Comparing children's night cough with wheeze: phenotypic ...

[Pages:35]medRxiv preprint doi: ; this version posted July 6, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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1 Comparing children's night cough with wheeze: phenotypic characteristics, healthcare use 2 and treatment

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4 Authors 5 Maria Christina Mallet1,2, Rebeca Mozun1,3, Cristina Ardura-Garcia1, Eva SL Pedersen1, Maja 6 Jurca1,4, Philipp Latzin5, LUIS study group6 , Alexander Moeller7, Claudia E. Kuehni1,5

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8 Affiliations

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1. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

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2. Graduate School for Health Sciences, University of Bern, Bern, Switzerland

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3. Department of Intensive Care and Neonatology, and Children's Research Center,

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University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland

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4. The University Children's Hospital Basel, Basel, Switzerland

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5. Division of Paediatric Respiratory Medicine and Allergology, Department of

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Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern,

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Switzerland

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6. A list of the LUIS study group members can be found in the acknowledgements

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section

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7. Department of Respiratory Medicine, University Children's Hospital Zurich and

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Children's Research Center, University of Zurich, Zurich, Switzerland

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22 Corresponding author: Prof. Claudia E. Kuehni, Institute of Social and Preventive Medicine, 23 University of Bern, Mittelstrasse 43, 3012, Bern, Switzerland; Tel: +41 31 684 35 07; email: 24 claudia.kuehni@ispm.unibe.ch

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29 Manuscript: Words: 2976/3000

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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

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It is made available under a CC-BY-NC-ND 4.0 International license .

31 Abstract 32 Population-based studies of children presenting with dry night cough alone compared with 33 those who also wheeze are few and inconclusive.

34 Luftibus in the school is a population-based study of schoolchildren conducted between 35 2013?2016 in Zurich, Switzerland. We divided children into four mutually exclusive groups 36 based on reported dry night cough (`cough') and wheeze and compared parent-reported 37 symptoms, comorbidities and exposures using multinomial regression, FeNO using quantile 38 regression, spirometry using linear regression and healthcare use and treatments using 39 descriptive statistics.

40 Among 3457 schoolchildren aged 6?17 years, 294 (9%) reported `cough', 181 (5%) reported 41 `wheeze', 100 (3%) reported `wheeze and cough' and 2882 (83%) were `asymptomatic.' 42 Adjusting for confounders in a multinomial regression, children with `cough' reported more 43 frequent colds, rhinitis and snoring than `asymptomatic' children; children with `wheeze' or 44 `wheeze and cough' more often reported hay fever, eczema and parental histories of 45 asthma. FeNO and spirometry were similar among `asymptomatic' and children with 46 `cough,' while children with `wheeze' or `wheeze and cough' had higher FeNO and evidence 47 of bronchial obstruction. Children with `cough' used healthcare less often than those with 48 `wheeze,' and they attended mainly primary care. Twenty-two children (7% of those with 49 `cough') reported a physician diagnosis of asthma and used inhalers. These had similar 50 characteristics as children with wheeze.

51 Our representative population-based study suggests only a small subgroup (7%) of 52 schoolchildren reporting dry night cough without wheeze have features typical of asthma,

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53 yet the majority (93%) should be investigated for alternative aetiologies, particularly upper 54 airway disease.

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It is made available under a CC-BY-NC-ND 4.0 International license .

55 Take home message

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57 Our population-based study found children with night cough alone clearly differ from those 58 with wheeze, suggesting different aetiologies and pathophysiology. Yet, a small subgroup 59 (7%) has features of asthma and may benefit from specific work-up.

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It is made available under a CC-BY-NC-ND 4.0 International license .

67 Introduction 68 Cough is a common symptom affecting children's and their families' quality of life and 69 burdening healthcare systems [1]. Respiratory tract infections are the most common cause 70 of cough, followed by asthma which is characterised by cough and wheeze [2-4]. Cough is 71 also present in rare lung diseases, such as cystic fibrosis, primary ciliary dyskinesia or 72 interstitial lung diseases [5]. In absence of an obvious respiratory infection or an underlying 73 severe disease, many children have so-called non-specific cough [2], which is a diagnostic 74 conundrum for physicians and a source of parental worries [6]. Underlying causes of non75 specific cough include environmental exposures, (e.g. tobacco smoke, allergens), ear, nose 76 and throat (ENT) problems, post-infectious cough or atypical asthma [5, 7-10]. Although 77 wheeze is a key symptom of asthma [11], some researchers proposed that children can have 78 `cough variant asthma' without audible wheeze [12], yet others fear this construct may lead 79 to asthma overdiagnosis, unnecessary treatments, side effects and increased costs [6, 1380 16].

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82 Previous studies on non-specific cough were small, included selected participants from 83 specialist clinics [17-19] or relied only on self-reported data [14, 20, 21]. Few were 84 population-based and included information on measurable asthma traits [22-25]. Only two 85 studies distinguished between children with wheeze alone or cough alone from those with 86 both symptoms [22, 26]. Our Luftibus in the school (LUIS) study of unselected schoolchildren 87 obtained information on parent-reported wheeze, cough, upper respiratory symptoms, 88 environmental exposures, and healthcare visits; we also measured fractional exhaled nitric 89 oxide (FeNO) and lung function, which are important asthma-related traits [27]. We

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90 determined how frequently schoolchildren reported dry night cough (henceforth `cough') 91 and wheeze alone and in combination and how these groups differed. Our underlying 92 motivation was gaining insight into the aetiology of non-specific cough and investigating 93 possibilities that some children may have a variant form of asthma. We compared four 94 groups (`cough', `wheeze', `wheeze and cough' and `asymptomatic') of children with respect 95 to sociodemographic and environmental information, family history, parent-reported 96 symptoms and comorbidities, FeNO and lung function, healthcare utilisation and asthma 97 diagnosis and treatment.

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99 Methods 100 Study design and population 101 We conducted LUIS from 2013?2016 in the canton of Zurich, Switzerland, as a cross102 sectional population-based study of 6?17-year-old schoolchildren (: 103 NCT03659838) [28]. All schools were invited and whole classes recruited. Parents completed 104 questionnaires about respiratory symptoms, diagnoses and treatments, lifestyle and 105 household characteristics. Trained lung function technicians measured FeNO and performed 106 spirometry in a mobile bus with lung function equipment. The ethics committee of the 107 canton of Zurich approved the study (KEK-ZH-Nr: 2014-0491); written informed consent was 108 obtained from parents and verbal and, where appropriate, written consent was obtained 109 from children.

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111 Outcomes: definition of cough and wheeze

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112 Previous studies used different definitions to assess non-specific cough, such as persistent 113 cough, recurrent cough, dry night cough or cough apart from cold [14, 20-24, 26, 29]. For 114 our study, we used the question from the International Study of Asthma and Allergy in 115 Childhood (ISAAC): "In the last 12 months has your child had a dry cough at night, apart 116 from a cough associated with a cold or a chest infection?" (Table S1). We also used a 117 question from ISAAC to assess wheeze: "Did your child have wheezing or whistling in the 118 chest in the past 12 months?" [30] Based on answers to these two questions, we defined 119 four mutually exclusive groups: `cough,' `wheeze,' `wheeze and cough' and `asymptomatic.'

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121 Characteristics: socioeconomic, environmental, comorbidities, healthcare utilisation and 122 treatment 123 Based on a literature search, we selected a range of exposures associated with cough, 124 wheeze or asthma, including a) sociodemographic factors [sex, age, country of origin, 125 socioeconomic status (Swiss socioeconomic position index, SSEP)]; b) environmental 126 exposures (urbanisation degree, household pets, siblings, parental smoking); c) 127 comorbidities [body mass index (BMI), frequency of colds, family history of asthma and 128 chronic cough, personal history of atopy (eczema, hay fever)] and ENT problems, such as 129 rhinitis apart from colds, otitis media, snoring (apart from colds and almost every night) and 130 adenotonsillectomy. We also investigated potential triggers for cough or wheeze, asking 131 specifically about exercise, respiratory infections, aeroallergens (house dust, pollen and 132 pets), physical factors (cold air/fog, laughter, weather/temperature changes) and certain 133 foods and drinks [14, 21, 22, 31, 32]. We include the questions in Table S1. We also

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medRxiv preprint doi: ; this version posted July 6, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

It is made available under a CC-BY-NC-ND 4.0 International license .

134 compared how different types of healthcare utilisation, frequency of physician asthma 135 diagnosis ever and asthma treatment in the past 12 months differed across the four groups.

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137 Measurements: FeNO and lung function 138 Trained technicians measured FeNO [expressed in parts per billion (ppb)] with the single139 breath online method according to the American Thoracic Society (ATS)/European 140 Respiratory Society (ERS) recommendations [33] using a chemiluminescence analyser 141 (CLD88, Eco Medics, D?rnten, Switzerland). Spirometry was performed using Masterlab, 142 Jaeger, W?rzburg, Germany according to ATS/ERS guidelines and paediatric pulmonologists 143 did a post hoc quality control of flow-volume curves [34]. Using Global Lung Initiative (GLI) 144 reference values [35], we derived z-scores for forced vital capacity (FVC), forced expiratory 145 volume in the first second (FEV1) and forced expiratory flow between the 25% and 75% of 146 the FVC (FEF 25?75). We also calculated the FEV1/FVC ratio.

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148 Statistical analysis 149 We compared sociodemographic information, environmental factors, family history and 150 symptoms between the four groups of children by calculating proportions, means with 151 standard deviations (SD), and medians with interquartile range (IQR). We first tested 152 differences between groups using chi-square tests for categorical variables and the Kruskal153 Wallis test for non-normally distributed continuous data and in a second step, using 154 multinomial logistic regression with `asymptomatic' as the reference group. We report 155 unadjusted and adjusted relative risk ratios (RRR) and 95% confidence intervals (95% CI). For 156 our final model, we included all variables that had a p-value of ................
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