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Ventilation Inhomogeneity in Infants with Recurrent Wheezing

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Ventilation Inhomogeneity in Infants with Recurrent Wheezing Paediatric lung disease ORIGINAL ARTICLE Thorax: first published as 10.1136/thoraxjnl-2017-211351 on 15 June 2018. Downloaded from Ventilation inhomogeneity in infants with recurrent wheezing Zihang Lu,1,2 Rachel E Foong,1,3 Krzysztof Kowalik,1 Theo J Moraes,1 Ayanna Boyce,1 Aimee Dubeau,1 Susan Balkovec,1 Per Magnus Gustafsson,4 Allan B Becker,5 Piush J Mandhane,6 Stuart E Turvey,7 Wendy Lou,2 Felix Ratjen,1 Malcolm Sears,8 Padmaja Subbarao1 ► Additional material is ABSTRact published online only. To view Background The care of infants with recurrent Key messages please visit the journal online (http:// dx. doi. org/ 10. 1136/ wheezing relies largely on clinical assessment. The thoraxjnl- 2017- 211351). lung clearance index (LCI), a measure of ventilation What is the key question? inhomogeneity, is a sensitive marker of early airway ► Does infant lung function as reported in lung 1Division of Respiratory disease in children with cystic fibrosis, but its utility has clearance index (LCI) measured from multiple Medicine and Translational not been explored in infants with recurrent wheezing. breath washout improve the phenotyping of Medicine, Department of infants who have a history of severe wheezing Pediatrics & Physiology, Hospital Objective To assess ventilation inhomogeneity using for Sick Children & University LCI among infants with a history of recurrent wheezing disorders? of Toronto, Toronto, Ontario, compared with healthy controls. What is the bottom line? Canada Methods This is a case–control study, including 2Dalla Lana School of Public ► LCI is elevated in a clinical cohort of 37 infants with recurrent wheezing recruited from Health, University of Toronto, infants referred for recurrent wheezing outpatient clinics, and 113 healthy infants from a Toronto, Ontario, Canada disorders suggesting persistent ventilation 3School of Physiotherapy longitudinal birth cohort, the Canadian Healthy Infant inhomogeneity. Elevated LCI was associated and Exercise Science, Curtin Longitudinal Development study. All infants, at a time with an elevated exhaled nitric oxide and University, Bentley, Western of clinical stability, underwent functional assessment Australia, Australia may represent an endotype of infant asthma 4 including multiple breath washout, forced expiratory Department of Pediatrics, that could not be distinguished using clinical flows and body plethysmography. Central Hospital, Skövde, characteristics alone. Sweden Results LCI z-score values among infants with 5 Department of Pediatrics and recurrent wheeze were 0.84 units (95% CI 0.41 to Why read on? Child Health, University of Manitoba, Children’s Hospital 1.26) higher than healthy infants (mean (95% CI): 0.26 ► Infants with severe wheezing illnesses http://thorax.bmj.com/ Research Institute of Manitoba, (−0.11 to 0.63) vs −0.58 (−0.79 to 0.36), p<0.001)). represent a heterogeneous group of patients. Winnipeg, Manitoba, Canada Nineteen percent of recurrently wheezing infants had Improved phenotyping using objective 6 Department of Pediatrics, LCI values that were above the upper limit of normal measures of lung function may improve our University of Alberta, Edmonton, (>1.64 z-scores). Elevated exhaled nitric oxide, but not Alberta, Canada understanding of infant wheezing disorders and 7Department of Pediatrics, BC symptoms, was associated with abnormal LCI values in trajectories to chronic airway diseases. Children’s Hospital, University infants with recurrent wheeze (p=0.05). of British Columbia, Vancouver, Conclusions Ventilation inhomogeneity is present in British Columbia, Canada clinically stable infants with recurrent wheezing. on September 26, 2021 by guest. Protected copyright. 8Department of Medicine, function measurements may be present at 1 month McMaster University, Hamilton, of age in infants destined to develop asthma by Ontario, Canada school age.1 4 5 Epidemiological surveys also suggest INTRODUCTION an infantile-onset, persistent wheeze endotype that Correspondence to Asthma is the most common chronic disease of child- is highly associated with atopy and occurs in up to Dr Padmaja Subbarao, The hood. Most adults with chronic asthma trace their 5% of the population.6 7 Studies in clinical cohorts Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; onset of symptoms to the preschool period. Longi- similarly describe a severe infant asthma endotype padmaja. subbarao@ sickkids. ca tudinal general population cohort studies report characterised by abnormal chest X-rays indicating reduced lung function (measured by spirometry) by pulmonary distention or atelectasis,8 which may Received 5 December 2017 school age in subjects who have asthma symptoms be a sequelae of persistent airway obstruction. The Revised 10 April 2018 that continue into adulthood when compared with site of airway obstruction is likely in the distal small Accepted 21 May 2018 healthy subjects.1 2 Among cohorts of children with airways in infants. This supposition is supported mild to moderate asthma, these changes are more by endobronchial studies that report the absence profound; nearly half had evidence of reduced lung of airway wall thickening and inflammation in the growth in childhood, and almost a quarter had central airways9 and is consistent with findings in evidence of fixed obstruction by early adulthood adults that cite the small airways as the primary site meeting Global Initiative for Chronic Obstructive of airway inflammation.10 To cite: Lu Z, Foong RE, Lung Disease (GOLD) criteria for chronic obstruc- Previous studies in infants with wheezing disor- Kowalik K, et al. Thorax Epub 3 ahead of print: [please tive pulmonary disease. It is unclear how early in ders have focused on flow measurements that in include Day Month Year]. life these lung growth changes manifest. Studies in older children may be less sensitive to changes in doi:10.1136/ high-risk groups, such as infants born to mothers the small airways.11 12 The lung clearance index thoraxjnl-2017-211351 with asthma, suggest that these decrements in lung (LCI), a parameter derived from the multiple breath Lu Z, et al. Thorax 2018;0:1–6. doi:10.1136/thoraxjnl-2017-211351 1 Paediatric lung disease washout (MBW) test, assesses overall ventilation homogeneity A mass spectrometer (AMIS 2000; Innovision ApS, Odense, Thorax: first published as 10.1136/thoraxjnl-2017-211351 on 15 June 2018. Downloaded from and is thought to be sensitive to changes in the peripheral Denmark) was used with a gas mixture of sulfur hexafluoride/ airways. Higher LCI values reflect greater ventilation inhomoge- helium as previously described.20 neity and thus worse lung disease. Limited data suggest that LCI is elevated in school-age children and adults with asthma13 even when spirometry is in the normal range.14–16 To our knowledge, Plethysmography and RVRTC Functional residual capacity (FRC ) was measured by body there are no studies of LCI in a clinical cohort of infants with pleth recurrent wheezing (RW) disorders. plethysmography (nSpire Infant Pulmonary Lab, Longmont, Colorado, USA) according to American Thoracic Society (ATS)/ A key limitation of previous studies describing lung func- 21 tion in infants with airway disease has been the lack of healthy European Respiratory Society (ERS) guidelines. Forced expira- control (HC) data.17 In this study, we prospectively collected tory volumes (such as FVC and forced expiratory volume in 0.5 s (FEV )) and forced expiratory flow between 25% and 75% of HC data from the general population enrolled in the Canadian 0.5 vital capacity (FEF25–75) were measured using the RVRTC tech- Healthy Infant Longitudinal Development (CHILD) study. Using 22 a case–control design, the purpose of the current study was to nique according to ATS/ERS guidelines. explore the use of LCI as a tool to objectively phenotype lung function in a clinical cohort of infants with a history of RW who Exhaled nitric oxide were free from exacerbation and compared them with HC from Exhaled nitric oxide (FE ) was measured during tidal breathing the CHILD study. We hypothesised that LCI would be elevated NO using an online chemoluminiscent analyser (CLD 88sp FENO in RW infants compared with HC. Finally, we sought to assess analyser, EcoMedics AG, Duernten, Switzerland) and analysed the strength of the association between LCI values and clinical according to ATS/ERS recommendations.23 Due to the known features of disease, as well as other physiological measures of effects of flow on nitric oxide levels, studies in infants have lung function including forced expiratory flows, lung volumes reported nitric oxide levels (FENO) adjusted for minute ventila- and inflammation including exhaled nitric oxide. tion and height.24 METHODS We designed a case–control study in which infants with RW Statistical analysis (cases) were compared with healthy infants (controls) (see online Subjects’ demographics were presented as median (range) for supplementary for details). continuous variables or frequency (percentage) for categorical variables. Height and weight measurements were converted to centiles using WHO growth charts (WHO 2006) for infants and HC infants 25 Healthy asymptomatic subjects participating in a general-pop- preschool children. Comparisons between RW and HC were ulation birth cohort, the CHILD study, were included in this performed using two-sample t tests or Mann-Whitney U tests sub-study of infant lung function18 (see online supplementary where appropriate for continuous variables and Fisher’s exact for details). tests for
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