Caffeine in Bronchiolitis, That Old Friend Who Always Has More Than One Trick Up Its Sleeve

David W. Brossier Catline Le Pallec Isabelle Goyer Caffeine and other methylxanthines have been used for decades in the management of apnoea associated with prematurity [1]. Caffeine antagonises adenosine receptors in the medulla oblongata and thus has stimulating properties on the respiratory centre [1]. In the former indication, caffeine has been shown to reduce the frequency of apnoea episodes and the need for mechanical ventilation during the first 7 days of treatment [2]. By analogy with this practice, caffeine has been regularly proposed over the past 30 years as a potential treatment for bronchiolitis-related apnoea in standard and intensive paediatric care units, with mixed results [3]. Therefore, unlike apnoea associated with prematurity, caffeine has not become a mainstay of treatment for bronchiolitis-related apnoea [4]. Nonetheless, beyond its stimulating action on the central respiratory centre, caffeine is also known to have peripheral actions which can contribute to a better respiratory function, especially its effects on the pulmonary system as well as on the respiratory muscles, more specifically the diaphragmatic function [5]. Often overlooked, these properties might give caffeine a much more important role in the management of respiratory disorders, one that is not limited to the treatment of central apnoea in neonatology [2, 6] but in paediatrics as well. In this regard, it is worth highlighting the prospective observational pilot study by Casabianca et al. published in Acta Paediatrica [7]. Conducted in two French paediatric centres, this prospective nonrandomized study aimed to evaluate the impact of caffeine prescribed to infants up to 8 weeks old hospitalised for a bronchiolitis episode, regardless of the presence of apnoea. This study sought to compare clinical outcomes between infants exposed to caffeine versus nonexposed to caffeine during their hospitalisation for bronchiolitis. Among the 186 included children, 65 (35%) were treated with caffeine as soon as they were hospitalised with bronchiolitis as a standard-of-practice in 1 of the 2 participating centres. It is noteworthy that among these, only 2 patients did present apnoea prior to caffeine initiation, which reflects the more systematic use of caffeine in this centre. None of the children included in the second centre received caffeine. The two main results of this study were the positive associations found between the use of caffeine and (1) the decrease in need for nutritional support and (2) a shorter length of continuous positive airway pressure (CPAP) use in infants who needed non-invasive ventilatory support. Children who received caffeine were less likely to require nutritional support during their hospital stay versus children who did not receive caffeine (48 (77.4) vs. 115 (95.0), p < 0.001). Among the 113 infants who needed non-invasive ventilatory support, the length of CPAP was significantly shorter in the caffeine group (4.1 [1.9–5.0] vs. 7.1 [3.5–10.7], p = 0.003). However promising, these results must be interpreted with caution. Indeed, the study was conducted as a pilot study and consequently was not designed to highlight a causal relationship between the use of caffeine and positive clinical outcomes. Therefore, it is only possible to conclude to a positive association between the use of caffeine and a decrease in the length of CPAP use and the need for nutritional support in this specific population of infants with bronchiolitis. Furthermore, several confounding factors were impossible to adjust for, given the nonrandomized design of this study. And above all, the main issue relies on the fact that all caffeine exposed patients were hospitalised in one centre whereas none of the children from the 2nd centre received caffeine. In consequence, this study consists more of a comparison of the 2 centres' global bronchiolitis management which precludes from concluding a causal relationship between a specific intervention and outcomes. In this study, the observed results might not be related to the use of caffeine but to differences in local clinical practices such as non-invasive ventilatory support criterion, the use of high-flow nasal oxygen, habits regarding nutritional support, etc. The authors also note that among the children that required respiratory support, the non-exposed to caffeine group reported more RSV related bronchiolitis episodes than the caffeine exposed group. RSV has been specifically linked to apnoea during bronchiolitis [8]. One could speculate that targeting infants with apnoea or with a documented RSV presence could benefit more from a caffeine treatment instead of a more systematic approach. Although this study by Casabian et al. suffers from methodological flaws that undermine the applicability of its results, we believe that its strengths go beyond its statistical findings. Firstly, this study confirmed the relative safety of caffeine exposure in infants with bronchiolitis, with very few adverse events reported and no major side effects. Determining whether caffeine is associated with minimal or no adverse effects, as opposed to more serious adverse effects, is useful in weighing the theoretical benefits of caffeine against its potential risks. But, of course, the absence of serious side effects is not a sufficient reason to resort to treatment, and its effectiveness must be demonstrated first. Secondly, this work showed that, although it is not recommended due to a lack of evidence, some paediatricians continue to believe that caffeine has a place in the therapeutic arsenal for bronchiolitis prescribing this off-label treatment systematically [9]. To our knowledge, this is the first study to evaluate the role of caffeine in bronchiolitis, independently of the presence of apnoea, thus opening new perspectives for exploration of the potential peripheral effects of caffeine treatment on respiratory function during bronchiolitis episodes in infants. This is of peculiar interest in the context of newly available therapies for RSV prevention (nirsevimab, RSV vaccines used during pregnancy) [10] and thus in the near future less of RSV apneic bronchiolitis episodes and more of other viruses associated bronchiolitis. Unfortunately, we are forced to consider that the difficulty in establishing the place of caffeine in the treatment of bronchiolitis, with or without apnoea, could be a sign of its ineffectiveness in this indication rather than a lack of scientific evidence. But, at this stage of scientific research, we believe that the use of caffeine in bronchiolitis should not be totally ruled out [11]. To demonstrate the relevance of caffeine in the management of bronchiolitis, there is a need to determine the specific population who might benefit from it and what the expected benefits could be in terms of robust clinical outcomes. Moreover, pharmacokinetic-pharmacodynamic studies are mandatory to determine the most appropriate dosing regimen in the full-term infant population as this has yet to be done. However, as some may consider caffeine to be an insufficiently promising drug, conducting such extensive and costly clinical trials raises questions. The authors have nothing to report.