Gastroesophageal Reux in Children With Idiopathic Bronchiectases: a Pilot Study

Background: The role of gastroesophageal reux in bronchiectasis development is still object of discussion. We aimed to characterize gastroesophageal reux (GER) in children with idiopathic bronchiectases (BC) and to analyse the relation with a morpho-functional High-Resolution Computed Tomography (HRCT) scoring system Methods: Multiple esophageal impedance-pH (MII-pH) parameters in children with respiratory symptoms with and without BC were compared. In children with BC spirometry was performed and HRCT score was calculated by evaluating in each lung lobe: 1.bronchiectasis-peribronchial wall thickening, 2.mucous plugging, 3.abscess-sacculations, 4.consolidations, 5.others. HRCT score was related to MII-pH results. HRCT score accuracy in predicting pathological MII-pH was evaluated by ROC curve.

BC are uncommon in pediatric ages, with prevalence ranges, in European countries, from 67 to 362 per 100,000 individuals. However, affected patients present poor quality of life and comorbidities, that are related with the progression of the disease [1][2][3][4].
Cystic brosis is the main underlying disease, but BC may be consequent to other disorders [1]. Diagnosis of BC is currently made through High Resolution Computed Tomography (HRCT) which is considered the gold standard investigation and the only reliable imaging test for the assessment of morphological changes of the lung parenchyma [5].
The pathogenesis of BC is complex and not well de ned [3]. The most recognized hypothesis is described by Cole's vicious cycle: an initial event compromises mucociliary clearance leading to chronic airway in ammation and progressive structural damage of the respiratory tract [3]. Different triggers have been considered and included: infections, immunode ciencies, genetic diseases or aspiration of gastrointestinal content [6].
The latter has been attributed to gastroesophageal re ux (GER) and GER may cause BC by microaspirations into the tracheobronchial tree and respiratory symptoms by vagally-mediated re ex bronchoconstriction [7,8]. The interaction between BC and GER is di cult to ascertain and GER disease (GERD) is frequently perceived as a risk factor that can exacerbate the underlying lung disease [7].
In children, the diagnosis of GERD is challenging due to clinical and technical confounding factors, interobserver variability, unclear report of symptoms, lack of speci c pediatric symptoms and questionnaires/scores, and of a gold standard diagnostic investigation. Currently, combined multichannel intraluminal impedance with pH monitoring (MII-pH) is considered the tool which best identi es, de nes and quanti es both acid and non-acid GER and symptoms association [7,9,10].
In this pilot study we aimed to: 1) characterize GER assessed by MII-pH, in children with idiopathic BC; 2) assess the relation between GER and respiratory function through spirometry; 3) assess the accuracy of a morpho-functional HRCT scoring system in predicting MII-pH results .

Methods
All children submitted to MII-pH, from July 2014 to May 2019, because of chronic respiratory symptoms and/or BC were prospectively enrolled.
Inclusion criteria were all of the followings: age 0-18 years; persisting unexplained respiratory symptoms, such as dysphonia, nonproductive chronic cough, hoarseness, apnea/desaturations, apparent lifethreatening episodes and/or BC con rmed by HRCT; informed consent signed by parents.
Children were excluded if: age ≥ 18 years; diagnosis of cystic brosis or ciliary dyskinesia or immune de ciency; esophageal or congenital chest malformation or previous gastrointestinal surgical intervention; current fever or acute infection; ongoing or recent (one week) antibiotic treatment; acid inhibitors or other GER treatment started before MII-pH or HRCT; absence of parental consent.
Children with and without BC were matched for age and sex.

MII-pH monitoring
All children underwent 24-hour MII-pH monitoring using the same MII-pH ambulatory system (Sandhill device, Bioview Software). Disposable catheters, with a diameter of 1.5-2 mm and different lengths according to patient's height: <15 cm, 15-18 cm or > 18 cm respectively in infants < 75 cm, children 75-150 cm or > 150 cm, were used [10]. Each catheter had two antimony pH sensors and six impedance electrodes, 1.5-2 cm apart, in infants or children probe. The pH-electrode was calibrated using buffer solutions with pH 4.0 and 7.0, according to manufacturer's instructions. The catheter was positioned transnasally and pH electrode was placed at the second vertebra above the diaphragmatic angle. Probe position was estimated by Strobel formula (0.252 x body length + 5) and then con rmed by chest X-Ray [10]. The MII-pH monitoring had to last at least 18 hours without artifacts to meet eligibility criteria. The patients were encouraged to conduct normal daily activities with no dietary restriction except extremely hot/ice-cold/acid foods and drinks and carbonated beverages. Meal times, body position and timing of symptoms were recorded both automatically, by a portable digital data recorder, and manually, by a symptoms-diary.
In each patient GER and MII-pH parameters were recorded, classi ed and analyzed as previously reported [10][11][12].
The tracing analysis was rst automatically analysed by a dedicated Sandhill software and then manually reviewed by a pediatric gastroenterologist with expertise in MII-pH.
The following parameters were evaluated: re ux index (RI), number of acid re uxes, total number of bolus re uxes (TNR), acid TNR (A TNR), weakly acidic TNR (WA TNR), alkaline TNR (Al TNR), proximal re uxes (PR), symptom index (SI) and symptom association probability (SAP). A summary of MII-pH parameters and de nitions is reported in Table 1. ≥ 95% pathological MII-pH was considered pathological when RI was ≥ 5% or when the TNR episodes were ≥ 70 in children older than 1 year or ≥ 100/24hours in infants, or when a signi cant association occurred between respiratory symptoms and re ux, based on SI (> 50%) or SAP (> 95%). Time window between re ux and symptoms for the automatic analysis was set at 2 minutes [9,10]. Analysis of MII-pH tracings was performed blind to the HRCT score.

Imaging evaluation
HRCT images were reviewed by an experienced pediatric radiologist. A morpho-functional scoring system (modi ed by Eichinger M.) was used to evaluate BC extent [5,13]. For each parameter, a semi-quantitative score from 0 to 2 was assigned (0 = no abnormality, 1 = < 50% of the lobe involved, 2 = ≥ 50% of the lobe involved). The maximum score per lobe was 10 and the maximum score per patient was 60. Analysis of HRCT score was performed blind to MII-pH results.

Spirometry
All children with BC underwent a basal spirometry and the following parameters were evaluated: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC and forced expiratory ow 25/75%.

Statistical analysis
All data were analyzed using Prism 8 statistical software. Mean and standard deviation were calculated. T-test or Mann Whitney test were used to compare the characteristics of GER and MII-pH parameters in children with or without BC. T-test was also used to compare spirometry results in children with BC with and without pathological MII-pH. Spirometry values were described as z-score, calculated by using the Global Lung Function Initiative 2012 equation.
HRCT score in children with BC was correlated to RI, TNR, A TNR, WA TNR, Al TNR and PR by Spearman test. HRCT scoring system results were compared in children with BC with or without pathological MII-pH. sensitivity, speci city, positive (PPV) and negative (NPV) predictive values of HRCT score were also calculated and HRCT score accuracy in predicting pathological MII-pH was evaluated by ROC curve. P-value < 0.05 was considered statistically signi cant.

Ethics
Research was conducted in accordance with the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013). Design and aims of the study were fully explained to all participant parents and informed consent was obtained before performing investigations. The most frequently reported respiratory symptom in children without BC was chronic non-productive cough (in 10/20, 50%, of children). In addition, laryngospasm, hoarseness, episodes of apnea, dysphonia, laryngitis, pharyngeal globe were reported (each symptom in 2/20 children), and/or posterior rhinorrhea, stridor, drooling and snore (each recorded in one patient). In both groups all patients reported more than one respiratory symptom.

MII-pH results
MII-pH was pathological in 7 (35%) patients with BC and in 8 (40%) children without BC. In particular, 4/7 patients with BC and 6/8 children without BC showed a signi cant association (positive SI or SAP) between respiratory symptoms and GER; 4/7 patients with BC and 4/8 children without BC had a pathological RI. No signi cant difference was found between the two groups of children (Table 2). Mean and standard deviation of MII-pH results in children with BC are showed in Table 3. As expected, in children with pathological MII-pH there were a signi cant higher RI and number of acid re uxes.

HRCT scoring system and GER
HRCT score in patients with BC ranged from 2 to 10 with a mean value of 5.45.
The mean value of HRCT score in children with a pathological or normal MII-pH was 6.571 and 4.846 respectively (p:0.0929).
There was no distinct lobe involvement or HRCT characteristic in children with pathological or normal MII-pH (Table 5); the lower and middle right lung lobes were affected by BC in 6 children with pathological MII-pH and in 9 children with normal MII-pH (p:0.412).  HRCT score > 6 was associated with a 57% Se, 69% Sp, 50% PPV and 75% NPV.
Assessing the HRCT scoring system accuracy in predicting pathological MII-pH by ROC Curve, the Area Under the Curve was 0.736 ( Fig. 1.). The score with the highest sensitivity and speci city resulted < 4.5 showing a NPV of 86,5% whilst a HCRT value > 7.5 had a PPV of 75%.

Discussion
This is the rst study characterizing GER through MII-pH and analyzing the relation between GER and a High Resolution Computed Tomography score in children with idiopathic BC.
In our population 35% of children with BC had a pathological MII-pH. Our result is consistent with previous data reported in pediatric and adult population with BC, in which the prevalence of GERD ranged from 11-32% in children and from 26-75% in adult patients [7,14,15]. At present, the role of GER in patients with BC is uncertain because of the limited number of studies, the small sample of patients and heterogeneity in diagnostic criteria.
We could not nd a signi cant difference in GER parameters and pathological MII-pH comparing children with or without BC. Conversely, adult patients with BC showed a doubled prevalence of GERD compared to healthy volunteers [16]. It is noteworthy that, for ethical reasons, MII-pH could not be performed in healthy children. Hence, our comparative group was represented by children without BC but with unexplained respiratory symptoms suspected to be GER related.
In our population, gastrointestinal symptoms such as vomit, heartburn, restrosternal and abdominal pain didn't aid in identifying pathological GER as they were reported in only 3/7 (42.85%) children with pathological MII-pH and in 7/13 (53.80%) children with normal MII-pH. Previous studies demonstrated the presence of GERD in patients with respiratory disorders regardless the presence of typical gastrointestinal symptoms [7,17].
The effect of GER in children with BC is still unclear. In our study, children with BC and pathological MII-pH did not show a different lung disease nor a more extensive lung involvement on HRCT scoring system.
In adult patients with BC, Lee et al. failed to observe a correlation between GERD and severity of lung disease [16]; conversely, Koh et al. reported a reduced lung function with higher HRCT score in case of GERD [17].
According to the literature, spirometry evaluation may miss early structural lung damage and may result completely normal in early stages of BC, while lung function imparing gradually, progressing to airway obstruction [18,19,20]. In our population, all spirometric parameters, but FVC, were worse in children with BC and normal MII-pH than with pathological MII-pH.
Whether our results are related to the young age of patients, with limited exposure time to GER, or to the use of a not reliable diagnostic tool is unclear.
Re ux may affect respiratory tract by (micro)aspirations into the tracheobronchial tree, chemical damage, in ammatory process or by vagally-mediated re ex [7]. We didn't nd any signi cant relation between our imaging score and MII-pH parameters, however a positive trend between HRCT score and re ux index, total acid re ux episodes and symptom indexes association (SI/SAP) was noticed, suggesting a possible role of acid GER in BC progression. Surprisingly, TNR and proximal re uxes appeared inversely associated with HRCT disproving a predominant pathogenic effect of GER aspiration in children with BC. The best therapeutic approach for GER in patients with BC is still a matter of debate. PPI are frequently used, despite they cannot contrast non acid GER neither treat microaspiration nor vagal dysregulation [7,21]. In refractory or long term PPI dependent patients surgical intervention is also considered [12].
Interestingly, we found HRCT as a moderate accurate imaging tool in predicting pathological MII-pH. In particular, a HRCT score ≤ 4.5 showed a NPV of 86.5%, while a value ≥ 7.5 showed the best speci city (92.3%), with a PPV of 75%. If these results are con rmed in a larger population, they could be used to better select patients to start empirical treatment with PPI or to submit to MII-pH. However, we are aware of some limitations in our study: First, this is a pilot study and data are collected on a small sample of children who could not allow to draw general conclusions. Idiopathic BC is a rare condition in children and incidence of BC strongly increases with age. A Finnish study estimated 4.9 children with BC per million person-years at age 0-14, and 103.8 affected patients aged ≥ 65 years [22]. However, the real prevalence of BC in children is di cult to determine due to selection of patients, lack of speci c symptoms and different diagnostic criteria and investigations. Next, de ning GERD in children is also challenging because of unspeci c clinical presentation and uncertain gold standard test. In our population we recorded both respiratory and gastrointestinal symptoms but we could not nd a signi cant correlation between symptoms and HRCT score. Besides, because we did not perform upper endoscopy, esophageal mucosal ndings could not be correlated. We analyzed GER parameters assessed by MII-pH which is currently considered the best diagnostic investigation to quantify and characterize re ux episodes and GER-symptom association. However, reference values in children with respiratory symptoms are limited and no data exist for pediatric patients with BC. Moreover, inter-observer variability in interpreting the tracings has been reported; inaccurate symptom recording is frequent and GER-symptom association time window and indexes are debated [10]. Finally, spirometry and HRCT were not performed in children without BC and our results may be biased by patient's selection. The major strength of our study is represented by combined analysis of MII-pH and spirometry parameters plus HRCT scores in a group of children with BC, not related to cystic brosis or other identi ed disorders. We also characterized GER parameters in these patients comparing them with age-matched children with persisting respiratory symptoms. Considering the negative impact of BC on patients' quality of life, a greater knowledge in their pathogenesis represent medical, social and economic unmeet need, particularly in pediatric age, when appropriate therapy may reverse the disease. To con rm the accuracy of HRCT score and to evaluate the effect of GER treatment in children with BC and pathological GER should be considered a priority of future large well-designed pediatric study. A correct management and treatment of GERD during childhood may eventually delay BC progression and improve adult outcomes.

Conclusions
The role of GER in BC development and lung function is still object of discussion, but 1/3 of children with BC presented a pathological MII-pH. We could not identify any respiratory symptom or MII-pH parameter characteristic of children with respiratory symptoms and BC. HRCT scoring system showed a moderate correlation with MII-pH results and a high negative predictive value when ≤ 4.5.  Figure 1 Analysis of the High-Resolution Computed Tomography scoring system accuracy in predicting gastroesophageal re ux disease by ROC Curve. The Area Under the Curve was 0.736.