Journal of the Formosan Medical Association 121 (2022) 1073e1080

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.jfma-online.com

Original Article

Clinical characteristics of recurrent

pneumonia in children with or without
underlying diseases
Li-Lun Chen a, Yun-Chung Liu a,b, Hsiao-Chi Lin a,
Tzu-Yun Hsing a, Yu-Cheng Liu a, Ting-Yu Yen a,c,*, Chun-Yi Lu a,
Jong-Min Chen a, Ping-Ing Lee a, Li-Min Huang a, Fei-Pei Lai b,d,e,
Luan-Yin Chang a

a
Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan
University, Taipei, Taiwan
b
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei,
Taiwan
c
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei,
Taiwan
d
Department of Computer Science and Information Engineering, National Taiwan University, Taipei,
Taiwan
e
Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan

Received 23 March 2021; received in revised form 19 July 2021; accepted 9 August 2021

KEYWORDS Background: Recurrent pneumonia is uncommon in children and few studies investigate the
Children; clinical impact of underlying diseases on this issue. This study aimed to explore the difference
Clinical outcomes; in clinical manifestations, pathogens, and prognosis of recurrent pneumonia in children with or
Etiology; without underlying diseases.
Recurrent Methods: We conducted a retrospective study of pediatric recurrent pneumonia from 2007 to
pneumonia; 2019 in National Taiwan University Hospital. Patients under the age of 18 who had two or more
Underlying diseases episodes of pneumonia in a year were included, and the minimum interval of two pneumonia
episodes was more than one month. Aspiration pneumonia was excluded. Demographic and
clinical characteristics of patients were collected and compared.
Results: Among 8508 children with pneumonia, 802 (9.4%) of them had recurrent pneumonia.
Among these 802 patients, 655 (81.7%) had underlying diseases including neurological disorders
(N Z 252, 38.5%), allergy (N Z 211, 32.2%), and cardiovascular diseases (N Z 193, 29.5%). Chil-
dren without underlying diseases had more viral bronchopneumonia (p < 0.001). Children with
underlying diseases were more likely to acquire Staphylococcus aureus (p Z 0.001), and gram-
negative bacteriae, more pneumonia episodes (3 vs 2, p < 0.001), a longer hospital stay

* Corresponding author. No. 8, Chung Shan S. Rd., Taipei 10041, Taiwan. Fax: þ886 2 2314 7450.
E-mail address: tingyu@ntu.edu.tw (T.-Y. Yen).

https://doi.org/10.1016/j.jfma.2021.08.013
0929-6646/Copyright ª 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 L.-L. Chen, Y.-C. Liu, H.-C. Lin et al.

(median: 7 vs. 4 days, p < 0.001), a higher ICU rate (28.8% vs 3.59%, p < 0.001), and a higher
case-fatality rate (5.19% vs 0%, p < 0.001) than those without underlying diseases.
Conclusion: Children with underlying diseases, prone to have recurrent pneumonia and more
susceptible to resistant microorganisms, had more severe diseases and poorer clinical out-
comes. Therefore, more attention may be paid on clinical severity and the therapeutic plan.
Copyright ª 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Background higher risks of recurrent pneumonia and to prevent

Pneumonia is an acute inflammation of the lower respira-
tory tract and is one of the leading causes of death among
children worldwide.1,2 Because of advances in vaccines and
public health, the number of children under five who died
of pneumonia markedly decreased between 2000 and
2015.1 However, pneumonia remains a high disease burden
for children. Pneumonia caused more than two million
deaths globally each year, of which 30% were children
under five years of age.2 Children with certain underlying
conditions such as immune insufficiency, hyper-reactive
airway, or cardiovascular diseases may be prone to pneu-
monia.3,4 In developed countries, the estimated annual
incidence of pneumonia in children under five years old is
3.3 cases per thousand people, and 1.45 cases per thousand
people among children under 16.5
In early childhood, the lungs are easily damaged by
infection and non-infectious factors, and further structural
and functional changes may occur.6 Pulmonary infection
can cause inflammation, which activates CD4þ T cells,
macrophages, and increases IL-8 expression, and this re-
action may damage the ciliated epithelium and infiltrate
the surrounding parenchyma.7 Therefore, during this crit-
ical period of development, recurrent pneumonia in chil-
dren may adversely affect the structure and function of the
lungs, and increase the risk of chronic lung diseases or
respiratory diseases when the child grows up.8 In a previous
study among adults who were diagnosed with bronchiec-
tasis, 30e60% of them had repeated lower respiratory tract
infections during childhood.8
Currently, there are some studies on childhood recurrent
pneumonia (RP) to delineate possible causes worldwide.
The number of cases in these studies ranged from 42 to
238.9,10 The incidence of RP in children with community-
acquired pneumonia ranges from 6% to 11%.11,12 For criti-
cally ill patients requiring intensive care, the incidence of
RP may even rise to 29%.13 The percentage of children with
underlying were between 69% and 92%. The majority of
studies focused on common underlying diseases included
recurrent aspiration, immunodeficiency, asthma, congen-
ital heart diseases, pulmonary anomalies, and gastro-
esophageal reflux, but the description of pathogen was
limited.10,14 Furthermore, there was no relevant studies
had ever been performed in Taiwan before. Therefore, the
main objective of this study is to identify clinical charac-
teristics such as underlying diseases and pathogens among
children with recurrent pneumonia. Hopefully, the results
will let physicians or parents be more alert on children with
sequelae or lung damage.
Methods
Study site
This study was conducted at National Taiwan University
Hospital (NTUH). The NTUH was built in 1895 and is a
national-level teaching hospital. It is responsible for
teaching, research, and service. At present, there are 6700
employees, 2600 hospital beds, and more than 8000
outpatient services per day.
Patients
The hospitalization records were retrospectively screened
through the electronic hospital information system. Pa-
tients who met all of the following conditions were
collected: (1) date of admission between January 2007 and
December 2019, (2) under 18 years of age, (3) the patients
were discharged with diagnosis of bronchopneumonia or
pneumonia according to ICD-9 or ICD-10 codes (Supplement
1), (4) the patients had two or more pneumonia episodes
which needed hospitalization for treatment within one
year, and complete recovery was required between each
admission. In addition, the minimum interval between two
episodes of pneumonia was more than one month. The
patient with aspiration pneumonia, defined as large-volume
aspiration of oropharyngeal or upper gastrointestinal con-
tents related pneumonia,15 was excluded through ICD code
507 and J69.
Data collection
We checked each electronical medical record and docu-
mented detailed information. First, we collected de-
mographics of age, gender, and the underlying diseases of
all eligible patients that had been recorded in previous
hospitalizations or medical visits. In order to comprehen-
sively understand the impact of underlying diseases on
recurrent pneumonia, our study includes all ICD codes
describing related underlying diseases and divides them
into 15 major categories, which were classified as allergy,
autoimmune diseases, congenital anomaly, genetic disor-
der, cardiovascular diseases, endocrinologic diseases,
gastrointestinal diseases, genital urinary tract diseases,
hematological diseases, hepatobiliary tract diseases,

1074
 Journal of the Formosan Medical Association 121 (2022) 1073e1080
immunodeficiency, malnutrition, neurological disorders,
prematurity, respiratory diseases and solid neoplastic dis-
eases. Take allergy for example, it included asthma,
allergic rhinitis, and bronchiectasis. The relevant ICD codes
were listed in Supplement 2.
Second, we collected clinical symptoms at admission,
including body temperature, respiratory rate, pulse rate
and oxygen saturation. Due to the missing data, a few re-
cords of vital signs were not included in the calculation. In
total, more than 80% of the vital sign data were included in
the analyses and compared with normal ranges. Heart rate
and respiratory rate were according to age-specific normal
ranges.16,17 Normal body temperature were defined be-
tween 36.6 and 37.9  C.18 Hypoxia was defined SpO2 below
or equal to 95%.19 Besides, blood gas, complete blood
count, biochemical examination, chest X-ray during hospi-
talization and the results of pathogen survey were also
collected.
The pathogens were divided into viruses, bacteriae,
and Mycoplasma pneumoniae. The viruses included influ-
enza, parainfluenza, rhinovirus, respiratory syncytial
virus, enterovirus and adenovirus. The bacteriae included
Streptococcus pneumoniae, Moraxella catarrhalis, Hae-
mophilus influenzae, Staphylococcus aureus, Pseudo-
monas aeruginosa, Klebsiella pneumoniae, Escherichia
coli, Burkholderia cepacia, Acinetobacter baumannii,
Stenotrophomonas maltophilia, and so on.
Statistical analysis
In the data of category variables, numbers and percentages
were mainly used for preliminary calculation, and then
investigated by the chi-square test and the multivariate
logistic regression model. For continuous variables,
KolmogoroveSmirnov test was used to test the distribution.
If the continuous variables were of normal distribution,
data would be shown as mean (standard deviation) and t
test was used to compare the difference. If the variables
were not of normal distribution, data would be shown as
median and interquartile range and ManneWhitney U test
was used to compare the difference between two groups. It
was considered significant if p value was <0.05. All analyses
were performed using SPSS (Version 24).
Ethical approval
The institutional review board had approved the use of de-
identified electronic health record for this study of the
Table 1 Baseline characteristics of children hospitalized with recurrent pneumonia.
Demographic Total (N Z 802)
Male/Female 449/353
Age of the first episode (Y) 2.2 (1.0e3.8)
Age of the last episode (Y) 3.7 (2.3e6.1)
Hospitalized pneumonia episodes 3.0 (2.0e4.0)
Data are shown as case number/number, or median (interquartile range).
N denotes case number. Y denotes years old. The statistics in this table are calculated based on the number of patient.
1075
National Taiwan University Hospital (201912131RINB). All
data were de-identified before being analyzed.
Results
Demography
During the 12-year study period, a total of 8508 hospitalized
children were diagnosed with pneumonia, of which 802
(9.4%) patients had recurrent pneumonia and were included
in this analysis. These patients were separated into 2
groups: Group A were 147 (18.3%) children without under-
lying diseases whereas Group B were 655 (81.7%) children
who had an underlying disease or more. Demographic data
and characteristics of two groups are shown in Table 1. Of
this study, male accounted for 56%. There was no significant
difference in the age of the first episode between the two
groups, but the age of the last episode was significantly
older in group B (p < 0.001). Besides, the patients with
underlying diseases had more hospitalized pneumonia epi-
sodes than the group without underlying diseases (3 vs 2,
p < 0.001).
Among the 655 patients of group B, underlying diseases
can be divided into 15 categories (Table 2). The top three
most common underlying disease categories in group B
included neurological disorders (N Z 252, 38.5%), allergy
(N Z 211, 32.2%) and cardiovascular diseases (N Z 193,
29.5%). Furthermore, the top 10 most common diseases
were as follows: asthma (30.8%), epilepsy (18.0%), acya-
notic congenital heart diseases20 (17.4%), cerebral palsy
(12.2%), congenital laryngomalacia (10.8%), cyanotic
congenital heart disease (8.9%), gastro-esophageal reflux
disease (8.9%), anemia (8.1%), heart failure (7.2%), and
neutropenia (6.4%).
Clinical manifestations and lab data
Table 3 showed the difference of clinical manifestations,
lab data, and radiological reports of chest plain films be-
tween two groups. On admission, the group B had more
abnormal respiratory rates (63.4% in group A vs. 69.5% in
group B, p Z 0.046) and more abnormal oxygen saturation
which was defined SpO2 below 95% (5.28% and 17.5%,
respectively, p < 0.001).17,19 Besides, compared the worst
lab data during whole hospitalization course, we found that
the group B had higher white blood count (9.98  109/L and
13.0  109/L, respectively, p < 0.001), higher neutrophil
percentage (51% and 70%, respectively, p < 0.001), higher
C-reactive protein (CRP) level (1.7 and 2.3 mg/dL,
Group A (N Z 147) Group B (N Z 655) p value
86/61 363/292 0.448
2.0 (1.2e3.0) 2.3 (1.0e4.1) 0.10
2.7 (1.8e3.8) 4.1 (2.5e7.1) <0.001
2.0 (2.0e2.0) 3.0 (2.0e5.0) <0.001
 L.-L. Chen, Y.-C. Liu, H.-C. Lin et al.

Etiology survey
Table 2 Underlying disease categories of Group B and
related most common diseases.
The organisms in each group are listed in Table 4. The
Underlying disease Total (N Z 655) Percentage positive rate of etiological surveys, included virus and my-
Neurological Disorders 252 38.5% coplasma polymerase chain reaction (PCR) was 11.7% (71/
Epilepsy 118 18.0% 605), influenza, parainfluenza, RSV and pneumococcal an-
Cerebral palsy 80 12.2% tigen test was 16.4% (442/2689), virus isolations was 22.5%
Allergy 211 32.2% (335/1487), and Mycoplasma IgM was 16.7% (60/360). For
Asthma 202 30.8% bacterial culture, the overall positive rate was 17.1% (924/
Allergic rhinitis 34 5.3% 5410), the most common specimen was sputum culture
Cardiovascular Disease 193 29.5% (15.5%, 436/2822), and the rest included blood, broncho-
Acyanotic congenital 114 17.4% alveolar lavage, pleural effusion, endotracheal aspirate,
heart disease throat or nasopharyngeal swab. Among the total of 2362
Cyanotic congenital 58 8.9% hospitalized pneumonia episodes, the most common viral
heart disease pathogens were respiratory syncytial virus (7.66%), influ-
Heart failure 47 7.2% enza (4.74%), parainfluenza (2.84%), and adenovirus
Congenital Anomaly/ 187 28.5% (2.79%). Group A had more infections of respiratory syncy-
Genetic Disorder tial virus, influenza, and adenovirus.
Congenital 71 10.8% On bacterial pathogens, children without underlying
laryngomalacia diseases had more S. pneumoniae infection. In contrast,
Gastrointestinal Disease 155 23.7% patients with underlying diseases were prone to have in-
Gastro-esophageal 58 8.9% fections of S. aureus, P. aeruginosa, K. pneumoniae, E. coli,
reflux disease B. cepacia, A. baumannii, and S. maltophilia infections.
Respiratory Disease 124 18.9% There was no statistical difference in the proportions of
Tracheostomy 28 4.3% Mycoplasma pneumoniae, M. catarrhalis, and H.
Trachea or bronchus 26 4.0% influenzae.
anomalies
Hematological Disease 98 15.0% Clinical severity and outcomes
Anemia 53 8.1%
Leukemia 36 5.5% We compared clinical outcomes between the two groups,
Immunodeficiency 88 13.4% and found that group B had longer hospitalization stay (4
Neutropenia 42 6.4% and 7 days, respectively, p < 0.001), higher rates of
Genital Urinary Tract 85 13.0% ventilator use (0.98% and 29.8%, respectively, p < 0.001),
Disease inotropic agent uses (1.31% and 17.6%, respectively, p <
Acute kidney failure 37 5.6% 0.001), ICU care (3.59% and 28.8%, respectively, p < 0.001),
Endocrinologic Disease 47 7.2% longer ICU stay (2.8 and 6.8 days, respectively, p < 0.001)
Solid Neoplasmic Disease 41 6.3% and higher case-fatality rate (0% and 5.19%, respectively, p
Hepatobiliary Tract 33 5.0% < 0.001) as shown in Table 5.
Disease
Autoimmune Disease 28 4.3%
Prematurity 12 1.8% Discussion
Malnutrition 8 1.2%
In our study, 9% of hospitalized children with pneumonia
N denotes case number. The statistics in this table were
had recurrent episodes, and similar to other studies, most
calculated based on the number of Group B patients.
of these children with underlying diseases (81.5%).10,14
Neurological disorders is the most common underlying dis-
ease category, and asthma, epilepsy, acyanotic congenital
heart diseases, cerebral palsy, congenital laryngomalacia
respectively, p Z 0.008), and lower lymphocyte percentage are common underlying diseases. Patients with underlying
(40% and 34%, respectively, p < 0.001). diseases had more severe pneumonia. Their vital signs and
During the hospitalization, group A had a significantly laboratory data were even more abnormal when they were
higher proportion of pneumonia patches (32.4% and 25.9%, admitted to the hospital, and their pathogenic bacteriae
respectively, p Z 0.018), while group B had a higher pro- tended to be more resistant. Because of the above reasons,
portion of pleural effusion (0.65% and 3.21%, respectively, they had more pneumonia episodes, longer hospitalization
p Z 0.013) in chest X-ray findings. Besides, the proportion stays, and required more ventilator and inotropic agent
of interstitial infiltration was similar between two groups supports. Their outcomes were poorer, including higher
(67.6% and 63.2%, respectively, p Z 0.134). Initially, a total complications and higher case-fatality rate. In contrast,
of 330 X-ray reports were negative, but after two pedia- children without underlying diseases had much more viral
tricians independently reviewed these films, 264 of them infections and were rarely fatal.
were found to have abnormal lung infiltration or paren- The age of the last recurrent pneumonia episode was
chymal lesions, so the final negative rate of all CXR was significantly older in the group with underlying diseases. It
2.8% (66/2362). is possible that the existence of underlying diseases may

1076
 Journal of the Formosan Medical Association 121 (2022) 1073e1080

Table 3 Clinical manifestations and lab data on admission.

Parameter Group A (N Z 306) Group B (N Z 2056) p value
Clinical manifestation
Fever or hypothermia 100/271 (36.9%) 540/1710 (31.5%) 0.082
Tachypnea or bradypnea 172/271 (63.4%) 1188/1709 (69.5%) 0.046
Tachycardia or bradycardia 194/271 (71.5%) 1100/1709 (64.3%) 0.02
Hypoxia 14/265 (5.28%) 290/1649 (17.5%) <0.001
Laboratory data
WBC (109/L) 9.98 (7.14e13.9) 13.0 (8.92e17.6) <0.001
Hemoglobin (g/dL) 12.3 (11.6e13.1) 12.2 (10.7e13.2) 0.005
Platelet (109/L) 258 (203e341) 303 (228e394) <0.001
Neutrophil (%) 51 (37e65) 70 (55e81) <0.001
Lymphocyte (%) 40 (26e55) 34 (20e50) <0.001
CRP (mg/dL) 1.7 (0.6e4.2) 2.3 (0.7e5.3) 0.008
ALT (U/L) 15 (11e22) 20 (13e42) <0.001
Creatinine (mg/dL) 0.3 (0.3e0.5) 0.4 (0.3e0.6) <0.001
Chest X-ray
Interstitial infiltration 207 (67.6%) 1300 (63.2%) 0.134
Pneumonia patch or consolidation 99 (32.4%) 533 (25.9%) 0.018
Pleural effusion 2 (0.65%) 66 (3.21%) 0.013
Due to the missing data, a few records of vital signs were not included in the calculation. Data are shown as number/number (%) or
median (interquartile range). Heart rate and respiratory rate were according to age-specific normal ranges.16,17 Normal body tem-
perature were defined between 36.6 and 37.9  C.18 Hypoxia was defined SpO2 below or equal to 95%.19.
ALT denotes alanine aminotransferase. CRP denotes C-reactive protein. N denotes total hospitalization number. WBC denotes white
blood cells. The statistics in this table were calculated based on the number of total pneumonia admission episodes.

Table 4 Comparison of pathogens between group A and group B.

Microorganisms Total (N Z 2362) Group A (N Z 306) Group B (N Z 2056) p value
Virus
Influenza A or B 112 (4.74%) 25 (8.16%) 87 (4.23%) 0.03
Parainfluenza 67 (2.84%) 4 (1.31%) 63 (3.06%) 0.084
Respiratory syncytial 181 (7.66%) 40 (13.07%) 141 (6.86%) <0.001
virus
Adenovirus 66 (2.79%) 20 (6.54%) 46 (2.24%) <0.001
Bacteria
Streptococcus 177 (7.49%) 40 (13.07%) 137 (6.66%) <0.001
pneumoniae
Moraxella catarrhalis 67 (2.84%) 8 (2.61%) 59 (2.87%) 0.802
Haemophilus 75 (3.18%) 14 (4.58%) 61 (2.97%) 0.134
influenzae
Mycoplasma 144 (6.10%) 23 (7.52%) 121 (5.89%) 0.266
pneumoniae
Staphylococcus aureus 330 (14.0%) 24 (7.84%) 306 (14.9%) <0.001
Pseudomonas 300 (12.7%) 6 (1.96%) 294 (14.3%) <0.001
aeruginosa
Klebsiella pneumoniae 128 (5.42%) 3 (0.98%) 125 (6.08%) <0.001
Escherichia coli 68 (2.88%) 1 (0.33%) 67 (3.26%) 0.004
Acinetobacter 89 (3.77%) 5 (1.63%) 84 (4.09%) 0.036
baumannii
Burkholderia cepacia 29 (1.23%) 0 (0.00%) 29 (1.41%) 0.037
Stenotrophomonas 74 (3.13%) 3 (0.98%) 71 (3.45%) 0.008
maltophilia
Data are shown as number (%). N denotes number. The statistics in this table were calculated based on the number of total pneumonia
admission episodes.

1077
 L.-L. Chen, Y.-C. Liu, H.-C. Lin et al.

Table 5 Comparison of clinical outcomes between group A and group B.

Prognosis of each episode Total (N Z 2362) Group A (N Z 306) Group B (N Z 2056) p value
Hospitalization days 6 (4e12) 4 (3e6) 7 (4e13) <0.001
Ventilator 615 (26.0%) 3 (0.98%) 612 (29.8%) <0.001
Inotropic agent 365 (15.5%) 4 (1.31%) 361 (17.6%) <0.001
ICU rate 604 (25.6%) 11 (3.59%) 593 (28.8%) <0.001
ICU days 6.6 (2.8e17.8) 2.8 (2.1e3.9) 6.8 (2.8e18.1) <0.001
Total (N Z 802) Group A (N Z 147) Group B (N Z 655) p value
Mortality 34 (4.24%) 0 (0%) 34 (5.19%) 0.005
Data are presented with N (%) and median (interquartile range).
N denotes number. The statistics in this table were calculated based on the number of total pneumonia admission episodes, except
mortality rate, which was calculated based on the number of total patients.

cause children to be hospitalized with pneumonia more
often when the age is young, and their hospital stay was
much longer due to more complicated diseases. According
to previous studies, the underlying diseases related to
recurrent pneumonia were oropharyngeal incoordination
with aspiration syndrome, bronchial asthma, immune dis-
orders, and congenital cardiac defects.10,21,22 All of the
above reasons may cause damage to the structure and
function of the lungs, and further make the lungs more
susceptible to other recurrent and subsequent infections.
The group with underlying diseases had significantly
higher rates of tachypnea and desaturation, which may be
due to a significant proportion of these children might had
respiratory muscle weakness, increased breathing effort, or
mismatched ventilation due to underlying cerebral palsy,
asthma, cardiovascular disease, and congenital airway ab-
normalities.23 These factors could contribute shortness of
breath and decreased saturation. In addition, the labora-
tory data in this group also had significantly higher white
blood cell count, neutrophil percentage, and CRP level, and
the reason may be more bacterial infections in children
with underlying diseases. Therefore, children with recur-
rent pneumonia and underlying diseases often presented
more seriously clinical manifestations and more bacterial
infections, which highlights the necessity of comprehensive
evaluation and determine the most suitable therapeutic
plan. On the other hand, more tachycardia was observed in
group A, and the median age of the last admission was
significantly younger among children without underlying
diseases (2.7 years vs. 4.1 years, p < 0.001), which might be
related to factors such as crying, fear, and poor coopera-
tion to fasten heart rate during the measurement.
We observed that the group with underlying had fewer
pneumonia patch in the interpretation of chest X-ray. The
possible reason is that even if pneumonia did not progress
to patch, these patients still need admitted to the hospital
due to poor clinical manifestations, such as tachypnea or
retraction. In addition, it was worth noting that these pa-
tients were more likely to find pleural effusion through
chest X-ray.
For pathogen survey, children without underlying dis-
eases had higher chance of getting influenza, respiratory
syncytial virus, adenovirus and S. pneumoniae. In contrast,
the children with underlying diseases were more suscepti-
ble to the following bacteriae: S. aureus, P. aeruginosa,
Klebsiella pneumonia, E. coli, A. baumannii, B. cepacia,
and S. maltophilia. The possible reasons included: their
immune functions might be defective, and they might have
more frequently outpatient visits and hospitalizations. As a
result they were more likely to colonize or infect these
resistant pathogens. Finally, broad-spectrum antibiotics,
which against anaerobic bacteriae, methicillin-resistant S.
aureus (MRSA) and Pseudomonas, were tended to be pre-
scribed especially in patients with multiple underlying dis-
eases.24 A study in 2013 pointed out that, if the pathogen
can be predicted more accurately, it was feasible to use
more precise spectrum antimicrobial for treatment.25 Our
results may provide basics for future microbiological
research and treatment guidelines to improve the care
quality and prognosis of these children, while reducing the
potential adverse effects of unnecessary broad-spectrum
antibiotics.
We analyzed the seasonal or annual trends of all path-
ogens and found that influenza and RSV epidemic trends
varied with the seasons. Influenza infection peaked in
winter and spring (42.9% (48/112) and 27.7% (31/112),
respectively), while the RSV infection rate increased in
autumn (69/181, 38.1%). These data are similar to those
observed in previous studies.26,27
For clinical outcome, children without underlying sys-
temic conditions had significantly shorter hospitalization
stay and ICU stay, lower rates of ventilator use, inotropic
agent, and intensive care when compared with the other
group. Children with underlying diseases had significantly
higher case-fatality rate. In the previous research, the
proportion of children who died directly due to underlying
diseases was about 22%e34%.28,29 This study shows the
presence of these underlying diseases also increased the
risk, complexity and severity of lung infections and leaded
to death. Furthermore, previous studies had shown that the
proportion of rehospitalization and medical expenses has
increased among children with underlying diseases.30e33
Therefore, if we can properly assess and manage underly-
ing diseases well and provide appropriate treatments, it
should be helpful for the prognosis of the disease and the
expenditure on medical costs.
Compared with previous studies, the advantage of our
study is a larger number of samples, a longer time frame,
and comprehensive etiology survey. However, there are
some limitations in this study. First, this article only

1078
 Journal of the Formosan Medical Association 121 (2022) 1073e1080
included the cases of single medical center, and our results
may not generally represent all childhood pneumonia.
Second, we mixed all the underlying diseases together for
analyses, which may fail to present the differences be-
tween different conditions, and we consider distinguishing
all underlying diseases for further analysis in the future.
Finally, the overall negative rate of CXR was about 2.8%
after two pediatricians independently reviewing. The
diagnosis of pneumonia in cases with negative CXR might be
based on physical examination, e.g. rales on auscultation,
nevertheless the possibility of overdiagnosis is still a
concern.
In conclusion, this study reveals that more than 80% of
children with recurrent pneumonia had underlying dis-
eases. Children with underlying diseases and recurrent
pneumonia had higher rates of bacterial infections, venti-
lator use, inotropic agent use and case-fatality. More
attention may be paid on clinical severity and the selection
of antibiotics in children with underlying diseases.
Declaration of competing interest
The authors have no conflicts of interest relevant to this
article.
Acknowledgments
This research was supported in part by Ministry of Science
and Technology, Taiwan (grant MOST 108-2321-B-002-016,
MOST 109-2634-F-002-029, and MOST 110-2634-F-002-032)
to LY Chang. The study is also supported partly by grants
from the National Taiwan University Hospital (NTUH.109-
N4488) to TY Yen. The authors would like to thank the
staff of the Department of Midical Research for providing
clinical data from the National Taiwan University Hospital-
integrated Medical Database for their generous support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jfma.2021.08.013.
References
1. McAllister DA, Liu L, Shi T, Chu Y, Reed C, Burrows J, et al.
Global, regional, and national estimates of pneumonia
morbidity and mortality in children younger than 5 years be-
tween 2000 and 2015: a systematic analysis. Lancet Glob
Health 2019;7:e47e57.
2. Bernadeta D, Max R. Pneumonia. OurWorldInData.org. Avail-
able from: https://ourworldindata.org/pneumonia. [Accessed
22 March 2021].
3. Jesenak M, Banovcin P, Jesenakova B, Babusikova E. Pulmonary
manifestations of primary immunodeficiency disorders in chil-
dren. Front Pediatr 2014;2:77.
4. Nguyen TKP, Tran TH, Roberts CL, Foxe GJ, Graham SM,
Marais BJ. Risk factors for child pneumonia - focus on the
Western Pacific Region. Paediatr Respir Rev 2017;21:95e101.
5. Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M,
et al. British Thoracic Society guidelines for the management
1079
of community acquired pneumonia in children: update 2011.
Thorax 2011;66:1e23.
6. Britt Jr RD, Faksh A, Vogel E, Martin RJ, Pabelick CM,
Prakash YS. Perinatal factors in neonatal and pediatric lung
diseases. Expet Rev Respir Med 2013;7:515e31.
7. Dagli E. Non cystic fibrosis bronchiectasis. Paediatr Respir Rev
2000;1:64e70.
8. Grimwood K, Chang AB. Long-term effects of pneumonia in
young children. Pneumonia (Nathan) 2015;6:101e14.
9. Patria MF, Longhi B, Lelii M, Tagliabue C, Lavelli M, Galeone C,
et al. Children with recurrent pneumonia and non-cystic
fibrosis bronchiectasis. Ital J Pediatr 2016;42:13.
10. Owayed AF, Campbell DM, Wang EE. Underlying causes of
recurrent pneumonia in children. Arch Pediatr Adolesc Med
2000;154:190e4.
11. Cabezuelo Huerta G, Vidal Micó S, Abeledo Gómez A, Frontera
Izquierdo P. Underlying causes of recurrent pneumonia. An
Pediatr (Barc) 2005;63:409e12.
12. Abdel Baseer KA, Sakhr H. Clinical profile and risk factors of
recurrent pneumonia in children at Qena governorate, Egypt.
Int J Clin Pract 2021;75:e13695.
13. Hoang KL, Ta AT, Pham VT. Severe recurrent pneumonia in
children: underlying causes and clinical profile in Vietnam. Ann
Med Surg (Lond) 2021;67:102476.
14. Hoving MFP, Brand PLP. Causes of recurrent pneumonia in
children in a general hospital. J Paediatr Child Health 2013;49:
e208e12.
15. Mandell LA, Niederman MS. Aspiration pneumonia. N Engl J
Med 2019;380:651e63.
16. Bernstein D. History and physical examination. In:
Kliegman RM, Stanton BF, Geme JWS, Schor NF, Behrman RE,
editors. Nelson textbook of pediatrics. 20th ed. Phialdelphia:
Elsevier; 2016. p. 2167.
17. Hartman ME, Cheifetz IM. Pediatric emergencies and resusci-
tation. In: Kliegman RM, Stanton BF, Geme JWS, Schor NF,
Behrman RE, editors. Nelson textbook of pediatrics. 20th ed.
Phialdelphia: Elsevier; 2016. p. 491.
18. Nield LS, Fever Kamat D. In: Kliegman RM, Stanton BF,
Geme JWS, Schor NF, Behrman RE, editors. Nelson textbook of
pediatrics. 20th ed. Phialdelphia: Elsevier; 2016. p. 1277.
19. Sarnaik AP, Clark JA, Sarnaik AA. Respiratory distress and
failure. In: Kliegman RM, Stanton BF, Geme JWS, Schor NF,
Behrman RE, editors. Nelson textbook of pediatrics. 20th ed.
Phialdelphia: Elsevier; 2016. p. 532.
20. Bernstein D. Evaluation and screening of the infant or child
with congenital heart disease. In: Kliegman RM, Stanton BF,
Geme JWS, Schor NF, Behrman RE, editors. Nelson textbook of
pediatrics. 20th ed. Phialdelphia: Elsevier; 2016. p. 2187.
21. Rijal P, Lama L, Shrestha S, Kakshapati P, Nayak R. Study of
children with recurrent pneumonia admitted in a tertiary
hospital. Nepal Med College J 2019;21:65e9.
22. Ciftçi E, Günes‚ M, Köksal Y, Ince E, Dogru U. Underlying causes
of recurrent pneumonia in Turkish children in a university
hospital. J Trop Pediatr 2003;49:212e5.
23. Sarnaik AP, Heidemann SM, Clark JA. Respiratory pathophysi-
ology and regulation. In: Kliegman RM, Stanton BF, Geme JWS,
Schor NF, Behrman RE, editors. Nelson textbook of pediatrics.
20th ed. Phialdelphia: Elsevier; 2016. p. 1984e8.
24. Leyenaar JK, Lagu T, Shieh MS, Pekow PS, Lindenauer PK.
Management and outcomes of pneumonia among children with
complex chronic conditions. Pediatr Infect Dis J 2014;33:
907e11.
25. Williams DJ, Hall M, Shah SS, Parikh K, Tyler A, Neuman MI,
et al. Narrow vs broad-spectrum antimicrobial therapy for
children hospitalized with pneumonia. Pediatrics 2013;132:
e1141e8.
26. Lee JT, Chang LY, Wang LC, Kao CL, Shao PL, Lu CY, et al.
Epidemiology of respiratory syncytial virus infection in northern
 L.-L. Chen, Y.-C. Liu, H.-C. Lin et al.

Taiwan, 2001-2005 - seasonality, clinical characteristics, and
disease burden. J Microbiol Immunol Infect 2007;40:293e301.
27. Moghadami M. A narrative review of influenza: a seasonal and
pandemic disease. Iran J Med Sci 2017;42:2e13.
28. Feudtner C, Feinstein JA, Satchell M, Zhao H, Kang TI. Shifting
place of death among children with complex chronic conditions
in the United States, 1989-2003. J Am Med Assoc 2007;297:
2725e32.
29. Kim MS, Lim NG, Kim HJ, Kim C, Lee JY. Pediatric deaths
attributed to complex chronic conditions over 10 years in
Korea: evidence for the need to provide pediatric palliative
care. J Kor Med Sci 2018;33:e1.
30. Simon TD, Berry J, Feudtner C, Stone BL, Sheng X, Bratton SL,
et al. Children with complex chronic conditions in inpatient
hospital settings in the United States. Pediatrics 2010;126:
647e55.
31. Berry JG, Hall DE, Kuo DZ, Cohen E, Agrawal R, Feudtner C,
et al. Hospital utilization and characteristics of patients
experiencing recurrent readmissions within children’s hospi-
tals. J Am Med Assoc 2011;305:682e90.
32. Berry JG, Hall M, Hall DE, Kuo DZ, Cohen E, Agrawal R, et al.
Inpatient growth and resource use in 28 children’s hospitals: a
longitudinal, multi-institutional study. JAMA Pediatr 2013;167:
170e7.
33. Cohen E, Berry JG, Camacho X, Anderson G, Wodchis W,
Guttmann A. Patterns and costs of health care use of
children with medical complexity. Pediatrics 2012;130:
e1463e70.

1080