Boost of mucosal secretory immunoglobulin A response by clarithromycin in paediatric influenza

Abstract

Background and objective:The antiviral neuraminidase inhibitor oseltamivir (OSV) is used to treat influenza. The macrolide clarithromycin (CAM) is used to treat bacterial infections and has anti-inflammatory and immunomodulatory activities. This retrospective study investigated the immunomodulatory effects of CAM in children presenting with influenza A. Methods: The study recruited 40 children with acute influenza, and grouped them according to the treatment received: 5-day treatment with OSV (n = 14), CAM (n = 8), OSV + CAM (n = 12) and untreated (n = 6). The before and after treatment comparisons were made of the level of secretory IgA (sIgA) against influenza A virus (H3N2) and (H1N1), total sIgA, viral RNA copy numbers in nasopharyngeal aspirates and disease symptoms. Results: Infection induced anti-viral mucosal sIgA in the nasopharyngeal aspirates of most patients of all treatment groups. Particularly prominent increases in the levels were found in the CAM and OSV + CAM groups. Low induction of anti-viral sIgA was observed in the OSV group, but the addition of CAM to OSV augmented sIgA production and restored local mucosal sIgA levels. The frequency of residual cough in the OSV + CAM group was significantly lower than in the other groups including the group treated with OSV. Conclusions: CAM boosted the nasopharyngeal mucosal immune response in children presenting with influenza A, even in those treated with OSV who had low production of mucosal anti-viral sIgA, and alleviated the symptoms of influenza.

Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data

“…These experiments were done because they had the unexpected finding that patients with paediatric influenza who were treated orally with oseltamivir for 5 days had significantly low levels (about 60% reduction on day five) of anti-influenza secretory-immunoglobulin A nasopharyngeal fluids compared with levels in patients who were not treated with oseltamivir. 134 Their findings are consistent with our findings that serum haemagglutinin inhibition antibody response was decreased by oseltamivir administration, although secretory immunoglobulin G antibody could not be analysed in our study because the data were not reported in the CSRs. 133,134 These findings are also consistent with the evidence on the mode of action of oseltamivir from animal models 8,58,135 and from viral challenge, randomised, placebo-controlled studies in humans.…”

“…134 Their findings are consistent with our findings that serum haemagglutinin inhibition antibody response was decreased by oseltamivir administration, although secretory immunoglobulin G antibody could not be analysed in our study because the data were not reported in the CSRs. 133,134 These findings are also consistent with the evidence on the mode of action of oseltamivir from animal models 8,58,135 and from viral challenge, randomised, placebo-controlled studies in humans. 27 Pro-inflammatory cytokines, including interleukin 6, tumour necrosis factor alpha and interferon gamma, were completely suppressed by oseltamivir administered 28 hours after the experimental inoculation of influenza virus, whereas the reduction of viral titre in nasal lavages was partial.…”

Long-term macrolide treatment for chronic respiratory disease

“…As such, a recent Cochrane review found minimal evidence in support of the use of macrolides in infants with bronchiolitis [109]. Finally, SAWABUCHI et al [110] have recently shown that the addition of clarithromycin to oseltamivir augmented secretory (s)IgA production and restored local mucosal sIgA levels in children with acute influenza, suggesting a boosting effect on the nasopharyngeal mucosal immune response in children with influenza A.…”

Oral Clarithromycin Enhances Airway Immunoglobulin A (IgA) Immunity through Induction of IgA Class Switching Recombination and B-Cell-Activating Factor of the Tumor Necrosis Factor Family Molecule on Mucosal Dendritic Cells in Mice Infected with Influenza A Virus

“…In this regard, we have previously reported that administration of CAM in influenza A virus (IAV)-infected mice resulted in suppression of tumor necrosis factor alpha and augmentation of interleukin-12 production in the blood, resulting in alleviation of the flu symptoms (18), while oral treatment with OSV attenuated the induction of respiratory anti-IAV specific secretory IgA (S-IgA) immune responses (39). Furthermore, we have recently verified in IAV-infected children that oral CAM augmented the nasopharyngeal mucosal immune responses, while OSV suppressed the production of mucosal anti-IAV S-IgA (37). Of interest, we have also reported that 75% of patients treated with the combination of CAM and OSV showed increases in S-IgA production to levels similar to those seen in patients treated with CAM alone (37).…”

“…Furthermore, we have recently verified in IAV-infected children that oral CAM augmented the nasopharyngeal mucosal immune responses, while OSV suppressed the production of mucosal anti-IAV S-IgA (37). Of interest, we have also reported that 75% of patients treated with the combination of CAM and OSV showed increases in S-IgA production to levels similar to those seen in patients treated with CAM alone (37). Others have also reported that CAM acted on the viral replication cycles, resulting in inhibition of progeny virus production in vitro (25,26), and modulated airway inflammation in IAV infection by reduction of the viral receptor, sialic acid with an ␣2,6 linkage on the airway epithelial cells, through inhibition of nuclear factor kappa B (NF-B) expression and increase in intraendosomal pH (45).…”