From clinical experience and scientific reports, it is apparent that preschool wheezers are a heterogeneous group of which only part will benefit from the use of ICS [ 8 — 10 ].
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We focus on the microbiological findings and discuss the possible pathophysiology of bronchial bacterial infection. As a tertiary referral centre, we are referred children for further evaluation and treatment of persistent wheezing despite ICS treatment and anti-reflux therapy in those with demonstrated GERD. Our initial assessment includes a detailed history of disease, symptoms, signs and treatment adherence, a check for the appropriateness of treatment administration and dosage, and a thorough physical examination.
Children with respiratory tract anomalies including malacia of the conductive airways, or with known underlying chronic conditions, such as cystic fibrosis, primary ciliary dyskinesia, immune deficiency, bronchopulmonary dysplasia, congenital heart diseases and neuromuscular disorders were also excluded. GERD was assessed by a positive 24 hour-oesophageal pH measurement, interpreted according to gastroenterological criteria [ 11 ]. BAL-samples were divided into 2 aliquots, which were immediately sent to the Microbiology lab and the Hematology lab.
Upon arrival in the lab, BAL-samples were processed for smear, bacterial culture, viral culture, and for the detection of influenzavirus A and B; parainfluenzavirus types 1, 2, 3; RSV; human metapneumovirus subtypes A and B; coronaviruses E and OC43, Mycoplasma pneumoniae and Chlamydophila pneumoniae using an in-house multiplex Polymerase Chain Reaction mPCR - protocol, as described previously [ 13 ].
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Gram staining of smear and bacterial BAL-culture were performed according to standard methods [ 14 , 15 ]. BAL-fluid was transported to the laboratory in a siliconized container on ice. The fluid was filtered through nylon gauze. A cell suspension of 2. Two hundred cells were examined for differential cell counts. Given that the median percentage of neutrophils in BAL-fluid of healthy children is 0. Multiple comparisons were handled by the Holm's method. Full parental consent was obtained orally after explanation of the procedure, its benefits and its risks.
Table 1 summarises the characteristics of the study population with respect to allergy and reflux testing results, and familial and environmental risk factors for asthma. Only 7 of 13 Significant bacterial cultures were found in 16 of 33 Aerobic bacteria were isolated as sole pathogen in 11 of 33 Mixed bacterial-viral infection and mixed bacterial-atypical infection were found in 4 of 33 Bacterial co-infection was found in 5 of 33 Respiratory viruses were detected in 7 of 32 Mycoplasma pneumoniae was detected in 1 of 19 cases, in a mixed infection with H.
Capsular typing of H.
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All 10 NTHi strains were evaluated for misidentification of non-haemolytic H. Susceptibility based antibiotic treatment in patients with a significant BAL-culture is routine in our centre. In contrast to viral infections, which are known to be associated with wheezing in young children, bacterial infections have long been considered of no importance in asthma and wheezing, and antibiotic therapy is not recommended in current asthma treatment guidelines [ 17 — 20 ]. However, several studies suggest that bacteria might play a role in wheezing in young children [ 9 , 10 , 17 , 19 , 20 ].
Moreover, it is increasingly appreciated that the human body is home to an extended microbiome, with asthmatic children harbouring different bacteria and a less diverse mix compared to healthy children [ 21 ]. Characterisation of the predominant bacteria in wheezing children is essential to understand the pathophysiology of persistent wheezing.
Recently, tracheobronchomalacia has been shown to be highly associated with bronchial inflammation and bacterial infection in children with persistent respiratory symptoms [ 22 ]. Nevertheless, it remains unclear whether bacterial infection is simply a consequence of impaired mucociliary clearance or whether it is an independent inflammatory stimulus in persistent wheezers.
We hypothesized that bacterial infection might indeed be an independent inflammatory stimulus in persistent preschool wheezers, and chose to study a selected group of patients without structural anomalies of the conductive airways. In our study, we found that bronchial bacterial infection is common in persistent preschool wheezers without apparent reasons for impaired mucociliary clearance, and that H.
We also found frequent bacterial co-infection involving these 3 pathogens. Our findings corroborate observations of other authors, who also described the predominance of this bacterial triad in children with persistent or recurrent wheezing [ 9 , 10 , 19 , 20 , 23 , 24 ]. The frequent upper respiratory tract colonisation with these aerobic bacteria in children, may provide difficulties to discriminate between contamination and true bronchial infection [ 25 ].
However, we consider our results to reflect true bronchial infection, as we applied procedural methods, which were shown to limit strongly the risk for contamination [ 13 , 20 , 26 , 27 ].
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The applied cut-off was also used previously by others, studying children with chronic bronchitis [ 30 ]. The presence of a significant increased neutrophilic inflammation in BAL-fluid of those patients in which NTHi was cultured, as compared to patients with a negative BAL-culture, supports the hypothesis that bacterial infection is indeed an inflammatory stimulus in children with persistent wheezing[ 24 ].
Although previously other authors have had similar results, isolated strains of H. To our knowledge this is the first report that associates bronchial infection with non-typeable H. Identification of NTHi as the predominant pathogen further supports our hypothesis that persistent wheezers present an underlying inflammation induced by chronic bacterial infection.
Chronic NTHI infection, resulting from the ability of NTHI to persist in the lower airways through several escape mechanisms from the host immune responses, has previously been reported by others [ 31 — 33 ].
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Moreover, in the lower airways of patients with chronic obstructive lung disease, NTHI has been demonstrated to be a major inflammatory stimulus [ 31 , 34 ]. The poor response of symptoms to an in-vitro susceptibility guided, adequately dosed antibiotic treatment that we found, is similar to poor response findings in 2 other disease entities involving H.
In the middle ear, biofilm formation has been demonstrated to be one of the major mechanisms for persistence and provides an explanation for unresponsiveness to antibiotic therapy [ 39 , 40 ]. Moreover, biofilm formation and intracellular infection are well established mechanisms of NTHi for persistence in the lower airways [ 31 — 33 ].
Although our study does not provide evidence of biofilm formation in the lower airways of young unresponsive wheezers, our findings of poor response to and frequent relapse after a short course of antibiotic treatment are suggestive for involvement of biofilm. Biofilm formation should be addressed in future studies, because its presence may have consequences for treatment.
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Wheeze monitoring provides quantitative and noninvasive information about the extent of nocturnal wheezing in children, correlates well with conventional indices of asthma activity and can assist in assessing efficacy of treatment. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.
Skip to main content. Wheeze monitoring in children for assessment of nocturnal asthma and response to therapy L. Bentur , R. Beck , M.