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The Intracell Research Group (IRG, www.intracellresearchgroup.com) is a global research consortium consisting of microbiologists, neuroscientists, asthma clinical researchers, physicians, life sciences professionals and others advocating for the study of chronic intracellular infections as potential causes for chronic inflammatory diseases of unknown etiology with emphasis on Alzheimer’s, Asthma, Coronary Heart Disease, and Crohn’s. We wish to comment on the exciting protocol of Kyvsgaard et al.1 published recently in BMJ Open, of a 3-day treatment with azithromycin or long-term vitamin D (to affect short- and long-term symptomatology, respectively) in preschool patients hospitalized with acute asthma-like episodes. Previous work by Stokholm et al.2 in children with asthma-like symptoms found that a 3-day treatment with azithromycin was effective in the short-term but did not significantly affect the time to next episode of troublesome lung symptoms in individual children. We applaud inclusion of microbiologic measurements in the protocol and wish to point out how the investigation of associations of infection and treatment response may be augmented.
The Kyvsgaard protocol microbiologic methods may fail to detect important atypical respiratory pathogens that are prone to produce chronic infections and that have been associated with asthma. In chronic infections, Chlamydia pneumoniae and Mycoplasma pneumoniae may re...
The Kyvsgaard protocol microbiologic methods may fail to detect important atypical respiratory pathogens that are prone to produce chronic infections and that have been associated with asthma. In chronic infections, Chlamydia pneumoniae and Mycoplasma pneumoniae may reside solely intracellularly deep in the lung and not be present in respiratory secretions.3 4 Difficulty in detecting these potential causative microbes requires proven alternate microbiologic methods such as measuring C. pneumoniae-specific IgE, which has been detected by immunoblotting in children with acute asthma5 and also in almost half of pediatric and adult chronic asthma patients.6 C. pneumoniae DNA has also been detected in the peripheral blood of 50% of C. pneumoniae-specific IgE positive asthma patients by polymerase chain reaction (PCR).7 M. pneumoniae Community Acquired Respiratory Distress Syndrome (CARDS) toxin has also been detected in a majority of children with acute and refractory asthma.8 Because direct detection of these two candidate atypical respiratory pathogens in chronic lung infection is problematic, we encourage Kyvsgaard et al.1 to include peripheral blood biomarkers for atypicals (C. pneumoniae-specific IgE by immunoblotting, M. pneumoniae CARDS toxin and PCR for C. pneumoniae in peripheral blood) in the array already under consideration. Additionally, PCR of nasal scrapings may reveal chronic C. pneumoniae infection of the olfactory system.9 Lastly, fungi have been firmly linked to asthma10 and asthma-like experimental disease.11 In addition to detecting C. pneumoniae and M. pneumoniae, Kyvsgaard et al. have an outstanding opportunity to study the presence of fungi in this cohort.
If chronic atypical infections are causal in some people with asthma, then the length of azithromycin treatment becomes a crucial consideration. Acute respiratory infection by M. pneumoniae may respond without relapse to a short course of azithromycin, but this is not the case for acute C. pneumoniae respiratory infections that are known to require longer treatment courses of either a macrolide or a tetracycline.12 Symptoms attributable to chronic C. pneumoniae infection are even harder to treat and require much longer azithromycin courses and combinations of antibiotics insome patients.13-15 One of us (DLH) has successfully treated many patients with severe, refractory asthma with azithromycin durations ranging from 3-6 months. Many of these patients contacted DLH because they noticed that their asthma improved consistently but only temporarily after a traditional short course of azithromycin. One possible explanation for lack of long-term response to a short course of azithromycin in the study of Stokholm et al.2 could be inadequate treatment of a chronic intracellular infection. We mention this possibility because it would be tragic if an important therapeutic response were to be missed simply because some important hypotheses were not addressed or implemented in the study protocol.
1. Kyvsgaard JN, Ralfkiaer U, Folsgaard N, et al. Azithromycin and high-dose vitamin D for treatment and prevention of asthma-like episodes in hospitalised preschool children: study protocol for a combined double-blind randomised controlled trial. BMJ Open 2022;12(4):e054762. doi: 10.1136/bmjopen-2021-054762 [published Online First: 2022/04/15]
2. Stokholm J, Chawes BL, Vissing NH, et al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2015 doi: 10.1016/S2213-2600(15)00500-7
3. Webley WC, Hahn DL. Infection-mediated asthma: Etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides. Respiratory Research 2017;18(1) doi: 10.1186/s12931-017-0584-z
4. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002;121(6):1782-8. doi: 10.1378/chest.121.6.1782 [published Online First: 2002/06/18]
5. Emre U, Sokolovskaya N, Roblin P, et al. Detection of Chlamydia pneumoniae-IgE in children with reactive airway disease. J Infect Dis 1995;172:265-67. doi: 10.1093/infdis/172.1.265
6. Hahn DL. Chlamydia pneumoniae and chronic asthma: Updated systematic review and meta-analysis of population attributable risk. PLoS One 2021;16(4):e0250034. doi: 10.1371/journal.pone.0250034 [published Online First: 2021/04/20]
7. Hahn DL, Schure A, Patel K, et al. Chlamydia pneumoniae-specific IgE is prevalent in asthma and is associated with disease severity. PLoS ONE 2012;7(4):e35945. doi10.1371/journal.pone.0035945. doi: 10.1371/journal.pone.0035945
8. Wood PR, Hill VL, Burks ML, et al. Mycoplasma pneumoniae in children with acute and refractory asthma. Ann Allergy Asthma Immunol 2013;110(5):328-34 e1. doi: 10.1016/j.anai.2013.01.022
9. Chacko A, Delbaz A, Walkden H, et al. Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer's disease risk. Sci Rep 2022;12(1):2759. doi: 10.1038/s41598-022-06749-9 [published Online First: 2022/02/19]
10. Li E, Knight JM, Wu Y, et al. Airway mycosis in allergic airway disease. Adv Immunol 2019;142:85-140. doi: 10.1016/bs.ai.2019.05.002
11. Porter P, Susarla SC, Polikepahad S, et al. Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi. Mucosal Immunol 2009;2(6):504-17.
12. Grayston JT. Chlamydia pneumoniae, strain TWAR. Chest 1989;95(3):664-69.
13. Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract 1995;41:345-51.
14. Hahn DL, Grasmick M, Hetzel S, et al. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med 2012;25(4):442-59. doi: 10.3122/jabfm.2012.04.110309
25/4/442 [pii] [published Online First: 2012/07/10]
15. Wagshul FA, Brown DT, Schultek NM, et al. Outcomes of Antibiotics in Adults with "Difficult to Treat" Asthma or the Overlap Syndrome. J Asthma Allergy 2021;14:703-12. doi: 10.2147/JAA.S313480 [published Online First: 2021/06/25]