Addition of a nutraceutical to montelukast or inhaled steroid in the treatment of wheezing during COVID-19 pandemic: a multicenter, open-label, randomized controlled trial. Recurrent wheezing and treatment.

Main Article Content

Giuseppe Fabio Parisi https://orcid.org/0000-0003-4291-0195
Sara Manti https://orcid.org/0000-0002-7664-3083
Maria Papale https://orcid.org/0000-0001-5036-2374
Alessandro Giallongo https://orcid.org/0000-0002-7966-5800
Cristiana Indolfi
Michele Miraglia del Giudice https://orcid.org/0000-0002-8369-5957
Carmelo Salpietro https://orcid.org/0000-0001-8794-2292
Amelia Licari https://orcid.org/0000-0002-1773-6482
Gian Luigi Marseglia https://orcid.org/0000-0003-3662-0159
Salvatore Leonardi https://orcid.org/0000-0002-2642-6400

Keywords

wheezing, children, montelukast, inhaled steroid, leucodif, covid-19, SARS-CoV2, clinical trial

Abstract

Background and aim


Recurrent wheezing is often triggered by viral respiratory infections. The aims of our study were: i) to evaluate whether the addition of a nutraceutical (Leucodif®), could improve the efficacy of montelukast or inhaled steroids (ICS) compared to the single treatment; ii) to verify whether a treatment is more effective than another. Our study was biased by the COVID-19 pandemic, which resulted in a lockdown of almost two months in Italy.


Methods


The multicenter, open-label study enrolled 84 children aged 2–6 years diagnosed with recurrent wheezing and randomized them into four treatment arms for three months: ICS treatment; ii) montelukast; iii) montelukast + Leucodif; iv) ICS + Leucodif.


Children were assessed at baseline and after one, two, and three months of treatment using the TRACK score for both the caregiver and the physician.


Results


Out of the 84 patients, 18 patients received ICS therapy, 22 patients ICS + Leucodif, 24 patients montelukast, and 20 patients montelukast + Leucodif. All four treatments resulted in a significant reduction in symptoms with no differences among the various groups.


Conclusions


Our study demonstrates that montelukast therapy appears to be equally effective as ICS therapy and that the addition of the nutraceutical Leucodif does not appear to improve the treatment outcome. However, in our opinion our study was strongly influenced and biased by the lockdown due to the COVID-19 pandemic, which inherently resulted in reduced exposure to the viruses that commonly cause respiratory infections in children.

Downloads

Download data is not yet available.
Abstract 133 | PDF Downloads 58

References

1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995 Jan 19;332(3):133–38. doi: 10.1056/NEJM199501193320301. PMID: 7800004.
2. Bisgaard H, Szefler S. Prevalence of asthma-like symptoms in young children. Pediatr Pulmonol. 2007 Aug;42(8):723-8. doi: 10.1002/ppul.20644. PMID: 17598172.
3. Rakes GP, Arruda E, Ingram JM, Hoover GE, Zambrano JC, Hayden FG, Platts-Mills TA, Heymann PW. Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. IgE and eosinophil analyses. Am J Respir Crit Care Med. 1999 Mar;159(3):785-90. doi: 10.1164/ajrccm.159.3.9801052. PMID: 10051251.
4. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, Printz MC, Lee WM, Shult PA, Reisdorf E, Carlson-Dakes KT, Salazar LP, DaSilva DF, Tisler CJ, Gern JE, Lemanske RF Jr. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008 Oct 1;178(7):667-72. doi: 10.1164/rccm.200802-309OC. Epub 2008 Jun 19. PMID: 18565953; PMCID: PMC2556448.
5. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, Frey U, Gappa M, Garcia-Marcos L, Grigg J, Lenney W, Le Souëf P, McKenzie S, Merkus PJ, Midulla F, Paton JY, Piacentini G, Pohunek P, Rossi GA, Seddon P, Silverman M, Sly PD, Stick S, Valiulis A, van Aalderen WM, Wildhaber JH, Wennergren G, Wilson N, Zivkovic Z, Bush A. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008 Oct;32(4):1096-110. doi: 10.1183/09031936.00002108. PMID: 18827155.
6. Schultz A, Devadason SG, Savenije OE, Sly PD, Le Souëf PN, Brand PL. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr. 2010 Jan;99(1):56-60. doi: 10.1111/j.1651-2227.2009.01508.x. PMID: 19764920.
7. Doull IJ, Lampe FC, Smith S, Schreiber J, Freezer NJ, Holgate ST. Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial. BMJ. 1997 Oct 4;315(7112):858-62. doi: 10.1136/bmj.315.7112.858. PMID: 9353508; PMCID: PMC2127557.
8. https://ginasthma.org/. Accessed on 11th November 2020
9. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF Jr, Strunk RC, Allen DB, Bloomberg GR, Heldt G, Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006 May 11;354(19):1985-97. doi: 10.1056/NEJMoa051378. PMID: 16687711.
10. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, Lee AJ, Turner J, Sant M. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007 Feb 15;175(4):323-9. doi: 10.1164/rccm.200510-1546OC. Epub 2006 Nov 16. PMID: 17110643.
11. Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr, Sorkness CA, Bloomberg GR, Morgan WJ, Paul IM, Guilbert T, Krawiec M, Covar R, Larsen G, Mellon M, Moss MH, Chinchilli VM, Taussig LM, Strunk RC; CARE Network. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008 Dec;122(6):1127-1135.e8. doi: 10.1016/j.jaci.2008.09.029. Epub 2008 Oct 30. PMID: 18973936; PMCID: PMC2753208.
12. Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, Savdie C, Collet JP, Khomenko L, Rivard G, Platt RW. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med. 2009 Jan 22;360(4):339-53. doi: 10.1056/NEJMoa0808907. PMID: 19164187.
13. Papi A, Nicolini G, Baraldi E, Boner AL, Cutrera R, Rossi GA, Fabbri LM; BEclomethasone and Salbutamol Treatment (BEST) for Children Study Group. Regular vs prn nebulized treatment in wheeze preschool children. Allergy. 2009 Oct;64(10):1463-71. doi: 10.1111/j.1398-9995.2009.02134.x. PMID: 19772514.
14. Souyoul SA, Saussy KP, Lupo MP. Nutraceuticals: A Review. Dermatol Ther (Heidelb). 2018;8(1):5-16. doi:10.1007/s13555-018-0221-x
15. Parisi GF, Carota G, Castruccio Castracani C, Spampinato M, Manti S, Papale M, Di Rosa M, Barbagallo I, Leonardi S. Nutraceuticals in the Prevention of Viral Infections, including COVID-19, among the Pediatric Population: A Review of the Literature. Int J Mol Sci. 2021 Feb 28;22(5):2465. doi: 10.3390/ijms22052465. PMID: 33671104; PMCID: PMC7957644.
16. Manti S, Parisi GF, Papale M, Licari A, Salpietro C, Miraglia Del Giudice M, Marseglia GL, Leonardi S. Bacteriotherapy with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray for treatment of upper respiratory tract infections in children: a pilot study on short-term efficacy. Ital J Pediatr. 2020 Apr 3;46(1):42.
17. Leonardi S, Parisi G, Papale M, et al. Small airways in children with allergic rhinoconjunctivitis: the potential role of a multicomponent nutraceutical. Acta Biomed. 2020;91(2):350-55. Published 2020 May 11. doi:10.23750/abm.v91i2.9641
18. Pulvirenti G, Parisi GF, Manti S, Licari A, Miraglia del Giudice M, Salpietro C, Marseglia GL, Leonardi S. The Immunomodulatory Role of Vitamin D in Respiratory Diseases. Current Respir Med Rev 2019; 15 (3):238-45. DOI: 10.2174/1573398X15666191114144230
19. Cohen HA, Varsano I, Kahan E, Sarrell EM, Uziel Y. Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study. Arch Pediatr Adolesc Med. 2004 Mar;158(3):217-21. doi: 10.1001/archpedi.158.3.217. PMID: 14993078.
20. Manti S, Licari A, Montagna L, Votto M, Leonardi S, Brambilla I, Castagnoli R, Foiadelli T, Marseglia GL, Cardinale F, Caffarelli C, Tosca MA, Cravidi C, Duse M, Chiappini E. SARS-CoV-2 infection in pediatric population. Acta Biomed. 2020 Sep 15;91(11-S):e2020003. doi: 10.23750/abm.v91i11-S.10298. PMID: 33004773.
21. Diaferio L, Parisi GF, Brindisi G, Indolfi C, Marchese G, Ghiglioni DG, Zicari AM, Marseglia GL, Miraglia Del Giudice M. Cross-sectional survey on impact of paediatric COVID-19 among Italian paediatricians: report from the SIAIP rhino-sinusitis and conjunctivitis committee. Ital J Pediatr. 2020 Oct 6;46(1):146. doi: 10.1186/s13052-020-00906-4. PMID: 33023616; PMCID: PMC7538039.
22. Cardinale F, Ciprandi G, Barberi S, Bernardini R, Caffarelli C, Calvani M, Cavagni G, Galli E, Minasi D, Del Giudice MM, Moschese V, Novembre E, Paravati F, Peroni DG, Tosca MA, Traina G, Tripodi S, Marseglia GL; and the SIAIP Task Force. Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic. Ital J Pediatr. 2020 Jun 16;46(1):84. doi: 10.1186/s13052-020-00843-2. PMID: 32546234; PMCID: PMC7296524.
23. Hatoun J, Correa ET, Donahue SMA, Vernacchio L. Social Distancing for COVID-19 and Diagnoses of Other Infectious Diseases in Children. Pediatrics. 2020 Oct;146(4):e2020006460. doi: 10.1542/peds.2020-006460. Epub 2020 Sep 2. PMID: 32879032.
24. Yang Y. Impact of the COVID-19 Pandemic on Biomedical and Clinical Research. Matter. 2020 Oct 7;3(4):970-973. doi: 10.1016/j.matt.2020.08.026. Epub 2020 Aug 29. PMID: 32904589; PMCID: PMC7456300.
25. Tuttle KR. Impact of the COVID-19 pandemic on clinical research. Nat Rev Nephrol. 2020 Oct;16(10):562-564. doi: 10.1038/s41581-020-00336-9. PMID: 32760016; PMCID: PMC7404075.
26. Murphy KR, Zeiger RS, Kosinski M, Chipps B, Mellon M, Schatz M, Lampl K, Hanlon JT, Ramachandran S. Test for respiratory and asthma control in kids (TRACK): a caregiver-completed questionnaire for preschool-aged children. J Allergy Clin Immunol. 2009 Apr;123(4):833-9.e9. doi: 10.1016/j.jaci.2009.01.058. PMID: 19348922.
27. http://www.governo.it/it/articolo/coronavirus-conte-firma-il-dpcm-11-marzo-2020/14299 . Accessed on 11th November 2020
28. Bisgaard H. Role of leukotrienes in asthma pathophysiology. Pediatr Pulmonol. 2000 Aug;30(2):166-76. doi: 10.1002/1099-0496(200008)30:2<166::aid-ppul15>3.0.co;2-l. PMID: 10922142.
29. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med. 1990 Sep 6;323(10):645-55. doi: 10.1056/NEJM199009063231006. PMID: 2166915.
30. Arm JP, Lee TH. Sulphidopeptide leukotrienes in asthma. Clin Sci (Lond). 1993 May;84(5):501-10. doi: 10.1042/cs0840501. PMID: 8389264.
31. Bernstein PR. Chemistry and structure--activity relationships of leukotriene receptor antagonists. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 2):S220-5; discussion S225-6, S247-8. PMID: 9647603.
32. Pecoraro R, Parisi GF, Lanzafame A, Trovato A, Barone P, Leonardi S. Leukotriene antagonist drugs: a tool to face Chronic Urticaria in Children? Journal of Pediatric Biochemistry 2013; 3:203-211
33. Haarman MG, van Hunsel F, de Vries TW. Adverse drug reactions of montelukast in children and adults. Pharmacol Res Perspect. 2017 Oct;5(5):e00341. doi: 10.1002/prp2.341. PMID: 28971612; PMCID: PMC5625152.
34. Aagaard L, Hansen EH. Adverse drug reactions associated with asthma medications in children: systematic review of clinical trials. Int J Clin Pharm. 2014 Apr;36(2):243-52. doi: 10.1007/s11096-014-9924-y. Epub 2014 Feb 23. PMID: 24562976.
35. Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review. Pediatr Pulmonol. 2018 Dec;53(12):1670-1677. doi: 10.1002/ppul.24176. Epub 2018 Nov 5. PMID: 30394700.
36. Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, Wang J, Sylvester J, Holbrook J, Wise R, Weiss ST, Barnes K. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med. 2006 Feb 15;173(4):379-85. doi: 10.1164/rccm.200509-1412OC. Epub 2005 Nov 17. PMID: 16293801; PMCID: PMC2662939.
37. Patria MF, Esposito S. Recurrent lower respiratory tract infections in children: a practical approach to diagnosis. Paediatr Respir Rev. 2013 Mar;14(1):53-60. doi: 10.1016/j.prrv.2011.11.001. Epub 2011 Dec 8. PMID: 23347661.
38. Carr RR, Nahata MC. Complementary and alternative medicine for upper-respiratory-tract infection in children. Am J Health Syst Pharm. 2006 Jan 1;63(1):33-9. doi: 10.2146/ajhp040613. PMID: 16373463.
39. Nieman DC, Henson DA, McMahon M, Wrieden JL, Davis JM, Murphy EA, Gross SJ, McAnulty LS, Dumke CL. Beta-glucan, immune function, and upper respiratory tract infections in athletes. Med Sci Sports Exerc. 2008 Aug;40(8):1463-71. doi: 10.1249/MSS.0b013e31817057c2. PMID: 18614945.
40. Sener G, Toklu H, Ercan F, Erkanli G. Protective effect of beta-glucan against oxidative organ injury in a rat model of sepsis. Int Immunopharmacol. 2005 Aug;5(9):1387-96. doi: 10.1016/j.intimp.2005.03.007. Epub 2005 Apr 9. PMID: 15953565.
41. Padhani ZA, Moazzam Z, Ashraf A, Bilal H, Salam RA, Das JK, Bhutta ZA. Vitamin C supplementation for prevention and treatment of pneumonia. Cochrane Database Syst Rev. 2020 Apr 27;4(4):CD013134. doi: 10.1002/14651858.CD013134.pub2. PMID: 32337708; PMCID: PMC7192369.
42. Dror DK, Allen LH. Vitamin E deficiency in developing countries. Food Nutr Bull. 2011 Jun;32(2):124-43. doi: 10.1177/156482651103200206. PMID: 22164974.
43. Lamberti LM, Fischer-Walker CL, Black RE. Prophylactic zinc supplementation for prevention of acute respiratory infections in infants and young children. Indian Pediatr. 2014 Oct;51(10):775-76. doi: 10.1007/s13312-014-0502-0. PMID: 25362005.

Most read articles by the same author(s)

1 2 3 4 5 > >>