Discussion
PCD is a lifelong disease that can promote occurrence of recurrent airway infections that finally resulted in bronchiectasis and declining lung function that, in turn, support development of respiratory infections and perpetuate a vicious cycle of disease. Interrupting this vicious cycle is vital in order to delay disease progression. In fact, results of several studies have shown that AZM treatment of patients with CF and non-CF bronchiectasis for 3-6 months improved lung function and nutritional status, while also reducing C-reactive protein levels, pulmonary exacerbations and hospitalization rates[7-10], but only one multicenter phase 3 trial study was performed that showed similar results included both pediatric and adult PCD patients [14]. Here, we retrospectively studied a school-age pediatric population with a mean age at baseline of 8.0 years and a mean age at follow-up of 11.03 years, parts of baseline data had been reported in previous study[15]. Our results revealed that pediatric PCD patients with long-term AZM use experienced significantly fewer respiratory infections than those who had not taken AZM, as observed in the previous study [14].
Azithromycin is currently widely used in chronic respiratory diseases including PCD [16], due to its ability to alleviate both infection and inflammation. More specifically, AZM plays an anti-infective role by inhibiting synthesis of bacterial proteins that can interfere with bacterial biofilm generation and production of other virulence factors [17]. Concurrently, AZM plays an anti-inflammatory role by inhibiting host production of IL-8 and tumor necrosis factor-α (TNF-α) [18-19]. Notably, the decreased frequency of respiratory infections in the AZM-treated group as compared to the control group may be related to relatively reduced daily sputum volume associated with AZM treatment effects on mucus properties and mucus production[20]. In addition, our results also revealed that PCD patients who received long-term AZM therapy exhibited less exercise intolerance as compared to control group. Which indicated that a history of long-term AZM use administered three times per week reduced the frequencies of respiratory infection-triggered inpatient and/or outpatient doctor visits, while also improving school attendance and overall quality of life.
Studies have shown that early in life, impairment of PCD patient lung function begins and increases with age, with magnitudes of PCD disease-induced effects on FEV1 and FVC values eventually resembling those reported in studies of CF patients [21-22]. However, few studies have investigated macrolide antibiotic treatment effects on FEV1 values of non-CF bronchiectasis produced conflicting results [23-25], with only one of the studies indicating improvement of FEV1 after treatment[23]. In this study, lung function varied widely among our patients and the mean follow-up time was 3.1 years and longest follow-up duration was 9.4 years. Importantly, baseline FEF25-75 of patients in the AZM-treated group were lower than that in corresponding control group. Moreover, AZM-treated group lung function improved slightly more than that of the control group, although the intergroup difference was of no apparent difference, due to small numbers of patients in both groups with both baseline and follow-up pulmonary function test results. Ultimately, the results collectively suggest that regularly long term AZM use may stabilized FEV1, FVC, and FEF25-75 in patients with poor lung function or more severe disease resulting from frequent infections.
In fact, that lung spirometry is less sensitive than high-resolution computed tomography (HRCT) at detecting functional and structural lung damage induced by PCD disease [26]. Thus, CT scans were used here to assess lung damage in our PCD patient cohort. Results of this study, which were of no statistically significant between-group differences at baseline, revealed that about 90% of patients in the AZM-treated group exhibited signs of stable or improved lung function as compared to about 75% of that in control group patients. However, this change did not differ apparently between the two groups which need to be confirmed by more detailed and rigorously designed studies due to the evaluation complexity of imaging changes.
Importantly, Goutaki M et al investigated a large group of over 3000 PCD patients, which indicated that both growth and nutrition are affected adversely in PCD patients from early life with delayed diagnosis[28]. However, other studies showed preschool referral to a PCD center was not associated with better BMI[29]. Our results revealed that BMI was a little lower in both groups at baseline which may be associated with late diagnosis in this cohort, while the mean heights were in normal range. Notably, although the average follow-up duration of the AZM-treated group was shorter than that of the control group, the percent increase in height of the AZM-treated group was slightly greater than that of controls, but the intergroup difference was of no statistical significance. Indeed, at first measurement, most PCD patients in this study were of normal height and weight. Thus, these indicators would not likely increase further with AZM treatment during follow-up.
The most common adverse reactions associated with AZM treatment which were observed in this study were that occasional and mild gastrointestinal reactions experienced only in three patients who received regular AZM treatment. Importantly, such reactions improved after patients adjusting the timing of AZM administration. Although hearing decrements were observed to be more common in the azithromycin group in a 12-month RCT in patients with chronic obstructive pulmonary disease [30], no serious adverse reactions, such as ototoxicity and cardiotoxicity, were observed.
A limitation of this retrospective study that lung function tests, chest CT scans, and sputum cultures were not regularly conducted during follow-up duration, which indicate that inadequate patient education and inconsistencies of disease management was exist in China. In the future, establishment of PCD follow-up treatment programs at medical research centers with standardized prospective collection of data related to characteristics and factors associated with PCD phenotypes may help to provide more scientifically based and comprehensive disease management evidence.