Department of PaediatricsFaculty of MedicineThe Chinese University of Hong Kong

UPDATE INPAEDIATRIC RESPIRATORYDISEASES 2020

PROCEEDINGS

ImprintProceedings of theUPDATE IN PAEDIATRICRESPIRATORY DISEASES 2020

EditorsProf. Albert Li Dr. Kate Chan

Published byPing Healthcare International Co LtdThis report was written by Dr Vaijayanti KarandikarFor more information contact Dr Francis Kwong (francis@pinghealthcare.com)

UPDATE INPAEDIATRIC RESPIRATORYDISEASES 2020

PROCEEDINGS

Update in Paediatric Respiratory Diseases 2020, the 7th Paediatric Respiratory Conference was held in February 2020 via a web conference. Keeping up with the rapid development in the field of paediatric respiratory medicine the scientific programme covered topics ranging from advances in intensive care management, update on guidelines and neonatal care to the practicalities of more common conditions such as asthma and chronic cough. An esteemed panel of experts shared their valuable and enlightening experiences and insights. Highlights of the conference are presented below.

ORGANISING COMMITTEE

Prof. Albert Li (Co-Director)

Dr. Kate Chan (Co-Director)

Dr. Lawrence Chan

Miss. Esther Lam

Dr. Simon Lam

Dr. Anna Lin

Ms. Connie Poon

Dr. Michelle Yu

Department of PaediatricsPrince of Wales HospitalThe Chinese University of Hong Kong

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TABLE OF CONTENTS

BANNING NEW AND TRADITIONAL TOBACCO PRODUCTS TOPROTECT CHILD LUNG HEALTH

Dr. Daniel SY Ho 2

EARLY LIFE DETERMINANTS OF LUNG HEALTHA/Prof. Ryan Au Yeung 3

PROTRACTED BACTERIAL BRONCHITIS AND BRONCHIECTASIS PARADIGM Prof. Anne B Chang 5

CHILDHOOD PNEUMONIA: LONG TERM CONSEQUENCESProf. Anne B Chang 6

MEMORABLE PAPERS THAT CHANGED MY PRACTICE IN RESPIRATORY MEDICINEA/Prof. Alfred Tam 7

UPDATE ON PAEDIATRIC ARDS MANAGEMENTDr. Lawrence Chan 9

ROLE OF ECLS IN RESPIRATORY DISEASESDr. Robin Chen 10

PAEDIATRIC CHRONIC COUGH GUIDELINES: WHAT IS NEW?Prof. Anne B Chang 11

WHAT’S NEW IN THE GINA GUIDELINES? Dr. Kate Ching-ching Chan 13

ASTHMA AND FENO IN CHILDRENProf. Anne B Chang 14

MY JOURNEY IN NEONATOLOGY – WHAT WAS, IS AND WILL BE?Prof. Tai Fai Fok 15

AN UPDATE ON THE LONG TERM RESPIRATORY HEALTH OF PREMIES Dr. Shannon Simpson 17

USING BENCH TO BEDSIDE METHODOLOGIES TO IMPROVE HEALTH Dr. Shannon Simpson 18

VENTILATORY STRATEGIES FOR PREMIES – WHAT HAS CHANGED?Dr. Simon Lam 19

NUSS IS PURELY COSMETIC Prof. Albert Li 21

NUSS IS NOT PURELY COSMETIC Dr. Michelle Yu 23

REFERENCES 25

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using e-cigarettes at 52-week follow-up and hence remained addicted to nicotine. Nicotine replacement therapy would be more effective in quitting both cigarettes and nicotine. Nicotine-containing e-cigarettes are illegal in Hong Kong.

Heated tobacco products emit chemicals commonly found in traditional cigarettes such as tar, volatile organic compound, carbon monoxide, carcinogenic polycyclic aromatic hydrocarbons and formaldehyde. The concentration of these chemicals varies, with that of tar and nicotine comparable to conventional cigarettes. The heating causes charring of the tobacco stick via pyrolysis and melting of the polymer-film filter, which releases toxic formaldehyde cyanohydrin. SSS 2018-19 found Hong Kong adolescent users of heated tobacco products had significantly higher prevalence of respiratory symptoms than non-users independent of cigarette smoking. The European Respiratory Society concluded that heated tobacco products are harmful and addictive, undermine smokers’ wish to quit and risk renormalising smoking.

Banning new and traditional tobacco productsDecades of tobacco control in Hong Kong has successfully denormalised smoking, reaching a daily adult smoking rate of 10.0% in 2017 that was among the lowest in the world and an adolescent current smoking rate of 2.5% in 2016-17. However, progress was slow in recent years and tobacco tax has not been increased since 2014. Of particular concern is the involuntary exposure to tobacco smoke in children and adolescents, which remains high. SSS 2010-11 found 63.3% of adolescents were exposed to tobacco smoke in the past 7 days from multiple sources, including secondhand smoke at home from inside (23.2%), secondhand smoke at home from neighbouring flats (17.1%), thirdhand smoke at home (16.9%) and secondhand smoke outside home (55.3%).

The sale of e-cigarettes and heated tobacco products has been banned in 42 and 7 countries or jurisdictions. The Hong Kong SAR government has proposed to ban new tobacco products including e-cigarettes and heated tobacco products, but the legislative process has been delayed amid fierce direct and indirect (e.g. front groups, legislators) opposition by the tobacco industry. The ban was strongly supported by the public and various sectors of society, which also demanded a clear timetable for banning all tobacco products. The government has a target smoking prevalence of 7.8% in 2025 and the Hong Kong Council on Smoking and Health has a target of 5% in 2027. With the difficulties of passing specific legislations for tobacco control and the threat of tobacco renormalisation by new tobacco products, further reduction of smoking prevalence has become increasingly uncertain. Building on the demand for a timetable to ban all tobacco products and strong public support (67%) to do so in 10 years, we propose to ban all tobacco products in Hong Kong in 2030. Once this becomes law, supportive legislations such as large increases in tobacco tax, banning point-of-sale display of tobacco products, and further extension of no-smoking areas will have to be in place to reduce smoking prevalence for a smooth transition to the smokefree era. This will effectively cease the tobacco epidemic in Hong Kong and protect our children and adolescents from active and passive smoking.

BANNING NEW AND TRADITIONAL TOBACCO PRODUCTS TO PROTECT CHILD LUNG HEALTH

Dr. Daniel SY Ho Associate Professor, School of Public HealthThe University of Hong Kong

Rapid increase in use of new tobacco products among youthTobacco use causes over 7 million deaths globally per year. Secondhand smoke causes another 1.2 million deaths, including 65000 children. One in two smokers will be killed by smoking and the ratio is up to two-thirds if smoking started young. Although cigarette smoking prevalence is gradually reducing in developed countries, new tobacco products such as e-cigarettes and heated tobacco products are rapidly emerging with their stylist designs and propaganda as less harmful products.

E-cigarette, also called electronic vaping device or electronic nicotine delivery system, is a nicotine delivery device that does not burn or use tobacco leaves but vapourises e-liquid to generate an aerosol that the user inhales. The United States National Youth Tobacco Survey 2019 (NYTS 2019) found a much higher prevalence of current e-cigarette use (27.5%) than cigarette use (5.8%) among high school (27.5% vs 5.8%) and middle school (10.5% vs 2.3%) students. Nearly one-third of adolescent e-cigarette users in NYTS 2016 have used e-liquid containing cannabis. In Hong Kong, territory-wide school-based smoking survey in 2018-19 (SSS 2018-19) found 7.7% of secondary school students and 1.4% of primary school students had ever used e-cigarettes; current use (past 30-day) was 0.8% and 0.2%, respectively.

Heated tobacco products are a battery driven tobacco heating system that heat a tobacco stick or capsule with high temperature without burning. SSS 2018-19 found 2.3% of secondary school students and 0.8% of primary school students had ever used heated tobacco products; current use was 0.5% and 0.1%, respectively.

Harmful effects of e-cigarettes andheated tobacco productsE-cigarettes contain chemical substances that can be toxic, carcinogenic and can cause significant impact on the cardio-respiratory system. Nicotine, tobacco-specific nitrosamines, aldehydes, metals, volatile organic compounds, solvent carriers and tobacco alkaloids found in different brands of e-cigarettes raise safety concerns around addiction and other adverse events. Nicotine is highly addictive and may have permanent effects on the brain and behaviours resulting in long-term difficulties with behavioural regulation, attention, memory, and motivation, especially affecting the developing adolescent brain. E-cigarettes have also been reported to explode and resulted in burn injuries and even deaths. Heavy use was associated with seizures in adolescents. E-cigarette, or vaping, product use-associated lung injury (EVALI) have resulted in 2,668 hospitalised cases in the US including 60 deaths as of 14 January 2020, mostly associated with cannabis-containing e-cigarettes. Hong Kong adolescent e-cigarette users were significantly associated with respiratory symptoms compared with non-users in both ever-smokers and never smokers. Multiple studies have shown e-cigarette use may act as a gateway to conventional cigarette use. A recent randomised controlled trial in the UK has found e-cigarettes more effective than nicotine replacement therapy in quitting cigarette smoking. However, 80% of subjects in the e-cigarette arm were stilling

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Figure 2: Passive smoking increases risk of asthma

Environmental toxins and respiratory infections Early life exposure to environmental chemicals such as traffic emissions and exposure to bisphenol A (BPA) is linked to increased risk of wheezing and asthma. Similarly, exposure to indoor biomass burning for cooking is associated with respiratory infections.7 Children exposed to higher levels of particulate matter with an aerodynamic diameter <2.5 μm (PM2.5) are at risk of developing asthma.12 A Chinese birth cohort in Hong Kong showed that higher prenatal and infant exposure to NO2 is associated with poorer airway function at 17.5 years, highlighting the role of prenatal and early childhood periods in adulthood lung function.13 A mass survey for adolescent respiratory health in Taiwan also revealed that exposure to O3 and PM10 is associated with reduced FVC and FEV1.14 Allergic sensitization and viral respiratory infections in infancy are also responsible for increased likelihood of childhood asthma.7

Influence of diet on respiratory diseases Maternal and childhood diet influence the development of respiratory diseases in later stage of life. Poor maternal nutrition during pregnancy increases the prevalence of obstructive airway disease. Conversely, breastfeeding has protective effects against childhood respiratory diseases and greater food diversity during the first year of life reduces the risk of childhood asthma and food allergies.7 Furthermore, rapid weight gain during infancy is an independent risk factor for preschool wheezing and school age asthma.8 Other dietary influences such as low magnesium intake in children and deficits in lung function15, vitamin A deficiency during pregnancy and adverse respiratory health16 and lower levels of Vitamin D in asthmatic children have also been implicated in the pathogenesis of respiratory diseases in children.17

EARLY LIFE DETERMINANTS OF LUNG HEALTH

A/Prof. Ryan Au Yeung Assistant Professor, School of Public HealthLKS Faculty of Medicine, The University of Hong Kong

Early-life origins of respiratory diseasesThough respiratory disorders, particularly asthma and chronic obstructive pulmonary disease (COPD) may become clinically apparent during later stage of life, it is evident that these disorders are linked to prenatal and perinatal events in the early stages of life.7 Gestational age is inversely related to the risk of developing asthma at school age. Younger gestational age at birth is associated with childhood asthma outcomes.8 The concentration of surfactant proteins in amniotic fluid is an important determinant of lung maturity in prematurely born infants, and defects in these proteins are linked to allergic airway disease.7 Infants born via cesarean section are found to be at an increased risk of respiratory disease in later life. The lower concentrations of matrix metalloproteinases in the amniotic fluid of mothers delivering by scheduled caesarean section is linked to airway disease in childhood.9 On the other hand, vaginal delivery is thought to protect against the onset of allergic asthma as the newborn acquires bacteria at birth.10

Figure 1: Pre and postnatal determinants of lung health

Passive smoking increases risk of childhood respiratory diseases Maternal smoking during pregnancy is a known risk factor for impaired lung function and respiratory disease in children. Passive smoking during the first year of life is also known to increase the risk of respiratory symptoms in children. Maternal smoking resulting in dysregulated cytokine production is believed to be the underlying mechanism affecting fetal lung development.7 A systematic review and meta-analysis of 79 prospective studies show that exposure to passive smoking increases the incidence of wheeze and asthma in children and young people by at least 20%. Reduction in second-hand smoke exposure during and after pregnancy is an avoidable risk factor for wheeze and asthma and crucial to prevent development of asthma in childhood.11

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References:

1. Scicchitano R et al. Curr Med Res Opin 2004; 20(9): 1403-18. 2. Kuna P et al. Int J Clin Pract, May 2007, 61, 5, 725–36. 3. Bousquet J et al. Respir Med 2007; 101: 2437-46. 4. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2019. https://www.ginaasthma.org. Accessed on 6 Jan 2020.

Presentation: Budesonide/Formoterol Turbuhaler. Indications: Regular treatment of asthma where combination therapy w/ inhaled corticosteroid & long-acting β-agonist is appropriate. 160/4.5 mcg & 320/9 mcg/dose Turbuhaler Symptomatic treatment of COPD. Dosage: Asthma 1) Symbicort maintenance therapy 80/4.5 mcg & 160/4.5 mcg Turbuhaler Adult ≥ 18yr: 1-2 inhalations bd. Max 4 inhalations bd. Adolescent 12-17 yr: 1-2 inhalations bd. Childn ≥ 6yr: 80/4.5 mcg Turbuhaler 2 inhalations bd. 320/9 mcg Turbuhaler Adult ≥ 18yr: 1 inhalation bd. Max: 2 inhalations bd. Adolescent 12-17 yr: 1 inhalation bd. 2) Symbicort maintenance and reliever therapy Taken as regular maintenance treatment and as needed in response to symptoms is appropriate. 80/4.5 mcg & 160/4.5 mcg Turbuhaler Adult and adolescent ≥12yr: Recommend maintenance dose is 1 inhalation bd or 2 inhalations in either the morning or evening. Some may need 2 inhalations bd. Patient should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. No more than 6 inhalations should be taken on any single occasion. No more than 8 inhalations per day should be taken, however, total daily dose up to 12 inhalations could be used for a limited period. Symbicort maintenance and reliever therapy is not recommended for children. COPD 160/4.5 mcg Turbuhaler Adult: 2 inhalations bd 320/9 mcg/dose Turbuhaler Adult: 1 inhalation bd. Contraindications: Hypersensitivity to the active substance(s) or to any of the excipients (lactose, which contains small amounts of milk proteins). Precautions: Used for the shortest duration of time required to achieve control of asthma symptoms and discontinue once asthma control is achieved; Only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications; Taper dose when discontinuing treatment; Thyrotoxicosis; Phaeochromocytoma; Diabetes mellitus; Untreated hypokalaemia; Hypertrophic obstructive cardiomyopathy; Idiopathic subvalvular aortic stenosis; Severe hypertension; Aneurysm or other severe cardiovascular disorders; Quiescent pulmonary TB; Fungal & viral infections in the airways; Patients should take Symbicort maintenance dose as prescribed even when asymptomatic. Symbicort as needed is not intended for regular prophylactic use, e.g. before exercise; If oropharyngeal thrush occurs, patients should rinse their mouth with water after inhalations; Pregnancy & lactation. Interactions: CYP3A4 potent inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors), beta-blockers, quinidine, disopyramide, procainamide, phenothiazines, terfenadine, tricyclic antidepressants, levodopa, L-thyroxine, oxytocin, alcohol, anaesthesia, other beta-adrenergic drugs or anticholinergic drugs, digitalis glycosides, xanthine derivatives, corticosteroids and diuretics . Undesirable e�ects: (Common) Palpitations, Candida infections in the oropharynx, pneumonia in COPD patients, headache, tremor, mild irritation in the throat, coughing, hoarseness. Full local prescribing information is available upon request. API.HK.SYM.0518

* Change in life based on quality of life (QoL) and the reduction of exacerbation risk, hospitalisations, inhaler use and days with asthma medication.

Please contact (852) 2420-7388 or HKPatientSafety@astrazeneca.com for adverse drug reactions (ADR) reporting to AZHK.

Symbicort and Turbuhaler are trade marks of the AstraZeneca group of companies.

AstraZeneca Hong Kong LimitedUnit 1-3, 11/F, 18 King Wah Road,North Point, Hong Kong.Tel: (852) 2420 7388 Fax: (852) 2422 6788

HK-3253 12/1/2020

Further information is available on request:

SYMBICORTTM

WITH MAINTENANCE 1-3 *CHANGES LIVES

SYMBICORT TM NOW A PREFERRED RELIEVER 4

in moderate-to-severe patients, uses their natural relief-seeking behaviour to

reduce exacerbations

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PROTRACTED BACTERIAL BRONCHITIS AND BRONCHIECTASIS PARADIGM

Prof. Anne B Chang Queensland Children’s Hospital, BrisbaneMenzies School Health Research, Darwin, Australia

Chronic wet cough in childrenChronic wet cough characterized by increased airway mucus lasting for a minimum of 4 weeks is a common complaint among children presenting to paediatricians.18 Respiratory infections in early childhood are the most common initiating event. Other conditions such as tracheobronchomalacia and neuromuscular diseases also increase the risk of bacterial colonization.19 Under-recognition and under-treatment of protracted bacterial bronchitis (PBB) can lead to the development of chronic suppurative lung disease (CSLD) and bronchiectasis.19 Children with PBB are typically very young and attend daycare and present with prolonged wet cough and parent-reported wheeze.20 Bronchiectasis is more common in developing countries and in underprivileged indigenous populations.18

Pathophysiology of chronic wet coughThe clinical and pathophysiological features of PBB, CSLD and bronchiectasis overlap each other. The pathogenesis of bronchiectasis is explained as a vicious circle of self-perpetuating infection, inflammation, and tissue damage.21

The vicious circle hypothesis proposes that if the initial first-line defence of mucociliary clearance is inadequate, the bacteria persist in the airways and produce the epithelium-damaging cilioinhibitory and ciliotoxic substances. The resulting inflammatory host response causes further airway and lung damage.22 Initial bacterial colonization results in increase of pro-inflammatory cytokines such as interleukin-8, tumour necrosis factor-α and interleukin-1β, which in turn cause migration of neutrophils to the airways. Despite the increased neutrophils, the bacterial infection persists due to the inhibitory effects of neutrophil elastase, neutrophil peptides and impaired complement activation. Furthermore, formation of biofilms, reduced motility and the down-regulation of virulence factors destabilize the innate immune mechanisms23 establishing the vicious cycle of bacterial colonization, airway inflammation and airway structural damage.

Clinical spectrum of PBB, CSLD and bronchiectasisPBB is characterized by presence of chronic wet cough, bacterial infection in broncho-alveolar lavage (BAL) and resolution of cough after 2 weeks of antibiotics. PBB represents the early spectrum of chronic endobronchial suppurative disease, while irreversible bronchiectasis represents the opposite late end characterized by abnormal dilatation of the airways from chronic inflammation and decline in lung function.23 Common clinical presentation of PBB and early bronchiectasis includes wet cough and report of wheeze or rattles. Chest radiographs show only peripheral changes and spirometry is normal. Digital clubbing and abnormal spirometry is seen with severe bronchiectasis.23 PBB is often unrecognized and misdiagnosed as asthma in children since both conditions may co-exist. Accurate diagnosis and treatment of PBB is extremely crucial not only for eliminating cough and improving quality of life but also for prevention of progression to bronchiectasis.24 Chronic suppurative lung disease (CSLD) lies between PBB and bronchiectasis. Children with CSLD have clinical features of bronchiectasis, but lack the radiographic evidence for this

diagnosis and require intravenous antibiotics. Chronic wet cough in CSLD is unresponsive to oral antibiotics but resolves with intravenous antibiotics and airway clearance therapy.23

Figure 1: Coles Vicious Cycle

Figure 2: Spectrum of PBB, CSLD and Bronchiectasis

Treatment of chronic wet coughEarly diagnosis and intensive treatment can stabilize and improve the clinical prognosis of children with bronchiectasis. Antibiotics form the cornerstone of bronchiectasis management in children, as they prevent exacerbations, reduce lower airway bacterial load and inflammation and preserve lung function.25 In most children with PBB, the chronic cough subsides with 2-4 weeks treatment of an appropriate antibiotic23 (usually amoxicillin- clavulanic acid), while azithromycin is used for long term management of bronchiectasis in children.25 Intravenous antibiotics are required to resolve chronic wet resulting from CSLD.23

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CHILDHOOD PNEUMONIA: LONG TERM CONSEQUENCES

Prof. Anne B Chang Queensland Children’s Hospital, BrisbaneMenzies School Health Research, Darwin, Australia

Consequences of childhood pneumoniaPneumonia is the most common cause of mortality in children under five years of age. It is estimated that out of the 156 million new episodes of pneumonia each year worldwide, 151 million episodes occur in the developing countries. Around 7-13% of pneumonia cases in children less than 5 years are life-threatening and require hospitalization. Pneumonia is responsible for about 19% of all deaths in children aged less than 5 years.26 Major consequences of pneumonia include restrictive lung disease and bronchiectasis and minor sequel include chronic bronchitis, asthma, other abnormal pulmonary function, and respiratory disease.27 Hospitalized children with severe pneumonia usually need oxygen and intravenous antibiotics, some need ventilatory support and have a longer duration of illness with greater damage to lung parenchyma.27

Aetiology of acute lower respiratory infectionsIdentifying the causes of acute lower respiratory infections in children is essential to allow implementation of prevention and case-management strategies. Most cases of bacterial pneumonia in children start off as an acute viral infection followed by mucosal invasion or drip aspiration of nasopharyngeal bacteria.28 The Pneumonia Etiology Research for Child Health (PERCH) Study Group report revealed that ten pathogens account for about 80% of WHO-defined pneumonia.29 The common pathogens included respiratory syncytial virus (RSV), streptococcus pneumoniae, parainfluenza virus, haemophilus influenzae, human metapneumovirus, and mycobacterium tuberculosis. PERCH also found that 14% of all cases of acute lower respiratory infections requiring hospital admission are vaccine preventable.29

Number of respiratory episodes linked to asthmaLower respiratory tract infections during the first year of life have been thought to be responsible for development of asthma in later life. As a result respiratory viruses such as rhinoviruses and respiratory syncytial virus infections in early childhood have been linked to asthma in children. However, it is clear that many respiratory viruses and bacteria trigger similar respiratory symptoms. Asthmatic patients have an altered immune response to rhinoviruses and have hyperreactive airways. It is believed that individual susceptibility and increased bronchial responsiveness to respiratory tract infections is linked to asthma in children. It is therefore suggested that the number of respiratory episodes in the first years of life and not any particular trigger is associated with asthma development in later childhood.30

Post-infectious bronchiolitis obliterans Bronchiolitis obliterans is a small airway injury-related chronic inflammation airflow obstruction syndrome. Post-infectious bronchiolitis obliterans (PIBO) occurs in children mainly following adenovirus and also M.pneumoniae infection. Severe adenovirus bronchiolitis and M. pneumoniae pneumonia increase the risk of PIBO.31 Majority of patients suffer from lower respiratory infections during the first 2 years of life and need hospitalization, oxygen and other supportive care.

Azithromycin and steroids are found to be beneficial in these cases.31

Figure 1: Aetiology of PIBO

Respiratory tract illness in infancy affects lung function Lower respiratory tract infections during infancy are associated with reduced lung function at 1 year and in late adult life.32-33 Childhood asthma, bronchitis, pneumonia, hayfever, eczema, parental asthma, and maternal smoking are known to predict adult COPD risk.34 Furthermore, young adult lung function values (FEV1 and FVC) are predictors of all-cause mortality in adults’ aged ≥35 years.35

Figure 2: Respiratory tract illness affects lung function

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MEMORABLE PAPERS THAT CHANGED MY PRACTICE IN RESPIRATORY MEDICINE

A/Prof. Alfred Tam Specialist in Paediatric respiratory medicineHon. Clinical Asso. Prof. in Paediatrics, HKU, CUHK

Evidence on treatment of bronchiolitisChildren below 3 years of age suffering from bronchiolitis present with cough, fast and difficult breathing, nasal congestion, fever and wheeze. It is commonly treated with bronchodilators and humidified air. However, there is not enough evidence on the effectiveness of humidified oxygen, mist therapy or steam inhalation in young children.36 Available evidence also does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalization.37 Furthermore, research shows combined epinephrine may be effective in outpatients, but effect of epinephrine in inpatients needs to be investigated further.38

Figure 1: Clinical management of bronchiolitis

ICS reduce exacerbation risk in mild asthmaLow-dose inhaled corticosteroids (ICS) are effective in reducing asthma exacerbations and mortality and are usually recommended for patients with symptoms on more than 2 days per week. A post-hoc efficacy analysis of the START study investigated whether symptom frequency affected response to budesonide with respect to asthma exacerbations, lung function, and asthma symptom control. The patients were divided in three sub-groups according to symptom frequency - symptom frequency 0-1 days per week, more than 1 and less than or equal to 2 symptom days per week and more than 2 symptom days per week. The study revealed that once daily, low-dose budesonide decreased the risk of severe asthma-related event, reduced decline in lung function and improved symptom control in patients across all subgroups.39

Intermittent ICS is as effective as regular ICS in recurrent wheezersRespiratory tract infections often trigger recurrent wheezing in preschool age children. Long-term daily inhaled glucocorticoid therapy is recommended in children under the age of 5 years who had at least four wheezing episodes during the previous year and have positive values on the modified asthma predictive index.40 However, there are concerns about daily adherence and effects of steroids on growth. A study that compared daily versus intermittent budesonide inhalation for 1 year has documented that daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Furthermore, daily dosing was also associated with greater exposure to budesonide.41

Figure 2: Intermittent ICS in recurrent wheezers

Azithromycin reduces chances of severe LRTISevere episodes of lower respiratory tract illness (LRTI) are common in preschool age children. About 14% to 26% of preschoolers present with recurrent wheezing during the first 6 years of life resulting in unscheduled visits to physician offices, urgent care, and emergency departments. Though most of these infections are viral, bacterial infections can also be responsible. Early use of azithromycin during an apparent respiratory tract infection in children with recurrent LRTIs reduced the likelihood of severe LRTI. However, major concern that needs to be explored with this approach is the development of antibiotic-resistant pathogens.42

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L.HK.COM.02.2020.2817

Effectively relieve symptoms ofallergic rhinitis and urticaria#

References:1. Federal Aviation Administration. (2018). Guide for Aviation Medical Examiners. 1-470. 2. Bachert, C., & Maurer, M. (2010). Safety and Efficacy of Desloratadine in Subjects with Seasonal Allergic Rhinitis or Chronic Urticaria. Clinical Drug Investigation, 30(2):109-122. 3. Simons, F. (2004). Advances in H 1 -Antihistamines. New England Journal of Medicine N Engl J Med, 351(21): 2203-2217. 4. Layton, D., & Wilton, L.(2006). Comparison of the Risk of Drowsiness and Sedation between Levocetirizine and Desloratadine. Drug Safety, 29(10) 897-909. 5. Aerius® Product insert

Aerius® Syrup 0.5mg/mL: Each mL of Aerius® Syrup contains 0.5mg desloratadine. Indications: Relief of nasal & non-nasal symptoms of seasonal allergic rhinitis in patients ≥2 years; perennial allergic rhinitis in patients ≥6 months; symptomatic relief of pruritus, reduction in number & size of hives, in patients with chronic idiopathic urticaria ≥6 months. Dosage: Adults & adolescents ≥12 years of age: 10mL (5mg). Children 6-11 years of age: 5mL (2.5mg), 1-5 years of age: 2.5mL (1.25mg), 6-11 months of age: 2mL2mL (1mg). All doses to be taken once daily. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Precautions: Efficacy and safety of Aerius® Syrup in children under 6 months of age have not been established. Not to be used during pregnancy unless the potential benefits outweigh the risks. Not recommended in breast-feeding women. Adverse reactions: In clinical trials in a pediatric population, Aerius® syrup was administered to a total of 246 children aged 6 months through 11 years.years. The overall incidence of adverse events in children 2 through 11 years of age was similar for Aerius® syrup and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse events reported in excess of placebo were diarrhea (3.7%), fever (2.3%) and insomnia (2.3%). Very rare cases of hypersensitivity reactions (including anaphylaxis and rash), tachycardia, palpitations, psychomotor, hyperactivity, seizures, elevations of liver enzymes, hepatitis, and increased bilirubin have been reported.Aerius® Tablet 5mg: Each Aerius® Tablet contains 5mg desloratadine. Indications: Symptomatic relief of allergic rhinitis & urticaria. Dosage: Adults & adolescents ≥12 years, 5mg tablet once daily. For oral use. Contraindications: Hypersensitive to the active substance or to any of the excipients. Precautions: Efficacy and safety of Aerius® Tablets in children under 12 years of age have not been established. Not to be used during pregnancy unless the potential benefits outweigh the risks. Not recommended in breast-feedingbreast-feeding women. Adverse reactions: headache, dry mouth, fatigue. Very rare cases of hypersensitivity reactions (including anaphylaxis and rash), tachycardia, palpitations, psychomotor, hyperactivity, seizures, elevations of liver enzymes, hepatitis, and increased bilirubin have been reported.

# AERIUS* Tablets are indicated for symptomatic relief of allergic rhinitis and urticaria, while AERIUS* Syrup is indicated for symptomatic relief of allergic rhinitis and chronic idiopathic urticaria.* Efficacy data were from four post marketing surveillance studies involving 77,880 subjects using oral desloratadine 5mg tablet daily for Seasonal Allergic Rhinitis and Chronic idiopathic Urticaria. Onset of action results were subject-related from post hoc analysis of these studies (n=17,575) where subjects had previously received monotherapy with another second generation antihistamine (cetirizine, fexofenadine, loratadine or mizolastine). AERIUS* shows fast onset of symptom relief compared with other analysis of these studies (n=17,575) where subjects had previously received monotherapy with another second generation antihistamine (cetirizine, fexofenadine, loratadine or mizolastine). AERIUS* shows fast onset of symptom relief compared with other second generation antihistamines rated by 67% of subjects.† Risk of sedation and drowsiness is lower than levocetirizine (P < 0.0001) in patients with allergic rhinitis without asthma/wheezing.‡ AERIUS* Syrup is indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 6 months of age and older.** ** In a driving performance & psychomotor performance study, at therapeutic dose of 5mg, no significant difference weree noted between desloratadine & placebo in standard deviation of lateral position (SDLP), one of the parameter to measure driving performance.

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UPDATE ON PAEDIATRIC ARDS MANAGEMENT

Dr. Lawrence Chan Associate ConsultantPrince of Wales Hospital, Hong Kong

AECC and Berlin ARDS definitionsAmerican-European Consensus Conference (AECC) and Berlin acute respiratory distress syndrome (ARDS) definitions focus on adult lung injury and therefore have drawbacks when applied to children. First, they need invasive measurement of arterial oxygen (PaO2), which is difficult in paediatric patients. Second, is the use of PaO2/FIO2 (P/F) ratio that not only requires Pao2 but is also affected by ventilator pressures, which vary across different clinical scenarios. Therefore, many paediatricians use oxygenation index (OI) and oxygen saturation index (OSI) to overcome the problem of less standardized approach to positive pressure ventilation in children. Furthermore, AECC and Berlin ARDS definitions do not consider the differences in risk factors, aetiologies, pathophysiology, and outcomes between adults and children.43

PALICC criteria and Montreux definitionThe Pediatric Acute Lung Injury Consensus Conference (PALICC) was convened to overcome the shortcomings of the AECC and Berlin ARDS definitions.43 The definition of Pediatric ARDS (PARDS) is based on recommendations by PALICC. PALICC definition identifies more children as having pediatric ARDS (PARDS); captures more patients with milder forms of PARDS and severity level at 6 hours is more predictive of mortality than Berlin definition.44

Figure 1: Paediatric ARDS – PALICC Criteria

Figure 2: Neonatal ARDS: Montreux Definition

Lung protective ventilation strategiesThe main principles of mechanical ventilation are provision of adequate gas exchange and minimization of ventilator induced lung injury. The Paediatric Acute Lung Injury Consensus Conference has developed recommendations for mechanical ventilation management of paediatric patients with ARDS. These recommendations advise tidal volume and inspiratory pressure limitation and permissive hypercapnia. The use of positive end-expiratory pressure levels greater than 15 cm H2O is recommended in severe ARDS along with monitoring of oxygen delivery, respiratory compliance, and haemodynamics. The use of recruitment maneuvers during rescue high frequency oscillatory ventilation (HFOV) is highly recommended.45

Newer imaging modalities available to titrate ventilationLung ultrasound is a noninvasive, radiation-free clinical imaging tool that allows real-time monitoring at bedside of changes in lung aeration and consolidation and allows diagnosis of community acquired and ventilator-associated pneumonia.46 Electrical impedance tomography is a noninvasive, radiation-free clinical imaging tool that provides real-time monitoring at bedside of both regional lung ventilation and perfusion. It is based on resistivity changes occurring across the lungs with breathing.47

L.HK.COM.02.2020.2817

Effectively relieve symptoms ofallergic rhinitis and urticaria#

References:1. Federal Aviation Administration. (2018). Guide for Aviation Medical Examiners. 1-470. 2. Bachert, C., & Maurer, M. (2010). Safety and Efficacy of Desloratadine in Subjects with Seasonal Allergic Rhinitis or Chronic Urticaria. Clinical Drug Investigation, 30(2):109-122. 3. Simons, F. (2004). Advances in H 1 -Antihistamines. New England Journal of Medicine N Engl J Med, 351(21): 2203-2217. 4. Layton, D., & Wilton, L.(2006). Comparison of the Risk of Drowsiness and Sedation between Levocetirizine and Desloratadine. Drug Safety, 29(10) 897-909. 5. Aerius® Product insert

Aerius® Syrup 0.5mg/mL: Each mL of Aerius® Syrup contains 0.5mg desloratadine. Indications: Relief of nasal & non-nasal symptoms of seasonal allergic rhinitis in patients ≥2 years; perennial allergic rhinitis in patients ≥6 months; symptomatic relief of pruritus, reduction in number & size of hives, in patients with chronic idiopathic urticaria ≥6 months. Dosage: Adults & adolescents ≥12 years of age: 10mL (5mg). Children 6-11 years of age: 5mL (2.5mg), 1-5 years of age: 2.5mL (1.25mg), 6-11 months of age: 2mL2mL (1mg). All doses to be taken once daily. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Precautions: Efficacy and safety of Aerius® Syrup in children under 6 months of age have not been established. Not to be used during pregnancy unless the potential benefits outweigh the risks. Not recommended in breast-feeding women. Adverse reactions: In clinical trials in a pediatric population, Aerius® syrup was administered to a total of 246 children aged 6 months through 11 years.years. The overall incidence of adverse events in children 2 through 11 years of age was similar for Aerius® syrup and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse events reported in excess of placebo were diarrhea (3.7%), fever (2.3%) and insomnia (2.3%). Very rare cases of hypersensitivity reactions (including anaphylaxis and rash), tachycardia, palpitations, psychomotor, hyperactivity, seizures, elevations of liver enzymes, hepatitis, and increased bilirubin have been reported.Aerius® Tablet 5mg: Each Aerius® Tablet contains 5mg desloratadine. Indications: Symptomatic relief of allergic rhinitis & urticaria. Dosage: Adults & adolescents ≥12 years, 5mg tablet once daily. For oral use. Contraindications: Hypersensitive to the active substance or to any of the excipients. Precautions: Efficacy and safety of Aerius® Tablets in children under 12 years of age have not been established. Not to be used during pregnancy unless the potential benefits outweigh the risks. Not recommended in breast-feedingbreast-feeding women. Adverse reactions: headache, dry mouth, fatigue. Very rare cases of hypersensitivity reactions (including anaphylaxis and rash), tachycardia, palpitations, psychomotor, hyperactivity, seizures, elevations of liver enzymes, hepatitis, and increased bilirubin have been reported.

# AERIUS* Tablets are indicated for symptomatic relief of allergic rhinitis and urticaria, while AERIUS* Syrup is indicated for symptomatic relief of allergic rhinitis and chronic idiopathic urticaria.* Efficacy data were from four post marketing surveillance studies involving 77,880 subjects using oral desloratadine 5mg tablet daily for Seasonal Allergic Rhinitis and Chronic idiopathic Urticaria. Onset of action results were subject-related from post hoc analysis of these studies (n=17,575) where subjects had previously received monotherapy with another second generation antihistamine (cetirizine, fexofenadine, loratadine or mizolastine). AERIUS* shows fast onset of symptom relief compared with other analysis of these studies (n=17,575) where subjects had previously received monotherapy with another second generation antihistamine (cetirizine, fexofenadine, loratadine or mizolastine). AERIUS* shows fast onset of symptom relief compared with other second generation antihistamines rated by 67% of subjects.† Risk of sedation and drowsiness is lower than levocetirizine (P < 0.0001) in patients with allergic rhinitis without asthma/wheezing.‡ AERIUS* Syrup is indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 6 months of age and older.** ** In a driving performance & psychomotor performance study, at therapeutic dose of 5mg, no significant difference weree noted between desloratadine & placebo in standard deviation of lateral position (SDLP), one of the parameter to measure driving performance.

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ROLE OF ECLS IN RESPIRATORY DISEASES

Dr. Robin Chen Consultant, Department of Pediatric CardiologyQueen Mary Hospital, Hong Kong

Indications for ECLSThe goal of extracorporeal membrane oxygenation (ECMO) is to provide respiratory and cardiac life support. The aim is to either provide a bridge to recovery, bridge to diagnosis or decision or bridge to bridge (e.g. transplant). Extracorporeal life support (ECLS) may be offered to children with hypoxaemia and/or hypercapneic respiratory failure unresponsive to other therapies. These include severe respiratory failure indicated by sustained PaO2/FiO2 ratios <60-80 or OI>40, lack of response to conventional mechanical ventilation and rescue therapy and elevated ventilator pressures. Other considerations include hypercapneic respiratory failure, rate of deterioration and how quickly ECLS can be initiated and absence of contraindications.48

Contraindications for ECLSAbsolute contraindications include lethal chromosomal abnormalities, severe neurological compromise, allogeneic bone marrow transplant recipients with pulmonary infiltrates and - incurable malignancy.48 Relative contraindications include duration of pre-ECLS mechanical ventilation, recent neurosurgical procedures or intracranial haemorrhage and pre-existing chronic illness with poor long-term prognosis.48 High-risk patients include infants with pertussis pneumonia or disseminated herpes simplex, cytomegalovirus infection, severe multi-organ failure and severe coagulopathy or thrombocytopaenia.48 There is a high-risk of poor outcomes in patients with repeat ECLS for the same condition.

Paediatric ECMO program in Hong Kong• Gramtham Hospital (2000) --> QMH (2009)

• Dept of Paed Cardiology + Cardiothoracic Surgical Dept

• Collaboration with P/NICU since translocation to QMH• Program

• Total number > 1-- runs• Average ~15 runs/year over past 3 years• 200 – Cardiac support • Post operative • Myocarditis• 2011 – respiratory support• 2012 – circulatory support • Sepsis / distributive shock• 2017 – ELSO centre• 2018 – extended neonatal indication

ECMO for respiratory indication• 21 ECMO runs in 19 patients

• Median age 51 months (newborn – 14.8yrs)

ECMO Indication

Table 1. Characteristics of ECMO patients

Table 2. Indications of ECMO and survival outcomes

Age, months, median (IQR) 51 (74)Male, n (%) 13 (68%)Weight, kg, median (IQR) 15.7 (11.8) 2.88 – 68Days of ECMO, median (IQR) 12 (22) 2 – 47Days of ICU stay, median (IQR) 22 (38) 2 – 92Days of Hospital stay, median (IQR) 50 (39) 2 – 113Pre-ECMO Oxygenation index, median (IQR) 38 (22.3)Pre-ECMO HFOV, n (%)* 4 (21%)Pre-ECMO Mean BP, mmHg, median (IQR) 72 (25)Pre-ECMO cardiac arrest, n (%) 5 (26.3%)

Indication Number Survive ECMO Survive to Discharge/ Transfer

n % n %Neonatal

PPHN 1 1 100 1 100Paediatric

Pneumonia 15 10 66.7 10 66.7Tracheal Stenosis* 1 0 0 0 0

Interstitial lung disease

1 0 0 0 0

Idiopathic pulmonary syndrome

1 0 0 0 0

PPHN: persistent pulmonary hypertension of newborn.* Tracheal stenosis: this is a case of left pulmonary artery sling associated with tracheal stenosis, with severe residual tracheal stenosis post operatively.

Bridge to decision

Bridge to diagnosis

Course & Outcome• Invasive procedures during ECMO

• 84% of patients had ≥ 1 procedure• Median 2 procedures (0–16)

• 68.4% BAL• 31.6% thoracotomy

• Decortication / lobectomy / pnemonectomy / harmostasis / wound irrigation

• 10.8% Neurosurgical• Craniectomy / clot evacuation / EVD / VP shunt

• Survival to hospital discharge 57.8%• Comparable to ELSO benchmark

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PAEDIATRIC CHRONIC COUGH GUIDELINES: WHAT IS NEW?

Prof. Anne B Chang Queensland Children’s Hospital, BrisbaneMenzies School Health Research, Darwin, Australia

ACCP evidence-based clinical practice guidelinesAetiological factors and treatment of cough are different in adults and children. Therefore children (aged < 15 years) with cough should be managed according to child-specific guidelines. The American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines have been established for evaluating chronic cough in paediatrics. These guidelines suggest that children with chronic cough require careful and systematic evaluation. A minimum of a chest radiograph and spirometry (if age appropriate) should be conducted with further investigations should be done as needed for specific cough. Children with chronic productive cough should be investigated to rule out bronchiectasis. The guidelines indicate that aetiology should be defined and treatment should be based on aetiology. 49

Algorithms in children wth chronic coughThe 2017 CHEST Guideline and Expert Panel Report showed that the use of cough management protocols or algorithms improves clinical outcomes in children aged ≤ 14 years. The expert panel report also indicates that management or testing algorithms should be based on the associated characteristics of the cough and clinical history.50 A multicentre, single-blind RCT nested within a prospective cohort study of children (<15 years) with chronic cough in Australia showed that applying an evidence-based cough management algorithm in non-specialist settings improves cough resolution.51

Figure 1: Need for guidelines on chronic cough

CHEST Guideline and Expert Panel Report provides recommendations on chronic cough and gastroesophageal reflux in children. For children aged ≤14-years with chronic cough (>4-weeks duration) without an underlying lung disease, treatment for GERD should not be used in the absence of gastro-intestinal clinical features of reflux; E.g. recurrent regurgitation, dystonic neck posturing in infants or heartburn/epigastric pain in older children (Grade 1B). Those who have symptoms, signs or tests consistent with GERD should be treated as per evidence-based GERD-specific guidelines. (Grade 1B) and acid suppressive therapy should not be used

solely for their chronic cough (Grade 1C). After treatment for 4-8-weeks response should be reevaluated (Ungraded Consensus–based Statement) 52

Figure 2: Elements of pediatric cough guidelines Recommendations on GERD related cough

Recommendations on acute viral bronchiolitis The ACCP CHEST Expert Panel Report provides guidelines on management of chronic cough related to acute viral bronchiolitis in children. For children with chronic cough (> 4 weeks) after acute viral bronchiolitis, cough should be managed according to the CHEST paediatric chronic cough guidelines. It is suggested that asthma medications should not be used for the cough unless other evidence of asthma is present (Ungraded Consensus–based Statement). It is also indicated that inhaled osmotic agents should not be used. (Ungraded Consensus–based Statement) 53

Somatic cough syndrome and tic coughPsychogenic cough, habit cough, or tic cough is explained as cough occurring in the absence of identified medical disease and that does not respond to medical treatment. The 2006 Cough Guidelines on psychogenic and habit cough have been updated by the American College of Chest Physicians (CHEST) Expert Panel.54 In adults and children with chronic cough the diagnosis of somatic cough can be made only after extensive evaluation has been performed that includes ruling out tic disorders and uncommon causes and the patient meets the DSM-5 criteria for a somatic symptom disorder (Grade 2C). The diagnosis of tic cough should be made when the patient manifests the core clinical features of tics that include suppressibility, distractibility, suggestibility, variability, and the presence of a premonitory sensation whether the cough is single or one of many tics (Grade 1C).54 In children with somatic cough disorder non-pharmacological trials of hypnosis or suggestion therapy or combinations of reassurance, counseling, or referral to a psychologist and/or psychiatrist is recommended. (Grade 2C) 54

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13

WHAT’S NEW IN THE GINA GUIDELINES?

Dr. Kate Ching-ching Chan Assistant Professor, Department of PaediatricsThe Chinese University of Hong Kong

Risks of mild asthma According to the Global Initiative for Asthma (GINA) classification mild asthma includes intermittent and mild persistent asthma. It is known that about 50-70% of asthmatic patients suffer from mild asthma, which can be associated with episodes of severe exacerbation. It is estimated that exacerbations in patients with mild asthma contribute to about 30% and 40% of exacerbations requiring emergency care.The frequency of severe exacerbation in patients with mild asthma is between 0.12 and 0.77 episodes per patient‐year. In children, mild asthma is more frequent, more symptomatic, and less well controlled compared to adults. Children with mild asthma also face the risk of severe complications and the need for emergency treatment.55 Appropriate and consistent management of mild asthma is therefore important.

Risks of short acting β2 agonist (SABA) alone treatmentSABAs are most commonly used for asthma as they provide symptom relief with a rapid onset of bronchodilation, protect against exercise-induced asthma and early asthmatic response to allergen.56 Global Initiative for Asthma (GINA) recommends that most patients with mild asthma should be treated with regular, low-dose inhaled glucocorticoids as controller medication to reduce the risk of exacerbations and SABAs should be used as needed for symptom relief.57 However, most patients exhibit low adherence to regular controller therapy and prefer to use SABAs to relieve symptoms.58 Several studies show the adverse effects with regular use or overuse of SABA. Frequent use of SABA increases airway hyper-responsiveness and is associated with a higher risk of fatal or near-fatal asthma.56 Furthermore, dispensing of ≥3 canisters per year (average 1.7 puffs/day) is associated with higher risk of exacerbations.60

Advantages of anti-inflammatory therapy in mild asthmaDespite relatively mild/intermittent symptoms in patients with mild asthma, use of anti-inflammatory therapy is found to be beneficial. Inhaled corticosteroids (ICS) are effective against mild persistent asthma symptoms and reduce the severe exacerbation risk.55 The START study revealed that early ICS therapy in mild asthma results in significant decrease in exacerbations and also reduces use of oral steroids.61 The IMPACT study showed that continuous budesonide treatment results in significant improvement in symptom score and in number of symptom-free days and also significantly reduces inflammation parameters - eosinophil concentration in sputum and exhaled nitric oxide levels.62 ICS are also known to provide a functional benefit to mild asthma patients and can alter asthma evolution in children by preventing bronchial remodelling.55

Anti-Inflammatory reliever therapy - ICS / FormoterolThe common drawback of using a regular inhaled corticosteroid (ICS) or an ICS with a long-acting β-agonist (LABA) as controller medication is the poor adherence and patients become dependent on SABA for symptom relief. If the patients can receive a fast-acting reliever plus an inhaled glucocorticoid when needed it can address both symptoms and exacerbation risk. The anti-inflammatory reliever therapy (AIR) with budesonide and formoterol is an on demand symptom-driven regimen with controller and reliever in the same single inhaler.63 Several studies such as SYGMA 1, 2, Novel START and PRACTICAL trials provide evidence of beneficial effects of anti-inflammatory reliever therapy in mild asthma.58,64-66

Figure 1: Efficacy of Anti-Inflammatory Reliever Therapy - ICS / Formoterol

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ASTHMA AND FENO IN CHILDREN

Prof. Anne B Chang Queensland Children’s Hospital, BrisbaneMenzies School Health Research, Darwin, Australia

FeNO is a measure of airway inflammation Measurement of fractional nitric oxide (NO) concentration in exhaled breath (FENO) is a quantitative, noninvasive, simple, and safe method of measuring airway inflammation. Abnormal FeNO level is seen in many respiratory conditions including asthma and is used as a biomarker in the assessment and management of airways diseases. FeNo allows detection of eosinophilic airway inflammation and corticosteroid responsiveness, allows monitoring of airway inflammation, assessment of need for corticosteroid and non- adherence to corticosteroid therapy.67 However, FeNO value can be influenced by atopy, age, height and smoking and genetic environmental factors as well as ethnicity.68-70

NICE guidelinesNICE recommends FeNO test for adults (aged 17 and over) if a diagnosis of asthma is being considered and a level of 40 parts per billion (ppb) or more is a positive test. FeNO test should be used in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment and a level of 35 ppb or more should be regarded as a positive test for diagnosis of asthma. NICE recommends a diagnosis of asthma in children and young people (aged 5 to 16) if they have symptoms suggestive of asthma and positive peak flow variability or obstructive spirometry and positive bronchodilator reversibility.71

Figure 1: NICE guidelines on FeNO

BTS/SIGN guidelinesThe British Thoracic Society (BTS) and the Scottish Intercollegiate Guideline Network (SIGN) also provide guidelines for asthma management. As a result there are two guidelines in England – the BTS/SIGN and the NICE guidelines. The methodology used by both to produce recommendations is significantly different. BTS/SIGN employs a multidisciplinary clinically led process while NICE uses critical appraisal of the literature with health economic modeling. Both NICE and BTS/SIGN consider FeNO as a surrogate marker of eosinophilic airway inflammation with variable sensitivity/specificity for predicting asthma.72 BTS highlights usefulness of FeNO in patients with intermediate probability of asthma and without spirometric evidence of obstruction or reversibility.72

Figure 2: BTS/SIGN Guidelines on FeNO

Figure 3: GINA guidelines on FeNO

American Thoracic Society (ATS) guidelinesATS recommends use of FENO to monitor airway inflammation in patients with asthma and to detect steroid responsiveness in patients with chronic respiratory symptoms due to airway inflammation.67 FENO greater than 50 ppb (more than 35 ppb in children) should be used to indicate eosinophilic inflammation and likely steroid responsiveness in symptomatic patients.67 A 20% increase in value over 50 ppb or more than 10 ppb increase for values below 50 ppb from one visit to the next is considered as a significant increase in FENO. Similarly, a 20% decrease in value over 50 ppb or more than 10 ppb for values below 50 ppb indicates a significant response to anti-inflammatory therapy.67 Agency for Healthcare Quality and Research (AHRQ) ReportThe AHRQ report provides key messages on clinical utility of FENO in asthma management.The report states that depending on the FeNO cutoff, in people ages 5 years and older with a positive FeNO test result the chances of having asthma increase by 2.8 to 7.0 times.73 The diagnostic accuracy is likely to be higher in nonsmokers, steroid-naïve asthmatics and children (ages 5-18). On the other hand it is unclear whether FeNO testing in children at ages 0-4 years with symptoms suggestive of asthma can predict a future asthma diagnosis.73

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MY JOURNEY IN NEONATOLOGY – WHAT WAS, IS AND WILL BE?

Prof. Tai Fai Fok Pro-Vice-Chancellor / Vice-PresidentChoh-Ming Li Professor of PaediatricsThe Chinese University of Hong Kong

Neonatology over the years The practice of neonatology has undergone tremendous development over the years evolving from Stone Age through non-evidence based medicine to technological advancements focusing on family centered care. Beginning with the therapeutic explosion of antibiotics, hospital births, and X-rays in 1940s, there was an increased understanding of role of thermoregulation and APGAR score in 1950s. The 1960s saw modernization of practice in neonatology with neonatologists, ventilators, microanalysis, disposable scalp vein needle and total parenteral nutrition. Further advances in 1970s lead to the availability of continuous positive airway pressure and arterial blood gas analysis. Family centered care was established in 1980s with family involvement in neonatal intensive care. More technological advancements, AIDS prevention, and new modes of ventilation were available in 1990s.The Hong Kong government’s Family Health Services includes 31 Maternal and Child health (MCH) centres and 3 Women’s Health Centres. MCH centres play a very important role in the primary health care of young children from newborns to 5 years of age even to this day.

ICU family-centered care recommendationsThe ICU family centered guidelines have been developed to provide clinicians with best practices for family-centered care in the ICU. These guidelines mainly focus on family presence in the ICU at bedside, during interdisciplinary rounds and during resuscitation efforts. Family support includes teaching the parents how to assist with the care of their critically ill neonate. This helps to improve parental confidence and competence and also has a positive effect on parental psychological health during and after the ICU stay.74 Family education programs are useful in reducing stress, anxiety and depression. Interdisciplinary communication between clinicians and family can improve family satisfaction and trust in clinicians. Spiritual support, use private rooms to improve patient and family satisfaction and overcoming sleep deprivation are also included in the recommendations.74

Current and future of neonatal careThe future of neonatal care involves big data analysis and artificial intelligence to improve neonatal outcomes. One such development is the use of predictive monitoring of vital signs to identify neonates who are at the risk of developing complications. Diagnosis of sepsis and necrotizing enterocolitis often does not occur until there is significant hemodynamic compromise. The heart rate characteristics index (HeRO) monitor is the first vital-sign predictive monitoring device developed for sepsis detection in the NICU. This device analyzes low heart rate variability and transient decelerations and has been demonstrated to reduce mortality in low birth weight infants.75 Another such development is the closed-loop control of inspired oxygen, which has been more effective than manual control in maintaining oxygenation targets in premature infants receiving supplemental oxygenation. It reduces hyperoxaemia, hypoxaemia, and exposure to high inspired oxygen levels. 76 In future, experimental models of artificial placenta providing extracorporeal lung support are envisaged as promising alternatives to mechanical ventilation in extremely premature infants.77

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AN UPDATE ON THE LONG TERM RESPIRATORY HEALTH OF PREMIES

Dr. Shannon Simpson Co-head, Children’s Lung HealthSenior Research Fellow, Telethon Kids InstitutePerth Children’s Hospital, Perth, Western Australia

Preterm birth leads to persistentrespiratory morbidityPreterm infants are at an increased risk of developing ongoing respiratory symptoms. Though cough is common in both preterm and term infants, wheeze, inhalation therapy and re-hospitalisations occur more frequently in preterm infants. Pramana et al reported that 80% of the preterm infants had cough with cold and 44%% suffered from wheeze. 25% of preterm infants had to be re-hospitalized for respiratory reasons and 13% of preterm infants needed long-term inhalation therapy of more than four weeks.78 In preterms born before 29 weeks, male sex, duration of oxygen therapy, older siblings and socioeconomic status are associated with respiratory symptoms in the first year of life.79 Severe respiratory outcomes are related to maximal peak inspiratory pressure, arterial cord blood pH, APGAR and CRIB-Score.78 Evidence shows that preterm birth particularly very preterm birth increases the risk of asthma.80

Figure 1: Respiratory symptoms in preterm infants

Figure 2: Respiratory outcomes in preterm birth survivors

BPD linked to poor outcomes inchildren and adultsBronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity is a major complication of preterm birth. It is the most common cause of chronic lung disease in infancy.81 BPD in preterm infants further increases the risk of poor respiratory outcomes not only through childhood, but also into adolescence and adulthood.82 The EPICure study, which measured lung function at 11 years in children born extremely preterm showed that BPD subjects are twice as likely to report wheeze and three times more likely to use asthma medication than controls.83 BPD survivors also report significantly more wheeze and shortness of breath in adulthood; are more likely to have an asthma diagnosis and have a lower quality of life than full-term controls.81

Preterm birth alters lung structure and functionPreterm infants not only suffer from increased respiratory symptoms, but have also documented to have altered lung structure, along with declining lung function throughout childhood.82 The EPICure study showed 56% of children born before 25 weeks of gestation have abnormal baseline spirometry and 27% have a positive bronchodilator response at 11 years of age indicating that impaired lung function persists through middle childhood.83 Furthermore, preterm children when tested at 9-11 years of age have demonstrated pulmonary obstruction and hyperinflation and abnormal peripheral lung mechanics compared with term controls.84 Subpleural opacities, bronchial wall thickening and hypoattenuated lung areas have been reported in survivors of preterm birth in mid-childhood.84 Residual functional and structural pulmonary abnormalities such as emphysema have also been documented in young adult survivors of BPD.85 In preterm infants, particularly in those with BPD, a significant obstructive lung disease persists into adolescence and young adulthood, increasing the risk of a COPD-like phenotype later in life.86

Figure 3: BPD and lung structure at age 11

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USING BENCH TO BEDSIDE METHODOLOGIES TO IMPROVE HEALTH

Dr. Shannon Simpson Co-head, Children’s Lung HealthSenior Research Fellow, Telethon Kids InstitutePerth Children’s Hospital, Perth, Western Australia

Bench to Bedside methodologies to understand lung function declinePremature birth together with co-existing risk factors such as sepsis, intrauterine growth retardation, sepsis, genetic factors, pulmonary infection, oxidative stress and inflammation play an important role in development of broncho-pulmonary dysplasia in the intensive care unit (ICU). Bench to bedside methodologies can be used to understand lung function decline in premature babies. Development of biomarkers, understanding mechanisms of lung function decline, identifying avenues for interventions, testing interventions in lab models and translating these interventions to clinical practice are some of the methodologies used to bridge the gap from bench to bedside.

Preterm Oxidative Stress Persists through Childhood and AdolescenceAnalysis of exhaled breath condensate (EBC) is a simple, easy and non-invasive method that allows the measurement of 8-Isoprostane, which is a marker of oxidative stress and Leukotrine B4, which is a marker of neutrophilic inflammation. Both 8-Isoprostane and Leukotrine B4 are detectable in EBC of preterm babies at age 12-18 months but not in healthy controls indicating that the oxidative stress and neutrophilic inflammation persist in preterm babies beyond the ICU. High levels of IL-8/protein values and sputum neutrophils have been demonstrated in a significant proportion of school children born preterm indicating the persistence of peripheral airway obstruction and neutrophilic lower airway inflammation. (Teig N et al. J Pediatr. 2012 Dec;161(6):1085-90) Furthermore, evidence of oxidative stress (higher 8-Isoprostane in EBC) has also been demonstrated in adolescents who were born prematurely indicating that BPD is associated with long-term respiratory abnormalities and ongoing airway disease after pre-term birth. (Filippone M et al. Eur Respir J. 2012 Nov;40(5):1253-9)

Biomarker Indicate Differences in Lung epithelium in Preterm Infants Biological sample collection (nasal epithelial cells, blood, urine and EBC) and lung function tests are currently being investigated to predict low or declining lung function in preterm infants. A study in 300 infants less than 32 weeks gestational age with or without BPD recruited in NICU were followed up at 12-15 months corrected age. Nasal brushings were obtained from the preterm infants while in NICU. The results of cellular morphology showed no difference in preterm and full term infants, however the proliferation rate in preterm infants was significantly lower. Significantly higher levels of CK-19 were seen in preterm infants indicating that the preterm cells are attempting to up-regulate the maturation process. Preterm cells also showed higher levels of IL-8/protein at baseline, which further increased following a viral infection. This explains why preterm infants are more susceptible to viral infections and likely to be hospitalized following viral infections. Preterm epithelium also demonstrates delayed wound healing and abnormal wound repair compared to epithelium in term infants. It is therefore clear that there are intrinsic differences in lung epithelium in preterm vs. term infants.

Figure 1:Inflammatory markers in induced sputum of school children born preterm

Figure 2:Oxidative stress persists in airways of adolescents born very pre-term

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VENTILATORY STRATEGIES FOR PREMIES – WHAT HAS CHANGED?

Dr. Simon Lam Associate Professor, Faculty of MedicineThe Chinese University of Hong Kong

Difficulties in ventilating a neonateMechanical ventilation is indicated in neonates who suffer from oxygenation failure and/or ventilation failure. However, unique physiological characteristics in neonates pose several challenges during mechanical ventilation. These include difficult airway maintenance and clearance, smaller airway caliber, few collateral airways, compliant chest wall, poor airway stability, and lower functional residual capacity.87 Correct sized endotracheal tube, positioning of the patient, nursing care and respiratory kinesiotherapy play an important role in ensuring effective neonatal ventilation. Furthermore, sedation and analgesia, and prevention of infection and other complications such as air leaks and pulmonary hemorrhage are crucial aspects of neonatal ventilation.87

Figure 1: Difficulties in neonatal ventilation

Disadvantages of positive pressure ventilationPositive pressure ventilation in newborns increases the risk of air leak syndromes and barotrauma and volutrauma. In addition, high ventilation pressure in neonates can result in decrease in cardiac output and increase venous pressure, leading to systemic hypotension and altered perfusion.88 Furthermore, prolonged invasive ventilation is considered an important risk factor for development of bronchopulmonary dysplasia. Positive pressure and excess volume during mechanical ventilation can result in lung over-distension followed by cellular injury and inflammation adding to the injury of the immature lung.89 Therefore, general strategy for neonatal ventilation is to minimize damage.

Ventilatory strategies in neonatesIt is suggested that permissive hypercapnia and/or permissive hypoxaemia are well tolerated and result in reduced lung injury in neonates on mechanical ventilation. Permissive hypercapnia is a strategy that minimizes baro and volutrauma by allowing the arterial PCO2 to rise above physiological levels, provided the arterial pH does not fall below a preset minimal value. Permissive hypercapnia minimizes the ventilator induced lung injury by reducing the lung stretch with reduced tidal volumes.90 Permissive hypoxaemia allows relatively lower levels of oxygen saturation to reduce oxygen toxicity, since preterm infants are especially vulnerable to oxygen toxic effects.

Pressure-limited ventilation (PLV) versus targeted ventilation (VTV)Traditionally pressure-limited ventilation (PLV) has been used in newborns where fixed volume of gas and preset peak inspiratory pressure is used over a defined time period. However, the main disadvantages of PLV include overexpansion (volutrauma) and under expansion/collapse (atelectrauma). Furthermore, it is clear that ventilator-induced lung injury is influenced more by the tidal volume than inflation pressure.91 On the other hand modern mode of volume-targeted ventilation (VTV) provides stable tidal volume, which helps to reduce lung damage and stabilises the partial pressure of carbon dioxide. VTV offers several advantages over PLV in neonates. Evidence shows that VTV mode in infants is associated with reduced rates of death or BPD, pneumothoraces, hypocarbia and severe cranial ultrasound pathologies and shorter duration of ventilation compared with infants ventilated using PLV modes.92

Patient-ventilator asynchronyPatient-ventilator asynchrony is the area where most innovations in ventilator technology have taken place in the last few years. Sensing the changes in airway pressure or flow allows detection of patient’s breathing. However, small tidal volumes, higher respiratory rate and air leak from an uncuffed intubation tube in neonates makes sensing difficult.93 When sensing is difficult, use of spontaneous ventilatory modes are challenging and therefore more controlled methods of ventilation are used in neonates. Nevertheless, controlled modes need higher levels of sedation, which in turn weaken the spontaneous breathing efforts further increasing need for ventilator support.93

Figure 2: Dealing with patient ventilator asynchrony

Neutrally Adjusted Ventilatory Assist (NAVA) Neutrally Adjusted Ventilatory Assist (NAVA) is a novel mode of ventilation that relies on diaphragmatic signal (Edi) to trigger the ventilator. Ventilatory support given is proportional to Edi, allowing the patient to self-adjust the support. NAVA is reported to significantly improve short-term patient-ventilator synchrony in a paediatric population.93 However, NAVA is not recommended in the first week of life in extreme low birth weight infants who have immature respiratory drive and already are at high risk of intraventricular haemorrhage and volume trauma. On the other hand larger and older infants are able to generate a strong Edi activity and can benefit from NAVA.94

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NUSS IS PURELY COSMETIC

Prof. Albert Li Professor, Faculty of MedicineThe Chinese university of Hong Kong

NUSS procedure for pectus excavatumPectus excavatum (PE) is a congenital chest wall deformity, which contributes to over 90% of all chest wall deformities. The incidence rate is about 0.1% with a male to female ratio of 4:1 Severe PE can affect the physical and psychological development of patients and surgical correction is recommended in such cases. NUSS procedure is a minimally invasive surgical procedure for correction of pectus excavatum without osteotomy.95 The NUSS procedure involves a small and hidden incision, and surgical time is shorter with less blood loss and thus allows faster recoveries. Additionally, the procedure does not require a chest wall muscle flap, does not require sternum cartilage or sternum resection. The NUSS procedure can retain chest expansion, flexibility, and elasticity for a long period of time. It has demonstrated satisfactory short to mid-term effects, however long-term effects are still to be confirmed.95

Effect of NUSS on cardio-pulmonary function Patients report significant subjective improvements in pulmonary symptoms following NUSS. Furthermore, short and medium term evaluations up to 2 years with the bar in place indicate modest improvement to cardiac function. Sustained improvement in cardiopulmonary function after bar removal following closed repair of pectus excavatum have also been demonstrated. The improved aerobic capacity is believed to be due to both pulmonary and cardiac effects.96

Complication of minimally invasive pectus surgerySeveral life-threatening complications such as cardiac perforation, haemothorax, major vessel injury, lung injury, liver injury, gastrointestinal problems, and diaphragm injury can occur during minimally invasive repair of pectus excavatum and bar removal.97 Factors affecting the risk of complications include operative technique, patient age, pectus severity and asymmetry, previous chest surgery, and the surgeon’s experience. Previous chest surgery, pectus severity and inexperience are known to increase the risk of complications.97 It is thus clear that the procedure does involve serious risks and individualized and careful patient selection and treatment is crucial.

Figure 1: Life-threatening complicationswith pectus surgery

Type of life-threatening complications related to MIRPE and bar removal identified between 1998 and 2016. Numbers in oarenthesis denote cases with ortality.

Type of complication Published UnreportedCardiac injury 12 (4) 15 (5)Aortic or major vascular injury 2 1Other visceral injury 2 2Massive hemo / pneumothorax 0 6Empyema / mediastinitis 1 2IMA injury and hemorrhage 2 0Cardiac / major vascular occlusion 3 0Sternal erosion / bleeding 2 0GI complications 0 2 (2)Hemorrhage with bar removal 3 4 (2)Total 27 32ww

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NUSS IS NOT PURELY COSMETIC

Dr. Michelle Yu Prince of Wales Hospital

NUSS procedure has become safer over yearsTechnical modifications over the past 21 years have made NUSS for pectus repair safer and more successful. Complications have dramatically decreased over 21 years with bar displacement rate requiring surgical repositioning going down from 12% to 1%. Allergy to nickel has been identified with switch to titanium bar in allergic patients.98 There has been a significant improvement in postoperative pulmonary function and a good to excellent anatomic surgical outcome is achieved in 95.8% of patients at the time of bar removal.98 Furthermore, changes in operative technique such as use of a lateral stabilizer and pericostal sutures have decreased complication and reoperation rates for NUSS.99

NUSS improves quality of lifeNUSS procedure in young adults has demonstrated a high rate of patient satisfaction, significant improvement in self-image, and excellent midterm cosmetic results.100 Pectus surgery does improve emotional wellbeing and self-esteem in both patients and their parents with a significant betterment of patient’s physical function. An improvement in heath related quality of life has been demonstrated with increase in physical and social activities at both 3 and 6 months postoperatively. Parents of children with pectus have reported reduction in their own level of distress due to the child’s condition.101

NUSS improves cardio-pulmonary outcomeWith lower cardio-pulmonary function relative to normal patients, pectus patients have shown improvement in both cardiac and lung function following surgery. A significant improvement in pulmonary function has been noted following NUSS and bar removal.102 It is also suggested that the heart returns to a normal position and shape following the procedure, which may contribute to improvement in cardiac function.103

Figure 1: Satisfactory mid-term result with Nuss procedure

Figure 2: Nuss procedure improves patient satisfaction

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