Dear Editors,
We are so glad to hear of the interest in our work titled ‘Outcome evaluation of clarithromycin, metronidazole and lansoprazole regimens in Helicobacter pylori positive or negative children with resistant otitis media with effusion'. In addition, we appreciate the focused interest from Dr Satvinder Singh Bakshi on our published papers and the enquiry comments.
I would like to reply to the comments made in the abovementioned letter.
First comment
This was ‘The role of H pylori in the pathogenesis of otitis media with effusion (OME) is a matter of debate, with studies both in favour of it and against it’. Dr Bakshi mentioned that some studies were against the role of H pylori in OME and used a study by Sudhoff et al.Reference Sudhoff, Rajagopal, Baguley, Ebmeyer, Schmelzer and Schreiber1 to support this. Sudhoff and colleagues found little evidence for the existence of H pylori associated OME, but did not deny its role, nor were they against it (as Dr Bakshi pertained in his letter). Moreover, Sudhoff et al. concluded by stating that further research is needed in order to delineate the presence of H pylori and its role in the pathogenesis of OME.Reference Sudhoff, Rajagopal, Baguley, Ebmeyer, Schmelzer and Schreiber1
In a recent study by Saki et al. heavy colonisation of H pylori was detected by polymerase chain reaction in adenoid tissue and the middle ear for OME cases.Reference Saki, Samarbaf Zadeh, Sheikhpour Jonaky, Noori, Kayedani and Nikakhlagh2 The authors concluded that H pylori had a role in the pathogenesis of OME and that the condition was resistant to medical treatment. In addition, Bai et al., in a 2012 study conducted in China on OME patients, confirmed that the middle-ear effusion was H pylori positive, as established by both culture and urease tests.Reference Bai, Wang, Fan, Han, Xu and Zhang3 Their findings suggest that H pylori is strongly involved in the aetiology of OME. Yilmaz et al. found significantly increased colonisation by H pylori of the middle ear, and tonsillar and adenoid tissue in patients with OME using culture and polymerase chain reaction analyses, and mentioned H pylori involvement in the pathogenesis of OME.Reference Yilmaz, Ceylan, Akyön, Ozçakýr and Gürsel4
There are many published papers on the involvement of H pylori in the pathogenesis of OME, that use many different investigative methods (culture, polymerase chain reaction, urease test, etc.), which support our work and results, with no published literature to support the comment against the role of H pylori.
Second comment
The author commented that ‘in the present study only the stool antigen has been used’. As part of our study, a pilot study was conducted, in which 10 children with OME with positive H pylori stool antigen results were subjected to ventilation tube insertion under general anaesthesia. Middle-ear fluid was aspirated with a micro-aspiration cannula (blood contamination was entirely avoided; effusion samples were collected under completely sterile conditions). Gastric lavage was performed with an orogastric Nelaton catheter. This was inserted into the stomach, and 10 cc of saline solution was injected and subsequently aspirated back into the injector. All ear and gastric lavage samples were processed within 4 hours of collection. They showed positive reactions for catalase, oxidase and urease. In addition, polymerase chain reaction analysis revealed that all samples were positive for H pylori infection (see Materials and methods – Procedure, page 1070). This investigative method is comparable with that used by Melake et al., who took samples of middle-ear fluid and gastric lavage for polymerase chain reaction analysis to detect the presence of H pylori.Reference Melake, Shaker and Salama5
Third comment
This was ‘H pylori in stool samples is non-specific and may not be significant’. We focus here on the newest investigative methods for the detection of H pylori, and consider its reliability, sensitivity and specificity.
Two categories of diagnostic methods usually used for the detection of H pylori are invasive tests, such as histology, rapid urease test and culture, and non-invasive tests, such as the 13C urea breath test and serology.Reference Makristathis, Pasching, Schütze, Wimmer, Rotter and Hirschl6 Serological tests and the urea breath test have certain disadvantages as they lack sufficient reliability. Furthermore, the urea breath test is expensive, it causes administrative difficulties and it is not available in all countries, although it is as reliable as invasive methods.Reference Oderda, Rapa, Ronchi, Lerro, Pastore and Staiano7
Gulcan et al. reported that the sensitivity, specificity, and positive and negative predictive values of the H pylori stool antigen test were 98 per cent, 100 per cent, 100 per cent and 96.5 per cent, respectively.Reference Gulcan, Varol, Kutlu, Cullu, Erkan and Adal8
The H pylori stool antigen test is a new non-invasive diagnostic method based on a sandwich enzyme immunoassay with antigen detection. It has high sensitivity and specificity, and was approved in the USA in 1998 for the diagnosis of H pylori infection and for monitoring the response to treatment in adult patients. The H pylori stool antigen test has sensitivity of up to 98 per cent and specificity of up to 99 per cent. In contrast, serology for immunoglobulin G has sensitivity of up to 85 per cent and specificity is 79 per cent. Endoscopy with biopsy for histology and culture testing has sensitivity of up to 80 per cent and specificity is 100 per cent, but it is an invasive technique.Reference Ables, Simon and Melton9
Iranikhah et al. reported the stool antigen test to be highly sensitive and specific for detecting H pylori infection in children, and found it to be a very reliable method for monitoring the response to treatment.Reference Iranikhah, Ghadir, Sarkeshikian, Saneian, Heiari and Mahvari10
Fourth comment
The author commented that ‘A few studies have explored the role of gastroesophageal reflux in the pathogenesis of otitis media’. We mentioned this relationship in the Introduction section of the paper (page 1069). Tasker et al. demonstrated that pepsinogen and pepsin could be found in the middle-ear fluid of OME patients, indicating that laryngopharyngeal reflux disease could be a significant aetiological factor in the development of OME.Reference Tasker, Dettmar, Panetti, Koufman, Birchall and Pearson11 O'Reilly et al. investigated the correlation between gastric pepsin and paediatric otitis media, and concluded that it is closely linked to the middle-ear inflammatory process and may worsen the disease in some children.Reference O'Reilly, Soundar, Tonb, Bolling, Yoo and Nadal12 Al-Saab et al. found that laryngopharyngeal reflux plays an important role in the pathogenesis of OME, as gastric reflux reaches the middle ear through the nasopharynx and eustachian tube to cause OME.Reference Al-Saab, Manoukian, Al-Sabah, Almot, Nguyen and Tewfik13
Fifth comment
This was ‘A further concern is the rising incidence of development of clarithromycin resistance in H pylori’. This statement is not supported by a reference. The standard H pylori triple therapy comprises clarithromycin (7.5 mg/kg twice daily), metronidazole (10 mg/kg twice daily) and lansoprazole (30 mg twice daily).Reference Gessner, Bruce, Parkinson, Gold, Muth and Dunaway14 In a recent study by Masoodi et al., the clarithromycin success rates for eradication of H pylori infection was 72.7 per cent.Reference Masoodi, Talebi-Taher, Tabatabaie, Khaleghi, Faghihi and Agah15 Mokhtare et al. mentioned that the clarithromycin regimen is encouraged in developing countries as a second-line treatment for H pylori infection because of the acceptable rate of eradication and low adverse effects.Reference Mokhtare, Agah, Fakheri, Hosseini, Rezaei Hemami and Ghafoori16 Harb et al. reported that a half-dose clarithromycin-based regimen is equally effective and better tolerated than its full-dose counterpart in the treatment of H pylori infection.Reference Harb, Chalhoub, Abou Mrad and Sharara17 In addition, Yoon et al. mentioned that clarithromycin-based standard triple therapy can still be effective for H pylori eradication in some parts of Korea.Reference Yoon, Park, Lee, Kim and Kim18
Sixth comment
The author remarked that ‘The evidence for the use of clarithromycin in OME is still unclear’. This comment appears to represent a perception and assumption not accompanied by any supporting literature. However, Iino et al. conducted a clinical study, published in 2015, to evaluate clarithromycin as a new method of treatment for persistent inflammation after otitis media in children, and the results illustrated that clarithromycin can reduce persistent middle-ear inflammation after acute otitis media.Reference Iino, Yoshida, Kato, Kakizaki, Miyazawa and Kakuta19 In addition, Chen et al. found that macrolides are effective for OME in children, and they have a significant effect on the treatment of early-stage OME for 88.7–92.5 per cent of participants (compared with 50.9–60.3 per cent of participants in a control group) after 8–12 weeks.Reference Chen, Wu, Jiang, Du and Jiang20 Furthermore, Iino, in 2001 referred to the efficacy of macrolide therapy for children with serous otitis media.Reference Iino21
Final remark
We would like to thank the author for the valuable letter and for his unlimited interest with any published paper from our institution. We hope our reply clarifies our knowledge and our ideas on this area of interest, and that the updated information fulfils our aim to focus future reading on the clinical methodology.
