[ Original Research Bronchiectasis ]

Protracted Bacterial Bronchitis in Children

Natural History and Risk Factors for Bronchiectasis
Danielle F. Wurzel, PhD; Julie M. Marchant, PhD; Stephanie T. Yerkovich, PhD; John W. Upham, PhD;
Helen L. Petsky, PhD; Heidi Smith-Vaughan, PhD; Brent Masters, PhD; Helen Buntain, PhD; and Anne B. Chang, PhD

BACKGROUND: Protracted bacterial bronchitis (PBB) and bronchiectasis are distinct diag-
nostic entities that share common clinical and laboratory features. It is postulated, but re-
mains unproved, that PBB precedes a diagnosis of bronchiectasis in a subgroup of children.
In a cohort of children with PBB, our objectives were to (1) determine the medium-term risk
of bronchiectasis and (2) identify risk factors for bronchiectasis and recurrent episodes of
PBB.
METHODS: One hundred sixty-one children with PBB and 25 control subjects were pro-
spectively recruited to this cohort study. A subset of 106 children was followed for 2 years.
Flexible bronchoscopy, BAL, and basic immune function tests were performed. Chest CT was
undertaken if clinical features were suggestive of bronchiectasis.
RESULTS: Of 161 children with PBB (66% boys), 13 were diagnosed with bronchiectasis over
the study period (8.1%). Almost one-half with PBB (43.5%) had recurrent episodes (> 3/y).
Major risk factors for bronchiectasis included lower airway infection with Haemophilus
influenzae (recovered in BAL fluid) (P ¼ .013) and recurrent episodes of PBB (P ¼ .003). H
influenzae infection conferred a more than seven times higher risk of bronchiectasis (hazard
ratio, 7.55; 95% CI, 1.66-34.28; P ¼ .009) compared with no H influenzae infection. The
majority of isolates (82%) were nontypeable H influenzae. No risk factors for recurrent PBB
were identified.
CONCLUSIONS: PBB is associated with a future diagnosis of bronchiectasis in a subgroup of
children. Lower airway infection with H influenzae and recurrent PBB are significant pre-
dictors. Clinicians should be cognizant of the relationship between PBB and bronchiectasis,
and appropriate follow-up measures should be taken in those with risk factors.
CHEST 2016; 150(5):1101-1108

KEY WORDS: bacterial infection; bronchiectasis; pediatric lung disease; respiratory infection;
viral infection

ABBREVIATIONS: CFU = colony-forming units; IQR = interquartile Transplant Service (Dr Yerkovich), Prince Charles Hospital, Brisbane,
range; PBB = protracted bacterial bronchitis Australia; School of Medicine (Drs Yerkovich and Upham), The Uni-
AFFILIATIONS: From Queensland Children’s Medical Research Institute versity of Queensland, Brisbane, Australia; Child Health Division (Drs
(Drs Wurzel, Marchant, Petsky, Masters, Buntain, and Chang), Brisbane, Smith-Vaughan and Chang), Menzies School of Health Research,
Australia; Queensland Children’s Health Service (Drs Marchant, Petsky, Charles Darwin University, Darwin, Australia; and School of Medi-
Masters, and Chang), Brisbane, Australia; Murdoch Children’s Research cine (Dr Smith-Vaughan), Griffith University, Gold Coast, Australia.
Institute (Dr Wurzel), Melbourne, Australia; Queensland Lung

journal.publications.chestnet.org 1101
Protracted bacterial bronchitis (PBB), first described in appears to be associated with a future diagnosis of
2006, is a major cause of chronic cough in children.1,2 bronchiectasis.
PBB has been studied by research groups in Australia,1-3
Europe,4 and the United States, with similar findings.5,6 PBB and bronchiectasis share many common features,
PBB is characterized by persistent wet cough, response spanning from respiratory symptoms (ie, chronic
to 2 weeks of appropriate antibiotic therapy, and absence wet cough) to intense neutrophilic lower airway
of indicators to suggest an alternative cause for cough.1,7 inflammation and innate immune system activation.10-12
PBB is more common in young boys and children who Lower airway microbiota,13 including the presence
have attended child care.8 When compared with control of adenovirus type C14 and a predominance of
subjects, children with PBB are more likely to have lower non-typeable Haemophilus influenzae1,8 are also alike.
airway infection with common respiratory bacteria and These similarities underpin the notion that PBB and
viruses.8 bronchiectasis represent a clinical continuum.15,16 To
date, the accuracy of this proposed continuum is
Currently, there are limited published data9 and no uncertain and warrants evaluation in a prospective
prospective follow-up studies evaluating the outcomes of cohort study.
children with PBB. This research gap limits the
clinician’s ability to prognosticate on the likely natural Hence, in 161 children with PBB and 25 control
history of PBB in any given child. Anecdotally, many subjects, we aimed to determine (1) the 2-year outcomes
otherwise healthy children experience recurrent episodes of children with PBB with respect to a diagnosis of
of PBB without appreciable longer-term consequences. bronchiectasis and (2) risk factors for bronchiectasis and
However, in a subgroup of children, recurrent PBB recurrent episodes of PBB.

Methods All children (excluding the 10 healthy control subjects) underwent

flexible bronchoscopy and BAL per clinical indication and were
Study Participants
recruited prior to the bronchoscopy procedure. BAL was processed
Participants were enrolled as part of a larger prospective cohort study for cellularity and microbiological features. Bacterial infection was
aimed at evaluating the long-term outcomes of children with chronic defined as a bacterial load of $ 104 colony-forming units (CFU)/mL
cough. Written informed consent was obtained from all parents/ BAL fluid.8,11 Laboratory tests for suppurative lung diseases were
guardians, and ethics approval was granted by The Queensland performed, as described previously.14 H influenzae characterization
Children’s Health Services Human Research Ethics Committee was undertaken at a research laboratory (Menzies School of Child
(HREC/03/QRCH/17). Health Research, Darwin, Australia) when BAL fluid was available
(e-Appendix 2).
Between March 2008 and October 2012, 343 children were enrolled. Of
them, 161 fulfilled criteria for PBB; 25 were recruited as control
Follow-up
participants (15 undergoing evaluation for respiratory symptoms
other than chronic cough plus 10 healthy control subjects). Data Follow-up included monthly contact (phone calls or e-mails by
from the 15 children undergoing respiratory evaluation have been research nurses) to capture respiratory exacerbations. Parents
previously described8 (e-Appendix 1). The 10 healthy control completed cough diaries during periods of illness. Antibiotic therapy
subjects were recruited from colleagues and friends. was usually prescribed by a family doctor when appropriate
according to usual clinical management. The majority of children
were seen by their pediatric pulmonologist three to four times per
year as part of routine clinical follow-up. At 2 years, a subset
This work was presented in abstract form at the European Respiratory (n ¼ 106) also underwent clinical assessment for bronchiectasis
Society (ERS) International Congress, September 26-30, 2015. Amsterdam, (D. F. W. or A. B. C., or both).
Netherlands.
FUNDING SUPPORT: This work was supported by the National Health Given the ethical considerations pertaining to research-related chest
and Medical Research Council (NHMRC) [project grant 1042601 and CT in children,17,18 CT imaging was performed only when clinical
Centre of Research Excellence grant 1040830] and the Financial features of bronchiectasis were present.19 Clinicians had similar
Markets Foundation for Children [project grant 2010-005]. D. W. was practices, whereby chest CT imaging was undertaken for (1) chronic
supported by scholarships from the Thoracic Society of Australia and wet cough that was nonresponsive to 4 weeks of antibiotic therapy,20
New Zealand/Allen and Hanbury’s, Queensland Children’s Medical
(2) persistent chest radiographic changes despite appropriate
Research Institute and NHMRC [1039688]. A. C. and H. S. V. are
supported by NHMRC fellowships [1058213 and 1024175]. The views antibiotic therapy, or (3) recurrent hospitalizations for acute
expressed in this publication are those of the authors and do not reflect respiratory events.
the views of the NHMRC.
CORRESPONDENCE TO: Danielle Wurzel, PhD, Murdoch Children’s
Definitions
Research Institute, Melbourne, VIC 3052, Australia; e-mail: danielle. PBB was defined as (1) a history of chronic ($ 4 weeks) wet cough,
[email protected] (2) prospective evidence (supported by cough diaries) of response to
Copyright Ó 2016 American College of Chest Physicians. Published by 2 weeks of treatment with amoxicillin clavulanate, and (3) an
Elsevier Inc. All rights reserved. absence of clinical pointers suggesting an alternative cause for
DOI: http://dx.doi.org/10.1016/j.chest.2016.06.030 cough.1 Diagnosis of bronchiectasis was based on pediatric

1102 Original Research [ 150#5 CHEST NOVEMBER 2016 ]

radiological (CT) criteria,21 in the context of a child having clinical data were nonnormally distributed. Pearson’s c2 test (or Fisher’s exact
symptoms of bronchiectasis. Two respiratory physicians blinded to test) was used for categorical variables, and the Mann-Whitney U test
each other’s assessment reviewed all CT images. Recurrent PBB was was used for continuous variables. Logistic regression was used to
defined as more than three episodes of PBB in the first year after calculate OR and 95% CI. A survival analysis (using Cox’s
enrollment. proportional hazards regression) examined the relationship between
time to diagnosis of, and risk factors for, bronchiectasis. A two-tailed
Statistical Analyses P value of < .05 was considered statistically significant. Statistical
Descriptive statistics were used to summarize demographic and clinical analyses were performed using IBM SPSS Statistics, version 21.0
characteristics. Median and interquartile range (IQR) were reported, as (SPSS, Inc.) and STATA, version 12.1 (StataCorp LP).

Results physician visits in the preceding 12 months compared

with the control subjects (Table 1).
Clinical and Demographic Characteristics of
Participants Compared with control subjects, at 2-year follow-up
Of the 161 children with PBB, 106 completed the 2-year children with PBB were more likely to be coughing
follow-up period and had clinician assessment for (44% vs 12%; P ¼ .005) and receiving antibiotic
bronchiectasis (Fig 1). The median duration of follow- therapy (20% vs 0%; P ¼ .012). The burden of
up was 25 months (IQR, 24-28) in children with PBB physician visits (in previous 5 years) was higher in the
and 27 months (IQR, 26-29) in control subjects children with PBB compared with the control subjects
undergoing bronchoscopy. (44% vs 5%; P ¼ .001), and those with PBB were more
likely to have had parent-reported wheezing in the
There was no difference between children who
preceding 12 months (58% vs 16%; P ¼ .001). Of the
completed the 2-year follow-up and those who did not
161 children with PBB, 154 had completed cough
(Table 1) with regard to duration of cough at
diaries until at least the 1-year time point. Of them, 67
recruitment (P ¼ .807), H influenzae status (P ¼ .518),
had recurrent PBB (43.5%) (more than three episodes
or proportion of subjects with 2þ siblings (P ¼ .260).
per year).
However, those completing the 2-year follow-up
(n ¼ 106) were significantly more likely to have had
recurrent PBB (P ¼ .003). Thus to reduce the potential Bronchiectasis Diagnoses on Chest CT Scan
for bias, 161 was used as the denominator in subsequent Multidetector CT with high-resolution CT
analyses. The 55 additional children who did not reconstruction was performed in 25 of 161 children
complete 2-year follow-up were assumed to be free of with PBB. Radiological evidence of bronchiectasis was
bronchiectasis at the 2-year time point. We assumed this present in 13 children (8.1%), and all had mild (ie,
because when these families were contacted by phone, cylindrical) bronchiectasis. CT imaging was performed
the vast majority of children had had resolution of their at a median duration of 9 months (IQR, 4-19) after
chronic coughs. Comparison of groups at baseline recruitment. Their median age was 38 months (IQR,
showed that children with PBB had a higher burden of 27-58).
Compared with those who did not undergo CT imaging,
Recruited to "cough study" (N = 343) children with PBB who underwent chest CT imaging
had similar rates of lower airway infection with H
Excluded (n = 182) influenzae (P ¼ .142) and Streptococcus pneumoniae
• Did not meet PBB criteria (P ¼ 0.135); however, those undergoing CT imaging
were less likely to have Moraxella catarrhalis infection
Included (n = 161)
"PBB total"
than were those who did not undergo CT imaging
(34.2% vs 17%; P ¼ .029) (likely to have been a chance
Excluded (n = 55) occurrence.) Similar rates of “recurrent PBB” status were
• Withdrew (n = 13) recorded in those who underwent CT imaging and those
• Incomplete cough diaries
(n = 42)
who did not (P ¼ .118).
No children in the control group experienced clinical
Included (n = 106)
features of bronchiectasis. Of the control group, three
"PBB followed-up"
children had CT imaging performed for other
Figure 1 – CONSORT diagram. PBB ¼ protracted bacterial bronchitis. indications. None had bronchiectasis.

journal.publications.chestnet.org 1103
TABLE 1 ] Baseline Demographic and Clinical Characteristics of Study Participants
PBB Followed-up PBB total Control Subjects
Variable (n ¼ 106) (N ¼ 161) (n ¼ 25) P Valuea
Sex, Male (female) 74 (32) 106 (55) 12 (13) .085
Age, mo 23 (14-53) 22 (13-50) 44 (7-97) .061
Prior pneumonia radiographically 24 (23) 35 (22) 2 (8) .109
confirmed, No. (%)b
Household tobacco smoke 36 (34) 55 (34) 6 (24) .662
exposure, No. (%)
Aboriginal or Torres Strait 3 (3) 10 (6) 0 .363
Islander, No. (%)
Current cough, No. (%) 89 (84) 134 (83) 2 (8) < .001
Length of current cough, median 26 (7-52) 26 (6-52) 0 < .001
(IQR), wk
Current antibiotics, No. (%) 16 (15) 19 (12) 1/15 (7) .695
>5 doctor visits past y for cough, 95 (90) 140 (87) 3/15 (20) < .001
No. (%)

PBB followed-up refers to the subset of patients with PBB who completed 2-year follow-up; PBB total refers to all patients with PBB, irrespective of whether
2-year follow-up was completed. Boldface denotes statistical significance, P < .05. IQR ¼ interquartile range; PBB ¼ protracted bacterial bronchitis.
a
Comparison of “PBB total” to control subjects.
b
Parent-reported prior pneumonia.

Risk Factors for Bronchiectasis and Recurrent PBB respectively. Total cell counts, percentage of
Univariate analysis showed that bronchiectasis was macrophages, and percentage of lymphocytes were
significantly more likely to be diagnosed during similar between groups. Although the percentage of
follow-up when the child had recurrent PBB, when eosinophils in BAL fluid was slightly higher in those in
H influenzae infection was present (ie, cultured at a whom bronchiectasis developed (BAL eosin %, 1 [IQR,
clinically significant level of $ 104 CFU/mL in BAL 0-2) vs 0 [IQR, 0-0]; P ¼ .001), the median eosinophil
fluid), or in children with two or more siblings (Table 2). count was within the normal range (ie, < 2.5%),22 and
There were no significant intergroup differences for hence this finding was considered to be clinically
other factors. insignificant. Further, the difference was no longer
observed when the major outlier was removed.
Multivariate logistic regression showed that recurrent
PBB status and H influenzae infection were significantly In the examination of predictors for recurrent PBB,
associated with bronchiectasis diagnosis (OR, 11.48; univariate and multivariate analyses showed no
95% CI, 2.33-56.50; P ¼ .003 and OR, 7.60; 95% CI, significant difference between children with and those
1.53-37.79; P ¼ .013, respectively), whereas having two without recurrent PBB for the factors examined (sex,
or more siblings was no longer significant (OR, 3.53; age, prior pneumonia, tobacco smoke exposure,
95% CI, 0.98-12.70; P ¼ .054). Survival analysis, using maternal tobacco smoking in pregnancy, indigenous
Cox regression, concurred with logistic regression status, number of children in household, child care
findings. Participants with H influenzae lower airway attendance, and BAL fluid cellularity and
infection were more than seven times more likely to be microbiological characteristics) (e-Table 1). Notably,
diagnosed with bronchiectasis per month of follow-up H influenzae infection seen in BAL fluid did not predict
than were those without H influenzae infection, and recurrent PBB.
recurrent PBB status conferred more than a nine times
greater risk of bronchiectasis diagnosis per month H influenzae Typing
(Table 3).
Thirty-four of 55 H influenzae-positive samples (62%)
The percentage of lower airway neutrophils was similar were available for further characterization. Of these,
in children with and those without a subsequent H influenzae from the majority of samples (n ¼ 28
diagnosis of bronchiectasis (BAL neutrophil %, 35 [IQR, [82%]) were identified as non-typeable H influenzae;
12-75] vs 25 [IQR, 10-55]; P ¼ .35) in the group with encapsulated H influenzae were not identified.
bronchiectasis and the group without bronchiectasis, H influenzae from the remaining six samples were

1104 Original Research [ 150#5 CHEST NOVEMBER 2016 ]

TABLE 2 ] Univariate and Multivariate Analysis of Risk Factors for Bronchiectasis in Children With PBB
Group 1 Group 2
Bronchiectasis Bronchiectasis
Risk Factor Present (n ¼ 13) Absent (n ¼ 148) OR (95% CI) P value
Univariate analysis
Sex, Male (Female) 8 (5) 98 (50) 0.816 (0.25-2.63) .733
Recruitment age, median (IQR), 29 (10-45) 22 (13-50) 0.99 (0.97-1.01) .521
mo
Prior pneumonia, No. (%) 3 (23) 32 (22) 1.09 (0.28-4.19) .903
Recurrent PBB (> 3 episodes/y), 11 (85) 56 (38) 9.04 (1.93-42.27) .005
No. (%)a
Household tobacco smoke 3 (23) 52 (35) 0.55 (0.14-2.08) .377
exposure, No. (%)
Maternal smoking in pregnancy, 3 (23) 18 of 85 (21) 1.40 (0.34-5.81) .647
No. (%)
Aboriginal or Torres Strait 1 (8) 9 (6) 1.29 (0.15-11.03) .818
Islander, No. (%)
No. of children in household, 3 (2-4) 2 (2-3) 1.28 (0.91-1.80) .156
median (IQR)
$ 2 siblings, No. (%) 8 (62) 47 (32) 3.44 (1.07-11.08) .039
$ 1 sibling, No. (%) 13 (100) 123 (83) ...
Childcare attendance, ever (%) 8 of 9 (89) 71 of 82 (87) 1.24 (0.14-1.90) .847
BAL fluid organism
Adenovirus positive (on PCR)b 3 of 12 (25) 26 of 138 (19) 1.44 (0.36-5.68) .606
H influenzae, No. (%)c 11 (85) 72 (49) 5.81 (1.24-27.10) .025
Moraxella catarrhalis, No. (%) 4 (31) 43 (29) 1.09 (0.32-3.71) .896
Streptococcus pneumoniae, 3 (23) 41 (28) 0.78 (0.21-2.99) .720
No. (%)
Staphylococcus aureus, 1 (8) 12 (8) 0.94 (0.11-7.90) .958
No. (%)
Multivariate analysis
H influenzae ... ... 7.60 (1.53-37.79) .013
$ 2 siblings ... ... 3.53 (0.98-12.70) .054
Recurrent PBB (> 3 episodes/y) 11.48 (2.33-56.50) .003

Boldface denotes statistical significance, P < .05. PCR ¼ polymerase chain reaction. See Table 1 legend for expansion of other abbreviation.
a
As determined at 1-year time point in study. Seven children had not reached the 1-year time point. For the purposes of the multivariate analysis, these
children were assumed to have nonrecurrent PBB.
b
Compared with previously published rate of 4% (adenovirus positivity) in BAL samples from control children.8
c
b-lactamase-positive strains of H influenzae were found in 17 of 83 isolates (20.5%). Of these, 3 occurred in children from group 1 (27%) and 14 from
group 2 (19%); OR, 2.87; 95% CI, 0.70-11.67; P for difference between groups ¼ 0.143.

reassigned as H haemolyticus following species-specific recurrent (more than episodes 3 per year) PBB and the
polymerase chain reaction. presence of H influenzae infection in the lower airways.
Further, H influenzae infection, compared with no
infection, conferred more than a seven times higher risk
Discussion
of a bronchiectasis diagnosis.
This is the first prospective longitudinal cohort study of
children with PBB. In our cohort, which was based in a Findings from this study, the first to investigate the
large tertiary pediatric hospital, almost 44% of subjects 2-year outcomes of children with PBB, support the
had recurrent episodes (more than three episodes in the hypothesis that PBB and bronchiectasis represent a
first year after recruitment) and approximately one in 12 clinical spectrum. Children with PBB have
were diagnosed with bronchiectasis at 2 years. We endobronchial bacterial infection and neutrophilic
identified two significant risk factors for bronchiectasis: airway inflammation, factors known to be injurious to

journal.publications.chestnet.org 1105
TABLE 3 ] Survival Analysis: PBB to Bronchiectasis In this study, bronchiectasis was diagnosed at an early age
(mo) (N ¼ 161) (median, 38 months), similar to our other cohorts of
HR (95% CI) P Value children with bronchiectasis.10,20,35 Together with findings
Univariate from earlier studies on PBB,8,14 this observation lends
H influenzaea 5.81 (1.28-26.37) .022 further support to the assertion that timing of airway
$ 2 siblings 3.18 (1.04-9.73) .042 infection (with bacteria or viruses, or both), with respect to
Recurrent PBB 7.65 (1.67-34.92) .009 age, is likely to be important.14 All children had mild or
(> 3 episodes/y) early cylindrical bronchiectasis, which is potentially
Multivariate reversible if treated early and intensively,36-38 prior to the
H influenzaea 7.55 (1.66-34.28) .009 development of severe (saccular or cystic) bronchiectasis.
Recurrent PBB 9.77 (2.13-44.80) .003
(> 3 episodes/y) In support of previous studies on PBB, the present study
showed that PBB is characterized by active lower airway
Boldface denotes statistical significance, P < .05. See Table 1 legend for
neutrophilic inflammation. Although the median
expansion of other abbreviation.
a
Lower airway infection with H influenzae defined as $ 104 CFU/mL neutrophil percentage in BAL fluid was greater in
growth on BAL fluid culture. children with PBB who were subsequently diagnosed
with bronchiectasis compared with those who were not
(median, 35% vs 25%, respectively), this difference was
the airways.23 Our findings suggest that in a subset of
not significant. This suggested that the degree of airway
children receiving close follow-up by pediatric
neutrophilia did not predict bronchiectasis. Regarding
pulmonologists, recurrent episodes (more than three per
the intergroup disparity in airway eosinophil levels
year) of PBB precede a diagnosis of bronchiectasis.
between those with and those without bronchiectasis,
Further, although a cause-effect relationship cannot be
this is unlikely to be of clinical relevance for two reasons.
concluded, an association between H influenzae
First, eosinophil levels in both groups were within
infection and bronchiectasis has been shown. This
normal reported ranges and second, when the major
finding is in accordance with the increasing recognition
outlier was removed (16% eosinophils in a child with
of the role of H influenzae in the pathogenesis of chronic
features consistent with persistent asthma in addition to
respiratory diseases.24
PBB), the difference was no longer significant.
H influenzae is the most common bacterial species
Several limitations to this study merit discussion. The
infecting the lower airways of children with
most significant limitation is the fact that we did not
endobronchial suppuration, including PBB,8 recurrent
perform CT imaging in all children at study entry and
or nonresponsive community-acquired pneumonia,25
exit. Given the potential increased lifetime risk of cancer
and bronchiectasis.8,10,26 H influenzae is also the major
associated with exposure to CT imaging (and the
bacterial pathogen associated with chronic respiratory
relatively common nature of PBB in otherwise well
disorders in adults, for example, bronchiectasis and
children),39 we could not justify performing two CT
COPD.24,27,28 Although H influenzae infection may be
scans on every child.18 The impact of this limitation is
an important risk factor for bronchiectasis,26,29-32 there
twofold. First, bronchiectasis may have been missed in
are likely to be other contributory factors.
some children at recruitment and indeed at follow-up.
Our earlier studies identified that children with PBB Hence, we cannot conclude that PBB progresses to
were significantly more likely than control subjects to bronchiectasis per se. Rather, our findings indicate that
have attended child care and to have viral infection of in children with PBB (who are followed closely by
their lower airways, particularly with adenovirus type pulmonologists), a proportion (approximately 8%) will
C.8,14 It is plausible, although beyond the scope of this be diagnosed with bronchiectasis on chest CT imaging at
study, that coinfection with specific pathogens—for 2 years. Second, we acknowledge the fact that
example, adenovirus C and H influenzae—33 initiates the performing CT imaging in only a select subgroup
vicious cycle of lower airway infection and inflammation introduces the possibility of selection bias in that
inherent to these conditions.34 Factors such as young age individual clinicians may have different indications for
at initial infection (and concomitant immune and performing chest CT imaging. To address this, we
respiratory system immaturity) may also play a key role compared children with PBB undergoing chest CT
in the etiopathogenesis.14 imaging with those who did not and found no

1106 Original Research [ 150#5 CHEST NOVEMBER 2016 ]

significant differences between groups with respect to does not, however, diminish the utility or relevance of
bronchiectasis risk factors. our findings. Irrespective of whether H influenzae is a
cause (or consequence) of bronchiectasis in young
To definitively address our major research question, an
children, its presence in a child with recurrent PBB
ideal study design would include a large cohort of
should alert the pulmonologist to the increased
healthy (cough-free) children. CT imaging to investigate
possibility of bronchiectasis, suggesting the need for
for bronchiectasis would need to be performed at both
closer monitoring or further investigation, or both. This
study entry and exit. Multiple lower airway samples
is a novel finding with direct clinical relevance to those
collected over time, in addition to clinical data on cough
managing children with chronic cough.
and episodes of PBB, would need to be obtained. This
would elucidate the temporal sequence of lower airway Findings from this longitudinal cohort study provide
infection, symptom onset, and bronchiectasis. further evidence to support a link between PBB and
Additionally, study numbers would need to be very bronchiectasis in young children. We have shown that
large. For example, to detect one child in whom approximately one in 12 children with PBB are
bronchiectasis develops in New Zealand (where diagnosed with bronchiectasis at 2-year follow-up, with
prevalence is estimated at 33 per 100,000 children aged many experiencing recurrent episodes of PBB. We have
0-14 years),40 several thousand children would need to identified potential risk factors for bronchiectasis, that is,
be enrolled. The ethical issues pertaining to performing H influenzae lower airway infection and recurrent
chest CT imaging and BAL in such a context are indeed episodes of PBB.
significant. Thus, from a practical and ethical
Clinicians should be cognizant of the need to monitor
standpoint, it would be extremely difficult to justify a
children with PBB over time and to consider chest CT
study with the ideal design.
imaging in those with risk factors for bronchiectasis.
The major strengths of this study are the longitudinal Further longitudinal studies examining the outcomes
nature of data collection and the inclusion of lower of children with PBB, ideally using novel (low-
airway inflammatory and microbiological findings. radiation dose) imaging techniques, are needed. Last,
However, as we performed bronchoscopy and BAL at further research into the potential role of H influenzae
only a single time point, the temporal relationship in the pathogenesis of bronchiectasis in children is
between infection with H influenzae and the needed to inform future preventive and therapeutic
development of bronchiectasis remains unclear. This interventions.

Acknowledgments Financial/nonfinancial disclosures: None Additional information: The e-Appendixes

declared. and e-Table can be found in the
Author contributions: D. F. W. co- Supplemental Materials section of the online
Role of sponsors: The sponsor had no role in
conceptualized the study, is responsible for article.
the design of the study, the collection and
the content of the manuscript including data
analysis of the data, or the preparation of the
analysis and manuscript preparation, and was
involved in data collection. J. M. M. co-
manuscript. References
conceptualized the study and contributed to Other contributions: We wish to thank the 1. Marchant JM, Masters IB, Taylor SM,
data interpretation and manuscript families that participated in this study. We also et al. Evaluation and outcome of young
preparation. S. T. Y. co-conceptualized the thank the Cough and Asthma Airways children with chronic cough. Chest.
study, contributed to aspects of data analyses, Research Group (CAARG) research team at 2006;129(5):1132-1141.
and provided critical review of the the Department of Respiratory and Sleep 2. Chang AB, Robertson CF, van
manuscript. J. W. U. co-conceptualized Medicine, Lady Cilento Children’s Hospital Asperen PP, et al. A cough algorithm for
the study and provided critical review of the (formerly The Royal Children’s Hospital), chronic cough in children: a multicenter,
manuscript. H. L. P. contributed to data Brisbane for their invaluable contribution. The randomized controlled study. Pediatrics.
acquisition and study coordination and members include Sophie Anderson-James, BN 2013;131(5):e1576-e1583.
provided critical review of the manuscript. (data collection, patient recruitment, study 3. Gibson PG, Chang AB, Glasgow NJ, et al.
H. S-V. was responsible for characterization coordination), Carol Willis (data entry), CICADA: Cough in Children and Adults:
of Haemophilus influenzae isolates and Sandra Goodwin (data entry), Joanne Tuppin, diagnosis and Assessment. Australian
provided critical review of the manuscript. BN, (data collection and patient recruitment) cough guidelines summary statement.
B. M. and H. B. contributed to acquisition of and Samantha Gardiner, BN (data collection Med J Aust. 2010;192(5):265-271.
the data and critical review of the manuscript. and patient recruitment). We also thank 4. Dinwiddie R. Anatomy and development
A. B. C. co-conceptualized the study and Jemima Beissbarth, BSc (Menzies School of of the respiratory system. In: Eber E,
contributed to all aspects, including Health Research, Charles Darwin University, Midulla F, eds. ERS Handbook of
hypothesis delineation, study design, data Darwin, Australia), for her laboratory work in Paediatric Respiratory Medicine. Sheffield,
acquisition, interpretation of results, and processing samples for non-typeable H UK: The European Respiratory Society;
manuscript preparation. influenzae data. 2013:1-10.

journal.publications.chestnet.org 1107
 5. Kompare M, Weinberger M. Protracted 18. Pearce MS, Salotti JA, Little MP, et al. 29. Sethi S, Murphy TF. Bacterial infection in
bacterial bronchitis in young children: Radiation exposure from CT scans in chronic obstructive pulmonary disease in
association with airway malacia. J Pediatr. childhood and subsequent risk of 2000: a state-of-the-art review. Clin
2012;160(1):88-92. leukaemia and brain tumours: a Microbiol Rev. 2001;14(2):336-363.
6. Zgherea D, Pagala S, Mendiratta M, et al. retrospective cohort study. Lancet.
30. Butt HL, Clancy RL, Cripps AW, et al.
Bronchoscopic findings in children with 2012;380(9840):499-505.
Bacterial colonisation of the respiratory
chronic wet cough. Pediatrics. 19. Chang AB, Bell SC, Byrnes CA, et al. tract in chronic bronchitis. Aust N Z J
2012;129(2):e364-e369. Chronic suppurative lung disease and Med. 1990;20(1):35-38.
7. Shields MD, Bush A, Everard ML, et al. bronchiectasis in children and adults in
Australia and New Zealand. Med J Aust. 31. Clancy RL, Dunkley M. Acute
BTS guidelines: recommendations for the exacerbations in COPD and their control
assessment and management of cough in 2010;193(6):356-365.
with oral immunization with non-typeable
children. Thorax. 2008:iii1-iii15. 20. Goyal V, Grimwood K, Marchant J, et al. haemophilus influenzae. Front Immunol.
8. Wurzel DF, Marchant JM, Yerkovich ST, Does failed chronic wet cough response to 2011;2:7.
et al. Prospective characterization of antibiotics predict bronchiectasis? Arch
Dis Child. 2014;99(6):522-525. 32. Bilton D, Pye A, Johnson MM, et al. The
protracted bacterial bronchitis in children. isolation and characterization of non-
Chest. 2014;145(6):1271-1278. 21. Kapur N, Masel JP, Watson D, et al. typeable Haemophilus influenzae from the
9. Pritchard MG, Lenney W, Gilchrist FJ. Bronchoarterial ratio on high-resolution sputum of adult cystic fibrosis patients.
Outcomes in children with protracted CT scan of the chest in children without Eur Respir J. 1995;8(6):948-953.
bacterial bronchitis confirmed by pulmonary pathology: need to redefine
bronchial dilatation. Chest. 2011;139(6): 33. Suzuki K, Bakaletz LO. Synergistic
bronchoscopy. Arch Dis Child.
1445-1450. effect of adenovirus type 1 and
2015;100(1):112.
nontypeable Haemophilus influenzae in a
10. Kapur N, Grimwood K, Masters IB, et al. 22. Pizzutto SJ, Grimwood K, Bauert P, chinchilla model of experimental otitis
Lower airway microbiology and cellularity et al. Bronchoscopy contributes to the media. Infect Immun. 1994;62(5):1710-
in children with newly diagnosed non-CF clinical management of indigenous 1718.
bronchiectasis. Pediatr Pulmonol. children newly diagnosed with
2012;47(3):300-307. bronchiectasis. Pediatr Pulmonol. 34. Cole PJ. Inflammation: a two-edged
2013;48(1):67-73. sword—the model of bronchiectasis. Eur J
11. Marchant JM, Gibson PG, Grissell TV, Respir Dis Suppl. 1986;147:6-15.
et al. Prospective assessment of protracted 23. Stockley RA. Lung infections. 1. Role of
bacterial bronchitis: airway inflammation bacteria in the pathogenesis and 35. Kapur N, Masters IB, Chang AB.
and innate immune activation. Pediatr progression of acute and chronic lung Longitudinal growth and lung function in
Pulmonol. 2008;43(11):1092-1099. infection. Thorax. 1998;53(1):58-62. pediatric non-cystic fibrosis
bronchiectasis: what influences lung
12. Simpson JL, Grissell TV, Douwes J, et al. 24. Van Eldere J, Slack MP, Ladhani S, et al. function stability? Chest. 2010;138(1):
Innate immune activation in neutrophilic Non-typeable Haemophilus influenzae, an 158-164.
asthma and bronchiectasis. Thorax. under-recognised pathogen. Lancet Infect
2007;62(3):211-218. Dis. 2014;14(12):1281-1292. 36. Gaillard EA, Carty H, Heaf D, et al.
Reversible bronchial dilatation in
13. van der Gast CJ, Cuthbertson L, 25. De Schutter I, De Wachter E, Crokaert F, children: comparison of serial high-
Rogers GB, et al. Three clinically distinct et al. Microbiology of bronchoalveolar resolution computer tomography scans
chronic pediatric airway infections share a lavage fluid in children with acute of the lungs. Eur J Radiol. 2003;47(3):
common core microbiota. Ann Am nonresponding or recurrent community- 215-220.
Thorac Soc. 2014;11(7):1039-1048. acquired pneumonia: identification of
nontypeable Haemophilus influenzae as a 37. Crowley S, Matthews I. Resolution of
14. Wurzel DF, Mackay IM, Marchant JM,
major pathogen. Clin Infect Dis. extensive severe bronchiectasis in an
et al. Adenovirus species C is associated
2011;52(12):1437-1444. infant. Pediatr Pulmonol. 2010;45(7):
with chronic suppurative lung diseases in
717-720.
children. Clin Infect Dis. 2014;59(1):34-40. 26. Hare KM, Binks MJ, Grimwood K,
15. Chang AB, Redding GJ, Everard ML. et al. Culture and PCR detection 38. Goyal V, Grimwood K, Marchant J, et al.
Chronic wet cough: protracted bronchitis, of Haemophilus influenzae and Pediatric bronchiectasis: No longer an
chronic suppurative lung disease and Haemophilus haemolyticus in orphan disease. Pediatr Pulmonol.
bronchiectasis. Pediatr Pulmonol. Australian Indigenous children with 2016;51(5):450-469.
2008;43(6):519-531. bronchiectasis. J Clin Microbiol. 39. Chang AB, Robertson CF, Van
2012;50(7):2444-2445. Asperen PP, et al. A multicenter study on
16. Chang AB, Upham JW, Masters IB, et al.
Protracted bacterial bronchitis: the last 27. Thanavala Y, Lugade AA. Role of chronic cough in children: burden and
decade and the road ahead. Pediatr nontypeable Haemophilus influenzae in etiologies based on a standardized
Pulmonol. 2016;51(3):225-242. otitis media and chronic obstructive management pathway. Chest. 2012;142(4):
pulmonary disease. Adv Otorhinolaryngol. 943-950.
17. Mathews JD, Forsythe AV, Brady Z, et al.
2011;72:170-175. 40. Goyal V, Grimwood K, Chang AB.
Cancer risk in 680,000 people exposed to
computed tomography scans in childhood 28. King P. Haemophilus influenzae and the Bronchiectasis: the arrival of better
or adolescence: data linkage study of 11 lung (Haemophilus and the lung). Clin evidence. Lancet Respir Med. 2014;2(1):
million Australians. BMJ. 2013;346:f2360. Transl Med. 2012;1(1):10. 12-13.

1108 Original Research [ 150#5 CHEST NOVEMBER 2016 ]