World Journal of Pediatrics

https://doi.org/10.1007/s12519-018-0193-z

ORIGINAL ARTICLE

Clinical features of postinfectious bronchiolitis obliterans in children

undergoing long‑term nebulization treatment
Xiao‑Mei Zhang1 · Ai‑Zhen Lu1 · Hao‑Wei Yang2 · Li‑Ling Qian1 · Li‑Bo Wang1 · Xiao‑Bo Zhang1

Received: 22 August 2018 / Accepted: 20 September 2018

© Children’s Hospital, Zhejiang University School of Medicine 2018

Abstract
Background  Limited data are available in relation to the clinical features of PIBO undergoing prolonged nebulization treat-
ment with budesonide, terbutaline and ipratropium bromide. This retrospective study aimed to outline the features of clini-
cal, high-resolution computed tomography (HRCT) and pulmonary function test (PFT) of PIBO, undergoing maintenance
therapy utilizing a triple nebulization treatment and to determine the factors associated with prognosis.
Methods  Children diagnosed with PIBO were followed up between April 2014 and March 2017. The clinical features after
maintenance nebulization treatment for 12 months were thereafter summarized.
Results  Thirty patients, 21 boys and 9 girls, were enrolled in the study. The median age of patients was 17.4 months, with a
range between 3.0 and 33 months. Persistent coughing and wheezing were detected whilst wheezing and crackles were the
common manifestations presented. HRCT scans revealed patchy ground and glass opacity, while PFT showed fixed airway
obstruction in all patients. Four patients were lost during follow-up. After treatment, the clinical symptoms were improved
greatly in all patients (P < 0.01). The mean increase in the percentage of TPEF%TE and VPEF%VE were improved greatly
(P < 0.01). Images of the HRCT scan indicated marked improvements in 18 patients (81.8%) in comparison with scans
obtained pre-treatment.
Conclusions  Our data suggest a potential role of long-term nebulization treatment of budesonide, terbutaline, ipratropium
bromide on PIBO, due to its efficacy as indicated in the improved clinical symptoms, pulmonary functions and CT manifesta-
tions identified in the children. New prospective and controlled studies are required to confirm this proposition.

Keywords  Clinical features · Nebulization treatment · Post-infectious bronchiolitis obliterans · Prognosis

Introduction caused by adenovirus, influenza, measles, respiratory syncy-

Bronchiolitis obliterans (BO) is an infrequent form of
chronic obstructive lung disease, yet it has a profound long-
term influence on patients. Many factors, including allo-
graft transplantation, collagen vascular diseases, inhalation
of toxic gases, and airway infections are proclaimed to be
associated with BO [1]. In children, it is mostly triggered
by severe lower respiratory tract infection, namely post-
infectious bronchiolitis obliterans (PIBO), which could be
* Xiao‑Bo Zhang
zhangxiaobo0307@163.com
1
Respiratory Department, Children’s Hospital of Fudan
University, 399 Wan Yuan Rd, Shanghai, China
2
Radiology Department, Children’s Hospital of Fudan
University, 399 Wan Yuan Rd, Shanghai, China
tial virus, or mycoplasma pneumoniae, etc [2–8].
Severe irritation to the airway epithelium followed by a
process of inflammation and fibrosis of the terminal and res-
piratory bronchioles is considered to eventually result in the
stenosis and/or complete obliteration of the smaller airway.
Subsequently, this is the pathological characteristic of PIBO
[9]. Accordingly, the prevailing clinical findings in PIBO are
fixed airflow obstruction in pulmonary function test (PFT)
and areas of mosaic attenuation pattern and air trapping
on chest high-resolution computed tomography (HRCT)
[10–12]. Persistent airway obstruction may cause recur-
rent lung infection, exercise intolerance, sleep-disordered
breathing, nutritional problems, etc. in children [12–14]. It
is expected to significantly reduce the life quality of these
children and have further impact on their development [15].
However, no universally acknowledged therapy has been
determined for the treatment of PIBO as of yet. High doses

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of inhaled corticosteroids [(ICS) fluticasone propionate,
500–940 ug two times daily] were suggested to stabilize
constrictive bronchiolitis after hematopoietic stem cell trans-
plantation (HSCT) and reduce the side-effects of systemic
treatment [16]. Combination treatment with budesonide/
formoterol, montelukast and n-acetylcysteine was proved
to be effective in improving lung function and respiratory
symptoms in patients with bronchiolitis obliterans syndrome
after HSCT without adverse events [17]. Prolonged inhaled
corticosteroids also served as supplementary treatment of
corticosteroid pulse therapy or as part of the combination
treatment with bronchodilators to reduce airway hyper reac-
tivity in PIBO patients [18, 19].
In a case report, combined therapy of inhaled beclometh-
asone dipropionate, formoterol and tiotropium was empiri-
cally prescribed to a 36-year-old man diagnosed with PIBO
for 3 years, after which, his lung function improved at the
endpoint [20]. Accordingly, long term ICS therapy may pro-
vide a novel and safe therapy for patients with PIBO. How-
ever, the impact of combined nebulization of budesonide,
terbutaline and ipratropium bromide has not been systemati-
cally studied in PIBO as a form of maintenance treatment.
The aim of the present study was to summarize the clini-
cal features of PIBO in children after combined nebuliza-
tion treatment of budesonide, terbutaline and ipratropium
bromide were administered for 1 year and subsequently,
determine the impact of this triple nebulization treatment
on childhood PIBO.
Methods
Children diagnosed with PIBO were followed up in pediat-
ric pulmonology outpatient clinics at Children’s Hospital
of Fudan University from April 2014 to March 2017. The
diagnosis of PIBO was made according to clinical cri-
teria: persistent obstructive respiratory disease triggered
by severe acute lower respiratory and unresponsiveness to
bronchodilators for a period more than 6 weeks; patchy,
ground glass opacity and/or mosaic pattern and/or bron-
chiectasis indicated in HRCT of the thorax. Other causes
of chronic obstructive pulmonary disease, including cystic
Table 1  Symptom score Symptoms Score
0 1
Cough None
Wheezing None
Exercise intolerance None
Lung physical signs None
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World Journal of Pediatrics
fibrosis, bronchopulmonary dysplasia, pulmonary tuber-
culosis, α1-antitrypsin deficiency, immunodeficiencies,
aspiration of foreign bodies and cardiac diseases, were
methodically excluded.
The enrolled children all received budesonide (Budeso-
nide Suspension for Inhalation, 0.5 mg/time; AstraZeneca
Pty Ltd), terbutaline (Terbutaline Sulphate Solution for
Nebulization, 2.5 mg/time; AstraZeneca AB), ipratropium
bromide (Ipratropium Bromide Solution for Inhalation,
125 μg/time; Laboratoire Unither) twice daily for mainte-
nance treatment. The compressed gas nebulizer is used to
deliver the drugs. During acute exacerbations, supportive
treatment, antibiotics and systemic corticosteroids, were
also administered. Patients received this treatment for
12 months or the treatment was regulated as their clinical
symptoms and lung function achieved great relief. There-
after, detailed medical information was recorded. Symp-
toms were recorded and evaluated on a scale from 0 (no
symptoms) to 12 (severe symptoms) (Table 1) [21]. Addi-
tionally, for pulmonary function tests, tidal breathing flow-
volume curves were analyzed by Master Screen Pad (Erich
Jaeger GmbH, Wuzburg, Germany). Indices including tidal
volume over body weight (VT/kg), ratio of time to peak
tidal expiratory flow to total expiratory time (TPEF%TE),
and ratio of volume to peak tidal expiratory flow to total
expiratory volume (VPEF%VE) were calculated. Radiolo-
gists reviewed the HRCT scans prior to treatment, as well
as post treatment to compare the treatment effects.
Statistics
Statistical analyses were carried out with SPSS (version
16.0, SPSS Inc). Categorical variables were expressed
as an absolute number and as a percentage. Continuous
variables were presented as mean ± standard deviation or
medians with ranges. Paired sample t tests were utilized to
compare paired groups (changes from baseline). Independ-
ent groups were compared using Mann–Whitney U test
for two groups. All P values were two sided, and P values
of < 0.05 were considered statistically significant.
2 3
Mild Moderate Severe
Intermittent Persistent Severe
With strenuous activity With mild activity With rest
Occasionally Persistent Severe
World Journal of Pediatrics

Results Pulmonary function test results

Characteristics of patients Lung function tests at baseline showed a marked decrease

Thirty patients were enrolled into this study (21 males and
9 females). The median age was 17.4 months, and ranged
between 3.0 and 33 months. Four patients were lost dur-
ing follow-up. The initial trigger that resulted in PIBO
in the majority of patients was pneumonia, excepting one
case that was found to be sequela of Stevens–Johnson syn-
drome. Adenovirus (n = 7, 23%) and mycoplasma pneumo-
nia (n = 5, 17%) were the most aetiological agents, how-
ever, other microorganisms, including parainfluenza virus
type 3 (n = 1), cytomegalovirus (n = 2), respiratory syn-
cytial virus (n = 2), measles virus (n = 1) and Legionella
pneumophila (n = 1) were also detected.
in TPEF%TE and VPEF%VE in all patients, the mean
value of which was 16.73 ± 4.61% and 20.74 ± 3.61%,
respectively. Compared with those at baseline, the
mean TPEF%TE (19.44 ± 6.49%) and VPEF%VE
(22.79 ± 4.78%) were improved significantly (Table  2,
P < 0.01). Lung function improved exclusively in 17
patients, of which, 2 indicated that lung function returned
to normal at 4 and 7 months, respectively, since the com-
bined treatment was administered.
Chest high‑resolution computed
tomography results

HRCT scan at baseline showed patchy, ground glass

Symptom scores opacity in all patients, with typical mosaic perfusion in
7, bronchial wall thickening in 5, localized atelectasis or
Coughing and wheezing persisted since the initial lung pulmonary consolidation in 5, airtrap in 13, and bronchi-
infection detected in all patients. Crackles and wheezing ectasis in 3 (Table 3). In 22 patients under HRCT scans,
were heard in most cases. At the endpoint, clinical symp- 18 had marked improvements at the endpoint of the com-
toms in 26 patients were all improved greatly (the mean bined treatment (Fig. 1a, b showing changes of one patient
symptom scores decreased from 6.3 ± 0.88 to 1.54 ± 1.33, before and after treatment); three had no changes and one
P < 0.05) (Table 2), and the exacerbation frequency and with deterioration. The most discernible improvement was
severity were reduced. No patients exhibited exercise that patchy, ground glass opacity and/or mosaic perfu-
intolerance or needed domiciliary oxygen therapy. sion improved in most cases (9 out of 13), with increased
ventilation improvement observed in the other 4 patients.
In four of the five patients with atelectasis or pulmonary
consolidation partial improvement was observed, however,
deterioration was observed in the one residual case. In
Table 2  Symptom score and lung function data before and after two of the three patients with bronchiectasis, improvement
nebulized treatment was observed; nevertheless, deterioration was observed
Variables Baseline Endpoint Change from baseline in the one the other case. Additionally, in three of the five
patients with bronchial wall thickening, improvement was
Symptom score 6.3 ± 0.88 1.54 ± 1.33 − 4.76 ± 1.33*
observed, however, one remained unchanged and deterio-
VT/kg 8.36 ± 1.23 8.42 ± 1.22 0.05 ± 1.79
ration was observed in one. And finally, in two of three
TPEF%TE 16.73 ± 4.61 19.44 ± 6.49 2.70 ± 6.25*
cases with bronchiectasis, improvement was observed,
VPEF%VE 20.74 ± 3.61 22.79 ± 4.78 2.05 ± 4.39*
however, deterioration was observed in one.
*P < 0.01

Table 3  Changes of CT images Manifestations of CT imaging Baseline (n) Endpoints

before and after nebulized
treatment (n = 22) Improved (n) Remained (n) Dete-
riorated
(n)

Mosaic pattern 7 5 1 1
Airtrap 13 9 4 0
Atelectasis or consolidation 5 4 1 0
Bronchiectasis 3 2 0 1
Bronchial wall thickening 5 3 1 1

13

Fig. 1  a and b showing HRCT
changes of one patient before
and after treatment, respectively
Discussion
The purpose of this study was to investigate the clinical fea-
tures of post-infectious bronchiolitis obliterans in children
undergoing maintenance nebulization treatment of budeson-
ide, terbutaline and ipratropium bromide. The findings were
summarized. After treatment, the respiratory symptoms of
the patients were significantly improved. Lung function and
HRCT results were partially improved without noticeable
adverse effects detected during follow-up, indicating that
this combined therapy benefited patients with PIBO.
The median age of the 30 patients in the study was
17.4 months, within a range of 3.0–33 months. This was
consistent with the previous literature reporting that infec-
tion resulting in PIBO affected predominantly pre-school-
aged children [22]. The initial trigger of PIBO in the major-
ity of our patients was pneumonia, with the exception of
one case, which was the sequela of Stevens–Johnson syn-
drome. Consistent with previous data, adenovirus (23.3%)
and mycoplasma pneumoniae (16.6%) were the most com-
mon microorganisms in this study and other pathogens, such
as parainfluenza virus type 3, cytomegalovirus, respiratory
syncytial virus, measles virus, L. pneumophila were also
detected. Though adenovirus was the most reported etio-
logical agent associated with PIBO, it seemed that it had no
substantial association with the prognosis in this study [23].
The clinical manifestations of PIBO are not specific. In
this study, all patients presented with complaints of repeated
coughing and wheezing from an initial acute infection of the
smaller airways. Crackles and wheezing were heard in most
cases. PIBO can be diagnosed with a history of lower res-
piratory tract infection and typical clinical features, certain
characteristics observed on HRCT scans, including patchy,
ground glass opacity, mosaic perfusion, air retention, bron-
chial wall thickening and bronchiectasis could additionally
increase the sensitivity and accuracy [24–26].
Treatment for PIBO has yet to be well developed. Several
clinical studies have indicated that affected children suffer
from ongoing impaired ventilation pattern with parameters
of PFT continuing to deteriorate. Furthermore, profiles
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World Journal of Pediatrics
of chest radiology demonstrate sparse improvement, even
under empirical therapy [12, 27, 28]. Some researchers
attribute the challenge of recovering from PIBO to the dura-
tive inflammatory and abnormal immunological reaction in
airways of PIBO patients [28–30]. Therefore, maintaining
the anti-inflammatory or immunomodulation treatments
appear to be fundamental and could be a potential strategy
to improve long-term outcomes of PIBO.
Presently, corticosteroids have been used to combat the
inflammatory component of children with PIBO, based
on the specific pathological changes of BO indicating an
abnormal inflammatory reaction in the small airways and
peribronchiolar fibrosis [15, 31, 32]. Terbutaline and iprat-
ropium bromide as bronchodilators are commonly applied to
patients with bronchoconstriction. Although, theoretically,
a bronchodilator response should be absent in children with
fixed airway obstruction such as in PIBO, 10–42.9% of the
children with PIBO still present positive response to bron-
chodilators [22, 28, 33]. However, both their effectiveness
in improving the outcomes for childhood PIBO and the opti-
mal way of administration are controversial. Some authors
argue that intravenous pulse therapy has the advantage of
enhancing the therapeutic effect while others prefer inhaled
corticosteroids to minimize the adverse systemic effects and
to reduce airway hyperreactivity. Tomikawa et al suggested
pulse therapy could be recommended for patients with BO
depending on oral corticosteroid therapy and reliance for
domiciliary oxygen therapy, as this therapy did cause sev-
eral adverse effects on the renal, cardiovascular and skeletal
systems during the infusion. Although these adverse effects
were temporary and none were considered serious [18].
Zhang et al preferred to use oral steroids rather than
inhaled steroids, arguing that obliterated lesions occurred
in the small airways and would disrupt the deposition of
the inhaled drugs [22]. Lobo et al suggested that support-
ive treatment, including oxygen therapy and a suitable
nutritional plan, along with aggressive treatment during
respiratory infections, could improve the clinical course
of these children, though all children in their study under-
went inhaled corticotherapy [19]. Our study found that
World Journal of Pediatrics
nebulized budesonide, terbutaline and ipratropium bro-
mide as maintenance treatment for PIBO in children could
improve the respiratory symptoms, lung function and
images of CT in children with PIBO. This, therefore, indi-
cated that this therapy reduces the hyper reactivity and
bronchoconstriction in the patients that it was adminis-
tered to and provided them with a greater clinical stability.
Although our study suggested that prolonged nebulized
budesonide, terbutaline and ipratropium bromide treat-
ment could alleviate the symptoms of PIBO, it is also safe
to assume that this combined treatment is a potentially
safe and convenient alternative that could be performed
at home for PIBO as a means of maintenance treatment.
Some researchers suggest that caution needs to be taken
when interpreting the phenomenon of clinical improve-
ment during the disease process; small airways are dispro-
portionately narrow in the early years of life and periph-
eral airway conductance gradually increases during the
growing-up period [30, 34]. Thus it is difficult to distin-
guish whether the effect is attributed to the natural growth
of the lungs or the treatment [18, 19]. In this sense, new
prospective, controlled studies are required to investigate
this hypothesis.
There are limitations in this study. First, the sample size
was relatively small which may reduce the power of the
study. Second, the follow-up period was not long enough
to cover the natural course of this disorder, which may
limit the assessment of long-term prognosis.
In conclusion, this study demonstrated the potential role
of nebulized budesonide, terbutaline and ipratropium bro-
mide as maintenance treatment for PIBO in children. Fur-
thermore, well-designed and controlled approaches need to
be enforced for further research to investigate the long-term
efficacy and safety of this prolonged therapy on PIBO.
Author contributions  XMZ, AZL and HWY had full access to all of
the data in the study and take responsibility for the integrity of the data
and the accuracy of the data analysis. XMZ, AZL, and XBZ. conceived
and designed the study. XMZ and AZL reviewed the scientific litera-
ture, did the statistical analysis, prepared all tables and figures, and
wrote the first draft of the report. LLQ, LBW and XBZ reviewed and
revised the article. All authors made a critical revision of the manu-
script for key intellectual content.
Funding  No financial or nonfinancial benefits have been received or
will be received from any party related directly or indirectly to the
subject of this article.
Compliance with ethical standards  JC. Follow-up on pediatric patients with bronchiolitis obliterans
Ethical approval  This study was approved by the Hospital’s Ethics
Committee, and all participants provided written consents.
Conflict of interest  The authors declare that they have no conflict of
interest.
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