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1 s2.0 S0196070919309032 Main PDF
1 s2.0 S0196070919309032 Main PDF
Am J Otolaryngol
journal homepage: www.elsevier.com/locate/amjoto
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 diseases is thought to have a harmful effect in the lower airway; how-
ever, definitive mechanisms of association between chronic cough and
Chronic cough is a common symptom, usually defined as a persis- rhinosinusitis have not been completely resolved [2].
tent cough lasting > 8 weeks. Chronic cough has many possible causes Chronic rhinosinusitis is a common disease, and patients with
including internal and external factors. Air pollution is a leading ex- chronic rhinosinusitis often have co-existing lower airway diseases
ternal factor of chronic cough. Smoke- or drug-induced chronic cough [3,4]. A recent study examined 1412 chronic cough patients and re-
has also been reported. Gastroesophageal disorders such as gastro- ported that 73.4% (1036/1412) of the patients were diagnosed with
esophageal reflux disease and pulmonary disorders (e.g., asthma and asthma and/or abnormalities on chest X-ray. In addition, 68.4% (257/
chronic obstructive pulmonary disease (COPD)) should be the focus of 376) had abnormal findings on computed tomography (CT) scans of the
examinations of chronic cough. Chronic upper respiratory tract diseases paranasal sinus, and 29.0% (109/376) had rhinosinusitis, based on the
such as rhinitis, rhinosinusitis, and laryngitis are also considered as European Position Paper on Rhinosinusitis (EPOS) guidelines [5,6].
possible causes of chronic cough [1]. Post-nasal drip due to sinonasal 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
Retrospective chart review was performed, and 32 patients with a SNOT-20 had five domains ((1) rhinologic domain: need to blow
chief complaint of chronic cough who visited the Department of nose, sneezing, runny nose, postnasal discharge, thick nasal discharge;
Respiratory Medicine were enrolled in this study. The patients were (2) ear and facial symptoms domain: ear fullness, dizziness, ear pain,
diagnosed as having chronic rhinosinusitis, based on the European facial pain/pressure; (3) sleep domain: difficulty falling asleep, waking
Position Paper on Rhinosinusitus and Nasal Polyps 2012 [5]. Patients up at night, lack of a good night's sleep; (4) psychological domain: fa-
using inhaled corticosteroids and/or a bronchodilator, asthmatic pa- tigue, reduced productivity, reduced concentration, frustration/rest-
tients, and patients with abnormal findings on auscultation and/or lessness/irritability, sadness, and embarrassment; (5) domain of
chest X-ray examination were excluded from the study. The patients symptoms not classified into these other domains: waking up tired,
who were previously diagnosed with asthma were also excluded. In- cough). SNOT-20 was used to evaluate the severity of subjective
formed consent was obtained from the enrolled subjects. The study was symptoms.
approved by the Institutional Review Board and performed in com-
pliance with the Declaration of Helsinki. 2.7. Statistical analysis
The patients were treated with low doses of clarithromycin
(200 mg/day) and carbocisteine (1500 mg/day) for > 3 months. Both Values are presented as mean ± standard deviation. The Mann-
before and after the treatment, the patients were examined by periph- Whitney U test was applied to compare two groups. The Wilcoxon
eral blood test, paranasal sinus CT scan, and pulmonary function test. A signed-rank test was used for comparisons between pre- and post-
Sino-Nasal Outcome Test (SNOT-20) was applied to assess the quality of treatment scores. Correlations were analyzed using Spearman's rank
life of the patients both before and after the treatment. correlation coefficient. P values < 0.05 were considered significant.
Statistical analyses were performed with IBM SPSS Statistic (IBM, New
2.2. Blood cell counts in peripheral blood York, USA).
Blood samples were taken in the outpatient clinic. The white blood 3. Results
cell counts and eosinophil count in peripheral blood were determined.
The mean age of the 32 enrolled chronic rhinosinusitis patients with
chronic cough was 59.2 ± 13.2 years. There were 21 males (age:
2.3. Lund-MacKay CT score
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-
The radiological severity of chronic rhinosinusitis was evaluated
ders. Of the 32 patients, 11 patients were never smokers, 16 patients
using the Lund-MacKay CT staging system [13].
were past smokers (Brinkman index (number of cigarettes smoked per
day multiplied by number of years of smoking): 290 ± 301), and 5
2.4. Pulmonary function test patients were current smokers (Brinkman index: 848 ± 589). The
Brinkman index in the past smokers was significantly lower than that in
Pulmonary function was tested in accordance with the American the current smokers (P = 0.021).
Thoracic Society/European Respiratory Society recommendations [14]. The Lund-MacKay CT score before and after the treatment was
The percent predicted vital capacity (%VC), forced vital capacity (FVC), 10.2 ± 5.6 and 6.0 ± 5.0, respectively. The Lund-MacKay CT score
forced expiratory volume in 1 s (FEV1.0), percent predicted FEV1.0 (% after the low-dose, long-term macrolide antibiotics treatment was a
FEV1.0), and FEV1.0/FVC ratio were measured or calculated. 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 chronic cough.
before (5972 ± 1227/μL) and after (6995 ± 1971/μL) the treatment Next, we examined the relationship between changes in the Lund-
was not statistically significant. The eosinophil level in peripheral blood MacKay CT score and pulmonary function before and after the treat-
was not significantly different between before (3.8 ± 1.7%) and after ment. Fig. 1A shows the relationship between changes in the Lund-
(4.2 ± 2.7%) the treatment. MacKay CT score and %VC before bronchodilator inhalation. The
The pulmonary function in chronic rhinosinusitis patients with horizontal axis shows changes in Lund-MacKay CT score values, sub-
chronic cough is shown in Table 1 for both before and after the treat- tracting the CT score before treatment from the CT score after treat-
ment. There was no statistically significant difference in %VC (a para- ment. The vertical axis shows changes in %VC values, subtracting pre-
meter showing restrictive lung function changes) between before and treatment %VC from post-treatment %VC. There was no statistically
after the treatment. In contrast, both before and after bronchodilator significant relationship between the changes in the Lund-MacKay CT
inhalation, FEV1.0, %FEV1.0, and the FEV1.0/FVC ratio (parameters score and %VC. In contrast, the changes in the Lund-MacKay CT score
showing obstructive lung function changes) improved significantly were significantly correlated to the respective changes in FVC
after the treatment (P < 0.05). The treatment with clarithromycin and (r = −0.409, P = 0.023), FEV1.0 (r = −0.392, P = 0.029), %FEV1.0
carbocisteine improved both the Lund-MacKay CT score and obstructive (r = −0.356, P = 0.047), and the FEV1.0/FVC ratio (r = −0.365,
lung function changes in the chronic rhinosinusitis patients with P = 0.042) before bronchodilator inhalation (Fig. 1B, C, D, and E,
3
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).
4
S. Kariya, et al. Am J Otolaryngol 41 (2020) 102315
inflammatory effects [20]. We showed in this study that long-term oral References
administration of low-dose macrolide antibiotics for chronic rhinosi-
nusitis could improve the obstructive lung function changes in chronic [1] Bucca CB, Bugiani M, Culla B, Guida G, Heffler E, Mietta S, et al. Chronic cough and
cough patients without asthma. Post-nasal drip is one of the possible irritable larynx. J Allergy Clin Immunol 2011;127:412–9. https://doi.org/10.1016/
j.jaci.2010.10.038.
factors in the pathophysiology of chronic cough. Examination of the [2] Plevkova J, Song WJ. Chronic cough in subjects with upper airway diseases - ana-
upper respiratory tract is recommended for chronic cough patients. Our lysis of mechanisms and clinical applications. Asia Pac Allergy 2013;3:127–35.
findings suggest that the treatment for chronic rhinosinusitis might be https://doi.org/10.5415/apallergy.2013.3.2.127.
[3] Ramakrishnan JB, Kingdom TT, Ramakrishnan VR. Allergic rhinitis and chronic
effective for the subjective symptoms as well as obstructive lung con- rhinosinusitis: their impact on lower airways. Immunol Allergy Clin North Am
ditions in non-asthmatic patients with chronic cough. 2013;33:45–60. https://doi.org/10.1016/j.iac.2012.10.009.
This study showed that the low-dose, long-term macrolide anti- [4] Philpott CM, Erskine S, Hopkins C, Kumar N, Anari S, Kara N, et al. Prevalence of
asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK
biotics treatment could improve lung function in non-asthmatic chronic National Chronic Rhinosinusitis Epidemiology Study. Respir Res 2018;19:129.
cough patients with normal chest X-ray findings; however, the defini- https://doi.org/10.1186/s12931-018-0823-y.
tive mechanism is unclear. There are two possible mechanisms. One is a [5] Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012:
European position paper on rhinosinusitis and nasal polyps 2012. A summary for
direct effect of macrolide antibiotics. Systemic administration of mac-
otorhinolaryngologists. Rhinology 2012;50:1–12. https://doi.org/10.4193/
rolide antibiotics may be able to improve the condition in both the si- Rhino50E2.
nonasal sinus and lung. As described above, macrolide antibiotics are a [6] Kariya S, Okano M, Higaki T, Tachibana T, Rikimaru T, Nishizaki K. Lund-Mackay
powerful treatment option in the management of chronic rhinosinusitis computed tomography score is associated with obstructive pulmonary function
changes in chronic cough patients. Am J Rhinol Allergy 2019;33:294–301. https://
[20]. In addition, the utility of long-term macrolides for the manage- doi.org/10.1177/1945892418825094.
ment of several lung diseases is also well known [21,22]. Similar pa- [7] Oakley GM, Christensen JM, Sacks R, Earls P, Harvey RJ. Characteristics of mac-
thophysiological conditions that could be improved by those macrolide rolide responders in persistent post-surgical rhinosinusitis. Rhinology
2018;56:111–7. https://doi.org/10.4193/Rhin17.049.
antibiotics could be observed in both the upper and lower airways in [8] Majima Y, Kurono Y, Hirakawa K, Ichimura K, Haruna S, Suzaki H, et al. Efficacy of
the subjects of this study. The other possible mechanism is an indirect combined treatment with S-carboxymethylcysteine (carbocisteine) and clari-
effect of macrolide antibiotics for the pulmonary function. At the first thromycin in chronic rhinosinusitis patients without nasal polyp or with small nasal
polyp. Auris Nasus Larynx 2012;39:38–47. https://doi.org/10.1016/j.anl.2011.04.
step, macrolide antibiotics reduced the severity of chronic rhinosinu- 015.
sitis. The levels of interleukin (IL)-1β and IL-5 in nasal discharge are [9] Hopkins C, Rimmer J, Lund VJ. Does time to endoscopic sinus surgery impact
related to pulmonary function in patients with chronic rhinosinusitis outcomes in chronic rhinosinusitis? Prospective findings from the National
Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis.
[23]. In this study, reduced post-nasal drip containing inflammatory Rhinology 2015;53:10–7. https://doi.org/10.4193/Rhin13.217.
cells and mediators might have a preferable effect on pulmonary [10] Hopkins C, Andrews P, Holy CE. Does time to endoscopic sinus surgery impact
function in chronic cough patients. outcomes in chronic rhinosinusitis? Retrospective analysis using the UK clinical
practice research data. Rhinology 2015;53:18–24. https://doi.org/10.4193/
There are several limitations in our study including a small sample
Rhin14.077.
size. The subjective symptom (cough score) was improved after treat- [11] Vashishta R, Soler ZM, Nguyen SA, Schlosser RJ. A systematic review and meta-
ment, but the changes did not reach the statistical significance. It may analysis of asthma outcomes following endoscopic sinus surgery for chronic rhi-
due to the small number of cases. In addition, the Lund-Mackay scores nosinusitis. Int Forum Allergy Rhinol 2013;3:788–94. https://doi.org/10.1002/alr.
21182.
were so low in this study, suggesting that most of the patients had mild [12] Rix I, Håkansson K, Larsen CG, Frendø M, von Buchwald C. Management of chronic
chronic rhinosinusitis. Further controlled study with a large number of rhinosinusitis with nasal polyps and coexisting asthma: a systematic review. Am J
subjects is needed. Rhinol Allergy 2015;29:193–201. https://doi.org/10.2500/ajra.2015.29.4178.
[13] Lund VJ, Mackay IS. Staging in rhinosinusitus. Rhinology 1993;31:183–4.
To explain the close association of upper and lower airway diseases, [14] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.
several hypotheses and mechanisms including systemic reactions, na- Standardisation of spirometry. Eur Respir J 2005;26:319–38. https://doi.org/10.
sobronchial reflex, pharyngobronchial reflex, the effect of nasal ob- 1183/09031936.05.00034805.
[15] Reid DJ, Carlson AA. Clinical use of aclidinium in patients with COPD. Int J Chron
struction, smoking, and inhalation of environmental pollutants have Obstruct Pulmon Dis 2014;9:369–79. https://doi.org/10.2147/COPD.S40193.
been reported [24–28]. In addition, the effect of chronic rhinosinusitis [16] Homma H, Yamanaka A, Tanimoto S, Tamura M, Chijimatsu Y, Kira S, et al. Diffuse
on the lower airway varied depending on the subtype of chronic rhi- panbronchiolitis. A disease of the transitional zone of the lung. Chest 1983;83:63–9.
https://doi.org/10.1378/chest.83.1.63.
nosinusitis [29]. These factors should also be considered in further
[17] Stevens WW, Lee RJ, Schleimer RP, Cohen NA. Chronic rhinosinusitis pathogenesis.
studies to reveal the definitive role of chronic rhinosinusitis in the pa- J Allergy Clin Immunol 2015;136:1442–53. https://doi.org/10.1016/j.jaci.2015.
thophysiology of chronic cough. 10.009.
[18] Hox V, Maes T, Huvenne W, Van Drunen C, Vanoirbeek JA, Joos G, et al. A chest
physician’s guide to mechanisms of sinonasal disease. Thorax 2015;70:353–8.
https://doi.org/10.1136/thoraxjnl-2014-205520.
5. Conclusion [19] Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, et al. The global epide-
miology of chronic cough in adults: a systematic review and meta-analysis. Eur
The pulmonary function in chronic cough patients with chronic Respir J 2015;45:1479–81. https://doi.org/10.1183/09031936.00218714.
[20] Lasso A, Masoudian P, Quinn JG, Cowan J, Labajian V, Bonaparte JP, et al. Long-
rhinosinusitis was improved by the low-dose, long-term macrolide an- term low-dose macrolides for chronic rhinosinusitis in adults - a systematic review
tibiotics treatment. Chronic rhinosinusitis patients had latent ob- of the literature. Clin Otolaryngol 2017;42:637–50. https://doi.org/10.1111/coa.
structive lung function changes [30–32]. Local and/or systemic treat- 12787.
[21] Faverio P, Bini F, Vaghi A, Pesci A. Long-term macrolides in diffuse interstitial lung
ment for chronic rhinosinusitis may be helpful for the management of
diseases. Eur Respir Rev 2017;26(146). https://doi.org/10.1183/16000617.0082-
chronic cough in patients with chronic rhinosinusitis. 2017. pii: 170082.
[22] Kondo M, Tamaoki J. Therapeutic approaches of asthma and COPD overlap.
Allergol Int 2018;67:187–90. https://doi.org/10.1016/j.alit.2017.09.002.
Declaration of competing interest [23] Kariya S, Okano M, Oto T, Higaki T, Makihara S, Haruna T, et al. Pulmonary
function in patients with chronic rhinosinusitis and allergic rhinitis. J Laryngol Otol
2014;128:255–62. https://doi.org/10.1017/S0022215114000450.
None. [24] Bachert C, Claeys SE, Tomassen P, van Zele T, Zhang N. Rhinosinusitis and asthma:
a link for asthma severity. Curr Allergy Asthma Rep 2010;10:194–201. https://doi.
org/10.1007/s11882-010-0096-0.
[25] Samitas K, Carter A, Kariyawasam HH, Xanthou G. Upper and lower airway re-
Acknowledgments
modelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the
one airway concept revisited. Allergy 2018;73:993–1002. https://doi.org/10.1111/
The authors thank Dr. Toru Rikimaru for data collection. This work all.13373.
was supported by JSPS KAKENHI (Grants-in-Aid for Scientific [26] Song WJ, Morice AH. Cough hypersensitivity syndrome: a few more steps forward.
Allergy Asthma Immunol Res 2017;9:394–402. https://doi.org/10.4168/aair.2017.
Research) Grant Number JP17K11329.
5
S. Kariya, et al. Am J Otolaryngol 41 (2020) 102315
9.5.394. [30] Kariya S, Okano M, Higaki T, Noyama Y, Haruna T, Ishihara H, et al. Chronic
[27] Morice AH, Millqvist E, Belvisi MG, Bieksiene K, Birring SS, Chung KF, et al. Expert rhinosinusitis patients have decreased lung function. Int Forum Allergy Rhinol
opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir 2014;4:828–33. https://doi.org/10.1002/alr.21370.
J 2014;44:1132–48. https://doi.org/10.1183/09031936.00218613. [31] Kariya S, Okano M, Higaki T, Noyama Y, Haruna T, Nishizaki K. Pulmonary func-
[28] Hennel M, Brozmanova M, Kollarik M. Cough reflex sensitization from esophagus tion in never-smoker patients with chronic rhinosinusitis. Int Forum Allergy Rhinol
and nose. Pulm Pharmacol Ther 2015;35:117–21. https://doi.org/10.1016/j.pupt. 2015;5:990–5. https://doi.org/10.1002/alr.21628.
2015.10.007. [32] Uraguchi K, Kariya S, Makihara S, Okano M, Haruna T, Oka A, et al. Pulmonary
[29] Watelet JB, Van Zele T, Brusselle G. Chronic cough in upper airway diseases. Respir function in patients with eosinophilic chronic rhinosinusitis. Auris Nasus Larynx
Med 2010;104:652–7. https://doi.org/10.1016/j.rmed.2009.11.020. 2018;45:476–81. https://doi.org/10.1016/j.anl.2017.07.020.