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Systematic Review
Objective: To assess the prognostic factors that predict favorable outcomes of low-dose macrolides (LDMs) in treating
chronic rhinosinusitis (CRS).
Methods: Randomized controlled trials studying the effects of LDMs in treating CRS were included. Data were pooled for
meta-analysis. Primary outcome was Sino-Nasal Outcome Test (SNOT). Six prognostic factors: CRS subtypes, serum immuno-
globulin (Ig)E level, membered lactone ring of macrolides, concurrent endoscopic sinus surgery (ESS), and dosage and duration
of the LDMs were assessed by subgroup analyses.
Results: Ten studies (608 patients) met the inclusion criteria. LDMs and placebo were not different in SNOT improvement
(standardized mean difference [SMD] = −0.23, 95% confidence interval [CI]: −0.69 to 0.24). Subgroup analyses showed that the
effects favored LDMs in the patients with CRS without polyps (SMD = −0.64, 95% CI: −1.01 to −0.27) compared to CRS with polyps,
and the patients receiving a half dose (SMD = −0.64, 95% CI: −1.01 to −0.27) compared to a very low dose. There was no difference
in SNOT improvement between LDMs plus standard treatment compared to standard treatment (SMD = −0.52, 95% CI: −1.57 to
0.53). Subgroup analyses showed that the effects favored LDMs in the patients receiving LDMs for a duration of 24 weeks
(SMD = −1.68, 95% CI: −2.40 to −0.95) compared to 8 and 12 weeks. There was no difference between the 14-membered and
15-membered ring LDMs. Assessment of concurrent ESS found mixed results. Serum IgE level could not be assessed.
Conclusions: LDMs provided favorable outcomes in patients with CRS without polyps. A half dose of macrolides should
be given for a duration of 24 weeks.
Key Words: Macrolides, sinusitis, nasal polyps, anti-inflammatory, dose-response relationship, intranasal surgery.
Level of Evidence: 1a
Laryngoscope, 9999:1–10, 2019
INTRODUCTION agents are the medical treatment for the long-term control
Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) of a variety of chronic inflammations.
and CRS without nasal polyps (CRSsNP) represent multi- Macrolides are acknowledged anti-inflammatory agents
ple overlapping entities with various inflammatory pat- with immunomodulatory effects.4,5 They modulate neutro-
terns.1 Diversity in the pathogenesis of CRS associates philic action by suppression of lipopolysaccharide-induced
with a wide spectrum of immunologic profiles and expres- neutrophil migration. The production of proinflammatory
sions of various T helper (Th) cell types and simultaneous cytokines, such as interleukin (IL)-8 and tumor necrosis
expression of multiple Th cell types has been shown in factor-alpha (TNF-α) is suppressed.6 In addition, they modu-
some patients.2 Thus, heterogeneity among patients with late the synthesis and secretion of mucus and alter mucus
CRS is so remarkable that patients may be classified into rheological properties, which results in effective clearance.6
10 clusters by characteristic cytokines.3 Anti-inflammatory Low-dose macrolides (LDMs) have been commonly utilized
for treating upper airway diseases after its clinical effective-
From the Department of Otolaryngology (K.S., D.K., K.S.); Faculty of
Medicine (N.S., C.S.), Chulalongkorn University, Bangkok, Thailand;
ness on diffuse panbronchiolitis was revealed.7
Endoscopic Nasal and Sinus Surgery Excellence Center (K.S., D.K., K.S.), Currently, long-term LDMs therapy in the manage-
King Chulalongkorn Memorial Hospital, Bangkok, Thailand; and the ment of CRS is controversial. Although recommended by
Department of Otolaryngology (W.C.), Rajavithi Hospital Hospital, Bangkok,
Thailand. international guidelines, the evidence supporting LDMs
Editor’s Note: This Manuscript was accepted for publication on therapy is mixed. The first randomized controlled trial (RCT)
January 22, 2019. showed clinical improvement,8 but another RCT showed
K.S. received honoraria for speaking at symposia for Merck Sharp
and Dohme, Mylan, and Menarini. no difference.9 In addition, there is no consensus among
The authors have no other funding, financial relationships, or con- international guidelines on patient selection. The European
flicts of interest to disclose.
Send correspondence to Kornkiat Snidvongs, MD, Department of Otolar- Position Paper on Rhinosinusitis and Nasal Polyps 2012
yngology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, (EPOS 2012)1 and the International Consensus Statement
Pathumwan, Bangkok 10330, Thailand. E-mail: drkornkiat@yahoo.com
on Allergy and Rhinology10 recommend macrolides for both
DOI: 10.1002/lary.27865 CRSsNP and CRSwNP subtypes. However, a systematic
*Study group received azithromycin 500 mg/d for 3 days during the first week followed by 500 mg/wk for 11 weeks.
†
Study group received clarithromycin 1,000 mg/d during the first 2 weeks, followed by 250 mg/d for 6 weeks.
CRS = chronic rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal polyps; CRSwNP = chronic rhinosinusitis with nasal polyps; ESS = endoscopic
sinus surgery; Mixed (sNP) = mixed population with predominant without polyps; Mixed (wNP) = mixed population with predominant with polyps; INCS = Intranasal
corticosteroids.
LDMs therapy to a standard treatment of intranasal steroid (SMD = 0.15, 95% CI: −0.25 to 0.54).16,18 Heterogeneity
spray.21 One trial was excluded from quantitative synthesis was substantial for the SNOT (I2 = 88%), symptom score
because the LDMs therapy was compared to herbal medicine, (I2 = 85%), endoscopy score (I2 = 98%). There was no het-
which was neither a placebo nor a standard treatment.17 erogeneity (I2 = 0%) for CT score.
1. CRS subtype LDMs vs. placebo Favor CRSsNP, Favor CRSsNP, N/D N/A
SMD −0.64 SMD −0.89
1.1 CRSwNP
(−1.01, −0.27) (−1.41, −0.37)
1.2 CRSsNP
LDMs plus Standard treatment N/D N/D N/D N/D
vs. standard treatment
LDMs vs. standard treatment N/A N/A N/A N/A
2. Serum IgE LDMs vs. placebo N/A N/A N/A N/A
2.1 low serum IgE LDMs plus standard treatment N/A N/A N/A N/A
2.2 high serum IgE vs. standard treatment
LDMs vs. standard treatment N/A N/A N/A N/A
3. Concurrent ESS LDMs vs. placebo N/D Favor LDMs N/D N/A
without ESS,
3.1 LDMs w/o ESS
SMD −0.89
3.2 LDMs with ESS
(−1.41, −0.37)
LDMs plus standard treatment Favor LDMs with N/D Favor LDMs With N/D
vs. standard treatment ESS, SMD ESS, SMD
−1.68 (−2.40, −3.79 (−4.85,
−0.95) −2.73)
LDMs vs. standard treatment N/D N/D N/D N/D
4. Dose LDMs vs. placebo Favor half dose, Favor half dose, N/D N/A
SMD −0.64 SMD −0.89
4.1 Half dose
(−1.01, −0.27) (−1.41, −0.37)
4.2 Less than half dose
LDMs plus standard treatment N/A N/D N/D N/A
vs. standard treatment
LDMs vs. Standard treatment N/A N/A N/A N/A
5. Lactone ring LDMs vs. placebo N/D N/A N/A N/A
5.1 14-membered ring LDMs plus standard treatment N/A N/A N/A N/A
5.2 15-membered ring vs. standard treatment
LDMs vs. standard treatment N/A N/A N/A N/A
6. Duration LDMs vs. placebo N/A N/A N/A N/A
6.1 > 12 weeks LDMs plus standard treatment Favor >12 weeks, Favor >12 weeks, Favor >12 weeks, N/D
6.2 12 weeks vs. standard treatment SMD −1.68 SMD −1.65 SMD −3.79
6.3 < 12 weeks (−2.40, −0.95) (−2.37, −0.93) (−4.85, −2.73)
LDMs vs. standard treatment N/A N/A N/A N/A
CRS = chronic rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal polyps; CRSwNP = chronic rhinosinusitis with nasal polyps; ESS = endo-
scopic sinus surgery; LDMs = low-dose macrolides; N/A = not applicable; N/D = no difference between subgroup; QOL = quality of life.
−0.89, 95% CI: −1.41 to −0.37) over patients with ESS 95% CI: −0.46 to 0.51). The subgroup difference was statisti-
(MD = 0.31, 95% CI: −0.21 to 0.83). The subgroup difference cally significant (P < .001). The improvement was not differ-
was statistically significant (P = .001). Improvements were ent between patients with and without ESS in symptom score
similar between patients with and without ESS in the (the patients without ESS, MD = −0.10, 95% CI: −0.59 to
SNOT improvement (patients without ESS, SMD = −0.20, 0.38), and the patients with ESS (SMD = −0.94, 95% CI:
95% CI: −1.03 to 0.63) and the patients with ESS (SMD = −2.27 to 0.39; P = .25).
−0.26, 95% CI: −1.04 to 0.53; P = .76) and endoscopy score
(patients without ESS, MD = −0.27, 95% CI: −0.77 to 0.22),
and patients with ESS (MD = −0.45, 95% CI: −0.97 to Prognostic Factor: Dose of Macrolides
0.08; P = .64). When subgroup analysis by dose of macrolides was
When LDMs plus standard treatment was compared performed, the effects favored the patients receiving a
with standard treatment, meta-analyses gave results in con- half dose of macrolides (SMD = −0.64, 95% CI: −1.01 to
trast to the comparison of LDMs versus placebo. LDMs −0.27), over the patients receiving less than a half dose of
brought greater SNOT and endoscopy score improvements macrolides (SMD = 0.18, 95% CI: −0.19 to 0.55; P = .002).
when given to patients with ESS. The improvement in the The data are displayed in Figure 3. Likewise, the effects
SNOT favored patients with ESS (MD = −1.68, 95% CI: −2.40 in symptom score improvement favored patients receiving
to −0.95) but not the patients without ESS (SMD = −0.01, a half dose of macrolides (MD = −0.89, 95% CI: −1.41 to
95% CI: −0.63 to 0.61). The subgroup difference was statisti- −0.37), over the patients receiving less than a half-dose of
cally significant (P < .001). The improvement in endoscopy macrolides (MD = 0.31, 95% CI: −0.21 to 0.83; P = .001).
score favored the patients with ESS (SMD = −3.79, 95% CI: There was no difference between the two subgroups
−4.85 to −2.73), but not the patients without ESS (MD = 0.02, (P = .64) in endoscopy score.
Prognostic Factor: Membered Lactone Ring LDMs (SMD = −0.21, 95% CI: −1.09 to 0.66; P = .96. The
of LDMs data are displayed in Figure 4.
When subgroup analysis by membered lactone ring of
LDMs was performed, the improvements in the SNOT were
similar between the patients receiving a 14-membered lac- Prognostic Factor: Duration of Treatment
tone ring of LDMs (SMD = −0.24, 95% CI: −0.98 to 0.50), When subgroup analysis by duration of LDMs treat-
and the patients receiving a 15-membered lactone ring of ment was performed, the effects in SNOT improvement
Fig. 3. Improvement in the SNOT at the end of treatment when low-dose macrolides therapy was compared with placebo and subgroup analy-
sis by dosage. CI = confidence interval; df = degrees of freedom; IV = inverse variance; LDM = low-dose macrolides; Random = random
effects; SD = standard deviation; SNOT = Sino-Nasal Outcome Test; Std. mean difference = standardized mean difference. [Color figure can
be viewed in the online issue, which is available at www.laryngoscope.com.]
favored patients receiving 24-week LDMs (SMD = –1.68, score8,12 (SMD = −0.17, 95% CI: −0.53 to 0.18), and no dif-
95% CI: −2.40 to −0.95), over patients receiving 12-week ference between the LDMs plus standard treatment and
LDMs (MD = −0.28, 95% CI: −0.77 to 0.21) and 8-week standard treatment in the symptom score19 (MD = −0.06,
LDMs (MD = 0.36, 95% CI: −0.33 to 1.04; P = .002). Like- 95% CI: −0.49 to 0.16). At the time point of 48 weeks, Peric
wise, the effects favored patients receiving 24-week LDMs et al.19 reported no difference between the LDMs plus stan-
in symptom improvement (MD = −1.65, 95% CI: −2.37 to dard treatment and standard treatment in the symptom
−0.93), over patients receiving 12-week LDMs (MD = −0.10, score (MD = −0.17, 95% CI: −0.61 to 0.27).
95% CI: −0.59 to 0.38) and 8-week LDMs (MD = −0.29, 95%
CI: −0.73 to 0.15; P = .001), and the effects favored patients
receiving 24-week LDMs in endoscopy score (MD = −3.79,
Risk of Bias of Included Studies
95% CI: −4.85 to −2.73), over patients receiving 12-week
The included studies had substantial selection bias
LDMs (MD = 0.02, 95% CI: −0.46 to 0.51; P < .001). The
for random sequence generation (60% low risk) and allo-
effects at 8 weeks in one RCT were not estimable. The
cation concealment (50% low risk). They had modest risks
improvement in CT score were similar between patients
in detection bias (70% low risk), attrition bias (80% low
receiving 12-week LDMs (MD = 0.08, 95% CI: –0.40 to 0.56),
risk), and reporting bias (80% low risk).
and patients receiving 8-week LDMs (MD = 0.28, 95% CI:
−0.40 to 0.96; P = .64).
Sensitivity Analysis
Adverse Effects The sensitivity analysis was performed by excluding
There were nine studies that reported gastrointesti- studies with multiple (more than one) high risks of bias from
nal and cardiac adverse effects.8,9,12,15–20 LDMs produced the meta-analysis. There were two RCTs excluded.19,20 Both
greater gastrointestinal adverse effects (5%) when com- RCTs compared LDMs plus standard treatment versus
pared to other treatments (1.05%) (risk ratio: 3.52; 95% CI: standard treatment. The results revealed two significant
1.29 to 9.60). There was no cardiac adverse effect reported prognostic factors in that the LDMs were effective in SNOT
in any patients. The data are displayed in Table III. improvement, which were CRSsNP and a half dose of LDMs,
and three prognostic factors in symptom improvement,
which were CRSsNP and a half dose of LDMs and LDMs
therapy without ESS.
Durability of Outcomes Improvement
There were four studies that reported data after the
end of the treatment at the time point of 24 weeks.8,9,12,19
The meta-analysis revealed no difference between the LDMs Meta-regression Analysis
and placebo in the improvement in 1) the SNOT8,9 Meta-regression analysis was not performed due to
(SMD = −0.28, 95% CI: −0.64 to 0.09) and 2) endoscopy the limited number of included studies.
Wallwork 2006 1 29 1 35 0 29 0 35
Videler 2011 2 29 2 31 0 29 0 31
Jiang 2012 0 27 0 26 0 27 0 26
Peric 2014 2 40 0 40 0 40 0 40
Korkmaz 2014 1 22 0 22 0 22 0 22
Varvyanskaya 2014 1 44 0 22 0 44 0 22
Amali 2015 0 22 0 44 0 22 0 44
Haxel 2015 6 29 0 29 0 29 0 29
Deng 2018 1 38 0 36 0 38 0 36
14 280 3 285 0 285 0 285