European Journal of Pediatrics

https://doi.org/10.1007/s00431-020-03852-9

ORIGINAL ARTICLE

Acute viral bronchiolitis as a cause of pediatric acute respiratory

distress syndrome
Marwa M. H. Ghazaly 1,2 & Nagla H. Abu Faddan 1 & Duaa M. Raafat 1 & Nagwa A. Mohammed 1 & Simon Nadel 1,2

Received: 21 July 2020 / Revised: 19 October 2020 / Accepted: 21 October 2020

# The Author(s) 2020

Abstract
The Pediatric Acute Lung Injury Consensus Conference (PALICC) published pediatric-specific guidelines for the definition,
management, and research in pediatric acute respiratory distress syndrome (PARDS). Acute viral bronchiolitis (AVB) remains
one of the leading causes of admission to PICU. Respiratory syncytial virus (RSV) is the most common cause of AVB. We aimed
to evaluate the incidence of PARDS in AVB and identify the risk of RSV as a trigger pathogen for PARDS. This study is a
retrospective single-center observational cohort study including children < 2 years of age admitted to the pediatric intensive care
unit at St Mary’s Hospital, London, and presented with AVB in 3 years (2016–2018). Clinical and demographic data was
collected; PALICC criteria were applied to define PARDS. Data was expressed as median (IQR range); non-parametric tests
were used. In this study, 144 infants with acute viral bronchiolitis were admitted to PICU in the study period. Thirty-nine infants
fulfilled criteria of PARDS with RSV as the most common virus identified. Bacterial infection was identified as a risk factor for
development of PARDS in infants with AVB.
Conclusion: AVB is an important cause of PARDS in infants. RSV is associated with a higher risk of PARDS in AVB.
Bacterial co-infection is a significant risk factor for development of PARDS in AVB.

Keywords Bronchiolitis . Children . ARDS . Intensive care . Respiratory syncytial virus . RSV

What is Known:
• Bronchiolitis is a common cause of respiratory failure in children under 2 years.
• ARDS is a common cause of PICU admission.
What is New:
• Evaluation of bronchiolitis as a cause of PARDS according to the PALLIC criteria.
• Evaluation of different viruses’ outcome in PARDS especially RSV as a commonest cause of AVB.

Communicated by Daniele De Luca

Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1007/s00431-020-
03852-9.

* Simon Nadel Nagwa A. Mohammed

s.nadel@imperial.ac.uk namma65@yahoo.com
Marwa M. H. Ghazaly 1
marwaghazally@med.au.edu.eg Department of Pediatrics, Children University Hospital, Faculty of
Medicine, Assiut University, Assiut, Egypt
Nagla H. Abu Faddan 2
Paediatric Intensive Care Unit, St Mary’s Hospital, Imperial College
nhi-af@hotmail.com
London Healthcare NHS Trust, London, UK
Duaa M. Raafat
duaa_raafat@hotmail.com
 Eur J Pediatr

List of abbreviations Aim

AVB Acute viral bronchiolitis
ETT Endotracheal tube Our study aimed to evaluate the prevalence of PARDS, based
HMPV Human metapneumovirus on the recent PALICC definitions, in children with acute viral
HFOV High frequency oscillating ventilation bronchiolitis (AVB) admitted to the PICU. We also aimed to
LRTI Lower respiratory tract infection compare patient characteristics and outcomes of PARDS with
LOS Length of stay infection due to different viruses as a cause of AVB.
MV Mechanical ventilation
NPA Nasopharyngeal aspirate
PALICC Pediatric Acute Lung Injury Consensus Methodology
Conference
PICU Pediatric intensive care unit Study design
PARDS Pediatric acute respiratory distress syndrome
PCR Polymerase chain reaction We carried out a retrospective, descriptive, observational study
PaO2 Partial pressure of arterial oxygen that included children aged under 2 years admitted to the PICU at
RSV Respiratory syncytial virus St Mary’s Hospital, London, who presented with acute respira-
tory failure due to AVB between January 2016 and June 2018.
Patients were classified into two groups: PARDS group,
patients with a diagnosis of AVB and met the PALICC criteria
Introduction for PARDS (Supplementary Table S1), and non-PARDS
group, patients with a diagnosis of AVB who did not meet
Acute respiratory distress syndrome (ARDS) is an acute lung the PALICC criteria for PARDS.
injury that can be triggered by a heterogeneous set of pulmo- We excluded patients with pre-existing lung disease or sig-
nary (direct lung injury) and extrapulmonary (indirect ling nificant intra-cardiac shunt diagnosed by echocardiographic
injury) etiologies. ARDS manifests as pulmonary inflamma- evaluation. We also excluded patients with missing records.
tion, alveolar edema, and hypoxemic respiratory failure [1, 2].
ARDS in children (pediatric ARDS—PARDS) has been Data collection
shown to have a lower mortality compared to adults [3, 4].
Furthermore, infections account for more than half of the Patients were identified using the electronic database of PICU
cases of PARDS, particularly lower respiratory tract infections admissions (Careview, Phillips, UK). Inclusion criteria were
such as pneumonia and bronchiolitis, with viruses frequently children aged < 24 months with a recorded diagnosis of bron-
implicated [3]. However, the importance of viral infections as chiolitis using the SNOMED diagnostic code [12].
a cause of PARDS in infants has not previously been de- Collected data included patient demographics (age, sex,
scribed [5, 6]. weight, race, ethnicity), comorbidities, daily recording of type,
About 3.5 million children under 5 years of age are admit- mode and parameters of ventilation, chest imaging, blood gas,
ted annually to hospitals due to lower respiratory tract infec- pulse oximetry data, duration of mechanical ventilation,
tion (LRTI) caused by respiratory syncytial virus (RSV) length of stay on PICU, and mortality.
worldwide [7]. RSV accounts for 22% of all acute LRTIs in
children and is responsible for 66,000–199,000 deaths world- Assessment of etiology
wide. Most childhood deaths due to RSV infection occur in
developing countries [7]. All children had standardized sample collection on admission
The Pediatric Acute Lung Injury Consensus Conference to PICU, which included nasopharyngeal aspirate (NPA) for
(PALICC) definition of PARDS was developed to overcome viral polymerase chain reaction (PCR), blood culture, endo-
the limitations of various definitions of ARDS, which were tracheal tube (ETT) aspirate in intubated patients for viral
primarily designed and validated for adults (e.g., the Berlin PCR and bacterial culture, and other relevant cultures depend-
definition of ARDS) [8]. ing on clinical presentation. All samples were collected and
The incidence of PARDS due to viral infection is still un- analyzed using a standardized protocol.
known [6]. RSV and rhinovirus are the most common respi- The NPA and ETT aspirate samples were routinely tested for
ratory pathogens in children under the age of 1 year and ac- the following viruses using real-time multiplex PCR: RSV; rhi-
count for many admissions to pediatric intensive care units novirus; adenovirus; parainfluenza viruses 1, 2, and 3; enterovi-
(PICUs) [9]. Despite this, few studies have investigated the rus; and influenza virus A and B. Extended analyses were con-
frequency of viral-induced PARDS in infants and its impact ducted on NPA or ETT specimens depending on advice from the
on prognosis [4, 5, 10, 11]. Infectious Diseases Service. The results of all other bacterial
Eur J Pediatr

cultures on respiratory specimens, urine, blood, or other cultures premature, and 44% (n = 17) had previous comorbidities. There
were also recorded. Some infants had similar diagnostic samples was no significant difference in baseline demographic character-
taken at their local hospital before transfer to PICU. istics in infants with and without PARDS (see Table 1).
All patients also had routine hematology and biochemistry Positive viral PCR results were reported in 90% of PARDS
samples taken on admission to PICU. cases, with RSV the most common pathogen (found in 51%),
followed by rhinovirus (28%), human metapneumovirus (HMPV)
Outcomes (13%), and co-infection with more than one virus (18%). Bacterial
co-infection was reported in 31% of cases (Table 2).
The primary outcome of this study was the development of All cases of PARDS required invasive ventilation. Twenty-
PARDS according to PALICC criteria. Other outcomes re- five patients required escalation to high frequency oscillating
corded included the duration of mechanical ventilation (MV) ventilation (HFOV).
and length of stay (LOS) in the PICU. In patients who required Our usual policy is to commence patients with respiratory
re-intubation after the first extubation, the time of first failure who are admitted to PICU on parenteral antibiotics.
extubation was used for analysis. Four children also received steroids as part of PARDS man-
agement. Two children died from their illness.
In regard of severity of PARDS, 17 cases were mild, 10
Statistical analysis cases were moderate, and 12 were severe. Table 1 describes
the patient factors associated with a diagnosis of PARDS.
Statistical analysis was done using SPSS version 20.0 (SPSS
Inc., Chicago, Illinois, USA). Statistical analysis for the compar-
ison of patient criteria, clinical course, and outcomes among PARDS associated with RSV
patients PARDS, RSV included Fisher's exact and Mann-
Whitney tests, as appropriate with significance set at a P-value Seventy-eight children had RSV as the cause of AVB, and
of <0.05. Univariate analysis was done first to identify potential RSV was the most commonly identified pathogen. Twenty
risk factors and we added some factors as age ,wt., comorbidity of these cases fulfilled PARDS criteria.
,RSV infection and bacterial coinfection them binary logistic Table 3 compares patient characteristics to differentiate be-
regression analysis for development of PARDS as dependent tween RSV positive PARDS and RSV negative PARDS.
and other factors as independent factors (age, comorbidity , rsv Infants with RSV were younger and weighed less than
infection, bacterial coinfection). infants with other viral etiologies. Infants with HMPV had
more ventilation days and PICU stay (p = 0.02), (Table 4).

Results
Risk factors for PARDS in acute viral
Between January 2016 and June 2018, 144 children < 2 years bronchiolitis
of age were admitted to the PICU with a diagnosis of AVB.
Thirty-nine patients (27%) fulfilled the criteria of PARDS Because the meaningfulness of logistic regression modeling we
according to PALICC criteria. Median age for patients with were restricted by the absolute number of PARDS cases, our
PARDS was 60 days (IQR 35–172.5 days), 66% (n = 26) were model included four variables to evaluate the associations with
male, 44% (n = 17) presented with apnea, 49% (n = 19) were the development of PARDS, choosing (RSV or not), age,

Table 1 A comparison of demographics and clinical characteristics of all bronchiolitis infants with PARDS vs those without PARDS

All (n = 144) PARDS (n = 39) No PARDS (n = 105) p Value

Age (days), median (IQR) 56 (28–180) 60 (35–173) 56 (28–150) 0.4

Weight, kg, median (IQR) 4.6 (3–6.5) 4.4 (3–6.4) 5.1 (3.6–6.9) 0.09
Male gender 89 (66%) 28 61 0.2
Prematurity 62 (44%) 19 43 0.3
Comorbidity 43 (33.4%) 17 26 0.2
Respiratory comorbidity 16 (37%) 8 10 0.1
Apnea 70 (48.6%) 19 51 0.4
PIM-2r % 0.9 (0.6–1.7) 1.2 (0.6–1.7) 0.97 (0.7–1.2) 0.08
Caucasian 59 20 39 0.06
 Eur J Pediatr

Table 2 Microbiological results and clinical outcomes of all bronchiolitis patients comparing patients with PARDS and without PARDS

All (n = 144) PARDS (n = 39) No PARDS (n = 105) p Value

RSV 68 20 48 0.5
Rhinovirus 28 6 22 0.63
HMPV 9 5 4 0.06
Adenovirus 3 2 1 0.17
influenza 6 1 5 1
Viral co-infection 23 6 17 0.06
Bacterial co-infection 22 12 10 0.002
Ventilation days 5.25 (3–8) 8 4.5 0.0001
PICU LOS 6.5 (5–10) 9.8 (5.6–10.8) 5.8 (2.7–6.1) 0.0001

PARDS pediatric acute respiratory distress syndrome, RSV respiratory syncytial virus, HMPV human metapneumovirus, PICU pediatric intensive care unit,
LOS length of stay; categories were compared with Fisher exact test, medians were compared by Mann-Whitney test; significant results with P value < 0.05

bacterial coinfection, comorbidity. The presence of bacterial co- bronchiolitis and viral pneumonia are overlapping, and it is
infection was significantly associated with the development of often difficult to differentiate between them, particularly in
PARDS (OR = 1.9, p = 0.02) (confidence interval: 1.19–5.68). children under 2 years of age. Viruses were the identified
pathogen in 92% of our patients, compared to 70% in a similar
study reported by Roberts et al. [5].
Discussion SV was the most common cause of PARDS in our study. It
was detected in 51% of cases, as has been demonstrated in
This study reports one unit’s experience of the incidence of previous studies [10, 14, 15]. Similar to previous studies, pa-
PARDS in children with AVB. We describe the frequency of tients with PARDS associated with RSV infection in our study
PARDS in this cohort and demonstrate that specific viruses were younger and weighed less when compared with those
are associated with different outcomes. with PARDS caused by other viruses. We thought this may be
We found that over one-quarter of children admitted to due to age is as a major risk in RSV viral bronchiolitis.
PICU with acute respiratory failure due to AVB developed However, RSV patients had a shorter length of stay and dura-
PARDS according to the PALICC criteria. Half of these tion of ventilation compared to children with other individual
PARDS cases had RSV as a trigger factor. viruses [9, 16, 11]. Both the overall incidence of PARDS as
Pneumonia has been reported as the most common precip- well as its severity stratification were similar in those with
itating cause of ARDS in children [3, 13, 14]. Acute viral RSV compared to children without RSV [15, 17, 18].

Table 3 Demographics and clinical characteristics of patients with RSV PARDS, HPMV PARDS and other viruses PARDS group

RSV with PARDS (n = 20) HMPV with PARDS (n = 5) Other viruses PARDS (n = 14) p Value

Age, days, median (IQR) 66 (36–95) 127 (56–180) 168 (118–226) 0.002
Weight, kg, median 3.7 (3–4.7) 4 (3.8–5) 5.2 (4.7–5.8) 0.04
Male gender, 15 3 6 0.7
Prematurity 9 3 4 0.2
Comorbidity 8 2 4 0.5
Apnea 13 2 2 0.3
Caucasian 12 2 6 0.4
Co-infection 5 2 7 0.1
MAP (cm H2O) 12 (11–14) 14 (11–16) 13 (11–15) 0.2
FiO2 (%) 50 (44–60) 60 (40–80) 57 (48–66) 0.03
PEEP (cm H2O) 6 (5–7) 8 (5–8) 7 (5–8) 0.1
Ventilation days 9 (7.6–10.5) 16.2 (6–25) 10.2 (8–12.5) 0.01
PICU LOS days 11.7 (9.6–13) 17.5 (9.1–25) 11.5 (10–14) 0.0.02

PARDS pediatric acute respiratory distress syndrome, RSV respiratory syncytial virus, IQR interquartile range, MAP mean airway pressure, FIO2 fraction
inhaled oxygen, PEEP positive end expiratory pressure, PICU pediatric intensive care unit, LOS length of stay; categories were compared with Fisher
exact test, medians were compared by Mann-Whitney test
Eur J Pediatr

Table 4 Demographics and baseline characteristics of infants with PARDS stratified by individual viruses

RSV (n = 15) Rhino (n = 6) Adeno (n = 3) HMPV (n = 5) Influenza (n = 1) RSV/others (n = 5)

Age in days 35 (30–270) 210 (90–250) 285 (277.5–293) 127 (56–180) 28 120 (35–180)
Weight 3.15 (3.5–7) 6.3 (5.5–7) 7.5 (6.5–8) 4 (3.8–5) 2.2 4.6 (3–7.5)
Male 12 5 1 3 0 3
Prematurity 6 3 0 3 1 3
Comorbidity 6 4 0 2 0 2
Apnea 10 1 0 2 1 3
OI 10.6 13.5 14 13.3 10.9 7.5
PICU LOS 9 (7.7–18) 12 (6–18) 6.2 (5–10.5) 17.5 (9.1–25) 11 8.1 (6.8–8.3)
PARDS severity
Mild 10 3 1 2 0 4
Moderate 4 0 1 1 1 1
Severe 1 3 1 2 0 0

Comparing AVB as a trigger for PARDS with other causes (NA, DR, NM, and SN) have revised and edited the manuscript and
accepted the final version of the manuscript.
of PARDS, AVB appears to have a more benign course as
most cases described were mild [13, 19].
Funding The author(s) disclosed receipt of the following financial support
As documented in previous studies, clinical course and for the research, authorship, and publication of this article: Imperial College
outcomes are worse in AVB with PARDS compared to those Healthcare NHS Trust and the Egyptian Ministry of Higher Education.
without PARDS [13, 19]; the mean duration of invasive me-
chanical ventilation was longer in children with PARDS com- Compliance with ethical standards
pared to those without PARDS [4, 10, 20].
Concerning risk factors, we highlighted a significant associa- Conflict of interest The authors declare that they have no conflict of interest.
tion between bacterial co-infection and development of PARDS
in our study cohort. This has also been shown in previous studies Ethical approval and consent to participate This study was approved
by the Medical Ethics Committee at Imperial College London Healthcare
which have shown an association between bacterial co-infection, NHS Trust, and consent forms were not needed as data recruited retro-
severe respiratory disease, and longer PICU stay [21]. None of spectively from patient notes.
the previous studies has demonstrated the association between
bacterial co-infection and PARDS in AVB. This could be due to Consent for publication NA.
increased lung inflammation in viral/bacterial co-infection, thus Open Access This article is licensed under a Creative Commons
making respiratory failure more severe. Attribution 4.0 International License, which permits use, sharing,
Limitations to our study include those related to retrospec- adaptation, distribution and reproduction in any medium or format, as
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was more common in children with RSV infection. Bacterial
co-infection was significantly associated with development of
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