How to reduce the use of antibiotics in infant bronchiolitis?

Bronchiolitis belongs to the leading causes for hospitalisations of western infants, and young age under 3 months even in the absence of any underlying illness has been documented as a significant risk factor for the need of intensive care and ventilatory support in bronchiolitis. The majority of bronchiolitis cases are caused by respiratory syncytial virus (RSV) at the age under 12 months, and by rhinoviruses at the age of 12-24 months.1 According to current knowledge, respiratory bacteria do not play any role in the emergence of bronchiolitis but may be involved with bronchiolitis by causing secondary infections in the airways primarily damaged by viruses. In addition, invasive infections outside the airways must also be considered especially in young infants with severe bronchiolitis. Antibiotics are frequently prescribed for infants during hospitalisation for bronchiolitis, particularly if the patient needs intensive care and ventilatory support. A recent review on treatment of bronchiolitis in the paediatric intensive care unit (PICU) included three observational studies and more than 600 patients,2 and 33%-72% of admitted infants received antibiotics during their PICU stay.3-5 In the nation-wide Canadian questionnaire study,6 36% of intensivists who treated infants admitted for viral bronchiolitis to the PICU prescribed antibiotics to all patients and 71% to intubated patients. One reason for the use of antibiotics in severe viral bronchiolitis is that there are no reliable diagnostic methods available for the distinction of bacterial from viral lower respiratory infection. Findings of bacteria by culture or staining in tracheal aspirates taken from intubated children provide some evidence for bacterial infection, but bacterial colonisation without any clinical relevance is common in this patient group. Instead, bacterial findings by culture, staining or antigen detection in specimens obtained from upper airways are of no diagnostic value. On the other hand, positive viral findings in antigen or genome detection tests in such specimens, though sensitive and specific for involvement with the virus in question, do not necessarily prove the virus-specific aetiology of lower airway infection, and do not rule out simultaneous bacterial co-infections. Procalcitonin (PCT) and C-reactive protein (CRP) are non-specific markers of the host response to tissue injury and inflammation, and their serum concentrations usually are higher in bacterial than in viral respiratory tract infections. Despite this, PCT or CRP or any combination of non-specific host response markers has not been sufficiently sensitive and specific to either prove true or rule out the bacterial aetiology of respiratory infection. The combination of CRP > 100 mg/L, white blood cell count > 15 × 109/L, PCT > 1.0 ng/mL and erythrocyte sedimentation rate > 65 mm/h showed a modest positive likelihood ratio (LR+) of 2.7 in the distinction between pneumococcal and viral pneumonia in children.7 LR+ was lower, when other cut-off limits were applied for these markers. Thus, LR+ did not reach by any combination the level of >5.0, which is considered to be the limit of a clinically significant likelihood ratio. Both short-term and long-term adverse effects of an exposure to antibiotics are more prominent when such exposure takes place during the first months of life compared with exposures in later childhood. The main long-term harmful effects are emergence of bacterial strains that are resistant to antibiotics, and changes in children's normal health-promoting bacterial flora. In a nation-wide Taiwanese 5-year register-based study,8 the use of antibiotics for bronchiolitis in infancy increased the risk of post-bronchiolitis asthma to over threefold, and among different antibiotics, macrolides and especially azithromycin were associated with the greatest attributable asthma risk after bronchiolitis. A disturbed intestinal microbiota was the probable causative factor beyond the increased asthma risk. Thus, there is an urgent need to lessen antibiotic treatments in young infants including in those who present with bronchiolitis. Since the reliable microbe-specific diagnosis of bacterial lower respiratory infection is seldom possible, a rationale way is to apply algorithms based on monitoring of non-specific inflammatory markers such as serum PCT or CRP to guide the prescription of antibiotics. Alejandre et al9 publish in the current issue of the journal their results on 706 Spanish infants treated in the PICU for bronchiolitis at the median age of 47 days during the surveillance period of 8 years. The start of antibiotics was refrained, if not necessary to treat an invasive bacterial infection as long as PCT stayed at the level of <1.0 ng/mL (and CRP < 70 mg/L), and correspondingly, antibiotics could be withdrawn if going-on when PCT fell back to <1.0 ng/mL. The final decision on starting or withdrawing of antibiotics and on stewardship to narrow-spectrum pathogen-specific antibiotics was always clinical, which probably increased the safety and decreased the effect of the programme. After implementation of these PCT-based guides, the use of antibiotics decreased from 89% to 72% of bronchiolitis patients,9 but the use was still much higher than for example the figures of 34%, 19% and 43% in infants treated for bronchiolitis in the PICU of our hospital during three 5-year surveillance periods in 2000-2015.5 Antibiotic stewardship and withdrawal decisions increased from 22.4% to 36.4% without any adverse outcomes caused by these decisions. The mean length of antibiotic courses decreased from 8.7 to 5.1 days.9 No doubt, such decrease of more than three days is clinically significant lessening both immediate and later harmful effects of antibiotics. However, the lengths of hospital and PICU stays were similar before and after implementation of the guides,9 in median 12 vs 13 days in the hospital and 6 vs 6 days in the PICU, and so, the programme was not necessarily cost saving. Alejandre et al9 used historical controls, since they compared 340 cases treated before the implementation of the PCT-based guides in 2010-2013 to 366 cases treated after the implementation in 2014-2017. The possible changes in bronchiolitis treatment during the 8-year surveillance period were not taken into account in the analyses. For example, high-flow oxygen therapy (HFOT) is an important new approach for bronchiolitis treatment, which was introduced in many hospitals just during these years. Irrespective of whether patients treated with a new method such as HFOT are included or not, the new widely used treatment modality influences the spectrum of eligible cases, and so, indirectly impacts on the results. In addition, RSV epidemics, though occurring every year, are different in terms of severity, extent and circulating viruses. When the study concerns diagnostic and therapeutic practices in the hospital such as management based on algorithms, the modern demands to produce prospective randomised controlled data are very challenging. Individual patients cannot be randomised to separate monitoring and treatment arms, such as to follow or not to follow the PCT-guided protocol. The practice of the whole hospital can be randomised between two arms, but the change of the practice for example monthly or even more seldom carries many practical and ethical problems. Such changes may decrease the confidence in the guides in general and the compliance of patients and staff members. In multi-centre studies, of course, different hospitals can be allocated to follow different protocols. In such cases, randomisation of the attending hospitals into the treatment arms is recommendable, and as in all prospective studies, the guardians of the children must receive an appropriate information on the study protocol and give an informed consent. The comparison of different hospitals with different clinically adopted practices means an exploratory pilot study that can provide only preliminary results. Finally, when diagnostic or treatment practices are studied, the only realistic possibility often is to compare two or more treatment periods in the same hospital, as Alejandre et al9 made. The reliability of the results can be increased by performing stratified, adjusted and sensitivity analyses for versatile testing of the hypotheses. In an optimal case, changes by time are the only factors that can cause bias. However, the changes by time are difficult or even impossible to be controlled. More than two surveillance periods are needed to confirm that the results are enduring. A recent statement of the European Academy of Pediatrics highlighted in particular two problems in the medical treatment of children in western countries: over-use of antibiotics at all ages and over-treatment of bronchiolitis in infancy.10 Paediatricians and intensivists who treat infants with severe bronchiolitis need to find an optimal balance in the use of antibiotics: not too often, not too seldom and not too long times. The author declared no conflicts of interest. Matti Korppi

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