- Email: [email protected]
Evaluation of nasal mucociliary clearance time in children with celiac disease
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Evaluation of nasal mucociliary clearance time in children with celiac disease
T
Atakan Combaa,∗, Doğan Atanb a b
Department of Pediatrics, Faculty of Medicine, Hitit University, Çorum, Turkey Department of Otolaryngology, Faculty of Medicine, Hitit University, Çorum, Turkey
A R T I C LE I N FO
A B S T R A C T
Keywords: Celiac disease Child Nasal mucociliary clearance Respiratory system Infection
Objectives: Celiac disease is an autoimmune disorder that develops because of sensitivity to gluten-containing grains in genetically disposed individuals. Nasal mucociliary clearance is the most important protective factor that protects the upper and lower airways from foreign particulates. This study aimed to investigate the effect of celiac disease on nasal mucociliary clearance. Methods: The study included patients with celiac disease and healthy children. Nasal mucociliary clearance time was measured using the saccharin test. The children's saccharin taste time was recorded in seconds. Results: Overall, 65 children were included: 43 patients with celiac disease (66.2%) and 22 healthy children (33.8%). Of all the children, 42 (64.6%) were female, and the average age was 11.8 ± 4 years. Nasal mucociliary clearance time of patients with celiac disease (531 ± 155 s) was significantly prolonged in comparison to that of healthy children (448 ± 80 s) (p = 0.006). No relationships were found between the diagnosis age, celiac type, and histopathological phase and compliance with the gluten-free diet and nasal mucociliary clearance time of patients with celiac disease. Conclusions: This study showed that nasal mucociliary clearance was prolonged in patients with celiac disease. A defect in nasal mucociliary clearance increases the risk of infection and inflammation in small airways. Studies reported a high prevalence of respiratory tract infection in patients with celiac disease, which was associated with malnutrition, vitamin deficiency, and hyposplenism. The findings of the present study indicated that impairment of nasal mucociliary clearance could play a role in the development of frequent lung infections in patients with celiac disease.
1. Introduction Celiac disease (CD) is an autoimmune, systemic disease that develops as a result of a permanent sensitivity to gluten in the diet in genetically disposed individuals, and the course of the disease involves gastrointestinal and non-gastrointestinal findings [1]. The disease classically progresses with findings such as chronic diarrhea, abdominal distension, and weight loss after gluten intake in the diet after 6–24 months [2]. Atypical CD, generally seen in advanced aged children and adolescents, have symptoms that include atypical digestive system findings, such as chronic abdominal pain and constipation, or nongastrointestinal findings, such as short stature, treatment-resistant anemia, osteopenia/osteoporosis, and dermatitis herpetiformis [3,4]. Mucociliary clearance is the ability to keep the mucosal surface humid and fresh with mucous gland secretions as well as to remove respiratory
mucosa and pathogens with regular ciliary activity. It is a vital defense mechanism of the respiratory tract, and it protects the body against the hazardous effects of inhaled particulates [5,6]. Assessment of the nasal mucociliary clearance time is a reliable index in demonstrating the lower and upper airways’ clearance [7]. Saccharin tests enable an objective assessment of the nasal mucociliary clearance time. It is a fast, easily applicable, cost-effective, and reliable method [8]. Prolonged transit times are considered to be indicative of impaired mucociliary clearance [9]. The purpose of this study is to evaluate nasal mucociliary clearance time in children with CD and to investigate the effects clinical features of patients with CD and the gluten-free diet treatment on this.
∗ Corresponding author. Hitit University Faculty of Medicine Training and Research Hospital Department of Pediatrics, Çepni Mahallesi, İnönü Cd. No:176, 19040, Çorum, Turkey. E-mail address: [email protected] (A. Comba).
https://doi.org/10.1016/j.ijporl.2020.109936 Received 27 October 2019; Received in revised form 10 January 2020; Accepted 6 February 2020 Available online 08 February 2020 0165-5876/ © 2020 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
A. Comba and D. Atan
2. Methods
Table 1 Characteristics of the children in the study.
This study was conducted between June 1, 2018, and January 1, 2019. The study included two groups of children involving patients with CD and healthy children. Children with CD were selected among children who were followed up at the Hitit University Medical Faculty Pediatric Gastroenterology, Hepatology, and Nutrition outpatient clinic. Celiac disease was diagnosed based on the European Society for Pediatric Gastroenterology Hepatology and Nutrition 2012 criteria [10]. Histopathology assessment of small bowel biopsies was performed using the modified Marsh (Oberhuber) classification [11]. The patients with CD were categorized in two groups: those who received a glutenfree diet and those who received a gluten-containing diet. The control group was composed of healthy children who were similar in terms of age and gender, presented to the general pediatric outpatient clinic and ENT outpatient clinic, and did not have a known chronic disease. Children who had selective IgA deficiency, could not cooperate, had a chronic disease, had an active infection disease, and used medication were not included in the study. Sociodemographic data, anthropometric measurements, hematologic and biochemical parameters, endomysium and tissue transglutaminase antibodies, endoscopies, and small bowel pathology findings of patients with CD were evaluated. Sociodemographic data and anthropometric measurements of the control group were recorded. Nasal mucociliary clearance time was measured using the saccharin test. A 1mm diameter saccharin tablet was placed on the medial surface of the inferior concha. The children were in the seating position throughout the test, and the test was repeated if there were incidences of coughing, sneezing, and/or a decrease in saccharin. The time indicating the receipt of the taste of saccharin in the children was measured with a chronometer and recorded in seconds. The study was approved by the Hitit University Clinical Research Ethical Board, and signed voluntary consent forms were obtained from parents of the study participants.
Groups (n)
Celiac patients (all) (n = 43) Celiac patients consumed GFD (n = 27) Celiac patients consumed GCD (n = 16) Healthy control (n = 22)
Ages (years) mean ± SD
Gender n (%) Girls
Boys
12.5 ± 3.8 13.1 ± 3.7
30 (69.8%) 19 (70.4%)
13 (30.2%) 8 (29.6%)
11.3 ± 3.8
11 (68.8%)
5 (31.2%)
10.7 ± 4.2
12 (54.5%)
10 (45.5%)
GFD, gluten free diet; GCD, gluten containing diet; SD, standard deviation.
typical CD, 34 (79%) had atypical CD, and 5 (11.7%) had silent CD. Fifteen (35%) of the small bowel histopathologic findings were Marsh 3a, 18 (41.8%) were Marsh 3b, and 10 (23.2%) were Marsh 3c. The follow-up duration of the children was 35.5 ± 33.5 (0–161) months. Of all the patients with CD, 27 (62.8%) consumed a gluten-free diet, and 16 (37.2%) consumed a gluten-containing diet. Nasal mucociliary clearance time of the all children was found to be 503 ± 139 (152–856) seconds. No relationships were found between the children's age, gender, height, weight, and body mass index and mucociliary clearance time. Nasal mucociliary clearance time of the patients with CD was found to be 531 ± 155 s and that of healthy children was 448 ± 80 s; the difference was found to be statistically significant (p = 0.006) (Fig. 1). No relationships were found between age, celiac type, and the Marsh phase of the patients with CD and follow-up durations and mucociliary clearance time. Nasal mucociliary clearance time of the patients with CD who had a gluten-free diet was 545 ± 128 s and that of children who had a gluten-containing diet was 511 ± 192 s; no significant differences were found between them (p = 0.701).
2.1. Statistical analysis 4. Discussion IBM SPSS version 22.0 (IBM Corp., Armonk, NY, USA) was used for all data analyses. Descriptive statistics are presented as numbers and percentages (%) for qualitative variables and as mean ± standard deviation and median (range) for quantitative variables. Normality distribution of data was evaluated using Kolmogorov–Smirnov and Shapiro–Wilk tests to guide statistical test choice. Homogeneity of variances was investigated using Levene test. Relationships between continuous variables were examined using Spearman's correlation coefficient. When interpreting the association based on Spearman's correlation coefficients, reference ranges were adopted as follows: 0.00 < r < 0.25, very weak; 0.26 < r < 0.49, weak; 0.50 < r < 0.69, moderate; 0.70 < r < 0.89, high; and 0.90 < r < 1.00, very high. When comparing the mean values between two independent groups, Student's t-test was used for data with normal distribution, and non-parametric Mann–Whitney U test for data without normal distribution. When comparing more than two groups, non-parametric Kruskal–Wallis test was used because of the unavailability of hypotheses. Following the variance analysis, post hoc pairwise comparison test was used to determine which group was different. A p-value < 0.05 was considered statistically significant.
Celiac disease is an immune enteropathy, emerging as a result of permanent sensitivity to gluten in genetically disposed individuals. The clinical spectrum of the disease might range from the subclinical form associated with the effects of genetic factors, the time of gluten intake in the diet, age, and breast milk intake to the severe malabsorption syndrome. The treatment in the disease is unarguably a lifelong adherence to a strict gluten-free diet [1–3]. There have been important changes in the age at diagnosis and application findings in the last two decades, and an increase has been indicated in the number of atypical
3. Results The study involved 65 children: 43 (66.2%) children with CD and 22 (33.8%) healthy children. Of all the children, 42 (64.6%) were female, and the average age was 11.8 ± 4 years. Neither age nor gender differences were found between the groups (Table 1). The average age of the patients with CD was 12.5 ± 3.8 (5–18) years; 30 patients (69.8%) were female. The average diagnosis age was 9.4 ± 3.8 (2–16) years. Of all the patients with CD, 4 (9.3%) had
Fig. 1. Nasal mucociliary clearance time according to the groups. 2
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
A. Comba and D. Atan
play an important role in the development of frequent lung infections in patients with CD. The reason for the deterioration of mucociliary clearance in patients with CD could not be explained in this study because ciliary and mucus structures could not be identified with histology or electron microscopy. Another limitation of the study is that the factors that have effects on mucociliary clearance in patients with CD could not be evaluated in detail due to the small patient groups. In conclusion, mucociliary clearance time was prolonged in CD. This case could be associated with increased respiratory tract infections in patients. Therefore, pneumococcus and influenza vaccinations could be a prevention strategy to counteract respiratory tract infections in patients with CD. There is a need for studies to be conducted with more patients and various methods in order to detect the factors that have effects on mucociliary clearance, identify the effects of a gluten-free diet, and conduct new comprehensive studies about the treatment approaches.
patients [4]. Approximately half of the current patients are diagnosed with atypical findings, such as short stature and anemia [12]. Skin, hematologic system, liver, thyroid, and musculoskeletal system influences are frequently seen in CD [1–4]. However, knowledge about the respiratory tract and lungs activation is limited. The literature rarely reports celiac patient cases with respiratory system findings. Hayat et al. [13] and Sarath et al. [14] reported two children diagnosed with CD who had chronic cough and lung infection and bronchiectasis complaints, respectively. These two cases gave fast and dramatic responses to gluten free diet. Another case report written by Brightling et al. [15] indicated a 65-year-old who had a CD diagnosis with chronic cough and lymphocytic bronchoalveolitis and displayed improvement with gluten free diet. This study reported that the nasal mucociliary clearance duration of patients with CD was prolonged significantly in comparison to that of healthy children. Maintaining a clear and humid mucosal surface in the respiratory tract and removing foreign particulates with pathogens depends on mucociliary activity [16]. Appropriate mucus production, coordinated ciliary activity, and mucus-cilia interactions are necessary for an effective mucociliary clearance. A defect in this system increases the risk of infection, inflammation, and obstruction in small airways. Cilia are present in the nose, nasopharynx, tympanum, paranasal sinuses, and tracheobronchial airways. Hence, an impairment in the mucociliary clearance increases the risk of infection in this area [5,17]. This study showed that nasal mucociliary clearance was impaired in patients with CD. Some studies have reported deterioration of mucociliary clearance in autoimmune diseases, such as diabetes, rheumatoid arthritis, and Behçet's disease [7,16,18]. It is thought that the pathogenesis of extraintestinal manifestations in CD, including storage of the autoantibodies circulating in organs and surrounding blood vessels or immune-mediated damage, resulted from cross-reactivity with tissue antigens, such as anti-tissue transglutaminases 2, 3, and 6 [19]. Thus, mucociliary clearance may have deteriorated in patients with CD because antibodies deteriorated the ciliary or mucus structure or the mucus–cilia interaction through immune mechanisms. A cohort study conducted in Sweden reported that applications to the hospital due to influenza infection were two times higher in patients CD in comparison to those in the normal population, and this proportion was found to remain the same 5 years after a biopsy [17]. A casecontrol study conducted in 2014 also reported that children with CD had both RSV and other viral bronchiolitis approximately 1.5 times more [20]. A meta-analysis conducted in 2018 reported that pneumococcal infection risk was higher in patients with CD in comparison to that in the normal population [21]. Patients with CD were found to experience invasive pneumococcus diseases 2 times more in a study conducted in England in 2008, 4 times more in Sweden in 2008, and 1.46 times more in Sweden in 2017 [22–24]. Three comprehensive studies conducted in England, Sweden, and Italy reported that the mortality of CD patients was largely associated with respiratory tract infections and sepsis [25–27]. A population-based cohort study conducted in Sweden in 2006 reported that the tuberculosis risk was 3–4 times more in patients with CD. Another study conducted in 2003 found that the death risk due to tuberculosis is 6 times more in patients with CD [28,29]. All of these studies associated the reasons of frequent respiratory tract infections with an impaired nutritional condition, malnutrition, lack of vitamin D, lack of folic acid, lack of B12, hyposplenism, and altered mucosal intestinal permeability in patients with celiac disease [17,20–24]. RSV and other bronchiolitis factor viruses, such as pneumococcus, influenza, and tuberculosis, are acquired in the body with respiration. Impairment in mucociliary clearance is known to affect the removal of the infectious factors in the respiratory tracts [5–7]. The present study showed that nasal mucociliary clearance time was significantly prolonged in patients with CD. This finding of the present study indicated that the impairment in mucociliary clearance could
Ethical approval The study was approved by the Hitit University Clinical Research Ethical Board, and signed voluntary consent forms were obtained from parents of the study participants. Funding No external funding for this manuscript. Informed consent Informed consent was obtained from all individual participants included in this study. Contributors Comba A., and Atan D. conceptualized and designed the study, collected data, carried out the initial analyses, wrote the manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Declaration of competing interest No conflict of interest was declared by the authors. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijporl.2020.109936. References [1] S. Guandalini, A. Assiri, Celiac disease, JAMA. Pediatrics 168 (2014) 272–278, https://doi.org/10.1001/jamapediatrics.2013.3858. [2] A.F. Rodrigues, H.R. Jenkins, Coeliac disease in children, Curr. Paediatr. 16 (2006) 317–321, https://doi.org/10.1016/j.cupe.2006.07.010. [3] A. Fasano, C. Catassi, Coeliac disease in children, Best Pract. Res. Clin. Gastroenterol. 19 (2005) 467–478, https://doi.org/10.1016/j.bpg.2005.01.008. [4] E. Lionetti, C. Catassi, New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment, Int. Rev. Immunol. 30 (2011) 219–231, https://doi.org/10.3109/08830185.2011.602443. [5] D.M. Utiyama, C.T. Yoshida, D.M. Goto, et al., The effects of smoking and smoking cessation on nasal mucociliary clearance, mucus properties and inflammation, Clinics 71 (2016) 344–350, https://doi.org/10.6061/clinics/2016(06)10. [6] S. Dülger, Ö. Akdeniz, F. Solmaz, et al., Evaluation of nasal mucociliary clearance using saccharin test in smokers: a prospective study, Clin. Res. J. 12 (2018) 1706–1710, https://doi.org/10.1111/crj.12733. [7] I. Ozbay, C. Kucur, F. Temizturk, et al., Assessment of nasal mucociliary activity in patients with Behçet’s disease, J. Laryngol. Otol. 130 (2016) 348–351, https://doi. org/10.1111/crj.12733.
3
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
A. Comba and D. Atan
ijrms20174964. [19] S. Nardecchia, R. Auricchio, V. Discepolo, R. Troncone, Extra-intestinal manifestations of coeliac disease in children: clinical features and mechanisms, Front. Pediatr. 7 (2019) 56, https://doi.org/10.3389/fped.2019.00056 https://search. crossref.org/?q=Extra-intestinal+manifestations+of+coeliac+disease+in +children%3A+clinical+features+and+mechanisms. [20] A.R. Tjernberg, J.F. Ludvigsson, Children with celiac disease are more likely to have attended hospital for prior respiratory syncytial virus infection, Dig. Dis. Sci. 59 (2014) 1502–1508, https://doi.org/10.1007/s10620-014-3046-1. [21] M. Simons, L.A.J. Scott-Sheldon, Y. Risech-Neyman, et al., Celiac disease and increased risk of pneumococcal infection: a systematic review and meta-analysis, Am. J. Med. 131 (2018) 83–89, https://doi.org/10.1016/j.amjmed.2017.07.021. [22] A. Röckert Tjernberg, J. Bonnedahl, M. Inghammar, et al., Coeliac disease and invasive pneumococcal disease: a population-based cohort study, Epidemiol. Infect. 145 (2017) 1203–1209, https://doi.org/10.1017/S0950268816003204. [23] H.J. Thomas, C.J. Wotton, D. Yeates, et al., Pneumococcal infection in patients with coeliac disease, Eur. J. Gastroenterol. Hepatol. 20 (2008) 624–628, https://doi.org/ 10.1097/MEG.0b013e3282f45764. [24] J.F. Ludvigsson, O. Olén, M. Bell, et al., Coeliac disease and risk of sepsis, Gut 57 (2008) 1074–1080, https://doi.org/10.1136/gut.2007.133868. [25] M.J. Grainge, J. West, T.R. Card, et al., Causes of death in people with celiac disease spanning the pre and post serology era: a population based cohort study from Derby, UK, Am. J. Gastroenterol. 106 (2011) 933–939, https://doi.org/10.1038/ ajg.2010.506. [26] U. Peters, J. Askling, G. Gridley, et al., Causes of death in patients with celiac disease in a population-based Swedish cohort, Arch. Intern. Med. 163 (2003) 1566–1572, https://doi.org/10.1001/archinte.163.13.1566. [27] G. Corrao, G.R. Corazza, V. Bagnardi, et al., Mortality in patients with coeliac disease and their relatives: a cohort study, Lancet 358 (2001) 356–361, https://doi. org/10.1016/s0140-6736(01)05554-4. [28] J.F. Ludvigsson, J. Wahlstrom, J. Grunewald, et al., Coeliac disease and risk of tuberculosis: a population based cohort study, Thorax 62 (2007) 23–28, https://doi. org/10.1136/thx.2006.059451. [29] U. Peters, J. Askling, G. Gridley, et al., Causes of death in patients with celiac disease in a population-based Swedish cohort, Arch. Intern. Med. 163 (2003) 1566–1572, https://doi.org/10.1001/archinte.163.13.1566.
[8] R. Aroor, Z. Sunu Ali, K.S. Gangadhara Somayaji, Do nasal surgeries affect mucociliary clearance? Indian J. Otolaryngol. Head Neck Surg. 69 (2017) 24–28, https:// doi.org/10.1007/s12070-016-1016-y. [9] C. Kucur, I. Ozbay, E. Gulcan, et al., Evaluation of nasal mucociliary activity in patients with chronic renal failure, Eur. Arch. Oto-Rhino-Laryngol. 273 (2016) 1167–1171, https://doi.org/10.1007/s00405-015-3712-8. [10] S. Husby, S. Koletzko, I.R. Korponay-Szabó, et al., ESPGHAN working group on coeliac disease diagnosis; ESPGHAN Gastroenterology committee; European society for pediatric Gastroenterology, Hepatology, and nutrition. European society for pediatric Gastroenterology, Hepatology, and nutrition guıdelines for the diagnosis of coeliac disease, J. Pediatr. Gastroenterol. Nutr. 54 (2012) 136–160, https://doi. org/10.1097/MPG.0b013e31821a23d0. [11] G. Oberhuber, G. Granditsch, H. Vogelsang, The histopathology of coeliac disease: time for a standardized report scheme for pathologists, Eur. J. Gastroenterol. Hepatol. 11 (1999) 1185–1194, https://doi.org/10.1097/00042737-19991000000019. [12] B. Admou, L. Essaadouni, K. Krati, et al., Atypical celiac disease from recognizing to managing, Gastroenterol. Res. Pract. 63 (2012) 71–87, https://doi.org/10.1155/ 2012/637187. [13] S. Hayat, P.K. Pitchaikani, N. Williams, et al., Coeliac disease presenting as chronic cough in an 8-year-old child, BMJ Case Rep. (2011) bcr1020115064, , https://doi. org/10.1136/bcr.10.2011.5064 2011: pii. [14] B. Sarath Balaji, S. Kalpana, Selladurai Elilarasi, et al., Respiratory symptoms as atypical manifestation of celiac disease, Pediatric. Oncall. 13 (2) (2016), https:// doi.org/10.7199/ped.oncall.2016.20. [15] C.E. Brightling, F.A. Symon, S.S. Birring, et al., A case of cough, lymphocytic bronchoalveolitis and coeliac disease with improvement following a gluten free diet, Thorax 57 (2002) 91–92, https://doi.org/10.1136/thorax.57.1.91. [16] J. Proença de Oliveira-Maul, H. Barbosa de Carvalho, et al., Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance, Chest 143 (2013) 1091–1097, https://doi.org/10.1378/chest.12-1183. [17] K. Mårild, H. Fredlund, J.F. Ludvigsson, Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden, Am. J. Gastroenterol. 105 (2010) 2465–2473, https://doi.org/10.1038/ajg.2010.352. [18] S. Deswal, J. Yadav, M. Deswal, H. Singh, Evaluation of nasal mucociliary clearance in rheumatoid arthritis: a comparative analysis using saccharin test, Int. J. Res. Med. Sci. 5 (2017) 5026–5029, https://doi.org/10.18203/2320-6012.
4
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Evaluation of nasal mucociliary clearance time in children with celiac disease
T
Atakan Combaa,∗, Doğan Atanb a b
Department of Pediatrics, Faculty of Medicine, Hitit University, Çorum, Turkey Department of Otolaryngology, Faculty of Medicine, Hitit University, Çorum, Turkey
A R T I C LE I N FO
A B S T R A C T
Keywords: Celiac disease Child Nasal mucociliary clearance Respiratory system Infection
Objectives: Celiac disease is an autoimmune disorder that develops because of sensitivity to gluten-containing grains in genetically disposed individuals. Nasal mucociliary clearance is the most important protective factor that protects the upper and lower airways from foreign particulates. This study aimed to investigate the effect of celiac disease on nasal mucociliary clearance. Methods: The study included patients with celiac disease and healthy children. Nasal mucociliary clearance time was measured using the saccharin test. The children's saccharin taste time was recorded in seconds. Results: Overall, 65 children were included: 43 patients with celiac disease (66.2%) and 22 healthy children (33.8%). Of all the children, 42 (64.6%) were female, and the average age was 11.8 ± 4 years. Nasal mucociliary clearance time of patients with celiac disease (531 ± 155 s) was significantly prolonged in comparison to that of healthy children (448 ± 80 s) (p = 0.006). No relationships were found between the diagnosis age, celiac type, and histopathological phase and compliance with the gluten-free diet and nasal mucociliary clearance time of patients with celiac disease. Conclusions: This study showed that nasal mucociliary clearance was prolonged in patients with celiac disease. A defect in nasal mucociliary clearance increases the risk of infection and inflammation in small airways. Studies reported a high prevalence of respiratory tract infection in patients with celiac disease, which was associated with malnutrition, vitamin deficiency, and hyposplenism. The findings of the present study indicated that impairment of nasal mucociliary clearance could play a role in the development of frequent lung infections in patients with celiac disease.
1. Introduction Celiac disease (CD) is an autoimmune, systemic disease that develops as a result of a permanent sensitivity to gluten in the diet in genetically disposed individuals, and the course of the disease involves gastrointestinal and non-gastrointestinal findings [1]. The disease classically progresses with findings such as chronic diarrhea, abdominal distension, and weight loss after gluten intake in the diet after 6–24 months [2]. Atypical CD, generally seen in advanced aged children and adolescents, have symptoms that include atypical digestive system findings, such as chronic abdominal pain and constipation, or nongastrointestinal findings, such as short stature, treatment-resistant anemia, osteopenia/osteoporosis, and dermatitis herpetiformis [3,4]. Mucociliary clearance is the ability to keep the mucosal surface humid and fresh with mucous gland secretions as well as to remove respiratory
mucosa and pathogens with regular ciliary activity. It is a vital defense mechanism of the respiratory tract, and it protects the body against the hazardous effects of inhaled particulates [5,6]. Assessment of the nasal mucociliary clearance time is a reliable index in demonstrating the lower and upper airways’ clearance [7]. Saccharin tests enable an objective assessment of the nasal mucociliary clearance time. It is a fast, easily applicable, cost-effective, and reliable method [8]. Prolonged transit times are considered to be indicative of impaired mucociliary clearance [9]. The purpose of this study is to evaluate nasal mucociliary clearance time in children with CD and to investigate the effects clinical features of patients with CD and the gluten-free diet treatment on this.
∗ Corresponding author. Hitit University Faculty of Medicine Training and Research Hospital Department of Pediatrics, Çepni Mahallesi, İnönü Cd. No:176, 19040, Çorum, Turkey. E-mail address: [email protected] (A. Comba).
https://doi.org/10.1016/j.ijporl.2020.109936 Received 27 October 2019; Received in revised form 10 January 2020; Accepted 6 February 2020 Available online 08 February 2020 0165-5876/ © 2020 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
A. Comba and D. Atan
2. Methods
Table 1 Characteristics of the children in the study.
This study was conducted between June 1, 2018, and January 1, 2019. The study included two groups of children involving patients with CD and healthy children. Children with CD were selected among children who were followed up at the Hitit University Medical Faculty Pediatric Gastroenterology, Hepatology, and Nutrition outpatient clinic. Celiac disease was diagnosed based on the European Society for Pediatric Gastroenterology Hepatology and Nutrition 2012 criteria [10]. Histopathology assessment of small bowel biopsies was performed using the modified Marsh (Oberhuber) classification [11]. The patients with CD were categorized in two groups: those who received a glutenfree diet and those who received a gluten-containing diet. The control group was composed of healthy children who were similar in terms of age and gender, presented to the general pediatric outpatient clinic and ENT outpatient clinic, and did not have a known chronic disease. Children who had selective IgA deficiency, could not cooperate, had a chronic disease, had an active infection disease, and used medication were not included in the study. Sociodemographic data, anthropometric measurements, hematologic and biochemical parameters, endomysium and tissue transglutaminase antibodies, endoscopies, and small bowel pathology findings of patients with CD were evaluated. Sociodemographic data and anthropometric measurements of the control group were recorded. Nasal mucociliary clearance time was measured using the saccharin test. A 1mm diameter saccharin tablet was placed on the medial surface of the inferior concha. The children were in the seating position throughout the test, and the test was repeated if there were incidences of coughing, sneezing, and/or a decrease in saccharin. The time indicating the receipt of the taste of saccharin in the children was measured with a chronometer and recorded in seconds. The study was approved by the Hitit University Clinical Research Ethical Board, and signed voluntary consent forms were obtained from parents of the study participants.
Groups (n)
Celiac patients (all) (n = 43) Celiac patients consumed GFD (n = 27) Celiac patients consumed GCD (n = 16) Healthy control (n = 22)
Ages (years) mean ± SD
Gender n (%) Girls
Boys
12.5 ± 3.8 13.1 ± 3.7
30 (69.8%) 19 (70.4%)
13 (30.2%) 8 (29.6%)
11.3 ± 3.8
11 (68.8%)
5 (31.2%)
10.7 ± 4.2
12 (54.5%)
10 (45.5%)
GFD, gluten free diet; GCD, gluten containing diet; SD, standard deviation.
typical CD, 34 (79%) had atypical CD, and 5 (11.7%) had silent CD. Fifteen (35%) of the small bowel histopathologic findings were Marsh 3a, 18 (41.8%) were Marsh 3b, and 10 (23.2%) were Marsh 3c. The follow-up duration of the children was 35.5 ± 33.5 (0–161) months. Of all the patients with CD, 27 (62.8%) consumed a gluten-free diet, and 16 (37.2%) consumed a gluten-containing diet. Nasal mucociliary clearance time of the all children was found to be 503 ± 139 (152–856) seconds. No relationships were found between the children's age, gender, height, weight, and body mass index and mucociliary clearance time. Nasal mucociliary clearance time of the patients with CD was found to be 531 ± 155 s and that of healthy children was 448 ± 80 s; the difference was found to be statistically significant (p = 0.006) (Fig. 1). No relationships were found between age, celiac type, and the Marsh phase of the patients with CD and follow-up durations and mucociliary clearance time. Nasal mucociliary clearance time of the patients with CD who had a gluten-free diet was 545 ± 128 s and that of children who had a gluten-containing diet was 511 ± 192 s; no significant differences were found between them (p = 0.701).
2.1. Statistical analysis 4. Discussion IBM SPSS version 22.0 (IBM Corp., Armonk, NY, USA) was used for all data analyses. Descriptive statistics are presented as numbers and percentages (%) for qualitative variables and as mean ± standard deviation and median (range) for quantitative variables. Normality distribution of data was evaluated using Kolmogorov–Smirnov and Shapiro–Wilk tests to guide statistical test choice. Homogeneity of variances was investigated using Levene test. Relationships between continuous variables were examined using Spearman's correlation coefficient. When interpreting the association based on Spearman's correlation coefficients, reference ranges were adopted as follows: 0.00 < r < 0.25, very weak; 0.26 < r < 0.49, weak; 0.50 < r < 0.69, moderate; 0.70 < r < 0.89, high; and 0.90 < r < 1.00, very high. When comparing the mean values between two independent groups, Student's t-test was used for data with normal distribution, and non-parametric Mann–Whitney U test for data without normal distribution. When comparing more than two groups, non-parametric Kruskal–Wallis test was used because of the unavailability of hypotheses. Following the variance analysis, post hoc pairwise comparison test was used to determine which group was different. A p-value < 0.05 was considered statistically significant.
Celiac disease is an immune enteropathy, emerging as a result of permanent sensitivity to gluten in genetically disposed individuals. The clinical spectrum of the disease might range from the subclinical form associated with the effects of genetic factors, the time of gluten intake in the diet, age, and breast milk intake to the severe malabsorption syndrome. The treatment in the disease is unarguably a lifelong adherence to a strict gluten-free diet [1–3]. There have been important changes in the age at diagnosis and application findings in the last two decades, and an increase has been indicated in the number of atypical
3. Results The study involved 65 children: 43 (66.2%) children with CD and 22 (33.8%) healthy children. Of all the children, 42 (64.6%) were female, and the average age was 11.8 ± 4 years. Neither age nor gender differences were found between the groups (Table 1). The average age of the patients with CD was 12.5 ± 3.8 (5–18) years; 30 patients (69.8%) were female. The average diagnosis age was 9.4 ± 3.8 (2–16) years. Of all the patients with CD, 4 (9.3%) had
Fig. 1. Nasal mucociliary clearance time according to the groups. 2
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
A. Comba and D. Atan
play an important role in the development of frequent lung infections in patients with CD. The reason for the deterioration of mucociliary clearance in patients with CD could not be explained in this study because ciliary and mucus structures could not be identified with histology or electron microscopy. Another limitation of the study is that the factors that have effects on mucociliary clearance in patients with CD could not be evaluated in detail due to the small patient groups. In conclusion, mucociliary clearance time was prolonged in CD. This case could be associated with increased respiratory tract infections in patients. Therefore, pneumococcus and influenza vaccinations could be a prevention strategy to counteract respiratory tract infections in patients with CD. There is a need for studies to be conducted with more patients and various methods in order to detect the factors that have effects on mucociliary clearance, identify the effects of a gluten-free diet, and conduct new comprehensive studies about the treatment approaches.
patients [4]. Approximately half of the current patients are diagnosed with atypical findings, such as short stature and anemia [12]. Skin, hematologic system, liver, thyroid, and musculoskeletal system influences are frequently seen in CD [1–4]. However, knowledge about the respiratory tract and lungs activation is limited. The literature rarely reports celiac patient cases with respiratory system findings. Hayat et al. [13] and Sarath et al. [14] reported two children diagnosed with CD who had chronic cough and lung infection and bronchiectasis complaints, respectively. These two cases gave fast and dramatic responses to gluten free diet. Another case report written by Brightling et al. [15] indicated a 65-year-old who had a CD diagnosis with chronic cough and lymphocytic bronchoalveolitis and displayed improvement with gluten free diet. This study reported that the nasal mucociliary clearance duration of patients with CD was prolonged significantly in comparison to that of healthy children. Maintaining a clear and humid mucosal surface in the respiratory tract and removing foreign particulates with pathogens depends on mucociliary activity [16]. Appropriate mucus production, coordinated ciliary activity, and mucus-cilia interactions are necessary for an effective mucociliary clearance. A defect in this system increases the risk of infection, inflammation, and obstruction in small airways. Cilia are present in the nose, nasopharynx, tympanum, paranasal sinuses, and tracheobronchial airways. Hence, an impairment in the mucociliary clearance increases the risk of infection in this area [5,17]. This study showed that nasal mucociliary clearance was impaired in patients with CD. Some studies have reported deterioration of mucociliary clearance in autoimmune diseases, such as diabetes, rheumatoid arthritis, and Behçet's disease [7,16,18]. It is thought that the pathogenesis of extraintestinal manifestations in CD, including storage of the autoantibodies circulating in organs and surrounding blood vessels or immune-mediated damage, resulted from cross-reactivity with tissue antigens, such as anti-tissue transglutaminases 2, 3, and 6 [19]. Thus, mucociliary clearance may have deteriorated in patients with CD because antibodies deteriorated the ciliary or mucus structure or the mucus–cilia interaction through immune mechanisms. A cohort study conducted in Sweden reported that applications to the hospital due to influenza infection were two times higher in patients CD in comparison to those in the normal population, and this proportion was found to remain the same 5 years after a biopsy [17]. A casecontrol study conducted in 2014 also reported that children with CD had both RSV and other viral bronchiolitis approximately 1.5 times more [20]. A meta-analysis conducted in 2018 reported that pneumococcal infection risk was higher in patients with CD in comparison to that in the normal population [21]. Patients with CD were found to experience invasive pneumococcus diseases 2 times more in a study conducted in England in 2008, 4 times more in Sweden in 2008, and 1.46 times more in Sweden in 2017 [22–24]. Three comprehensive studies conducted in England, Sweden, and Italy reported that the mortality of CD patients was largely associated with respiratory tract infections and sepsis [25–27]. A population-based cohort study conducted in Sweden in 2006 reported that the tuberculosis risk was 3–4 times more in patients with CD. Another study conducted in 2003 found that the death risk due to tuberculosis is 6 times more in patients with CD [28,29]. All of these studies associated the reasons of frequent respiratory tract infections with an impaired nutritional condition, malnutrition, lack of vitamin D, lack of folic acid, lack of B12, hyposplenism, and altered mucosal intestinal permeability in patients with celiac disease [17,20–24]. RSV and other bronchiolitis factor viruses, such as pneumococcus, influenza, and tuberculosis, are acquired in the body with respiration. Impairment in mucociliary clearance is known to affect the removal of the infectious factors in the respiratory tracts [5–7]. The present study showed that nasal mucociliary clearance time was significantly prolonged in patients with CD. This finding of the present study indicated that the impairment in mucociliary clearance could
Ethical approval The study was approved by the Hitit University Clinical Research Ethical Board, and signed voluntary consent forms were obtained from parents of the study participants. Funding No external funding for this manuscript. Informed consent Informed consent was obtained from all individual participants included in this study. Contributors Comba A., and Atan D. conceptualized and designed the study, collected data, carried out the initial analyses, wrote the manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Declaration of competing interest No conflict of interest was declared by the authors. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijporl.2020.109936. References [1] S. Guandalini, A. Assiri, Celiac disease, JAMA. Pediatrics 168 (2014) 272–278, https://doi.org/10.1001/jamapediatrics.2013.3858. [2] A.F. Rodrigues, H.R. Jenkins, Coeliac disease in children, Curr. Paediatr. 16 (2006) 317–321, https://doi.org/10.1016/j.cupe.2006.07.010. [3] A. Fasano, C. Catassi, Coeliac disease in children, Best Pract. Res. Clin. Gastroenterol. 19 (2005) 467–478, https://doi.org/10.1016/j.bpg.2005.01.008. [4] E. Lionetti, C. Catassi, New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment, Int. Rev. Immunol. 30 (2011) 219–231, https://doi.org/10.3109/08830185.2011.602443. [5] D.M. Utiyama, C.T. Yoshida, D.M. Goto, et al., The effects of smoking and smoking cessation on nasal mucociliary clearance, mucus properties and inflammation, Clinics 71 (2016) 344–350, https://doi.org/10.6061/clinics/2016(06)10. [6] S. Dülger, Ö. Akdeniz, F. Solmaz, et al., Evaluation of nasal mucociliary clearance using saccharin test in smokers: a prospective study, Clin. Res. J. 12 (2018) 1706–1710, https://doi.org/10.1111/crj.12733. [7] I. Ozbay, C. Kucur, F. Temizturk, et al., Assessment of nasal mucociliary activity in patients with Behçet’s disease, J. Laryngol. Otol. 130 (2016) 348–351, https://doi. org/10.1111/crj.12733.
3
International Journal of Pediatric Otorhinolaryngology 133 (2020) 109936
A. Comba and D. Atan
ijrms20174964. [19] S. Nardecchia, R. Auricchio, V. Discepolo, R. Troncone, Extra-intestinal manifestations of coeliac disease in children: clinical features and mechanisms, Front. Pediatr. 7 (2019) 56, https://doi.org/10.3389/fped.2019.00056 https://search. crossref.org/?q=Extra-intestinal+manifestations+of+coeliac+disease+in +children%3A+clinical+features+and+mechanisms. [20] A.R. Tjernberg, J.F. Ludvigsson, Children with celiac disease are more likely to have attended hospital for prior respiratory syncytial virus infection, Dig. Dis. Sci. 59 (2014) 1502–1508, https://doi.org/10.1007/s10620-014-3046-1. [21] M. Simons, L.A.J. Scott-Sheldon, Y. Risech-Neyman, et al., Celiac disease and increased risk of pneumococcal infection: a systematic review and meta-analysis, Am. J. Med. 131 (2018) 83–89, https://doi.org/10.1016/j.amjmed.2017.07.021. [22] A. Röckert Tjernberg, J. Bonnedahl, M. Inghammar, et al., Coeliac disease and invasive pneumococcal disease: a population-based cohort study, Epidemiol. Infect. 145 (2017) 1203–1209, https://doi.org/10.1017/S0950268816003204. [23] H.J. Thomas, C.J. Wotton, D. Yeates, et al., Pneumococcal infection in patients with coeliac disease, Eur. J. Gastroenterol. Hepatol. 20 (2008) 624–628, https://doi.org/ 10.1097/MEG.0b013e3282f45764. [24] J.F. Ludvigsson, O. Olén, M. Bell, et al., Coeliac disease and risk of sepsis, Gut 57 (2008) 1074–1080, https://doi.org/10.1136/gut.2007.133868. [25] M.J. Grainge, J. West, T.R. Card, et al., Causes of death in people with celiac disease spanning the pre and post serology era: a population based cohort study from Derby, UK, Am. J. Gastroenterol. 106 (2011) 933–939, https://doi.org/10.1038/ ajg.2010.506. [26] U. Peters, J. Askling, G. Gridley, et al., Causes of death in patients with celiac disease in a population-based Swedish cohort, Arch. Intern. Med. 163 (2003) 1566–1572, https://doi.org/10.1001/archinte.163.13.1566. [27] G. Corrao, G.R. Corazza, V. Bagnardi, et al., Mortality in patients with coeliac disease and their relatives: a cohort study, Lancet 358 (2001) 356–361, https://doi. org/10.1016/s0140-6736(01)05554-4. [28] J.F. Ludvigsson, J. Wahlstrom, J. Grunewald, et al., Coeliac disease and risk of tuberculosis: a population based cohort study, Thorax 62 (2007) 23–28, https://doi. org/10.1136/thx.2006.059451. [29] U. Peters, J. Askling, G. Gridley, et al., Causes of death in patients with celiac disease in a population-based Swedish cohort, Arch. Intern. Med. 163 (2003) 1566–1572, https://doi.org/10.1001/archinte.163.13.1566.
[8] R. Aroor, Z. Sunu Ali, K.S. Gangadhara Somayaji, Do nasal surgeries affect mucociliary clearance? Indian J. Otolaryngol. Head Neck Surg. 69 (2017) 24–28, https:// doi.org/10.1007/s12070-016-1016-y. [9] C. Kucur, I. Ozbay, E. Gulcan, et al., Evaluation of nasal mucociliary activity in patients with chronic renal failure, Eur. Arch. Oto-Rhino-Laryngol. 273 (2016) 1167–1171, https://doi.org/10.1007/s00405-015-3712-8. [10] S. Husby, S. Koletzko, I.R. Korponay-Szabó, et al., ESPGHAN working group on coeliac disease diagnosis; ESPGHAN Gastroenterology committee; European society for pediatric Gastroenterology, Hepatology, and nutrition. European society for pediatric Gastroenterology, Hepatology, and nutrition guıdelines for the diagnosis of coeliac disease, J. Pediatr. Gastroenterol. Nutr. 54 (2012) 136–160, https://doi. org/10.1097/MPG.0b013e31821a23d0. [11] G. Oberhuber, G. Granditsch, H. Vogelsang, The histopathology of coeliac disease: time for a standardized report scheme for pathologists, Eur. J. Gastroenterol. Hepatol. 11 (1999) 1185–1194, https://doi.org/10.1097/00042737-19991000000019. [12] B. Admou, L. Essaadouni, K. Krati, et al., Atypical celiac disease from recognizing to managing, Gastroenterol. Res. Pract. 63 (2012) 71–87, https://doi.org/10.1155/ 2012/637187. [13] S. Hayat, P.K. Pitchaikani, N. Williams, et al., Coeliac disease presenting as chronic cough in an 8-year-old child, BMJ Case Rep. (2011) bcr1020115064, , https://doi. org/10.1136/bcr.10.2011.5064 2011: pii. [14] B. Sarath Balaji, S. Kalpana, Selladurai Elilarasi, et al., Respiratory symptoms as atypical manifestation of celiac disease, Pediatric. Oncall. 13 (2) (2016), https:// doi.org/10.7199/ped.oncall.2016.20. [15] C.E. Brightling, F.A. Symon, S.S. Birring, et al., A case of cough, lymphocytic bronchoalveolitis and coeliac disease with improvement following a gluten free diet, Thorax 57 (2002) 91–92, https://doi.org/10.1136/thorax.57.1.91. [16] J. Proença de Oliveira-Maul, H. Barbosa de Carvalho, et al., Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance, Chest 143 (2013) 1091–1097, https://doi.org/10.1378/chest.12-1183. [17] K. Mårild, H. Fredlund, J.F. Ludvigsson, Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden, Am. J. Gastroenterol. 105 (2010) 2465–2473, https://doi.org/10.1038/ajg.2010.352. [18] S. Deswal, J. Yadav, M. Deswal, H. Singh, Evaluation of nasal mucociliary clearance in rheumatoid arthritis: a comparative analysis using saccharin test, Int. J. Res. Med. Sci. 5 (2017) 5026–5029, https://doi.org/10.18203/2320-6012.
4