THE PROINFLAMMATORY ROLE OF SERUM IL-6 IN ACUTE OTITIS MEDIA IN CHILDREN
Keywords:
ACUTE OTITIS MEDIA, CHILDREN, IL-6, S100A12 PROTEIN
Abstract
Acute otitis media (AOM) represents the leading cause of health care visits and antibiotic prescriptions in children. In order to reduce the unnecessary antibiotic prescriptions and to avoid the burden of potential complications, new biomarkers may be useful for the diagnosis and follow-up of children with AOM. Material and methods: We performed a prospective study in pediatric patients with AOM hospitalized in a tertiary hospital in Iasi, Romania, during a 1-year period (between November 2021 and November 2022). We assessed the utility of serum interleukin-6, S100A12 protein, ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) in the diagnosis of children with clinical signs of AOM. Results: A total of 88 children, aged between 2 months old to 17 years old were included (46 with AOM and 42 healthy controls). The differences between the control group and AOM group were statistically significant (p<0.001) for ESR, CRP and IL-6 (median values being much higher in the case of patients with AOM). The differences between the control group and the one with AOM were only random (p=0.326 > 0.05) in case of S100A12 protein. ESR > 27 mm/hour was associated with a 2 times higher risk (RR=2.022) of having concomitant adenoiditis. Conclusions: IL-6 could offer a powerful tool for the objective evaluation of AOM. Further research is needed to fully elucidate the role of IL-6 in AOM and to determine whether it may be a useful biomarker for predicting treatment outcomes.
References
1. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics 2013; 131(3): e964-99 / doi: 10.1542/peds.2012-3488.
2. Spoială EL, Stârcea IM, Ioniuc IK, et al. Watchful Waiting in Pediatric Acute Otitis Media: A Real Practice Approach or an Intangible Desideratum? Medicina (Kaunas) 2023; 59(3): 520 / doi: 10.3390/medicina59030520.
3. Hu T, Done N, Petigara T, et al. Incidence of acute otitis media in children in the United States before and after the introduction of 7- and 13-valent pneumococcal conjugate vaccines during 1998-2018. BMC Infect Dis 2022; 22(1): 294 / doi: 10.1186/s12879-022-07275-9.
4. Kaur R, Morris M, Pichichero ME. Epidemiology of Acute Otitis Media in the Postpneumococcal Conjugate Vaccine Era. Pediatrics 2017; 140(3): e20170181 / doi: 10.1542/peds.2017-0181.
5. Gavrilovici C, Spoială EL, Miron IC, et al. Acute Otitis Media in Children-Challenges of Antibiotic Resistance in the Post-Vaccination Era. Microorganisms 2022; 10(8): 1598 / doi: 10.3390/ micro-organism 10081598.
6. Elzinga HBE, van Oorschot HD, Stegeman I, Smit AL. Relation between otitis media and sensorineural hearing loss: a systematic review. BMJ Open 2021; 11(8): e050108 / doi: 10.1136/bmjopen-2021-050108.
7. Siddiq S, Grainger J. The diagnosis and management of acute otitis media: American Academy of Pediatrics Guidelines 2013. Arch Dis Child Educ Pract Ed 2015; 100(4): 193-197 / doi: 10.1136/ archdischild-2013-305550.
8. Spoială EL, Stanciu GD, Bild V, Ababei DC, Gavrilovici C. From Evidence to Clinical Guidelines in Antibiotic Treatment in Acute Otitis Media in Children. Antibiotics (Basel) 2021; 10(1): 52 / doi: 10.3390/antibiotics10010052.
9. Suzuki HG, Dewez JE, Nijman RG, Yeung S. Clinical practice guidelines for acute otitis media in children: a systematic review and appraisal of European national guidelines. BMJ Open 2020; 10(5): e035343 / doi: 10.1136/bmjopen-2019-035343.
10. Uciechowski P, Dempke WCM. Interleukin-6: A Masterplayer in the Cytokine Network. Oncology 2020; 98(3): 131-137 / doi: 10.1159/000505099.
11. Scharer G, Zaldivar F, Gonzalez G, Vargas-Shiraishi O, Singh J, Arrieta A. Systemic inflammatory responses in children with acute otitis media due to Streptococcus pneumoniae and the impact of treatment with clarithromycin. Clin Diagn Lab Immunol. 2003; 10(4): 721-724 / doi: 10.1128/ cdli.10.4.721-724.2003.
12. Pietzsch J, Hoppmann S. Human S100A12: a novel key player in inflammation? Amino Acids 2009; 36(3): 381-389 / doi: 10.1007/s00726-008-0097-7.
13. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16(5): 448-457 / doi: 10.1038/ni.3153.
14. Rose-John S. The soluble interleukin-6 receptor and related proteins. Best Pract Res Clin Endocrinol Metab 2015; 29(5): 787-97 / doi: 10.1016/j.beem.2015.07.001.
15. Aliyu M, Zohora FT, Anka AU, et al. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int Immunopharmacol 2022; 111: 109130 / doi: 10.1016/j.intimp.2022.109130.
16. Rose-John S, Winthrop K, Calabrese L. The role of IL-6 in host defense against infections: immuno-biology and clinical implications. Nat Rev Rheumatol 2017; 13(7): 399-409 / doi: 10.1038/nrrheum.2017.83.
17. Skovbjerg S, Martner A, Hynsjö L, et al. Gram-positive and gram-negative bacteria induce different patterns of cytokine production in human mononuclear cells irrespective of taxonomic relatedness. J Interferon Cytokine Res 2010; 30(1): 23-32 / doi: 10.1089/jir.2009.0033.
18. Heikkinen T, Ghaffar F, Okorodudu AO, Chonmaitree T. Serum interleukin-6 in bacterial and non-bacterial acute otitis media. Pediatrics 1998; 102(2 Pt 1): 296-299 / doi: 10.1542/peds.102.2.296.
19. Chkhaidze I, Nemsadze K, Gotsadze K, Nikoleishvili E, Gordeladze G. Systemic inflammatory re-sponses in patients with acute otitis media and the impact of treatment with sinupret. Georgian Med News 2007; (151): 40-44.
20. Serban R, Filip C, Radulescu LM, et al. IL-1α, IL-6 and IL-8 serum values in patients with chronic suppurative otitis media. Exp Ther Med 2021; 22(5): 1226 / doi: 10.3892/etm.2021.10660.
21. Landegger LD, Vasilijic S, Fujita T, et al. Cytokine Levels in Inner Ear Fluid of Young and Aged Mice as Molecular Biomarkers of Noise-Induced Hearing Loss. Front Neurol 2019; 10: 977 / doi: 10.3389/fneur.2019.00977.
22. Kerschner JE, Meyer TK, Yang C, Burrows A. Middle ear epithelial mucin production in response to interleukin-6 exposure in vitro. Cytokine 2004; 26(1): 30-36 / doi: 10.1016/j.cyto.2003.12.006.
23. Wakabayashi K, Fujioka M, Kanzaki S, et al. Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea. Neurosci Res. 2010; 66(4): 345-352 / doi: 10.1016/ j.neures. 2009.12.008.
24. Guignard F, Mauel J, Markert M. Identification and characterization of a novel human neutrophil protein related to the S100 family. Biochem J. 1995;309 ( Pt 2)(Pt 2):395-401/doi: 10.1042/bj3090395.
25. Foell D, Seeliger S, Vogl T, et al. Expression of S100A12 (EN-RAGE) in cystic fibrosis. Thorax 2003; 58(7): 613-617 / doi: 10.1136/thorax.58.7.613.
26. Hsu K, Champaiboon C, Guenther BD, et al. ANTI-INFECTIVE PROTECTIVE PROPERTIES OF S100 CALGRANULINS. Antiinflamm Antiallergy Agents Med Chem 2009; 8(4): 290-305 / doi: 10.2174/187152309789838975.
27. Singh P, Ali SA. Multifunctional Role of S100 Protein Family in the Immune System: An Update. Cells 2022; 11(15): 2274 / doi: 10.3390/cells11152274.
28. Miranda LP, Alewood PF. Accelerated chemical synthesis of peptides and small proteins. Proc Natl Acad Sci USA 1999; 96(4): 1181-1186/ doi: 10.1073/pnas.96.4. 1181.
29. Han EC, Cho SB, Ahn KJ, et al. Expression of Pro-inflammatory Protein S100A12 (EN-RAGE) in Behçet’s Disease and Its Association with Disease Activity: A Pilot Study. Ann Dermatol 2011; 23(3): 313-320 / doi: 10.5021/ad.2011.23.3.313.
30. Türkmenoğlu Y, Güney E, Bezen D, İrdem A, Ertürk B, Dursun H. Evaluation of S100A12 protein levels in children with familial Mediterranean fever. Turk J Med Sci 2021; 51(3): 1396-1405 / doi: 10.3906/sag-2009-187.
31. Li SC, Tsai KW, Huang LH, et al. Serum proteins may facilitate the identification of Kawasaki disease and promote in vitro neutrophil infiltration. Sci Rep 2020; 10(1): 15645 / doi: 10.1038/s41598-020-72695-z.
32. Meijer B, Gearry RB, Day AS. The role of S100A12 as a systemic marker of inflammation. Int J Inflam 2012; 2012: 907078 / doi: 10.1155/2012/907078.
33. Liu K, Kaur R, Almudevar A, Pichichero ME. Higher serum levels of interleukin 10 occur at onset of acute otitis media caused by Streptococcus pneumoniae compared to Haemophilus influenzae and Moraxella catarrhalis. Laryngoscope 2013; 123(6): 1500-1505 / doi: 10.1002/lary.23973.
34. Shank JM, Kelley BR, Jackson JW, et al. The Host Antimicrobial Protein Calgranulin C Participates in the Control of Campylobacter jejuni Growth via Zinc Sequestration. Infect Immun 2018; 86(6): e00234-18 / doi: 10.1128/IAI.00234-18.
35. Haley KP, Delgado AG, Piazuelo MB, et al. The Human Antimicrobial Protein Calgranulin C Partic-ipates in Control of Helicobacter pylori Growth and Regulation of Virulence. Infect Immun 2015; 83(7): 2944-2956 / doi: 10.1128/IAI.00544-15.
36. Ravasi T, Hsu K, Goyette J, et al. Probing the S100 protein family through genomic and functional analysis. Genomics 2004; 84(1): 10-22 / doi: 10.1016/j.ygeno. 2004. 02. 002.
37. Liu K, Pichichero ME. Clinical significance of serum S100A12 in acute otitis media in young children. Pediatr Infect Dis J 2012; 31(3): e56-58 / doi: 10.1097/ INF.0b013 e318 24672cb.
38. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007; 81(1): 28-37 / doi: 10.1189/jlb.0306170.
39. Shiotsu Y, Mori Y, Nishimura M, et al. Plasma S100A12 level is associated with cardiovascular disease in hemodialysis patients. Clin J Am Soc Nephrol 2011; 6(4): 718-723 / doi: 10.2215/CJN.08310910.
40. Ye F, Foell D, Hirono KI, Vogl T, et al. Neutrophil-derived S100A12 is profoundly upregulated in the early stage of acute Kawasaki disease. Am J Cardiol 2004; 94(6): 840-844 / doi: 10.1016/j.amjcard.2004.05.076.
41. Thierolf M, Hagmann ML, Pfeffer M, et al. Towards a comprehensive proteome of normal and ma-lignant human colon tissue by 2-D-LC-ESI-MS and 2-DE proteomics and identification of S100A12 as potential cancer biomarker. Proteomics Clin Appl 2008; 2(1): 11-22 / doi: 10.1002/prca.200780046.
42. Hinze CH, Foell D, Johnson AL, et al. Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Dis-continuation of Therapy. Arthritis Rheumatol 2019; 71(3): 451-459 / doi: 10.1002/art.40727
43. Pichichero ME, Morris MC, Almudevar A. Three Innate Cytokine Biomarkers Predict Presence of Acute Otitis Media and Relevant Otopathogens Biomark Appl 2018; 2(1): 10.29011/2576-9588.100018 / doi: 10.29011/2576-9588.100018.
44. Gavrilovici C, Oprea L. Clinical ethics, research ethics and community ethics. The moral triad of nowadays society. Rev. Romana Bioet 2013; 11: 55-57.
45. Choi SY, Yon DK, Choi YS, Lee J, Park KH, Lee YJ, Kim SS, Kim SH, Yeo SG. The Impact of the COVID-19 Pandemic on Otitis Media. Viruses 2022; 14(11): 2457 / doi: 10.3390/v14112457.
46. Torretta S, Cantoni B, Bertolozzi G, et al. Has Otitis Media Disappeared during COVID-19 Pandemic? A Fortuitus Effect of Domestic Confinement. J Clin Med. 2021; 10(13): 2851 / doi: 10.3390/ jcm10132851.
2. Spoială EL, Stârcea IM, Ioniuc IK, et al. Watchful Waiting in Pediatric Acute Otitis Media: A Real Practice Approach or an Intangible Desideratum? Medicina (Kaunas) 2023; 59(3): 520 / doi: 10.3390/medicina59030520.
3. Hu T, Done N, Petigara T, et al. Incidence of acute otitis media in children in the United States before and after the introduction of 7- and 13-valent pneumococcal conjugate vaccines during 1998-2018. BMC Infect Dis 2022; 22(1): 294 / doi: 10.1186/s12879-022-07275-9.
4. Kaur R, Morris M, Pichichero ME. Epidemiology of Acute Otitis Media in the Postpneumococcal Conjugate Vaccine Era. Pediatrics 2017; 140(3): e20170181 / doi: 10.1542/peds.2017-0181.
5. Gavrilovici C, Spoială EL, Miron IC, et al. Acute Otitis Media in Children-Challenges of Antibiotic Resistance in the Post-Vaccination Era. Microorganisms 2022; 10(8): 1598 / doi: 10.3390/ micro-organism 10081598.
6. Elzinga HBE, van Oorschot HD, Stegeman I, Smit AL. Relation between otitis media and sensorineural hearing loss: a systematic review. BMJ Open 2021; 11(8): e050108 / doi: 10.1136/bmjopen-2021-050108.
7. Siddiq S, Grainger J. The diagnosis and management of acute otitis media: American Academy of Pediatrics Guidelines 2013. Arch Dis Child Educ Pract Ed 2015; 100(4): 193-197 / doi: 10.1136/ archdischild-2013-305550.
8. Spoială EL, Stanciu GD, Bild V, Ababei DC, Gavrilovici C. From Evidence to Clinical Guidelines in Antibiotic Treatment in Acute Otitis Media in Children. Antibiotics (Basel) 2021; 10(1): 52 / doi: 10.3390/antibiotics10010052.
9. Suzuki HG, Dewez JE, Nijman RG, Yeung S. Clinical practice guidelines for acute otitis media in children: a systematic review and appraisal of European national guidelines. BMJ Open 2020; 10(5): e035343 / doi: 10.1136/bmjopen-2019-035343.
10. Uciechowski P, Dempke WCM. Interleukin-6: A Masterplayer in the Cytokine Network. Oncology 2020; 98(3): 131-137 / doi: 10.1159/000505099.
11. Scharer G, Zaldivar F, Gonzalez G, Vargas-Shiraishi O, Singh J, Arrieta A. Systemic inflammatory responses in children with acute otitis media due to Streptococcus pneumoniae and the impact of treatment with clarithromycin. Clin Diagn Lab Immunol. 2003; 10(4): 721-724 / doi: 10.1128/ cdli.10.4.721-724.2003.
12. Pietzsch J, Hoppmann S. Human S100A12: a novel key player in inflammation? Amino Acids 2009; 36(3): 381-389 / doi: 10.1007/s00726-008-0097-7.
13. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16(5): 448-457 / doi: 10.1038/ni.3153.
14. Rose-John S. The soluble interleukin-6 receptor and related proteins. Best Pract Res Clin Endocrinol Metab 2015; 29(5): 787-97 / doi: 10.1016/j.beem.2015.07.001.
15. Aliyu M, Zohora FT, Anka AU, et al. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int Immunopharmacol 2022; 111: 109130 / doi: 10.1016/j.intimp.2022.109130.
16. Rose-John S, Winthrop K, Calabrese L. The role of IL-6 in host defense against infections: immuno-biology and clinical implications. Nat Rev Rheumatol 2017; 13(7): 399-409 / doi: 10.1038/nrrheum.2017.83.
17. Skovbjerg S, Martner A, Hynsjö L, et al. Gram-positive and gram-negative bacteria induce different patterns of cytokine production in human mononuclear cells irrespective of taxonomic relatedness. J Interferon Cytokine Res 2010; 30(1): 23-32 / doi: 10.1089/jir.2009.0033.
18. Heikkinen T, Ghaffar F, Okorodudu AO, Chonmaitree T. Serum interleukin-6 in bacterial and non-bacterial acute otitis media. Pediatrics 1998; 102(2 Pt 1): 296-299 / doi: 10.1542/peds.102.2.296.
19. Chkhaidze I, Nemsadze K, Gotsadze K, Nikoleishvili E, Gordeladze G. Systemic inflammatory re-sponses in patients with acute otitis media and the impact of treatment with sinupret. Georgian Med News 2007; (151): 40-44.
20. Serban R, Filip C, Radulescu LM, et al. IL-1α, IL-6 and IL-8 serum values in patients with chronic suppurative otitis media. Exp Ther Med 2021; 22(5): 1226 / doi: 10.3892/etm.2021.10660.
21. Landegger LD, Vasilijic S, Fujita T, et al. Cytokine Levels in Inner Ear Fluid of Young and Aged Mice as Molecular Biomarkers of Noise-Induced Hearing Loss. Front Neurol 2019; 10: 977 / doi: 10.3389/fneur.2019.00977.
22. Kerschner JE, Meyer TK, Yang C, Burrows A. Middle ear epithelial mucin production in response to interleukin-6 exposure in vitro. Cytokine 2004; 26(1): 30-36 / doi: 10.1016/j.cyto.2003.12.006.
23. Wakabayashi K, Fujioka M, Kanzaki S, et al. Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea. Neurosci Res. 2010; 66(4): 345-352 / doi: 10.1016/ j.neures. 2009.12.008.
24. Guignard F, Mauel J, Markert M. Identification and characterization of a novel human neutrophil protein related to the S100 family. Biochem J. 1995;309 ( Pt 2)(Pt 2):395-401/doi: 10.1042/bj3090395.
25. Foell D, Seeliger S, Vogl T, et al. Expression of S100A12 (EN-RAGE) in cystic fibrosis. Thorax 2003; 58(7): 613-617 / doi: 10.1136/thorax.58.7.613.
26. Hsu K, Champaiboon C, Guenther BD, et al. ANTI-INFECTIVE PROTECTIVE PROPERTIES OF S100 CALGRANULINS. Antiinflamm Antiallergy Agents Med Chem 2009; 8(4): 290-305 / doi: 10.2174/187152309789838975.
27. Singh P, Ali SA. Multifunctional Role of S100 Protein Family in the Immune System: An Update. Cells 2022; 11(15): 2274 / doi: 10.3390/cells11152274.
28. Miranda LP, Alewood PF. Accelerated chemical synthesis of peptides and small proteins. Proc Natl Acad Sci USA 1999; 96(4): 1181-1186/ doi: 10.1073/pnas.96.4. 1181.
29. Han EC, Cho SB, Ahn KJ, et al. Expression of Pro-inflammatory Protein S100A12 (EN-RAGE) in Behçet’s Disease and Its Association with Disease Activity: A Pilot Study. Ann Dermatol 2011; 23(3): 313-320 / doi: 10.5021/ad.2011.23.3.313.
30. Türkmenoğlu Y, Güney E, Bezen D, İrdem A, Ertürk B, Dursun H. Evaluation of S100A12 protein levels in children with familial Mediterranean fever. Turk J Med Sci 2021; 51(3): 1396-1405 / doi: 10.3906/sag-2009-187.
31. Li SC, Tsai KW, Huang LH, et al. Serum proteins may facilitate the identification of Kawasaki disease and promote in vitro neutrophil infiltration. Sci Rep 2020; 10(1): 15645 / doi: 10.1038/s41598-020-72695-z.
32. Meijer B, Gearry RB, Day AS. The role of S100A12 as a systemic marker of inflammation. Int J Inflam 2012; 2012: 907078 / doi: 10.1155/2012/907078.
33. Liu K, Kaur R, Almudevar A, Pichichero ME. Higher serum levels of interleukin 10 occur at onset of acute otitis media caused by Streptococcus pneumoniae compared to Haemophilus influenzae and Moraxella catarrhalis. Laryngoscope 2013; 123(6): 1500-1505 / doi: 10.1002/lary.23973.
34. Shank JM, Kelley BR, Jackson JW, et al. The Host Antimicrobial Protein Calgranulin C Participates in the Control of Campylobacter jejuni Growth via Zinc Sequestration. Infect Immun 2018; 86(6): e00234-18 / doi: 10.1128/IAI.00234-18.
35. Haley KP, Delgado AG, Piazuelo MB, et al. The Human Antimicrobial Protein Calgranulin C Partic-ipates in Control of Helicobacter pylori Growth and Regulation of Virulence. Infect Immun 2015; 83(7): 2944-2956 / doi: 10.1128/IAI.00544-15.
36. Ravasi T, Hsu K, Goyette J, et al. Probing the S100 protein family through genomic and functional analysis. Genomics 2004; 84(1): 10-22 / doi: 10.1016/j.ygeno. 2004. 02. 002.
37. Liu K, Pichichero ME. Clinical significance of serum S100A12 in acute otitis media in young children. Pediatr Infect Dis J 2012; 31(3): e56-58 / doi: 10.1097/ INF.0b013 e318 24672cb.
38. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007; 81(1): 28-37 / doi: 10.1189/jlb.0306170.
39. Shiotsu Y, Mori Y, Nishimura M, et al. Plasma S100A12 level is associated with cardiovascular disease in hemodialysis patients. Clin J Am Soc Nephrol 2011; 6(4): 718-723 / doi: 10.2215/CJN.08310910.
40. Ye F, Foell D, Hirono KI, Vogl T, et al. Neutrophil-derived S100A12 is profoundly upregulated in the early stage of acute Kawasaki disease. Am J Cardiol 2004; 94(6): 840-844 / doi: 10.1016/j.amjcard.2004.05.076.
41. Thierolf M, Hagmann ML, Pfeffer M, et al. Towards a comprehensive proteome of normal and ma-lignant human colon tissue by 2-D-LC-ESI-MS and 2-DE proteomics and identification of S100A12 as potential cancer biomarker. Proteomics Clin Appl 2008; 2(1): 11-22 / doi: 10.1002/prca.200780046.
42. Hinze CH, Foell D, Johnson AL, et al. Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Dis-continuation of Therapy. Arthritis Rheumatol 2019; 71(3): 451-459 / doi: 10.1002/art.40727
43. Pichichero ME, Morris MC, Almudevar A. Three Innate Cytokine Biomarkers Predict Presence of Acute Otitis Media and Relevant Otopathogens Biomark Appl 2018; 2(1): 10.29011/2576-9588.100018 / doi: 10.29011/2576-9588.100018.
44. Gavrilovici C, Oprea L. Clinical ethics, research ethics and community ethics. The moral triad of nowadays society. Rev. Romana Bioet 2013; 11: 55-57.
45. Choi SY, Yon DK, Choi YS, Lee J, Park KH, Lee YJ, Kim SS, Kim SH, Yeo SG. The Impact of the COVID-19 Pandemic on Otitis Media. Viruses 2022; 14(11): 2457 / doi: 10.3390/v14112457.
46. Torretta S, Cantoni B, Bertolozzi G, et al. Has Otitis Media Disappeared during COVID-19 Pandemic? A Fortuitus Effect of Domestic Confinement. J Clin Med. 2021; 10(13): 2851 / doi: 10.3390/ jcm10132851.
Published
2023-06-30
Section
SURGERY
COPYRIGHT
Once an article is accepted for publication, MSJ requests a transfer of copyrights for published articles.
COPYRIGHT TRANSFER FORM FOR
REVISTA MEDICO-CHIRURGICALĂ A SOCIETĂȚII DE MEDICI ȘI NATURALIȘTI DIN IAȘI /
THE MEDICAL-SURGICAL JOURNAL OF THE SOCIETY OF PHYSICIANS AND NATURALISTS FROM IASI
We, the undersigned authors of the manuscript entitled
_____________________________________________________________________________________
_____________________________________________________________________________________
warrant that this manuscript, which is submitted for publication in the REVISTA MEDICO-CHIRURGICALĂ, has not been published and it is not under consideration for publication in another journal.
- we give the consent for publication in the REVISTA MEDICO-CHIRURGICALĂ, in printed and electronic format and we transfer unconditioned and complete the copyright of this manuscript to the REVISTA MEDICO-CHIRURGICALĂ, in the event of its acceptance.
- the manuscript does not break the intellectual property rights of any other person.
- we have read the submitted version of the manuscript and we are fully responsible for the content.
Names and signatures of authors / copyright owners (the following sequence is the authorship of the article):
- ______________________________/_________________________
- ______________________________/_________________________
- ______________________________/_________________________
N.B. All the authors must sign this form
