Prospects in non-invasive diagnosis of bronchial asthma-related gastroesophageal reflux disease: a single-stage open uncontrolled non-randomised observational study

Background. Respiratory symptoms of bronchial asthma (BA) comorbid with gastroesophageal reflux disease (GERD) may provoke duodenogastroesophageal reflux (DGER) via aggressive agents like pepsinogens and bilirubin.

Objectives. A clinical and functional study of the saliva pepsinogen and bilirubin-associated BA-comorbid GERD for non-invasive DGER diagnosis.

Methods. A total of 29 patients with an allergic BA phenotype, comorbid GERD and 50,2 ± 2,4 years mean age have been examined. Biochemical blood panel included bilirubin, C-reactive protein and allergen-specific IgE. Saliva bilirubin was estimated in colorimetry, and the pepsinogen-1, -2 content — in immunological tests. Grade A–D reflux oesophagitis (RO) in oesophagoscopy was assigned to erosive reflux disease, and grade N–M oesophageal mucosa (OM) lesions — to non-erosive reflux disease. External respiratory function (ERF) was assessed with forced expiratory volume (FEV1, L/s), forced vital capacity (FVC), Tiffeneau index (FEV1/FVC), pre- and post-berodual FEF1 and FVC dynamics.

Results. The BA–GERD patients were markedly polymorbid. Cough and chest tightness associated with age, and the tight chest rate — with a higher body mass index and lower FEV1/FVC. The association between higher pepsinogen-I and lower FEV1/FVC–FVC in response to inhaled berodual, as well as between higher saliva bilirubin and lower FVC–FEV1 after berodual intake reflects a significant high-DGER effect on BA representation.

Conclusion. In BA–GERD patients, saliva pepsinogen and bilirubin are biomarkers of both DGER and respiratory inflammation with bronchospasm.

1. Harding S. M. Review article: reflux and asthma —mechanisms of interaction and asthma outcomes. Aliment. Pharmacol. Ther. 2011; 33(Suppl.1):43-47. DOI:10.1016/s0002-9343(01)00817-8

2. Asano K., Suzuki H. Silent acid reflux and asthma control. N. Engl. J. Med. 2009; 360(15): 1551–1553. DOI: 10.1056/NEJMe0900117

3. Campagnolo A.M., Priston J., Thoen R.H., Medeiros T., Assunção A.R. Laryngopharyngeal reflux: diagnosis, treatment, and latest research. Int. Arch. Otorhinolaryngol. 2014; 18(2): 184–191. DOI: 10.1055/s-0033-1352504

4. Hayat J.O., Gabieta-Somnez S., Yazaki E., Kang J.Y., Woodcock A., Dettmar P., Mabary J., Knowles C.H., Sifrim D. Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease. Gut. 2015; 64(3): 373–380. DOI: 10.1136/gutjnl-2014-307049

5. Sifrim D. The Role of Salivary Pepsin in the Diagnosis of Reflux. Gastroenterol. Hepatol. 2015; 11(6):417–419. PMC4843037

6. Mayev I.V., Kazyulin A.N., Yurenev G.L., Vyuchnova E.S., Lebedeva E.G., Dicheva D.T., Busarova G.A. Masks of gastroesophageal reflux disease. Results of 20-year observation. Farmateka. 2018; 13: 30–43 (In Russ., English abstract). DOI: dx.doi.org/10.18565/pharmateca.2018.13.30-43

7. Saber H., Ghanei M. Extra-esophageal manifestations of gastroesophageal reflux disease: controversies between epidemiology and clicnic. Open Respir. Med. J. 2012; 6: 121–126. DOI: 10.2174/1874306401206010121

8. De Corso E., Baroni S., Agostino S., Cammarota G., Mascagna G., Mannocci A., Rigante M., Galli J. Bile acids and total bilirubin detection in saliva of patients submitted to gastric surgery and in particular to subtotal Billroth II resection. Ann. Surg. 2007; 245(6): 880–885. DOI: 10.1097/01.sla.0000255574.22821.a1

9. Meyer K.C. Gastroesophageal reflux and lung disease. Expert. Rev. Respir. Med. 2015; 9(4): 383–385. DOI: 10.1586/17476348.2015.1060858

10. Dent J., El-Serag H.B., Wallander M.A., Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005; 54(5): 710–717. DOI: 10.1136/gut.2004.051821

11. Vakil N., van Zanten S.V., Kahrilas P., Dent J., Jones R.; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am. J. Gastroenterol. 2006; 101(8): 1900–1920; quiz 1943. DOI: 10.1111/j.1572-0241.2006.00630.x

12. Curjuric I., Imboden M., Bridevaux P.O., Gerbase M.W., Haun M., Keidel D., Kumar A., Pons M., Rochat T., Schikowski T., Schindler C., von Eckardstein A., Kronenberg F., Probst-Hensch N.M. Common SIRT1 variants modify the effect of abdominal adipose tissue on aging-related lung function decline. Age (Dordr). 2016; 38(3): 52. DOI: 10.1007/s11357-016-9917-y

13. Kozhevnikova S.A., Tribuntseva L.V., Budnevsky A.V. Hyperammonaemia in patients with chronic obstructive pulmonary disease and obesity: association mechanisms, detection rate and correction. Therapeutic Archive. 2020; 92(2): 55–60 (In Russ., English abstract). DOI: 10.26442/00403660.2020.02.000562

14. Carpaij O.A., van den Berge M. The asthma-obesity relationship: underlying mechanisms and treatment implications. Curr. Opin. Pulm. Med. 2018; 24(1): 42–49. DOI: 10.1097/MCP.0000000000000446

15. Bates J.H.T., Poynter M.E., Frodella C.M., Peters U., Dixon A.E., Suratt B.T. Pathophysiology to Phenotype in the Asthma of Obesity. Ann. Am. Thorac. Soc. 2017; 14(Supplement_5): S395–S398. DOI: 10.1513/AnnalsATS.201702-122AW

16. Peters U., Dixon A.E., Forno E. Obesity and asthma. J. Allergy. Clin. Immunol. 2018; 141(4): 1169–1179. DOI: 10.1016/j.jaci.2018.02.004

17. Tariq K., Schofield J.P.R., Nicholas B.L., Burg D., Brandsma J., Bansal A.T., Wilson S.J., Lutter R., Fowler S.J., Bakke, Caruso M., Dahlen B., Horváth I., Krug N., Montuschi P., Sanak M., Sandström T., Geiser T., Pandis I., Sousa A.R., Adcock I.M., Shaw D.E., Auffray C., Howarth P.H., Sterk P.J., Chung K.F., Skipp P.J., Dimitrov B., Djukanović R.; U-BIOPRED Study Group. Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma. Respir. Med. 2019; 150: 66–73. DOI: 10.1016/j.rmed.2019.02.008

18. Hunt E.B., Ward C., Power S., Sullivan A., Pearson J.P., Lapthorne S., O’Byrne P.M., Eustace J., Plant B.J., Maher M.M., MacSharry J., Murphy D.M. The Potential Role of Aspiration in the Asthmatic Airway. Chest. 2017; 151(6): 1272–1278. DOI: 10.1016/j.chest.2017.03.005

19. Mermelstein J., Chait Mermelstein A., Chait M.M. Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions. Clin. Exp. Gastroenterol. 2018; 11: 119–134. DOI: 10.2147/CEG.S121056

20. Leem A.Y., Kim H.Y., Kim Y.S., Park M.S., Chang J., Jung J.Y. Association of serum bilirubin level with lung function decline: a Korean community-based cohort study. Respir. Res. 2018; 19(1): 99. DOI: 10.1186/s12931-018-0814-z

21. Tsoukali E., Sifrim D. The role of weakly acidic reflux in proton pump inhibitor failure, has dust settled? J. Neurogastroenterol. Motil. 2010; 16(3): 258–264. DOI: 10.5056/jnm.2010.16.3.258

22. Lee A.L., Button B.M., Denehy L., Roberts S., Bamford T., Mu F.T., Mifsud N., Stirling R., Wilson J.W. Exhaled Breath Condensate Pepsin: Potential Noninvasive Test for Gastroesophageal Reflux in COPD and Bronchiectasis. Respir. Care. 2015; 60(2): 244–250. DOI: 10.4187/respcare.03570

23. Rasijeff A.M.P., Jackson W., Burke J.M., Dettmar P.W. PWE-172 Does salivary pepsin measurement change diagnostic outcome in patients investigated by 24h ph monitoring? Gut. 2015; 64: A287–A288. DOI: 10.1136/gutjnl-2015-309861.619

24. Wang Y.J., Lang X.Q., Wu D., He Y.Q., Lan C.H., Xiao X., Wang B., Zou D.W., Wu J.M., Zhao Y.B., Dettmar P.W., Chen D.F., Yang M. Salivary Pepsin as an Intrinsic Marker for Diagnosis of Sub-types of Gastroesophageal Reflux Disease and Gastroesophageal Reflux Disease-related Disorders. J. Neurogastroenterol. Motil. 2020; 26(1): 74–84. DOI: 10.5056/jnm19032

25. Broers C., Tack J., Pauwels A. Review article: gastro-oesophageal reflux disease in asthma and chronic obstructive pulmonary disease. Aliment. Pharmacol. Ther. 2018; 47(2): 176–191. DOI: 10.1111/apt.14416

26. Ciorba A., Bianchini C., Zuolo M., Feo C.V. Upper aerodigestive tract disorders and gastro-oesophageal reflux disease. World J. Clin. Cases. 2015; 3(2): 102–111. DOI: 10.12998/wjcc.v3.i2.102

27. Vakil N. Salivary pepsin to diagnose GORD? Gut. 2015; 64(3): 361–362. DOI: 10.1136/gutjnl-2014-307485

28. Johnston N., Ondrey F., Rosen R., Hurley B.P., Gould J., Allen J., DelGaudio J., Altman K.W. Airway reflux. Ann. N. Y. Acad. Sci. 2016; 1381(1): 5–13. DOI: 10.1111/nyas.13080

29. Strugala V., Woodcock A.D., Dettmar P.W., Faruqi S., Morice A.H. Detection of pepsin in sputum: a rapid and objective measure of airways reflux. Eur. Respir. J. 2016; 47(1): 339–341. DOI: 10.1183/13993003.00827-2015

30. de Bortoli N., Martinucci I., Bertani L., Russo S., Franchi R., Furnari M., Tolone S., Bodini G., Bolognesi V., Bellini M., Savarino V., Marchi S., Savarino E.V. Esophageal testing: What we have so far. World J. Gastrointest. Pathophysiol. 2016; 7(1): 72–85. DOI: 10.4291/wjgp.v7.i1.72

31. Du X., Wang F., Hu Z., Wu J., Wang Z., Yan C., Zhang C., Tang J. The diagnostic value of pepsin detection in saliva for gastro-esophageal reflux disease: a preliminary study from China. BMC Gastroenterol. 2017; 17(1): 107. DOI: 10.1186/s12876-017-0667-9

32. Hayat J.O., Yazaki E., Moore A.T., Hicklin L., Dettmar P., Kang J.Y., Sifrim D. Objective detection of esophagopharyngeal reflux in patients with hoarseness and endoscopic signs of laryngeal inflammation. J. Clin. Gastroenterol. 2014; 48(4): 318–327. DOI: 10.1097/MCG.0000000000000011

33. Spyridoulias A., Lillie S., Vyas A., Fowler S.J. Detecting laryngopharyngeal reflux in patients with upper airways symptoms: Symptoms, signs or salivary pepsin? Respir. Med. 2015; 109(8): 963–969. DOI: 10.1016/j.rmed.2015.05.019

34. Ocak E., Kubat G., Yorulmaz İ. Immunoserologic pepsin detection in the saliva as a non-invasive rapid diagnostic test for laryngopharyngeal reflux. Balkan. Med. J. 2015; 32(1): 46–50. DOI: 10.5152/balkanmedj.2015.15824

35. Marshall S., McCann A.J., Samuels T.L., Blair A., Bonne V., Johnston N., Koufman J. Detection of pepsin and IL-8 in saliva of adult asthmatic patients. J. Asthma. Allergy. 2019; 12: 155–161. DOI: 10.2147/JAA.S205482