Paediatric Respiratory Reviews xxx (xxxx) xxx

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini symposium: Pneumonia and empyema

Outcomes of paediatric community acquired pneumonia

S. Haggie a, I.M. Balfour-Lynn b,⇑
a
Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, Australia
b
Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK

Educational Aims

The reader will come to appreciate:

 The impact of infection on the developing lung.
 The outcomes of simple pneumonia to better inform parents.
 The outcomes of severe pneumonia with complications to better inform parents.

a r t i c l e i n f o a b s t r a c t

Keywords: Community acquired pneumonia is among the most common causes of hospitalisation in children,
Pneumonia despite most cases being successfully managed in ambulatory care. Empyema is the most common com-
Empyema plication of hospitalised pneumonia, and although associated with considerable morbidity, death is rare,
Chest infection even in severe disease.
Beyond the acute infection, there is a recognised association of paediatric lower respiratory tract infec-
tion and impaired lung function over the whole life span. Longitudinal birth cohorts highlight the dele-
terious effect of paediatric pneumonia on lung function and the development of chronic obstructive
pulmonary disease and a near doubling of respiratory associated mortality in adults. Less clear is how
to reconcile this worrisome data with most children only having mild abnormalities on spirometry in
paediatric follow up. Recurrent or severe pneumonia is infrequently associated with irreversible lung
injury such as bronchiectasis or bronchiolitis obliterans.
Ó 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and
similar technologies.

Community acquired pneumonia (CAP) is a leading cause of This process involves the folding of alveolar septae to form new
childhood illness and hospitalisation. Children aged under five alveolar units, and microvascular maturation of the double layered
years’ experience more severe disease and higher rates of compli- capillary network of the alveolar septa is reduced to a single layer.
cated pneumonia than older children. Furthermore, serious lower Following microvascular maturation, the enlargement of the gas
respiratory infections in young children are implicated in the exchange area is achieved by lung growth and not by the addition
development of chronic obstructive pulmonary disease in later life. of new alveolar units. When precisely alveolarisation is complete,
In this review, we consider the immediate and longer-term out- has not been well defined, estimates range from 2–3 years to
comes of community acquired pneumonia and its complications. 8 years [1]. Genes that regulate alveolar development are differen-
tially expressed during the period of alveolar septation. During this
key phase of lung development, data from bronchopulmonary dys-
IMPACT OF INFECTION ON THE DEVELOPING LUNG plasia animal models suggest inflammation and infection are asso-
ciated with altered gene expression. This has downstream impact
The final phase of lung development – ‘alveolarisation’, involves on fibroblast activity, extracellular matrix composition, and alveo-
the enlargement of the gas exchange area of the lung parenchyma. lar septal thickness [2].
The onset of chronic obstructive pulmonary disease can arise
⇑ Corresponding author at: Royal Brompton Hospital, Sydney Street, London SW3 from either a failure to attain adequate peak lung function by early
6NP, UK. adulthood, or an accelerated decline in lung function. Childhood
E-mail address: [email protected] (I.M. Balfour-Lynn).

https://doi.org/10.1016/j.prrv.2024.10.003
1526-0542/Ó 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Please cite this article as: S. Haggie and I.M. Balfour-Lynn, Outcomes of paediatric community acquired pneumonia, Paediatric Respiratory Reviews,
https://doi.org/10.1016/j.prrv.2024.10.003
S. Haggie and I.M. Balfour-Lynn Paediatric Respiratory Reviews xxx (xxxx) xxx

Fig. 1. Potential lung trajectories throughout the life course. With permission from Agusti & Faner, Lancet Resp Med 2019;7:358–64. (Ref 5).

risk factors, which include respiratory infection (as well as envi- on parental questionnaires to record variables such as LRTI status,
ronmental tobacco smoke, asthma and parental asthma) are which introduces recall bias and diagnostic misclassification. Con-
strongly associated with an accelerated decline in lung function, cerning the prospective cohorts, most predate infant immunisation
and, paired with a genetic susceptibility underpin the origins of programmes for pneumococcus and maternal immunisation
adult chronic obstructive pulmonary disease (COPD) [3]. Bui against pertussis and more recently RSV. Additionally, there have
et al. modelled lung function trajectories from a large Tasmanian been major modifications to respiratory support in neonatal care
birth cohort and showed most adult COPD followed a lifetime (exogenous surfactant; lung protective ventilation strategies; ante-
course of lower peak attained lung function in childhood with sub- natal corticosteroid administration; strategies to minimise oxygen
sequent normal or accelerated decline. Patients with pneumonia in toxicity; and corticosteroids to facilitate positive pressure wean-
the first 6 years of life were twice as likely to have low peak lung ing). The literature also cannot determine if respiratory infection
function and accelerated decline (OR 2.0, 95 % CI 1.2,3.25) [4]. in early life is an independent causative factor for later poor respi-
Fig. 1 shows a schema of lung function trajectories over the life ratory health or if children with low lung function are predisposed
span [5]. to early life respiratory infection. None the less, clinicians have a
Several longitudinal birth cohorts have reported early life lower key role in promoting pneumonia immunisation programs, clean
respiratory tract infections, including pneumonia, to be associated air policies at an environmental level, and education of parents
with obstructive lung function impairment. The Tucson study by and young people about the dangers of primary and environmental
Martinez et al. reported a nearly two-fold increase in asthma in tobacco smoke exposure and e-cigarettes.
children with pneumonia (especially due to RSV) during the first
3 years of life (OR 1.95 95 % CI 1.11–3.44) and significantly lower
expiratory flows at 11 years [6,7]. A Lancet systematic review com- SIMPLE COMMUNITY ACQUIRED PNEUMONIA – ACUTE
pared a primary outcome measure of abnormal spirometry (FEV1 OUTCOMES
or FVC) of children aged  5 years with lower respiratory tract
infections [8]. Eight of fourteen articles reported significant reduc- Despite being a leading cause of paediatric hospitalisation, most
tions in FEV1 values, and six of twelve studies reported reductions CAP is managed in primary care. In a large US data linkage study of
in FVC values compared with unexposed controls. Of the included >250,000 children managed in ‘primary’ care (emergency depart-
studies, most reported a restrictive spirometry pattern, the magni- ment or ambulatory hospital clinic), fewer than 1 % of cases
tude of this restriction was FEV1 z score 0.29 95 %CI 0.55 to required admission to hospital, when followed up at 1 week [11]
0.03) to 1.8 ( 3.4 to 0.2) and FVC z-score from 3.2 (95 %CI (Fig. 2).
4.8 to 1.6) to 0.13 (95 %CI 0.22 to 0.04) [8]. The US national guideline for paediatric CAP management (last
RSV is an important pathogen in paediatric pneumonia, evidence updated 2011), recommends 10 days of oral antibiotics for the
from observational and interventional studies suggest early life RSV management of uncomplicated CAP [12]. This is longer than the
disease predisposes to recurrent lower respiratory tract infections UK recommendation of 3–5 days, which also emphasises the need
(LRTI), to greater extent than non-RSV LRTI. This suggests an RSV for review to ensure clinical improvement and screening for com-
specific pathogenesis of recurrent LRTI and may relate to interac- plications at 48 h after commencement of oral antibiotics [13]. A
tions between RSV and other pneumonia causing pathogens. Post 2022 systematic review including both these national guidelines
hoc analyses of early life immunisation studies reported early life and twelve other clinical practice guidelines, highlighted the need
RSV immunisation to reduce all cause LRTI by 20.6 % (95 %CI 3.1 for further evidence to guide management in several key areas,
to 35.0) [9]. Early childhood LRTI is associated with a near doubling including duration of antibiotic therapy [14].
of early death from respiratory disease in adulthood (HR 1.93, 95 % Several recent well-designed studies have compared shorter
CI 1.1 to 3.4), independent of smoking and other risk factors [10]. antibiotic courses with clinical outcomes. A recent randomised
There are several major limitations relevant to these longitudi- controlled study compared outcomes following a 5- or 10-day
nal studies which include cross-sectional data, particularly reliance course of oral antibiotics for children with CAP managed in ambu-
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S. Haggie and I.M. Balfour-Lynn Paediatric Respiratory Reviews xxx (xxxx) xxx

Fig. 2. Simple right sided community-acquired pneumonia.

latory care. The shortened approach resulted in a similar clinical care setting, where most CAP management occurs. Limitations of
response and antibiotic associated adverse effects, while reducing CAP outcome studies among hospitalised cases include variable
antibiotic exposure and resistance [15]. A comparative effective- definitions of disease and disease severity, selective microbial test-
ness study of children hospitalised for uncomplicated CAP, com- ing and inclusion criteria limiting the generalisability of findings.
pared treatment with short course (5–7 days) vs prolonged Outcome data is further confounded by the changing pneumococ-
course (8–14 days) antibiotic therapy, against a composite primary cal vaccination program and more recently the impact of the
outcome of treatment failure. Treatment failure was defined as COVID-19 pandemic and primary health response.
unanticipated emergency department visit, hospital readmission Several unanswered questions of relevance to this topic include
or death (attributed to pneumonia) within 30 days of completing the management of children with comorbid conditions, at higher
antibiotic therapy. Of the 439 patients included, four percent expe- risk of CAP and severe disease, who are often excluded from trials.
rienced treatment failure with no differences observed between The PARROT trial (registration ACTRN12619001597189) is a multi-
treatment groups [16]. centre prospective randomised placebo-controlled trial in patients
An older but important UK study (PIVOT trial) of hospitalised with neurological impairment and will compare regular azithro-
paediatric pneumonia demonstrated therapeutic equivalence mycin vs placebo and assess CAP outcomes over 52 weeks. In addi-
between oral and intravenous antibiotics. This multicentre ran- tion, there are high quality data regarding the benefits of
domised non blinded equivalence trial, of children with non- corticosteroids in treating adult CAP with a lower incidence of pro-
severe pneumonia (excluding hypoxia SpO2 < 85 % in room air, gression to ICU admission and mechanical ventilation. The role of
shock or complicated pneumonia) reported no difference in the corticosteroids in paediatric CAP is poorly understood.
primary outcomes of time for fever to settle and oxygen require-
ment to cease, median time 1.3 days. The study also reported
longer term outcomes including time to resolution of symptoms SIMPLE COMMUNITY ACQUIRED PNEUMONIA – LONG TERM
(cough and return to usual activities) with a median of 9 days in OUTCOMES
both treatment groups. Eight children received a further course
of antibiotics, and one child was readmitted for intravenous antibi- Large airway injury
otics [17]. A cost analysis undertaken alongside this trial estimated
costs to the individual, health service and community from the Post-infective bronchiectasis in high income countries is reported
time of pre-admission to full recovery. Oral amoxicillin and intra- to range between 4% and 36 % [19] (Fig. 3). The more common cau-
venous benzylpenicillin had equivalent efficacy, but children trea- sative pathogens, in otherwise well children, include tuberculosis,
ted with intravenous antibiotics were found to have longer adenovirus and pertussis [20]. Although less common than cystic
hospital stays 3.1 vs 1.9 days p < 0.001) and at greater expense fibrosis and primary ciliary dyskinesia as a cause of bronchiectasis,
(£1256 vs £769 difference of means £488; 95 % CI £233 to £750) post-infection is still a major cause, with its main clinical manifes-
compared to oral treatment [18]. tation being recurrent pneumonia [21]. Airway infection and neu-
Of the available data reporting CAP outcomes, there are com- trophilic inflammation are potential precursors to airway
paratively few studies describing outcomes from the ambulatory dilatation and bronchiectasis. The term ‘post-infectious’ is used
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Fig. 3. Bronchiectasis following left lower lobe pneumonia. Mucus plugging also evident, with linear atelectasis in right middle lobe, left lower lobe and lingula.

imprecisely in the literature, some authors describing a single sev-

ere infectious event and others referring to multiple events. Fur-
thermore, studies have not sub-grouped the contributions of
complicated pneumonia cases to bronchiectasis, as distinct from
protracted bacterial bronchitis, or wheeze episodes, or other vari-
ants of LRTI.
Some insight to the most useful investigations to assess for
lower airway injury and inflammation in younger children can be
garnered from paediatric cystic fibrosis data. There is useful posi-
tive predictive value of the lung clearance index (LCI), a measure
of ventilation inhomogeneity, in children with airways disease,
though a poor negative predictive value. Recent studies in paedi-
atric cystic fibrosis suggest CT and multiple breath washout are
sensitive routine clinical tools to detect early lung disease. Though
data has not shown an association between the extent of structural
lung disease on imaging and single measures of LCI. Longitudinal
LCI measures and chest CT are positively associated with structural Fig. 4. Post adenovirus obliterative bronchiolitis. Marked mosaicism indicating air
lung disease. The best adult data of radiographic resolution post trapping, with collapsed left lower lobe.
CAP reported 6 % of patients had a persisting abnormality [22],
and although this is a low proportion, it translates into a large
infectious bronchiolitis obliterans (PIBO) is a rare complication of
number of patients.
CAP (Fig. 4). Across studies the most common pathogen associated
Higher rates of pneumonia are reported among indigenous chil-
with bronchiolitis obliterans is adenovirus followed by others
dren in Australia, New Zealand and Canada than their non-
including: Bordetella pertussis, Mycoplasma pneumoniae and Influ-
indigenous counterparts. Indigenous Australian children hospi-
enza A [25]. PIBO can develop at all ages but is much more common
talised with pneumonia were 15 times more likely to develop
in children.
bronchiectasis (OR 15.2 95 % CI 4.4, 52.7) [23]. The number of
Among a cohort of children hospitalised with adenovirus CAP,
pneumonia episodes, malnutrition, premature birth and low birth
the reported incidence of obliterative bronchiolitis within 5 years
weight were important variables associated with pneumonia and
was 48 % [26]. A meta-analysis reported obliterative bronchiolitis
bronchiectasis, whilst breastfeeding was protective (OR 0.2; 95 %
was more likely in more severe cases with hypoxaemia, mechani-
CI 0.1, 0.7). These observations are supported by combined data
cal ventilation and longer hospital stays, with wheeze as a common
(Australia, New Zealand and Alaska) associating bronchiectasis
presenting feature. While cases of PIBO worldwide are relatively
with substantial disparities in poverty indices and risk factors (en-
rare, the prevalence in Latin America appears significantly elevated
vironmental tobacco smoke exposure, household crowding, pre-
with over 700 cases reported in the literature [27].
maturity and early onset respiratory infections) [24].
The mainstay of treatment involves systemic steroids and long-
term azithromycin, although treatment is unsuccessful in revers-
Small airway injury ing airway injury or lung function, and recurrent hospitalisation
with respiratory infections is common [28]. A recent systematic
Bronchiolitis obliterans involves injury to respiratory bronchioles review and meta-analysis of PIBO in children reported moderate
which conduct air distally and participate in gas exchange; post obstruction as the most common spirometry outcome. Pooled esti-
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S. Haggie and I.M. Balfour-Lynn Paediatric Respiratory Reviews xxx (xxxx) xxx

Fig. 5. Moderate sized right sided empyema with a chest drain inserted.

Fig. 6. Severe right sided empyema.

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S. Haggie and I.M. Balfour-Lynn Paediatric Respiratory Reviews xxx (xxxx) xxx

Fig. 7. Severe left sided necrotising pneumonia with resolution at 1 month and excellent radiographic outcome at 6 months.

mates of FEV1 z-score 2.6 (95 %CI, 4.2 to 0.9) and FEV1/FVC of CAP, however most are not clinically relevant in as far as they do
ratio pooled estimates were 2.0 (95 %CI, 2.5 to 1.5) [28]. There not require altered management [13].
is considerable research interest in the management of bronchioli- In high income countries, mortality from complicated pneumo-
tis obliterans secondary to chronic lung allograft dysfunction or nia is rare, estimated at 1 % [32–34]. Complicated pneumonia mor-
pulmonary graft versus host disease, and these advances may bidity is associated with lengthy hospitalisations (median 12–
inform future therapies transferable to PIBO [29]. 16 days [32,33]), invasive drainage procedures 22–73 % [35,36]),
bacteraemia and prolonged intravenous antibiotic treatments. The
SEVERE COMPLICATED PNEUMONIA – ACUTE OUTCOMES presence or development of a bronchopleural fistula considerably
extends the median duration of pleural drainage by approximately
Complicated pneumonia refers to advanced pulmonary disease 16 days and subsequent hospitalisation by 18 days [37].
and encompasses the singular or more often coexisting pathologies Intensive care admission rates are higher among complicated
of parapneumonic effusion, empyema, necrotising pneumonia, pneumonia than uncomplicated; a large multicentre US cohort
bronchopleural fistula, pulmonary abscess and acute respiratory reported rates in 2011–2018 as 24 % in complicated vs 12 %, in
distress syndrome (Figs. 5–8). uncomplicated cases (p < 0.01) [38]. Complicated pneumonia cases
The burden of pneumonia-related hospitalisation is highest managed with intensive care treatment still have high rates of sur-
among preschool age children, median ages 24–28 months vival when supported by mechanical ventilation (92%) and extra
[30,31]. Complication rates among hospitalised CAP are conserva- corporeal membranous oxygenation (ECMO) (88 %) [39]. Veno-
tively estimated as 12–23 %, based on patients receiving invasive venous ECMO is the ideal extracorporeal modality to support these
drainage procedures or intensive care admission [30,31]. The pre- patients if left ventricular function is not depressed [40]. ECMO
cise proportion of complicated pneumonia is difficult to estimate survival rates in the setting of complicated pneumonia, compares
and may well be considerably higher, for example the British Tho- favourably with other indications such as sepsis where survival is
racic Society reported parapneumonic effusions to complicate 40 % generally less than 50 % [41].

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S. Haggie and I.M. Balfour-Lynn Paediatric Respiratory Reviews xxx (xxxx) xxx

Fig. 8. Abscess in right upper lobe.

Surgical interventions beyond lung decortication, including Pulmonary function

wedge resection or lobectomy, are rarely performed in Australia
and the UK for the management of necrotising pneumonia. Our There is an emerging evidence base demonstrating impaired lung
experience is that with time and enough patience, the disease function following complicated pneumonia, though studies are
resolves without the need for surgery and its resulting loss of lung inconsistent as to whether this deficit persists long term. The most
tissue. However, internationally the experience is varied with recent described abnormality on lung function, for patients managed with
case series from Mexico, Czechia and Taiwan reporting a more rou- invasive pleural drainage procedure(s) is a restrictive lung disease,
tine approach to surgical resection in cases of cavitating lung disease detectable at 3 months post discharge [49,50]. Of the 76 cases
involving 50 % of the involved lobe [42–44]. Operative lung resec- reported in these studies, all were asymptomatic, and most recov-
tion was more common in patients with necrotising pneumonia and ered when pulmonary function tests were repeated 1 year.
air leak receiving mechanical ventilation [44]. A novel emerging The proposed mechanism of restrictive spirometry pattern in
interventional pulmonology technique, for the management of air parapneumonic effusion or empyema is residual pleural scarring
leak complicating necrotising pneumonia, involves the placement and fibrosis with focal changes in lung compliance. Obstructive
of endobronchial valves [45]. The valves limit air entry into selected patterns meanwhile are thought to be associated with airway
regions of lung at the level of the bronchus into which it is placed, inflammation and a reduction in calibre affording increased airway
facilitating local deflation and healing of the parenchymal or bron- resistance [51].
chopleural fistula. The valves are designed for easy removal with There are scant data on dynamic lung function testing with car-
standard biopsy forceps following resolution of the air leak (typi- diopulmonary exercise testing (CPET); a cohort of 51 children post
cally 4–6 weeks post insertion) [46,47]. complicated pneumonia, performed spirometry and cycle ergome-
Readmission rates among children previously hospitalised with ter CPET, and these were compared with 20 healthy male controls
pneumonia, from a US multicentre cohort study of nearly 83,000 chil- [52]. This study reported no difference in maximal oxygen utilisa-
dren reported an 8 % all cause readmission within 30 days, with 3 % tion (VO2 max) though differences were observed in the pneumo-
due to pneumonia [48]. The strongest factors associated with hospi- nia cases with a lower mean breathing reserve during exercise
tal readmission are younger age (<1 year), complicated pneumonia, (31 % vs 37 %, p = 0.05) and a hyperventilatory response to exercise
and the presence of pre-exiting chronic medical conditions [38,48]. (30 % vs 27 %, p = 0.03). These small but statistically significant val-
ues were of unclear clinical significance.
Therefore, among a subset of patients, paediatric empyema is
associated with a persistent reduction in lung function. This is of par-
ticular concern in acknowledging the contribution of the origins of
SEVERE COMPLICATED PNEUMONIA – LONG TERM OUTCOMES
adult chronic lung disease from lung injury acquired in early life [53].
The clinical long-term outcomes of complicated pneumonia are
generally excellent, especially compared to adults who often have Structure
significant co-morbidities. Functional impairment and, in the
absence of underlying immune deficiency or other co-morbidity, Among a Finnish cohort of 26 patients managed for empyema at
repeat hospitalisation for CAP is rare. a mean age 4.4 yrs, with contrast enhanced 1.5 T MRI imaging,
7
S. Haggie and I.M. Balfour-Lynn Paediatric Respiratory Reviews xxx (xxxx) xxx

without anaesthetic, at mean 12.6 yrs of age, abnormalities were [6] Chan JY, Stern DA, Guerra S, Wright AL, Morgan WJ, Martinez FD. Pneumonia in
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