Received: 25 August 2019 | Accepted: 29 November 2019

DOI: 10.1002/ppul.24598

ORIGINAL ARTICLE: INFECTION AND IMMUNITY

Respiratory sequelae and quality of life in children one‐year

after being admitted with a lower respiratory tract infection:
A prospective cohort study from a developing country

Anna M. Nathan MRCPCH1,2 | Cindy S.J. Teh PHD3 | Kah Peng Eg MMed1,2 |
Kartini A. Jabar Mpath3 | Rafdzah Zaki DrPH4 | Shih Ying Hng MMed1 |
Caroline Westerhout MRad5 | Surendran Thavagnanam FRCPCH1,2 |
Jessie A. de Bruyne MRCP1,2

1
Department of Paediatrics, University
Malaya, Kuala Lumpur, Malaysia Abstract
2
Child Health Research Group, University Introduction: Respiratory tract infections in children can result in respiratory
Malaya, Kuala Lumpur, Malaysia
sequelae. We aimed to determine the prevalence of, and factors associated with
3
Department of Microbiology, University
Malaya, Kuala Lumpur, Malaysia persistent respiratory sequelae 1 year after admission for a lower respiratory tract
4
Department of Social & Preventive Medicine, infection (LRTI).
Centre for Epidemiology and Evidence‐Based
Methodology: This prospective cohort study involved children 1 month to 5‐years‐old
Practice, Kuala Lumpur, Malaysia
5
Department of Biomedical Imaging,
admitted with an LRTI. Children with asthma were excluded. Patients were reviewed at
University Malaya Medical Centre, Kuala 1‐, 6‐, and 12‐months post‐hospital discharge. The parent cough‐specific quality of life, the
Lumpur, Malaysia
depression, anxiety, and stress scale questionnaire and cough diary for 1 month, were
Correspondence administered. Outcomes reviewed were number of unscheduled healthcare visits,
Anna M. Nathan, Department of Pediatrics,
University Malaya Medical Centre, 50603
respiratory symptoms and final respiratory diagnosis at 6 and/or 12 month‐review by
Kuala Lumpur, Malaysia. pediatric pulmonologists.
Email: psr9900@hotmail.com
Results: Three hundred patients with a mean ± SD age of 14 ± 15 months old were
Funding information recruited. After 1 month, 239 (79.7%) returned: 28.5% (n = 68/239) had sought
University Malaya Research Grant,
Grant/Award Number: UMRG‐RP026‐14HTM
medical advice and 18% (n = 43/239) had cough at clinic review. Children who
received antibiotics in hospital had significantly lower total cough scores (P = .005) as
per the cough diary. After 1 year, 26% (n = 78/300) had a respiratory problem,
predominantly preschool wheezing phenotype (n = 64/78, 82.1%). Three children had
bronchiectasis or bronchiolitis obliterans. The parent cough‐specific quality of life
(PCQOL) was significantly lower in children with respiratory sequelae (P < .01). In
logistic regression, the use of antibiotics in hospitals (adjusted odds ratio, 0.46;
P = .005) was associated with reduced risk of respiratory sequelae.
Conclusion: In children admitted for LRTI, a quarter had respiratory sequelae, of
which preschool wheeze was the commonest. The use of antibiotics was associated
with a lower risk of respiratory sequelae.

KEYWORDS
children, developing country, Malaysia, outcome, respiratory sequelae

Pediatric Pulmonology. 2019;1–11. wileyonlinelibrary.com/journal/ppul © 2019 Wiley Periodicals, Inc. | 1

2 |
1 | INTRODUCTION
Acute respiratory illnesses are a common cause of admission,
especially in the young. Most of these infections are self‐limiting
and resolve quickly without medication. However, some children
continue to have either recurrent or persistent symptoms,
especially cough.
The post‐infectious cough should last no longer than 4
weeks.1-3 However, this is data from children in the primary care
setting. It is postulated that children hospitalized with a lower
respiratory tract infection (LRTI) have more severe respiratory
illness and a longer recovery period. Trenholme et al 4 from New
Zealand followed up 94 children less than 2 years old who were
admitted for an LRTI. One year later, the authors found that 30%
had a history of chronic wet cough and/or an abnormal chest
finding, and in those with chronic cough, 62% had an abnormal
chest radiograph. 4 What was more alarming was that three
children had radiological changes consistent with bronchiectasis.
In an older study, Eastham et al found that children previously
admitted for severe pneumonia had an increased risk of
persistent cough compared with controls. Furthermore, children
with no family history of atopy had an increased risk of asthma.5
Therefore, children admitted for an LRTI require follow‐up to
monitor for possible respiratory sequelae.
Studies looking at factors associated with respiratory seque-
lae have found that children of indigenous descent or from
marginalized backgrounds, who are malnourished or living in an
overcrowded household as well as infection with organisms like
Adenovirus and Mycoplasma pneumoniae, have an increased risk
of recurrent pneumonia and subsequent complications. 6-11
However, these studies were done in Europe and Africa, not
South East Asia and hence complications and risk factors may
differ.
The aims of this study were to determine (a) the prevalence of
respiratory complications, (b) the diagnostic outcome, and (c) factors
associated with persistent respiratory sequelae 1 year following
admission for an LRTI.
2 | METHODOLOGY
2.1 | Study setting
University Malaya medical center (UMMC) is a government‐funded
teaching hospital serving an urban population in Kuala Lumpur, the
capital of Malaysia, a developing country with a population of 32.6
million, with access to a two‐tier health care system consisting of a
private as well as a government based universal system. UMMC has
more than 1500 beds serving a population of more than 1 000 000.
The pediatric block has five pediatric wards, a pediatric intensive
care unit (PICU) and a neonatal intensive care unit with a total bed
capacity of 150. We also have a dedicated pediatric emergency
department.
NATHAN ET AL.
2.2 | Study design and ethical approval
This was a prospective cohort study conducted in the pediatric
department at UMMC. Ethical approval was obtained from the
UMMC Ethics committee (MEC IDNO 20146‐336) and informed
consent from parents was obtained. Patients were recruited via
convenient sampling and all information is anonymised.
2.3 | Study population, flow, and outcomes
This study included children aged 1‐month to 5‐years‐old, who were
admitted to UMMC from 1 October 2014 to 31 October 2016 with
severe pneumonia which was defined as history of cough and/or
shortness of breath with examination findings of age‐defined
tachypnoea (defined as respiratory rate >60/min for infants
<2 months; >50/min for infants 2–12 months; >40/min for children
>12–60 months; and >30/min for children >60–144 months) and any
one of the following: recessions, saturation <92% on air, poor feeding
or lethargy as per the WHO definition.12 Children who refused blood
taking were unable to come for follow‐up, had symptoms present
>7 days or no chest radiograph performed and those with doctor‐
diagnosed asthma or recurrent wheezing of childhood (more than
two episodes) or chronic disease were excluded. Patients were
recruited via convenient sampling from the pediatric wards during
working hours only.
Patients were subsequently followed up after discharge at a
dedicated research clinic, from 1 November 2014 till 31 October
2017. At discharge, parents were given a cough diary, to monitor the
severity of cough for 1 month. Parents were reminded by phone call,
to attend their clinic review and a minimum of three phone call
attempts were made to ensure the best follow‐up rate, including
adjusting clinic review days, if possible. Patients were seen at 4 ± 2
weeks, 6 ± 1 months, and 12 ± 2 months.
At every clinic review, a standardized questionnaire was used to
determine the following outcomes: need for unscheduled healthcare
visits for respiratory symptoms, hospitalization for respiratory
disease, persistent cough, presence of recurrent wheeze, presence
of doctor‐diagnosed wheeze or doctor‐diagnosed asthma, growth
parameters and vital signs, and respiratory examination findings. The
final diagnosis was made based on assessments made at the 6 and/or
12 months follow up. All patients were seen by certified pediatric
pulmonologists.
2.3.1 | Tools of assessment
At discharge, a cough diary was given to all parents. Parents were
instructed to gauge the overall severity of their child's cough, from
1 to 10 (1 being no cough and 10 being very severe cough) daily for
30 days.
Each participating parent also completed the following two
questionnaires at admission, discharge, and every clinic review: Short
NATHAN ET AL.
parent cough‐specific quality of life (PC‐QOL) questionnaire and
depression, anxiety, and stress scale (DASS21) questionnaire.
The short PC‐QOL consists of eight questions, whereby the initial
five questions are related to the parental burden or worry, and the
remaining three questions were related to the parental perception of
the burden of cough on the childʼs function.13 Each of the responses
is marked on a 7‐point Likert scale, giving it a maximum score of 56.
The higher the score, the better the quality of life (QOL) with a
minimal important difference is 0.9. The PCQOL is validated in
14
Bahasa Malaysia and this version was used for this study.
The DASS21 is a self‐reported scale with 21‐items measuring
three dimensions of emotional distress construct: depression,
anxiety, and stress. Participants responded to each item on a
4‐point severity scale from 0 to 3 with higher scores indicate worse
mental health and it has been translated to Bahasa Malaysia and is
validated.15
2.3.2 | Study definitions and outcomes
Life‐threatening LRTI was defined as those requiring either invasive
or noninvasive ventilation, PICU or illness resulting in death.
Previous lung infection was defined as any previous history of an
LRTI with a history of shortness of breath. Exposure to environ-
mental tobacco smoke (ETS) was defined as presence of a family
member living in the same household who smokes.16 Out‐of‐home
care was defined as any child looked after either at a childcare facility
or a baby‐sitterʼs house. A family history of asthma included nuclear
family members with either a current or previous history of asthma.
Abnormal chest radiograph was defined as the presence of either
focal or diffuse infiltrates silhouette sign, pleural effusion, or air
bronchogram.17 Bacterial etiology was presumed if there was a
positive chest radiograph (CXR), significant bacterial count via
polymerase chain reaction (PCR) in induced sputum samples and
either fever (≥38°) or neutrophil count ≥8.0 × 109/L. Viral etiology
was presumed if they had severe pneumonia (WHO definition) with a
virus detected either via PCR, immunofluorescence or viral culture in
induced sputum. Co‐infection (bacteria and virus) etiology would
include children who had both a significant bacteria (as described
above) and virus detected in the induced sputum. Unknown etiology
was presumed if the above three criteria were not satisfied.
Patients were seen by one of the 3 pediatric pulmonologist in our
center. Diagnoses were made based on clinical symptoms and signs.
Further investigations like high‐resolution computed tomography
(HRCT) ± bronchoscopy + bronchoalveolar lavage (to look for TB,
fungus, and bacteria), primary immunological deficiency screening
and sweat test or fecal fats were performed in children with
suspected bronchiolitis obliterans (BO) or bronchiectasis (BE).
Final diagnoses were categorized into the following: well‐child
(including recurrent upper respiratory tract infections), pre‐school
wheezing phenotype (asthma, viral episodic wheeze, or multiple
trigger wheeze), chronic lung disease (bronchiectasis ± bronchiolitis
obliterans ± nonspecific lung fibrosis), and chronic bronchitis
| 3
(defined as chronic wet cough ≥4 weeks). In this study, a diagnosis
of chronic bronchitis was made even at 1 month when the child had
chronic wet cough since discharge.
To reduce the loss of data for children who defaulted both the
6‐ and 12‐month review, hospital records for the year for these
children were also reviewed for respiratory problems.
2.4 | Specimen collection and analysis
18
During admission for their LRTI, induced sputum (with 3% saline
nebulizer) and blood was taken within 24 hours of admission for
determination of etiology of their LRTI. The 11 viruses investigated
for via PCR are as follows: influenza A virus, influenza B virus, human
metapneumovirus (hMPV), human parainfluenza virus type 1
(hPIV‐1), hPIV‐2, hPIV‐3, human adenovirus, human respiratory
syncytial virus type A (hRSV‐A), hRSV‐B, human rhinovirus, and
human bocavirus. Blood and nasopharyngeal aspirate (NPA) were
tested for bacteria via PCR for Staphylococcus aureus, Streptococcus
pneumoniae, Haemophilus influenzae, Bordetella pertussis, Mycoplasma
pneumoniae, and Chlamydophila pneumoniae. Moraxella catarrhalis was
considered a significant pathogen if induced sputum culture had a
pure growth of Moraxella catarrhalis, that is, in the presence of
epithelial cells: pus cell <1:10.19,20 Chest radiographs were reviewed
by a designated radiologist who was blinded to the signs and
symptoms of the patient.
2.5 | Data collection
During admission, data including sociodemographic data, personal
and family history of asthma and atopy, environmental factors
(out‐of‐home care, number of siblings, number of members in the
house, number sleeping in the same room, exposure to ETS, economic
status, past medical history, personal and family history of atopy, and
vaccination history was acquired through face‐to‐face interviews.
The severity of illness, duration of admission, baseline laboratory, and
radiological investigations were also documented. Weight was
represented with z scores from centers for disease control and
prevention (CDC).21
2.6 | Statistical analysis
Data analysis was performed using a statistical package for social
science software version 16.0 (IBM). Continuous data were ex-
pressed as mean (standard deviation) or median (interquartile range
[IQR]) if not normally distributed. The χ2 test was used for comparing
categorical variables between two groups and odds ratio (OR) and
95% confidence interval (CI) were reported, where appropriate. The
Mann‐Whitney U test was used when comparing continuous
(numerical) variables without normal distribution between the two
groups. Wilcoxon rank was used when comparing continuous
4 | NATHAN ET AL.

variables without normal distribution, at different time points. H. influenzae (n = 22, 29.3%), S. aureus (n = 18, 24.0%), S. pneumoniae
Univariate analysis was used to determine significant factors (n = 17, 22.7%), M. catarrhalis (n = 4,5.3%), multiple bacteria (n = 11,
(P ≤ .1) and these were entered into a bivariate logistic regression 14.7%), B. pertussis (n = 1,1.3%), M. pneumoniae (n = 1,1.3%), and P.
to determine independent factors. All tests were calculated in a aeruginosa (n = 1,1.3%).
two‐tailed manner and significance was defined by a P < .05. More than a third of patients (n = 111, 37.0%) had viruses
detected in their induced sputum: virus alone in 23.7% (n = 71) and
virus with bacteria in 13% (n = 40). Viruses isolated alone were
3 | RES U LTS rhinovirus (n = 22, 31.0%), RSV (n = 12, 16.9%), hMPV (n = 16, 22.5%),
influenza (n = 4, 5.6%), parainfluenza (n = 3,4.2%), adenovirus (n = 3,
3.1 | Demographic characteristics 4.2%), bocavirus (n = 2, 2.8%), and multiple viruses (n = 9, 12.7%).
Co‐infection (virus + bacteria) was seen in 13.3% (n = 40) of
The mean ± SD age of the 300 patients was 14 ± 15 months old, with patients. Commonest viruses isolated were RSV (n = 15, 37.5%),
age range from 1 to 137 months and there was a male predominance rhinovirus (n = 10, 25.0%), and hMPV (n = 6, 15.0%). Similarly,
(n = 184, 61%). As for ethnicity, they were mostly Malays (n = 263, significant bacteria were H. influenzae (n = 16, 40.0%), S. aureus
87.7%), followed by Indians (n = 21, 7.0%) and Chinese (n = 11, 3.7%). (n = 9,22.5%), and S. pneumoniae (n = 7, 17.5%).
Weight at admission based on median (range) z scores was −1.07
(−5.54 to 4.00). Diagnoses given at discharge were pneumonia
(n = 115,38.3%) and bronchiolitis (n = 74, 24.7%) while diagnoses 3.3 | Prevalence of respiratory complications
were missing for 37% (n = 111) of patients. Median (IQR) duration of
hospitalization was 4 (3‐5) days. More than one‐third (n = 116, Table 1 shows the unscheduled visits, the prevalence of respiratory
38.7%) were breastfed for ≥6 months and nearly half (n = 143, 47.7%) symptoms, and examination findings at the three‐time points.
were exposed to indoor smoke, of which none was due to cooking At 1‐month post‐discharge, out of the 239 that returned for clinic
fumes from coal but due to ETS predominantly from fathers (46.7%, review, 28.5% (n = 68) had sought medical advice for a respiratory
n = 140). Nearly 2 out of 3 (n = 192, 64%) were in out‐of‐home care. problem. Diagnoses at the unscheduled visits could not be validated
Looking at other environmental factors, median (IQR) number of and hence not reported on. Chronic cough was seen in 18% (n = 43)
people in the household was 5 (4‐6) with median (range) of 3 (1‐10) of patients and was almost twice as common as recurrent wheezing
people sleeping in the same room. As for vaccination status, 90% (9.2%, n = 22). Abnormal examination findings present were: Harri-
(n = 270) had received the Hib vaccine while only 8.7% (n = 26) and sons sulci (26%), rhonchi (8.7%), recessions (7.5%), and crepita-
3.7% (n = 11) had received the pneumococcal (@Prevenar 13) and tions (6.3%).
influenza vaccine, respectively. Only half of the parents (n = 151,
50.3%) had heard of the pneumococcal vaccine. The pneumococcal
vaccine uptake is low as it is not included in the national T A B L E 1 Respiratory morbidity and clinical examination findings
of children seen at clinic reviews, 1 mo, 6 mo, and 1 y post a severe
immunization program.
lower respiratory tract infection
Three hundred patients were initially recruited, however, despite
rigorous attempts to ensure adherence to clinic review, the attrition 1 mo 6 mo 12 mo
N = 239 N = 188 N = 154
rate was significant. At 1, 6, and 12 months, 79.7% (n = 239), 62.7%
Respiratory morbidity N (%) N (%) N (%)
(n = 188) and 51.3% (n = 154) of patients returned for their clinic
Unscheduled outpatient visits 68 (28.5) 105 (55.9) 71 (46.1)
review, respectively. Three children who did not come for the
6‐month clinic review came for the 12‐month clinic review while 37 Hospitalized 10 (4.2) 19 (10.1) 17 (11.0)
Current symptoms
children who came for the 6‐month clinic review did not come for the
Recurrent wheeze 22 (9.2) 26 (13.8) 25 (16.2)
12‐month review. Two children who defaulted both 6‐ and 12‐month
Chronic cough 43 (18.0) 13 (6.9) 10 (6.5)
clinic reviews were seen in our hospital: one with wheezing was
1 mo 6 mo 12 mo
diagnosed as a preschool wheezing phenotype and another (n = 1)
N = 239 N = 188 N = 154
was a well‐baby followed up in our vaccination clinic. We also Respiratory
examination N (%) N (%) N (%)
diagnosed children with chronic bronchitis at 1 month (n = 5), though
Weight Z score, −0.41 (−1.45 −1.04 (−1.71 −0.76 (−1.41
not all received antibiotics. Therefore, final diagnoses were available
median (IQR) to 0.89) to −0.28) to 0.04)
for 198 (66.0%) patients.
Harrisons sulci 62 (26) 56 (29.8) 59 (38.3)
Tachypnoea 16 (6.6) 3 (1.6) 1 (0.6)
Recessions 18 (7.5) 5 (2.7) 1 (0.6)
3.2 | Etiology of pneumonia
Rhonchi 21 (8.7) 8 (4.3) 3 (1.9)

Seventy‐five (25.0%) children had a definite bacterial pneumonia, and Crepitations 15 (6.3) 11 (5.9) 2 (1.3)

40 (13.30%) had a co‐infection. Bacteria implicated were as follows: Abbreviation: IQR, interquartile range.
NATHAN ET AL.
At 6‐ and 12‐month clinic review, the need for unscheduled visits
was still high, with at least one in two children consulting a doctor for
a respiratory problem, and about 1 in 10 children requiring
hospitalization. However, the number of children with chronic cough
was lower compared with at 1 month. A symptom of wheeze was still
a problem at 6‐ and 12‐month review. Finally, abnormal examination
findings were more likely to be seen at 1‐month post‐discharge
compared with at 6‐ and 12‐month review.
3.4 | Tools used to assess respiratory symptoms
Cough diaries were returned by 115 (38.3%) patients at the 1‐month
clinic review. Mean ± SD duration of cough was 14 ± 1 days and
median (range) cough score over the last 3 days before the 1‐month
clinic review, was 1 (1‐9.33) per day. Thirty‐six of 131 (27.5%)
children were still coughing at clinic review according to the cough
diary. Children with life‐threatening infection had a significantly
longer duration of cough (P = .008, z = −2.654) but did not have a
higher average cough score over the last 3 days (P = .159, z = −1.410).
Using total cough diary scores, children treated with antibiotics in
hospital, had a significantly lower total mean ± SD) score 60 ± 35
compared with those without 83 ± 48 (z = −2.82, P = .005) However
total duration of cough (P = .107, z = −1.613) and average cough score
in the last 3 days (P = .183, z = −1.331) were not significantly lower in
the group treated with antibiotics.
FIGURE 1 Enrollment and follow up of patients
| 5
3.5 | DASS 21 and PCQOL median (IQR) values at
1, 6, and 12 months
DASS21 scores and PCQOL scores were compared at different time
points: admission with discharge, discharge with a 1‐month review,
1‐month with 6‐month review, and 12‐month review. DASS21 score
was significantly lower at discharge compared with admission
(z = −6.271, P < .001) and between 6‐month review and 12‐month
review (z = −3.26, P = .001) but did not differ significantly at other
time points: 1 month versus discharge (z = −0.96, P = .34,), 6‐month vs
1 month (z = −1.87, P = .06).
PCQOL score was significantly higher at discharge compared
with admission (z = −3.045, P = .002) but the biggest improvement in
QOL scores was seen at the 1‐month review compared with
discharge (z = −6.583, P < .001). QOL scores did not significantly
change at the other time points: 6 months versus 1 month (z = −0.18,
P = .86), 12 months versus 6 months (P = .10, z = −1.65) (Figure 1).
3.6 | DASS 21 and PCQOL median (IQR) values at
1, 6, and 12 months between children with and
without respiratory sequelae
When comparing the scores between patients with and without
respiratory disease, the PCQOL scores were not significantly
different at admission and discharge, however, at 1, 6, and 12‐month
6 | NATHAN ET AL.

F I G U R E 2 DASS21 and PCQOL scores of children with and without respiratory sequelae seen at 1, 6, and 12 mo review. DASS21,
depression, anxiety, and stress scale; PCQOL, parent cough‐specific quality of life

review, patients with respiratory sequelae had significantly lower
QOL scores compared with those without disease. See Figure 2
The DASS21 scores were not significantly different throughout
the follow‐up period, between those with and without respiratory
disease.
Looking at the mean scores of the individual questions in the
PCQOL at 1 month, lowest scores were obtained for the following
questions: overprotecting the child because of the cough (mean ± SD,
4.41 ± 2.19), scared because of your child's cough (mean ± SD,
4.45 ± 2.15) and worry about leaving your child with others because
of the cough (mean ± SD, 4.63 ± 2.03)
crepitations and wheeze had confirmed BO+BE with classic HRCT
changes of mosaic pattern and bronchoscopy showing evidence of
increased mucoid secretions and normal immune screen. The other
two children with post‐infectious BE had chronic wet cough that
improved temporarily with antibiotics. They had a normal immuno-
logical screen too. One child had bronchoscopy which showed
purulent secretions with normal airway anatomy. The other refused
bronchoscopy. The subglottic stenosis was diagnosed by broncho-
scopy (Figure 3).
Organisms isolated in children with respiratory sequelae, during
their admission, are shown in Table 2.

3.7 | Respiratory sequelae

The final diagnosis of respiratory illness was available for 198 (66%)
patients with 26% (n = 78/300) having respiratory sequelae. The
commonest respiratory sequelae were preschool wheezing pheno-
type in 82.1% (n = 64/78). Chronic bronchitis (n = 8/78, 10.3%) was
diagnosed in five children at 1‐month review and three children at
6‐ or 12‐month review. Of note, half of these children (n = 4 out of 8)
were given antibiotics in the hospital. This was the only respiratory
problem that we chose to report even though it is a diagnosis made
at 1 month, as we felt this was a problem in a significant number of
children.
Three children were diagnosed with bronchiectasis/bronchiolitis F I G U R E 3 Respiratory sequelae of the children previously
obliterans. A 5‐year‐old boy with persistent physical signs of admitted for a severe lower respiratory tract infection
 NATHAN
ET AL.

T A B L E 2 Organisms isolated in children with respiratory sequelae

Respiratory sequelae Number with organisms isolated Viruses Bacteria Mixed None
(n = 78) n (%) N N N N
Bronchiolitis obliterans (n = 1) 1 (100) 0 0 1 0
Adenovirus + Haemophilus Influenzae
Chronic suppurative lung disease (n = 2) 0 (0) 0 0 0 2
Chronic bronchitis (n = 8) 6 (75) 2 4 0 2
Rhinovirus (n = 1) Bordetella pertussis (n = 1)
Influenzae (n = 1) Haemophilus influenzae (n = 1)
Streptococcus pneumoniae (n = 1)
Staphylococcus aureus (n = 1)
Preschool wheezing phenotype (n = 64) 20 (31) 14 0 6a 44
Bocavirus (n = 1)
Human Metapneumovirus (n = 3)
Respiratory Syncytial Virus (n = 3)
Rhinovirus (n = 4)
Multiple (n = 3)
Others (n = 3) 2 (66.7) 0 0 2b 1
a
Bocavirus/Staphylococcus aureus/Streptococcus pneumoniae (n = 1), RSV/Haemophilus influenzae (n = 1), human metapneumovirus/rhinovirus/Staphylococcus aureus (n = 1), human metapneumovirus/
rhinovirus/Streptococcus pneumoniae/Haemophilus influenzae (n = 1), human metapneumovirus/RSV/Staphylococcus aureus (n = 1), rhinovirus/Streptococcus pneumoniae (n = 1).
b
Adenovirus/Haemophilus influenzae(n = 1), bocavirus/adenovirus/Haemophilus influenzae (n = 1).
|
7
8 | NATHAN ET AL.

T A B L E 3 Possible factors associated with respiratory sequelae in children seen at 6 ± 12 mo after admission for a very severe lower
respiratory tract infection

Disease Disease
Factors Yes No
Crude OR/Z
Demographic factors N = 78 (%) N = 222 (%) score 95% CI P value Adj OR 95% CI P value
Age, mo
Median (IQR) 9 (6,15) 10.5 (5,17) −0.53 ⋯ .59 ⋯ ⋯ ⋯
Sexc
Male 54 (69) 130 (59) 1.50 0.92‐2.76 .10 1.50 0.85‐2.67 .16
Female 24 (31) 92 (41) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Term
Yes 77 (99) 219 (99) 0.70 0.06‐7.76 .77 ⋯ ⋯ ⋯
No 1 (1) 2 (1) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Duration of breast feeding, mo
Median (IQR) 4 (2‐7) 4 (2‐6) 0.39 ⋯ .70 ⋯ ⋯ ⋯
BF ≥6 mo
Yes 32 (41) 84 (38) 1.14 0.67‐0.92 .64 ⋯ ⋯ ⋯
No 46 (59) 137 (62) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Out‐of‐home care
Yes 50 (64) 142 (64) 1.04 0.60‐1.82 .80 ⋯ ⋯ ⋯
No 25 (32) 79 (36) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
No. of children in household, 2 (2‐3) 5 (4‐6) 0.21 ⋯ .83 ⋯ ⋯ ⋯
median (IQR)
No. of people in household, median 5 (4‐6) 3 (3‐4) 0.86 ⋯ .39 ⋯ ⋯ ⋯
(IQR)
No. of people co‐sleeping with child, 4 (3‐4) 3 (3‐4) 1.2 ⋯ .20 ⋯ ⋯ ⋯
median (IQR)
Total income
Median (IQR) 5000 (3750‐6388) 5000 (3100‐7000) 0.70 ⋯ .99 ⋯ ⋯ ⋯
Past history of lower respiratory tract diseasea
Yes 18 (23) 52 (23) 0.98 0.53‐1.80 .95 ⋯ ⋯ ⋯
No 60 (77) 170 (77) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Eczema
Yes 14 (18) 26 (12) 1.64 0.81‐3.33 .17 ⋯ ⋯ ⋯
No 64 (82) 195 (88) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Fhx of asthma
Yes 29 (37) 68 (31) 1.32 0.78‐2.29 .30 ⋯ ⋯ ⋯
No 49 (63) 153 (69) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
ETS exposure
Yes 37 (47) 113 (51) 0.87 0.51‐1.50 .60 ⋯ ⋯ ⋯
No 41 (53) 109 (49) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Pneumococcal vaccination
Yes 7 (9) 19 (9) 1.04 0.39‐2.54 .91 ⋯ ⋯ ⋯
No 71 (91) 201 (91) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Prior antibiotic use
Yes 23 (29) 64 (29) 0.95 0.54‐1.64 .87 ⋯ ⋯ ⋯
No 59 (76) 143 (64) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Diagnosis of LRTI
Yes 18 (23) 52 (23) 0.98 0.53‐1.81 .95 ⋯ ⋯ ⋯
No 60 (77) 170 (77) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Disease Disease
Yes No
Investigation results N = 78 (%) N = 222 (%) Crude OR/Z score 95% CI P value
Chest radiograph
Abnormalb 69 (88) 194 (87) 1.25 0.54‐2.86 .61
Normal 8 (10) 28 (13) ⋯ ⋯ ⋯
(Continues)
NATHAN ET AL. | 9

TABLE 3 (Continued)

Disease Disease
Yes No
Investigation results N = 78 (%) N = 222 (%) Crude OR/Z score 95% CI P value
Bacteria only
Yes 31 (40) 108 (49) 0.70 0.41‐1.18 .18
No 47 (60) 114 (51) ⋯ ⋯ ⋯
Virus only
Yes 26 (33) 85 (38) 0.81 0.46‐1.39 .44
No 52 (67) 137 (62) ⋯ ⋯ ⋯
Co‐infection
Yes 13 (17) 27 (12) 1.44 0.70‐2.97 .31
No 65 (83) 195 (88) ⋯ ⋯ ⋯
RSV +ve
Yes 7 (9) 24 (11) 0.81 0.31‐1.92 .67
No 71 (91) 198 (89) ⋯ ⋯ ⋯
CRP, mg/L
Median (IQR) 1.4 (0.6‐2.2) 1.6 (0.6‐4.3) 0.85 ⋯ .40
Disease Disease
Yes No
Management in hospital N = 78 N = 222 Crude OR/Z score 95% CI P value Adj OR 95% CI P value
c
Antibiotics
Yes 37 (47) 148 (67) 0.45 0.27‐0.76 .003 0.46 0.27‐0.79 .005
No 41 (53) 74 (33) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Need for oxygen
Yes 57 (73) 142 (64) 1.55 0.87‐2.76 .14 ⋯ ⋯ ⋯
No 20 (26) 77 (35) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Life‐threatening illnessc
Yes 17 (22) 32 (14) 1.66 0.86‐3.19 .13 1.96 0.99‐3.87 .05
No 61 (78) 190 (86) ⋯ ⋯ ⋯ ⋯ ⋯ ⋯
Duration of hospitalization, d
Median (IQR) 4 (3‐5) 4 (3‐5) 0.57 ⋯ .57 ⋯ ⋯ ⋯
Abbreviations: Adj, adjusted; CI, confidence interval; CRP, C‐reactive protein; CXR, chest radiograph; ETS, environmental tobacco smoke; IQR,
interquartile range; LRTI, lower respiratory tract infection; OR, odds ratio; RSV, respiratory syncytial virus.
a
Variables entered into logistic regression model.
b
Premorbid wheezing or lung disease.
c
Abnormal CXR is one with infiltrates, consolidation, or air bronchogram.

3.8 | Factors associated with respiratory sequelae
When looking for significant factors associated with a final diagnosis
of respiratory disease, only the use of antibiotics during admission
(adjusted OR, 0.46; 95% CI, 0.27‐0.79; P = .005) was associated with
reduced risk of respiratory sequelae (Table 3).
4 | D IS C U S S IO N
In this study, which prospectively followed‐up children admitted with
an LRTI for a year, one in three children had respiratory symptoms
requiring unscheduled health care visits 1‐month post‐discharge
mainly for cough or wheeze. Furthermore, during the follow‐up
period, one quarter had a newly diagnosed respiratory condition, of
which preschool wheezing phenotype was the commonest. The use of
antibiotics during hospital admission was associated with reduced
cough severity at 1 month, as seen in total cough scores as well as
reduced risk of respiratory sequelae at 1 year. Life‐threatening
disease was not associated with an increased risk for respiratory
sequelae.
We undertook this study as there is limited literature on
respiratory sequelae after LRTI and none from South East Asia. This
was also part of an “Etiology of LRTI” study, as we wanted to see the
relationship between etiology and persistent respiratory symptoms,
explaining why we excluded children with previous wheezing,
diagnosis of asthma or any chronic disease that could by itself
contribute to the respiratory complications.
We excluded children with previous wheezing, diagnosis of
asthma or any chronic disease that could by itself contribute to
respiratory complications as we wanted to see the relationship
between etiology and persistent respiratory symptoms.
A comprehensive meta‐analysis, published in 2012 by Edmond
et al,11 systematically reviewed papers published from 1970 to 2011,
10 | NATHAN
looking at long term respiratory sequelae in children under 5 years
old. Out of the 13 papers that were deemed suitable,10 papers
investigated respiratory sequelae in hospitalized children, most
(n = 7) were specifically looking at risk of disease associated with
pathogens, hence leaving only three prospective studies that were
not pathogen‐specific: two from Africa9,22 and one from Europe.23
Analyzing all these 13 papers, the risk of major complications
(defined as presence of obstructive, restrictive lung disease, or
bronchiectasis) was 13.6% (95% CI, 6.2‐21.1%). Even in children
without a pathogen detected 17.6% (95% CI, 10.9‐24.3%) had major
complications. The risk of minor sequelae (defined as chronic
bronchitis, asthma, or another undefined lung disease apparent on
lung function or persistent symptoms) was lower at 7.1% (95% CI,
1.0‐13.4%).
In our study, four children had a “major” complication, that is, one
bronchiolitis obliterans, two bronchiectasis, and one subglottic
stenosis, while the “minor” complications were seen in 25% of
children. Such a big disparity of major complications is most likely
due to the different demography of patients, comparing Africa and an
urban Asian population like ours. However, lung function tests were
not performed in our study as these were young children. Hence, we
could be underestimating the prevalence of major complications.
Perhaps another contributing factor is that we excluded children
with pre‐morbid disease including asthma, and that would reduce the
prevalence of chronic lung disease.
In a more recent study that systematically followed‐up children
presenting to the emergency department (ED) with respiratory
infections, the authors found that 20.4% of children still had cough
28 days later.24 Of the children who had chronic cough and were
seen by a pediatric pulmonologist, protracted bacterial bronchitis
(PBB) was their commonest diagnosis, seen in 47% while asthma was
diagnosed in 14.5%, of children investigated for chronic cough. Other
diagnoses were tracheobronchomalacia, recurrent upper respiratory
tract infection, obstructive sleep apnea, and aspiration syndrome.
Bronchiectasis was diagnosed in 3.4% of patients.
OʼGradyʼs results concur with our results as within the first
month, 31.5% had visited a doctor for respiratory symptoms and
27.5% of those who returned with a cough diary still had a cough.
Similarly, at 1 month the commonest symptom was cough (66.1%)
rather than wheeze (33.8%). At the end of our study, three (1.0%)
children had significant lung disease: one child with bronchiolitis
obliterans, two with BE. This is almost a similar finding to
24
OʼGradyʼs who found bronchiectasis in 0.7% of all children seen
4
at the last visit but differs from Trenholme et al.
Trenholme et al4 in 2014 looked at 94 young children (<2 years
old) 1 year after admission for severe bronchiolitis or pneumonia. He
found that 32% had a wet cough or “crackles” on examination and in
those with abnormal findings, 62% had an abnormal CXR. Interest-
ingly, the prevalence of bronchiectasis in his cohort (diagnosed on
high‐resolution computer tomography) was high (n = 3, 3.2%), even
though children with co‐morbidities were excluded. Eastham et al5
looked at 103 children 5 years after a diagnosis of pneumonia and
found that these children were 2.9 times more likely to develop
ET AL.
persistent cough and 5.6 times more likely to develop abnormal chest
shape. This study noted chest deformity, that is, Harrisons sulci, in a
third of children at 1 year.
We found wheezing phenotype was the commonest diagnosis in a
third of children (n = 64/300, 21.3%) while chronic bronchitis was
seen in 2.7% of all children.
We then sought to determine risk factors for persistent
symptoms. In the systematic review of studies before 2012, life‐
threatening infection was an independent factor associated with
respiratory sequelae. Similarly, in a case‐control study, involving
indigenous children with and without bronchiectasis, children
hospitalized with pneumonia, recurrent hospitalization for pneumo-
nia and more severe pneumonia episodes with longer hospital stay
and requirement for oxygen were significantly associated with
respiratory sequelae.25 As for etiology, it was noted that 50% of
children who had an adenovirus infection had respiratory sequelae.
In Trenholmeʼs study, presence of mold was associated with
respiratory sequelae.4 We did not inquire about mold exposure in
this study.
The association between use of antibiotics and reduced risk of
respiratory sequelae is an interesting finding. We postulate that
compared with children managed at the ambulatory level,
patients who require admission for a LRTI have severe disease
due to a possible co‐infection. In this study, in univariate analysis,
co‐infections were not associated with respiratory sequelae.
However, we defined a bacterial etiology in the presence of a
high absolute neutrophil count, positive chest radiograph, and
positive bacterial count. This very strict definition may have
excluded many children who have a positive co‐infection and
hence giving a type II error.
Studies are emerging showing a positive link between
“colonization” of bacteria in the upper respiratory tract and risk
of respiratory symptoms or disease in infants.26,27 Does the use
of antibiotics, when reducing bacterial load alleviate respiratory
symptoms? PBBs and its link with chronic cough also support the
need for antibiotics in children who do not have an acute lung
infection but a bacterial airway infection. In a study of persistent
wheezy young children, use of antibiotics reduced the symptoms
in 92% of children. 27
Questionnaires were used to determine the impact of cough
on parents and child, and this had not been used in the previous
studies. While the DASS21 and PCQOL showed significant
improvement from admission to discharge, only the PCQOL
detected significantly higher QOL scores at 1‐month post‐
discharge. PCQOL was also significantly lower in children with
persistent respiratory symptoms. This further substantiates the
presence of respiratory disease in these children, as well as
confirms the PCQOL is a good tool at assessing severity of cough
in children, as shown in other studies. 3
Limitations of this study are recognized. The high dropout rate
was disappointing but unavoidable, especially in an urban city where
parents may default because of lack of symptoms or seek medical
help elsewhere due to convenience. As mentioned earlier, the
NATHAN ET AL.
inability to perform lung function tests would have reduced the
ability to detect changes in lung function that would not have
manifested as symptoms.
However, the prospective nature of this study, the fact that all
outcomes were defined apriori and the use of tools like the cough diary,
the PCQOL and DASS21 are added benefits and strengths in our study.
In conclusion, in this study, which was done in an urban population
from a developing country, we found that one in three children had
respiratory symptoms requiring unscheduled health care visits 1‐month
post‐discharge the majority being for persistent cough or wheeze.
Furthermore, as the follow‐up continued, one quarter had a newly
diagnosed respiratory condition, of which the preschool wheezing
phenotype was the commonest. Use of antibiotics in hospital was
associated with reduced cough at 1 month and reduced risk of
respiratory sequelae at the end of the study.
OR CID
Anna M. Nathan http://orcid.org/0000-0003-3618-5820
Surendran Thavagnanam http://orcid.org/0000-0002-4414-7915
REFERENC ES
1. Hay AD, Wilson A, Fahey T, Peters TJ. The duration of acute cough in
pre‐school children presenting to primary care: a prospective cohort
study. Fam Pract. 2003;20:696‐705.
2. Hay AD, Wilson AD. The natural history of acute cough in children
aged 0 to 4 years in primary care: a systematic review. Br J Gen Pract.
2002;52:401‐409.
3. Marchant JM, Newcombe PA, Juniper EF, Sheffield JK, Stathis SL,
Chang AB. What is the burden of chronic cough for families? Chest.
2008;134:303‐309.
4. Trenholme AA, Byrnes CA, McBride C, et al. Respiratory health
outcomes 1 year after admission with severe lower respiratory tract
infection. Pediatr Pulmonol. 2013;48:772‐779.
5. Eastham KM, Hammal DM, Parker L, Spencer DA. A follow‐up study
of children hospitalised with community‐acquired pneumonia. Arch
Dis Child. 2008;93:755‐759.
6. Chang AB, Bell SC, Byrnes CA, et al. Chronic suppurative lung disease
and bronchiectasis in children and adults in Australia and New
Zealand. Med J Aust. 2010;193:356‐365.
7. Chang AB, Masel JP, Boyce NC, Wheaton G, Torzillo PJ. Non‐CF
bronchiectasis: clinical and HRCT evaluation. Pediatr Pulmonol. 2003;
35:477‐483.
8. Glezen P, Denny FW. Epidemiology of acute lower respiratory
disease in children. N Engl J Med. 1973;288:498‐505.
9. Puchalski Ritchie LM, Howie SR, Arenovich T, et al. Long‐term
morbidity from severe pneumonia in early childhood in the Gambia,
West Africa: a follow‐up study. Int J Tuberc Lung Dis. 2009;13:
527‐532.
10. Wesley AG, Kalideen JM. A retrospective study of children after
pneumonia. S Afr Med J. 1984;66:325‐326.
11. Edmond K, Scott S, Korczak V, et al. Long term sequelae from
childhood pneumonia; systematic review and meta‐analysis. PLoS
One. 2012;7:e31239.
| 11
12. Newcombe PA, Sheffield JK, Chang AB. Parent cough‐specific quality
of life: development and validation of a short form. J Allergy Clin
Immunol. 2013;131:1069‐1074.
13. Nathan AM, Muthusamy A, Thavagnanam S, Hashim A, de Bruyne J.
Chronic suppurative lung disease in a developing country: impact on
child and parent. Pediatr Pulmonol. 2014;49:435‐440.
14. Crawford JR, Henry JD. The depression anxiety stress scales (DASS):
normative data and latent structure in a large non‐clinical sample. Br
J Clin Psychol. 2003;42:111‐131.
15. Musa R, Fadzil MA, Zain Z. Translation, validation, and psychometric
properties of Bahasa Malaysia version of the depression anxiety and
stress scales (DASS). ASEAN Journal of Psychiatry. 2007;8:82‐80. 2007.
16. CDC growth charts 2009. Available from: www.cdc.gov/
growthcharts/zscore.htm. Accessed October 30, 2014.
17. Wesley AG. Prolonged after‐effects of pneumonia in children. S Afr
Med J. 1991;79:73‐76.
18. Piippo‐Savolainen E, Remes S, Kannisto S, Korhonen K, Korppi M.
Asthma and lung function 20 years after wheezing in infancy: results
from a prospective follow‐up study. Arch Pediatr Adolesc Med. 2004;
158:1070‐1076.
19. O'Grady KF, Drescher BJ, Goyal V, et al. Chronic cough postacute
respiratory illness in children: a cohort study. Arch Dis Child. 2017;
102:1044‐1048.
20. Singleton RJ, Valery PC, Morris P, et al. Indigenous children from
three countries with non‐cystic fibrosis chronic suppurative lung
disease/bronchiectasis. Pediatr Pulmonol. 2014;49:189‐200.
21. Twiss J, Metcalfe R, Edwards E, Byrnes C. New Zealand national
incidence of bronchiectasis ““”too high” for a developed country. Arch
Dis Child. 2005;90:737‐740.
22. Edwards EA, Asher MI, Byrnes CA. Paediatric bronchiectasis in the
twenty‐first century: experience of a tertiary childrenʼs hospital in
New Zealand. J Paediatr Child Health. 2003;39:111‐117.
23. Valery PC, Torzillo PJ, Mulholland K, Boyce NC, Purdie DM,
Chang AB. Hospital‐based case‐control study of bronchiectasis in
indigenous children in Central Australia. Pediatr Infect Dis J. 2004;
23:902‐908.
24. Vissing NH, Chawes BL, Bisgaard H. Increased risk of pneumonia and
bronchiolitis after bacterial colonization of the airways as neonates.
Am J Respir Crit Care Med. 2013;188:1246‐1252.
25. von Linstow ML, Schonning K, Hoegh AM, Sevelsted A, Vissing NH,
Bisgaard H. Neonatal airway colonization is associated with trouble-
some lung symptoms in infants. Am J Respir Crit Care Med. 2013;188:
1041‐1042.
26. Chang AB, Upham JW, Masters IB, et al. Protracted bacterial
bronchitis: The last decade and the road ahead. Pediatr Pulmonol.
2016;51:225‐242.
27. Schwerk N, Brinkmann F, Soudah B, Kabesch M, Hansen G.
Wheeze in preschool age is associated with pulmonary bacterial
infection and resolves after antibiotic therapy. PLoS One. 2011;6:
e27913. https://doi.org/10.1371/journal.pone.0027913
How to cite this article: Nathan AM, The CSJ, Peng EK, et al.
Respiratory sequelae and quality of life in children one‐year
after being admitted with a lower respiratory tract infection:
A prospective cohort study from a developing country.
Pediatric Pulmonology. 2019;1–11.
https://doi.org/10.1002/ppul.24598