the Lund-MacKay CT score were
significantly correlated with the respective changes of the pulmonary
function parameters showing obstructive lung function changes: FEV1.0
(r = −0.461, P = 0.010), %FEV1.0 (r = −0.446, P = 0.013), and
FEV1.0/FVC ratio (r = −0.508, P = 0.005) after bronchodilator
Since the establishment of the “one airway, one disease” concept,
numerous studies have examined the relationship between asthma and
upper respiratory diseases (allergic rhinitis and chronic rhinosinusitis).
In addition, increasing evidence also suggests that chronic rhinosinu-
sitis is related to non-asthmatic lung diseases including cystic fibrosis,
primary ciliary dyskinesia, COPD, and sinobronchial syndrome
[15–17]. However, respiratory physicians tend to overlook upper
airway diseases in the management of lower airway diseases [18].
Chronic cough is a common disease, and a systematic review
showed that the incidence of chronic cough was 9.6% around the
world. Regional differences were reported, and the prevalence of
chronic cough was higher in Oceania (18.1%), Europe (12.7%), and
America (11.0%) as compared with Asia (4.4%) and Africa (2.3%) [19].
Asthma is the major cause of chronic cough; however, the etiology
of chronic cough is varied and complex. A recent study showed that
29% of chronic cough patients without asthma had chronic rhinosinu-
sitis [6]. The low-dose, long-term macrolide antibiotics treatment is
recommended for patients with chronic rhinosinusitis for its anti-

4
S. Kariya, et al.
inflammatory effects [20]. We showed in this study that long-term oral
administration of low-dose macrolide antibiotics for chronic rhinosi-
nusitis could improve the obstructive lung function changes in chronic
cough patients without asthma. Post-nasal drip is one of the possible
factors in the pathophysiology of chronic cough. Examination of the
upper respiratory tract is recommended for chronic cough patients. Our
findings suggest that the treatment for chronic rhinosinusitis might be
effective for the subjective symptoms as well as obstructive lung con-
ditions in non-asthmatic patients with chronic cough.
This study showed that the low-dose, long-term macrolide anti-
biotics treatment could improve lung function in non-asthmatic chronic
cough patients with normal chest X-ray findings; however, the defini-
tive mechanism is unclear. There are two possible mechanisms. One is a
direct effect of macrolide antibiotics. Systemic administration of mac-
rolide antibiotics may be able to improve the condition in both the si-
nonasal sinus and lung. As described above, macrolide antibiotics are a
powerful treatment option in the management of chronic rhinosinusitis
[20]. In addition, the utility of long-term macrolides for the manage-
ment of several lung diseases is also well known [21,22]. Similar pa-
thophysiological conditions that could be improved by those macrolide
antibiotics could be observed in both the upper and lower airways in
the subjects of this study. The other possible mechanism is an indirect
effect of macrolide antibiotics for the pulmonary function. At the first
step, macrolide antibiotics reduced the severity of chronic rhinosinu-
sitis. The levels of interleukin (IL)-1β and IL-5 in nasal discharge are
related to pulmonary function in patients with chronic rhinosinusitis
[23]. In this study, reduced post-nasal drip containing inflammatory
cells and mediators might have a preferable effect on pulmonary
function in chronic cough patients.
There are several limitations in our study including a small sample
size. The subjective symptom (cough score) was improved after treat-
ment, but the changes did not reach the statistical significance. It may
due to the small number of cases. In addition, the Lund-Mackay scores
were so low in this study, suggesting that most of the patients had mild
chronic rhinosinusitis. Further controlled study with a large number of
subjects is needed.
To explain the close association of upper and lower airway diseases,
several hypotheses and mechanisms including systemic reactions, na-
sobronchial reflex, pharyngobronchial reflex, the effect of nasal ob-
struction, smoking, and inhalation of environmental pollutants have
been reported [24–28]. In addition, the effect of chronic rhinosinusitis
on the lower airway varied depending on the subtype of chronic rhi-
nosinusitis [29]. These factors should also be considered in further
studies to reveal the definitive role of chronic rhinosinusitis in the pa-
thophysiology of chronic cough.
5. Conclusion
The pulmonary function in chronic cough patients with chronic
rhinosinusitis was improved by the low-dose, long-term macrolide an-
tibiotics treatment. Chronic rhinosinusitis patients had latent ob-
structive lung function changes [30–32]. Local and/or systemic treat-
ment for chronic rhinosinusitis may be helpful for the management of
chronic cough in patients with chronic rhinosinusitis.
Declaration of competing interest
None.
Acknowledgments
The authors thank Dr. Toru Rikimaru for data collection. This work
was supported by JSPS KAKENHI (Grants-in-Aid for Scientific
Research) Grant Number JP17K11329.
5
Am J Otolaryngol 41 (2020) 102315
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