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Fulltext Improving the Diagnosis, Management, and Outcomes of Children with Pneumonia: Where are the Gaps?

Chang AB, Ooi MH, Perera D, Grimwood K

Front Pediatr, 2013;1:29.
PMID: 24400275 DOI: 10.3389/fped.2013.00029

Pneumonia is the greatest contributor to childhood mortality and morbidity in resource-poor regions, while in high-income countries it is one of the most common reasons for clinic attendance and hospitalization in this age group. Furthermore, pneumonia in children increases the risk of developing chronic pulmonary disorders in later adult life. While substantial advances in managing childhood pneumonia have been made, many issues remain, some of which are highlighted in this perspective. Multiple studies are required as many factors that influence outcomes, such as etiology, patient characteristics, and prevention strategies can vary between and within countries and regions. Also, outside of vaccine studies, most randomized controlled trials (RCTs) on pneumonia have been based in resource-poor countries where the primary aim is usually prevention of mortality. Few RCTs have focused on medium to long-term outcomes or prevention. We propose different tiers of primary outcomes, where in resource-rich countries medium to long-term sequelae should also be included and not just the length of hospitalization and readmission rates.
Aspergillus and progression of lung disease in children with cystic fibrosis

Harun SN, Wainwright CE, Grimwood K, Hennig S, Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group

Thorax, 2019 02;74(2):125-131.
PMID: 30275132 DOI: 10.1136/thoraxjnl-2018-211550

BACKGROUND: The impact of Aspergillus on lung disease in young children with cystic fibrosis is uncertain.
AIMS: To determine if positive respiratory cultures of Aspergillus species are associated with: (1) increased structural lung injury at age 5 years; (2) accelerated lung function decline between ages 5 years and 14 years and (3) to identify explanatory variables.
METHODS: A cross-sectional analysis of association between Aspergillus positive bronchoalveolar lavage (BAL) cultures and chest high-resolution CT (HRCT) scan findings at age 5 years in subjects from the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study was performed. A non-linear mixed-effects disease progression model was developed using FEV1% predicted measurements at age 5 years from the ACFBAL study and at ages 6-14 years for these subjects from the Australian Cystic Fibrosis Data Registry.
RESULTS: Positive Aspergillus BAL cultures at age 5 years were significantly associated with increased HRCT scores for air trapping (OR 5.53, 95% CI 2.35 to 10.82). However, positive Aspergillus cultures were not associated with either FEV1% predicted at age 5 years or FEV1% predicted by age following adjustment for body mass index z-score and hospitalisation secondary to pulmonary exacerbations. Lung function demonstrated a non-linear decline in this population.
CONCLUSION: In children with cystic fibrosis, positive Aspergillus BAL cultures at age 5 years were associated contemporaneously with air trapping but not bronchiectasis. However, no association was observed between positive Aspergillus BAL cultures on FEV1% predicted at age 5 years or with lung function decline between ages 5 years and 14 years.
Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis

Harun SN, Holford NHG, Grimwood K, Wainwright CE, Hennig S, Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group

Thorax, 2019 08;74(8):740-748.
PMID: 31203197 DOI: 10.1136/thoraxjnl-2018-211548

BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown.
AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years.
METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years.
RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event.
CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.
Fulltext Antibiotics in childhood pneumonia: how long is long enough?

Grimwood K, Fong SM, Ooi MH, Nathan AM, Chang AB

Pneumonia (Nathan), 2016;8:6.
PMID: 28702286 DOI: 10.1186/s41479-016-0006-x

Improved access to healthcare, vaccines and treatment with antibiotics has reduced global mortality from childhood community-acquired pneumonia. However, as respiratory viruses are responsible for most episodes of pneumonia, important questions remain over who should receive these agents and the length of each treatment course. Worldwide concerns with increasing antibiotic resistance in respiratory pathogens and appeals for more prudent antibiotic prescribing provide further urgency to these clinical questions. Unfortunately, guidelines for treatment duration in particular are based upon limited (and often weak) evidence, resulting in national and international guidelines recommending treatment courses for uncomplicated pneumonia ranging from 3 to 10 days. The advantages of short-course therapy include a lower risk of developing antibiotic resistance, improved adherence, fewer adverse drug effects, and reduced costs. The risks include treatment failure, leading to increased short- or long-term morbidity, or even death. The initial challenge is how to distinguish between bacterial and non-bacterial causes of pneumonia and then to undertake adequately powered randomised-controlled trials of varying antibiotic treatment durations in children who are most likely to have bacterial pneumonia. Meanwhile, healthcare workers should recognise the limitations of current pneumonia treatment guidelines and remember that antibiotic course duration is also determined by the child's response to therapy.
Fulltext Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa

Heffernan AJ, Sime FB, Lim SMS, Naicker S, Andrews KT, Ellwood D, et al.

Drugs R D, 2021 Jun;21(2):203-215.
PMID: 33797739 DOI: 10.1007/s40268-021-00344-5

BACKGROUND: Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing.
OBJECTIVE: The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing.
METHODS: Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance.
RESULTS: In the presence of broth alone, there was rapid and extensive (> 6 - log10) bacterial killing, with emergence of resistance identified in amikacin concentrations < 976 mg/L. In contrast, the rate and extent of bacterial killing was reduced (≤ 5 - log10) when exposed to an acidic pH and mucin. Surfactant did not appreciably impact the bacterial killing or resistance emergence when compared with broth alone for either isolate. The combination of mucin and an acidic pH further reduced the rate of bacterial killing, with the maximal bacterial killing occurring 24 h following initial exposure compared with approximately 4-8 h for either mucin or an acidic pH alone.
CONCLUSIONS: Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.
A decade on: Follow-up findings of indigenous children with bronchiectasis

McCallum GB, Singleton RJ, Redding GJ, Grimwood K, Byrnes CA, Valery PC, et al.

Pediatr Pulmonol, 2020 04;55(4):975-985.
PMID: 32096916 DOI: 10.1002/ppul.24696

OBJECTIVE: The sole prospective longitudinal study of children with either chronic suppurative lung disease (CSLD) or bronchiectasis published in the current era was limited to a single center. We sought to extend this study by evaluating the longer-term clinical and lung function outcomes and their associated risk factors in Indigenous children of adolescents from Australia, Alaska, and New Zealand who participated in our previous CSLD or bronchiectasis studies during 2004-2010.
METHODS: Between 2015 and 2018, we evaluated 131 out of 180 (72.8%) children of adolescents from the original studies at a single follow-up visit. We administered standardized questionnaires, reviewed medical records, undertook clinical examinations, performed spirometry, and scored available chest computed tomography scans.
RESULTS: Participants were seen at a mean age of 12.3 years (standard deviation: 2.6) and a median of 9.0 years (range: 5.0-13.0) after their original recruitment. With increasing age, rates of acute lower respiratory infections (ALRI) declined, while lung function was mostly within population norms (median forced expiry volume in one-second = 90% predicted, interquartile range [IQR]: 81-105; forced vital capacity [FVC] = 98% predicted, IQR: 85-114). However, 43 out of 111 (38.7%) reported chronic cough episodes. Their overall global rating judged by symptoms, including ALRI frequency, examination findings, and spirometry was well (20.3%), stable (43.9%), or improved (35.8%). Multivariable regression identified household tobacco exposure and age at first ALRI-episode as independent risk factors associated with lower FVC% predicted values.
CONCLUSION: Under our clinical care, the respiratory outcomes in late childhood or early adolescence are encouraging for these patient populations at high-risk of premature mortality. Prospective studies to further inform management throughout the life course into adulthood are now needed.
Fulltext HOspitalised Pneumonia Extended (HOPE) Study to reduce the long-term effects of childhood pneumonia: protocol for a multicentre, double-blind, parallel, superiority randomised controlled trial

Chang AB, Fong SM, Yeo TW, Ware RS, McCallum GB, Nathan AM, et al.

BMJ Open, 2019 Apr 24;9(4):e026411.
PMID: 31023759 DOI: 10.1136/bmjopen-2018-026411

INTRODUCTION: Early childhood pneumonia is a common problem globally with long-term complications that include bronchiectasis and chronic obstructive pulmonary disease. It is biologically plausible that these long-term effects may be minimised in young children at increased risk of such sequelae if any residual lower airway infection and inflammation in their developing lungs can be treated successfully by longer antibiotic courses. In contrast, shortened antibiotic treatments are being promoted because of concerns over inducing antimicrobial resistance. Nevertheless, the optimal treatment duration remains unknown. Outcomes from randomised controlled trials (RCTs) on paediatric pneumonia have focused on short-term (usually <2 weeks) results. Indeed, no long-term RCT-generated outcome data are available currently. We hypothesise that a longer antibiotic course, compared with the standard treatment course, reduces the risk of chronic respiratory symptoms/signs or bronchiectasis 24 months after the original pneumonia episode.
METHODS AND ANALYSIS: This multicentre, parallel, double-blind, placebo-controlled randomised trial involving seven hospitals in six cities from three different countries commenced in May 2016. Three-hundred-and-fourteen eligible Australian Indigenous, New Zealand Māori/Pacific and Malaysian children (aged 0.25 to 5 years) hospitalised for community-acquired, chest X-ray (CXR)-proven pneumonia are being recruited. Following intravenous antibiotics and 3 days of amoxicillin-clavulanate, they are randomised (stratified by site and age group, allocation-concealed) to receive either: (i) amoxicillin-clavulanate (80 mg/kg/day (maximum 980 mg of amoxicillin) in two-divided doses or (ii) placebo (equal volume and dosing frequency) for 8 days. Clinical data, nasopharyngeal swab, bloods and CXR are collected. The primary outcome is the proportion of children without chronic respiratory symptom/signs of bronchiectasis at 24 months. The main secondary outcomes are 'clinical cure' at 4 weeks, time-to-next respiratory-related hospitalisation and antibiotic resistance of nasopharyngeal respiratory bacteria.
ETHICS AND DISSEMINATION: The Human Research Ethics Committees of all the recruiting institutions (Darwin: Northern Territory Department of Health and Menzies School of Health Research; Auckland: Starship Children's and KidsFirst Hospitals; East Malaysia: Likas Hospital and Sarawak General Hospital; Kuala Lumpur: University of Malaya Research Ethics Committee; and Klang: Malaysian Department of Health) have approved the research protocol version 7 (13 August 2018). The RCT and other results will be submitted for publication.
TRIAL REGISTRATION: ACTRN12616000046404.
Fulltext Study Protocol for Preventing Early-Onset Pneumonia in Young Children Through Maternal Immunisation: A Multi-Centre Randomised Controlled Trial (PneuMatters)

Chang AB, Toombs M, Chatfield MD, Mitchell R, Fong SM, Binks MJ, et al.

Front Pediatr, 2021;9:781168.
PMID: 35111703 DOI: 10.3389/fped.2021.781168

Background: Preventing and/or reducing acute lower respiratory infections (ALRIs) in young children will lead to substantial short and long-term clinical benefits. While immunisation with pneumococcal conjugate vaccines (PCV) reduces paediatric ALRIs, its efficacy for reducing infant ALRIs following maternal immunisation has not been studied. Compared to other PCVs, the 10-valent pneumococcal-Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) is unique as it includes target antigens from two common lower airway pathogens, pneumococcal capsular polysaccharides and protein D, which is a conserved H. influenzae outer membrane lipoprotein. Aims: The primary aim of this randomised controlled trial (RCT) is to determine whether vaccinating pregnant women with PHiD-CV (compared to controls) reduces ALRIs in their infants' first year of life. Our secondary aims are to evaluate the impact of maternal PHiD-CV vaccination on different ALRI definitions and, in a subgroup, the infants' nasopharyngeal carriage of pneumococci and H. influenzae, and their immune responses to pneumococcal vaccine type serotypes and protein D. Methods: We are undertaking a parallel, multicentre, superiority RCT (1:1 allocation) at four sites across two countries (Australia, Malaysia). Healthy pregnant Australian First Nation or Malaysian women aged 17-40 years with singleton pregnancies between 27+6 and 34+6 weeks gestation are randomly assigned to receive either a single dose of PHiD-CV or usual care. Treatment allocation is concealed. Study outcome assessors are blinded to treatment arms. Our primary outcome is the rate of medically attended ALRIs by 12-months of age. Blood and nasopharyngeal swabs are collected from infants at birth, and at ages 6- and 12-months (in a subset). Our planned sample size (n = 292) provides 88% power (includes 10% anticipated loss to follow-up). Discussion: Results from this RCT potentially leads to prevention of early and recurrent ALRIs and thus preservation of lung health during the infant's vulnerable period when lung growth is maximum. The multicentre nature of our study increases the generalisability of its future findings and is complemented by assessing the microbiological and immunological outcomes in a subset of infants. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374381, identifier: ACTRN12618000150246.