JOURNAL READING

“Association between multiple respiratory viral infections and pediatric

intensive care unit admission among infants with bronchiolitis”

Diajukan Untuk Memenuhi Tugas Akhir Kepaniteraan Klinik Madya SMF Ilmu Kesehatan
Anak Rumah Sakit Umum Daerah Jayapura

Pembimbing :

dr. Theresia Ratna Sarungallo,Sp.A

Oleh :
Evi Kende Suma 2019086016308
Obaja Yohanes Anoga 20180811018124
Riski M Handayani 20180811018175
Sarital Boron 20180811018148
Sopia L Paa 20170811018027

SMF ILMU KESEHATAN ANAK

RUMAH SAKIT UMUM DAERAH JAYAPURA
FAKULTAS KEDOKTERANUNIVERSITAS CENDERAWASIH
JAYAPURA
2020

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 HALAMAN PENGESAHAN

Telah disetujui dan diterima oleh Penguji Journal Reading dengan judul:
“Association between multiple respiratory viral infections and pediatric

intensive care unit admission among infants with bronchiolitis” Sebagai salah
satu Syarat Ujian Kepaniteraan Klinik Madya pada SMF Anak Rumah Sakit Umum Abepura
Fakultas Kedokteran Universitas Cenderawasih Jayapura

yang dilaksanakan pada:

Hari/tanggal : Selasa,29 September2020

Mengesahkan
Penguji Jurnal Reading Bagian SMF Anak
Fakultas Kedokteran Universitas Cenderawasih

dr. Theresia Ratna Sarungallo,Sp.A

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 DAFTAR ISI

HALAMAN PENGESAHAN....................................................................................................2

DAFTAR ISI..............................................................................................................................3

JOURNAL READING “Association between multiple respiratory viral infections and

pediatric intensive care unit admission among infants with
bronchiolitis”……………………………………………………………………...………...
4

Hubungan Multipel Infeksi Virus Pernapasan Dan Ruang Perawatan Intensif Anak Pada
Bayi Yang Masuk Dengan Bronkiolitis...................................................................................12

PPT...........................................................................................................................................24

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 JOURNAL READING
Archives de Pe´diatrie 27 (2020) 39–44

Available online at

ScienceDirect
www.sciencedirect.com

Research paper

Association between multiple respiratory viral infections and

pediatric intensive care unit admission among infants with
bronchiolitis
a, a a a a a b
P. Tsou *, A. Vadivelan , M. Kovvuri , N. Garg , M. Thangavelu , Y. Wang , S. Raj
a Department of Pediatrics, Driscoll Children’s Hospital/Texas A&M College of Medicine, Corpus Christi, TX, United States
bDepartment of Critical Care Medicine, Driscoll Children’s Hospital/Texas A&M College of Medicine, Corpus Christi, TX, United States

ARTICLE INFO

Article history:
Received 26 July 2019
Received in revised form 14 October 2019 Accepted 11 November 2019 Available online 25 November 2019

Keywords:
Bronchiolitis
Infants
Pediatric intensive care
Multiple respiratory viral

ABSTRACT

Background: It is unclear whether multiple respiratory viral infections are associated with more severe bronchiolitis requiring pediatric intensive care unit
(PICU) admission. We aimed to identify the association between multiple respiratory viral infections and PICU admission among infants with bronchiolitis.

Methods: We performed a 1:1 case-control study enrolling previously healthy full-term infants ( 12 months) with bronchiolitis admitted to the PICU as cases
and those to the general pediatric ward as controls from 2015 to 2017. Multiplex polymerase chain reaction (PCR) was used for detection of the respiratory
viruses. We summarized the characteristics of infants admitted to the PICU and the general pediatric unit. Multivariable logistic regression analysis was used to
fit the association between multiple respiratory viral infections ( 2 strains) and PICU admission.

Results: A total of 135 infants admitted to the PICU were compared with 135 randomly selected control
infants admitted to the general pediatric unit. The PICU patients were younger (median: 2.2 months, interquartile range: 1.3–4.2) than the general ward patients
(median: 3.2 months, interquartile range: 1.6–6.4). Respiratory syncytial virus (74.1%), rhinovirus (28.9%), and coronavirus (5.9%) were the most common
viruses for bronchiolitis requiring PICU admission. Patients with bronchiolitis admitted to the PICU tended to have multiple viral infections compared with
patients on the general ward (23.0% vs. 10.4%, P < 0.001). In the multivariable logistic regression analysis, bronchiolitis with multiple viral infections was
associated with higher odds of PICU admission (adjusted odds ratio: 2.56, 95% confidence interval: 1.17–5.57, P = 0.02).

Conclusion: Infants with multiviral bronchiolitis have higher odds of PICU admission compared with those with a single or nondetectable viral infection.

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 C 2019 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

1. Introduction

Bronchiolitis is an acute viral respiratory infection that is characterized by bronchiolar obstruction with edema, mucus, and cellular
debris in children under 2 years of age. Affected children typically have fever, cough, and respiratory distress (e.g., retrac-tion, wheezing)
[1]. Bronchiolitis is an important issue as it is one of the leading causes of hospitalization among children. The total annual costs for
bronchiolitis-related hospitalizations in the United States were $543 million [2]. Approximately 2–3% of

* Corresponding author. Department of Pediatrics, Driscoll Children’s Hospital/ Texas A&M College of Medicine, 3533 S. Alameda street, 78411 Corpus Christi, TX,
United States.

E-mail address: poyangtsou@gmail.com (P. Tsou).

affected children require hospitalization for a higher level of care, leading to 149,000 hospitalizations annually [2]. The majority of children
with bronchiolitis have mild-to-moderate illness, but 2–6% of hospitalized children require pediatric intensive care unit (PICU) admission,
and 2–3% of the hospitalized children need high-flow oxygenation or mechanical ventilation [3].
Established risk factors for hospital admission or PICU admis-sion include prematurity, younger age, the presence of a com-orbidity, and
environmental factors. Respiratory syncytial virus (RSV) is most frequently associated with bronchiolitis, accounting for 43–74% of all
cases [4]. The recent introduction and widespread use of molecular-based methods (real-time multiplex polymerase chain reaction [PCR])
has helped identify an increased number of concomitant viral infections (e.g., metapneumovirus) in addition to RSV in children with acute
bronchiolitis. Other viruses frequently found in children with bronchiolitis include rhinovirus,

https://doi.org/10.1016/j.arcped.2019.11.006
0929-693X/ C 2019 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

P. Tsou et al. / Archives de Pe´diatrie 27 (2020) 39–44

coronavirus, human metapneumovirus, parainfluenza virus, and adenovirus [5,6]. Concomitant viral infection in hospitalized children with
bronchiolitis ranges from 10% to 40% [7–11]. How-ever, it remains unanswered whether multiple concomitant respiratory viral infections
are associated with more severe bronchiolitis. Prior studies were limited for only providing descriptive statistics without accounting for
confounders or for having inadequate sample size [10–12]. It is important to know whether multiple respiratory viral infections are linked to
worse respiratory outcomes, since early intensive care given to this vulnerable population might decrease the need for rapid response on the
pediatric ward and potentially adverse outcomes. To address these issues, we conducted a case-control study and performed a multivariable
regression analysis to determine the association between severe bronchiolitis resulting in PICU admis-sion and the number of viral co-
infections among previously healthy infants hospitalized for acute bronchiolitis, while account-ing for confounders.

2. Material and methods

2.1. Study design
This study was approved by the Driscoll Children’s Hospital Institutional Review Board. This was a 1:1 case-control study of infants
aged 12 months or younger who were admitted to our 18-bed tertiary care pediatric intensive care unit (PICU). The study sample was
chosen based on the ICD code for bronchiolitis during the study period. Infants with bronchiolitis admitted to the PICU were identified as
cases and were compared with infants with bronchiolitis admitted to the general pediatric unit as controls. As cases, we included all patients
with bronchiolitis admitted to the PICU from whom a nasopharyngeal swab (NPS) sample had been collected for real-time multiplex PCR at
our institution from January 2015 to December 2017. PCR analysis was performed based on the physician’s decision regarding the need for
additional testing that might change patient management. As controls, the same number of neonates (<28 days; n = 20) and infants (n = 135)
were randomly selected among the 890 patients (age 1 year) with bronchiolitis admitted to the general pediatric unit, and for whom PCR
was performed during the same study period, using a random sampling method. Sensitivity analysis was conducted to determine whether
there was a significant difference between patients with bronchiolitis admitted to the general pediatric unit for whom PCR was performed
and those for whom PCR was not performed. We retrospectively reviewed the electronic medical records (EMR) of eligible patients and
documented the demo-graphic, clinical, laboratory, imaging, and outcome data. Patients who were premature or had significant underlying
medical illness (e.g., tracheostomy, baseline oxygen requirement, cyanotic heart disease, chromosomal disorders, neurologic disorders) were
excluded from the study.

2.2. Exposure of interest: respiratory viral infection

The real-time multiplex PCR used in our institution is the FilmArray Respiratory Panel 2 (RP2) by BioFire that allows for rapid
detection (around 45 min) of 22 viral and atypical bacterial pathogens directly from NPS samples. The detectable pathogens include
adenovirus, coronavirus 229E, coronavirus HKU1, corona-virus NL63, coronavirus OC43, human metapneumovirus, human
rhinovirus/enterovirus, influenza virus A, influenza virus A H1, influenza virus A H1-2009, influenza virus A H3, influenza virus B,
parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, respiratory syncytial virus, Bordetella
pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, Middle East respiratory syndrome – coronavirus, and Bordetella parapertussis.
FilmArray RP2 is a reliable and accurate assay that has an overall percentage of agreement of 99.2% with the gold standard [13]. Infection
with multiple viruses is defined as the presence of two or more viral strains.

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2.3. Outcome measures
The primary outcome was admission to the PICU, as a surrogate outcome for the severity of bronchiolitis. The criteria for admission to
the PICU in our institution include, but are not limited to, hypoxia with oxygen requirement of 40% or respiratory distress requiring
mechanical and nonmechanical ventilation (e.g., high-flow oxygen), hemodynamic instability not responding to initial fluid resuscitation
(i.e., 60 mL/kg normal saline bolus), or the clinicians’ discretion. Our secondary outcome was intubation after hospital admission.

2.4. Statistical analysis

Exploratory data analysis was conducted to describe the characteristics of infants with bronchiolitis admitted to the general pediatric
ward and the PICU. Further, the type and the number of respiratory viral infections were compared between infants admitted to the PICU
and those admitted to the general pediatric ward. Categorical variables are presented as frequency and percentage, and were compared using
2
the Chi test. Continu-ous variables are presented as mean or median and were compared with the t test or Wilcoxon rank-sum test as
appropriate, for non-normally distributed continuous variables and normally distribut-ed continuous variables.

To assess the association between the number of respiratory viral infections and primary (i.e., PICU admission) as well as secondary
outcomes (i.e., intubation), multivariable logistic regression analyses controlling for potential confounders were conducted. The following
factors were adjusted for: age category (neonates, infants), weight, bronchodilator use, feeding type, antibiotic use, systemic steroid use, and
heart rate at admission. Covariates were initially determined based on the potential relevance reported in the literature and on their
association with the outcome in the bivariate analysis at a significance level of P < 0.1. Statistical analysis was conducted using Stata 12.0
(Stata Corp, College Station, TX, USA).

3. Results
3.1. Patient demographics and clinical characteristics
During the study period, there were 135 infants in the PICU who were compared with 135 control infants randomly selected out of 890
infants admitted to general pediatric ward. Among 135 patients admitted to the PICU, 20 patients (14.8%) were neonates, of whom 61
(45.2%) were female, with a median age of 2.2 months (interquartile range [IQR]: 1.3–4.2 months). By comparison, among 135 patients
admitted to the general pediatric ward as controls, 20 patients (14.8%) were neonates, of whom 54 (40.0%) were female, with a median age
of 3.2 months (IQR: 1.6– 6.4 months). The characteristics between patients with bronchiol-itis admitted to the PICU and those admitted to
the general pediatric ward are summarized in Table 1. Compared with patients admitted to the general pediatric ward, patients admitted to
the PICU were younger, weighed less, were more likely to have received bronchodilators, antibiotics, feeding tube (NG/ND), and had a
longer hospital stay. There was no mortality among the cases or the controls.
P. Tsou et al. / Archives de Pe´diatrie 27 (2020) 39–44 41

Table 1
Characteristics of bronchiolitis patients with PICU admission and non-PICU admission.

Non-PICU admission PICU admission P

(n = 135) (n = 135)
Age in months, median (IQR) 3.2 (1.6, 6.4) 2.2 (1.3, 4.2) 0.015
Neonate, n (%) 20 (14.8) 20 (14.8) 1.00
Female, n (%) 54 (40.0) 61 (45.2) 0.39
Weight (kg), median (IQR) 7.1 (5.0, 11.5) 4.9 (3.9, 6.1) <0.001
3
WBC (10 /mL), median (IQR) 10.5 (7.7, 13.9) 9.6 (7.3, 12.6) 0.31
Hgb (g/dL), median (IQR) 11.7 (10.8, 12.5) 11.1 (10.2, 12.0) 0.047
Bronchodilator use, n (%) 36 (26.7) 84 (62.2) <0.001
ICS use, n (%) 33 (24.4) 9 (6.7) <0.001
Systemic steroid use, n (%) 44 (32.6) 22 (16.3) 0.002
HTS use, n (%) 115 (85.2) 125 (92.6) 0.053
Antibiotic use, n (%) 37 (27.4) 84 (62.2) <0.001
HR at hospital admission, median (IQR) 155.0 (137.0, 173.0) 166.0 (150.0, 180.0) <0.001
RR at hospital admission, median (IQR) 46.0 (40.0, 55.0) 48.0 (39.0, 61.0) 0.14
O2 flow at hospital admission, median (IQR) 0.0 (0.0, 0.0) 3.0 (1.0, 8.0) <0.001
SpO2 at hospital admission, median (IQR) 98.0 (97.0, 100.0) 98.0 (95.0, 100.0) 0.45
Duration of Abx, median (IQR) 48.0 (48.0, 72.0) 48.0 (24.0, 72.0) 0.15
Feeding method, n (%)
NG/ND 19 (14.1) 69 (51.1) <0.001
PO 116 (85.9) 66 (48.9)
Length of hospital stay (h), median (IQR) 44.0 (30.0, 67.0) 130.0 (94.0, 214.0) <0.001

IQR: interquartile range; PICU: pediatric intensive care unit; ICS: inhaled corticosteroids; HTS: hypertonic saline; HR: heart rate; RR: respiratory rate; NG: nasogastric;
ND:
nasoduodenal; PO: per os; h: hour.

3.2. Respiratory viral profiles

The type and the number of respiratory viruses detected via PCR are summarized in Table 2. During the study period, 87.75% (781/890)
of patients diagnosed with bronchiolitis and admitted to the general ward had PCR testing, while 100% (135/135) of patients diagnosed with
bronchiolitis admitted to the PICU had PCR testing. There were no significant differences in age, gender, and length of hospital stay
between those admitted to the general ward with and without PCR testing (P > 0.05). All study subjects (135 cases and 135 controls) were
tested for viral PCR either prior to admission or during their stay in the hospital. PCR detected one or more viruses in 132 (97.8%) and 100
(74.1%) infants admitted to the PICU and to

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the general ward, respectively. Infections with a single virus and multiple viruses were found in 101 (74.8%) and 31 (23.0%) of infants
admitted to the PICU, respectively. On the other hand, infections with a single virus and multiple viruses were found in 86 (63.7%) and 14
(10.4%) of infants admitted to the general ward, respectively. RSV, rhinovirus, and coronavirus were the top three causes of acute
bronchiolitis for both the patients admitted to the general ward and the PICU. Compared with patients with bronchiolitis admitted to the
general ward, those admitted to the PICU were more likely to have co-infection of RSV and adenovirus (0% vs. 4.4%, P = 0.013), as well as
RSV and mycoplasma (3.7% vs. 11.9%, P = 0.012) (Table 2). Fig. 1 shows the proportion of PICU patients with bronchiolitis caused by
each respiratory virus for the

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Table 2
Respiratory viral characteristics and types by PICU admission status.

Non-PICU admission PICU admission P

(n = 135) (n = 135)
Multiple virus infection, n (%)
None 35 (25.9) 3 (2.2) <0.001
Single 86 (63.7) 101 (74.8)
Multiple 14 (10.4) 31 (23.0)
Numbers of virus infection, mean (SD) 0.9 (0.6) 1.2 (0.5) <0.001
Type of respiratory virus/organism
RSV, n (%) 79 (58.5) 100 (74.1) 0.007
Coronavirus, n (%) 7 (5.2) 8 (5.9) 0.79
Human metapneumovirus, n (%) 2 (1.5) 6 (4.4) 0.15
Parainfluenza virus, n (%) 8 (5.9) 5 (3.7) 0.39
Adenovirus, n (%) 2 (1.5) 6 (4.4) 0.15
Mycoplasma, n (%) 0 (0.0) 1 (0.7) 0.32
Rhinovirus/enterovirus, n (%) 17 (12.6) 39 (28.9) <0.001
Types of viral/organism co-infection
RSV + coronavirus, n (%) 5 (3.7) 7 (5.2) 0.55
RSV + human metapneumovirus, n (%) 0 (0.0) 1 (0.7) 0.32
RSV + parainfluenza virus, n (%) 3 (2.2) 1 (0.7) 0.31
RSV + adenovirus, n (%) 0 (0.0) 6 (4.4) 0.013
RSV + mycoplasma, n (%) 5 (3.7) 16 (11.9) 0.012
Coronavirus + adenovirus, n (%) 1 (0.7) 1 (0.7) 1.00
Parainfluenza virus + mycoplasma, n (%) 0 (0.0) 1 (0.7) 0.32
Parainfluenza virus + rhinovirus/enterovirus, n (%) 2 (1.5) 2 (1.5) 1.00

PICU: pediatric intensive care unit; SD: standard deviation; RSV: respiratory syncytial virus. There were no detectable co-infection for RSV + rhinovirus/enterovirus,
coronavirus + human metapneumovirus, coronavirus + parainfluenza virus, coronavirus + mycoplasma, coronavirus + rhinovirus/enterovirus, human metapneumovirus + -
parainfluenza virus, human metapneumovirus + adenovirus, human metapneumovirus + mycoplasma, human metapneumovirus + rhinovirus/enterovirus, parainfluenza virus
+ adenovirus, adenovirus + mycoplasma, adenovirus + rhinovirus/enterovirus, human metapneumovirus + rhinovirus/enterovirus.

P. Tsou et al. / Archives de Pe´diatrie 27 (2020) 39–44

Fig. 1. Trend of respiratory virus/organism causing bronchiolitis associated with PICU admission for the period 2015–2017. PICU: pediatric intensive care unit.

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period 2015–2017. Compared with the patients admitted to the general ward, those admitted to the PICU were more likely to have multiple
viral infections and a high average number of respiratory viral infections (Table 2).

3.3. Association between multiple viral infections and PICU admission as well as endotracheal intubation

In multivariable logistic regression models adjusted for age category, gender, weight, bronchodilator use, feeding type, antibiotic use,
systemic steroid use, and heart rate at hospital admission, bronchiolitis with multiple viral infections ( 2 strains) was associated with higher
odds of PICU admission (adjusted odds ratio [OR]: 2.42, 95% CI: 1.14–5.27, P = 0.03). Further, the odds of having bronchiolitis associated
with PICU admission increased with the number of viral infections at admission (adjusted OR: 2.86, 95% CI: 1.28–6.42, P = 0.01). For the
secondary outcome, multiple respiratory viral infections were not associated with increased odds of endotracheal intubation in the
multivariable logistic regression (adjusted OR: 0.82, 95% CI: 0.19–3.44, P = 0.78) (Table 3).

4. Discussion

This case-control study is important from epidemiological and clinical perspectives. It summarizes the prevalence of multiple respiratory
viral infections from a single hospital cohort for three consecutive years. Furthermore, it confirms and quantifies the independent association
between multiple viral infections and severe bronchiolitis leading to PICU admission using a multivariable logistic regression model that
controls for potential confounders. Our findings are crucial as they could help clinicians readily identify a vulnerable population more likely
to develop severe bronchiolitis who may require PICU admission. Close monitoring and early intervention could be implemented for this
population to decrease morbidity and mortality associated with bronchiolitis.

RSV is the most commonly detected virus both for children with bronchiolitis admitted to the PICU and for those admitted to the general
pediatric ward. The RSV detection rates of 74% and 59% for cases and controls, respectively, were compatible with historical numbers (60–
80%) reported in various studies [14–16]. Similarly, rhinovirus was the second most common virus found in 27% and 12% of the children
admitted to the PICU and the general pediatric ward, respectively, while the detection rate reported in the literature was 20–40% [10,12,17].
Interestingly, different from the results reported in previous studies, the third most common virus detected among children admitted to the
PICU in this study varies according to the year. Potential reasons could be the yearly and geographical variation in the viral prevalence.
Secondly, different study populations might partially explain the variation, as the majority of patients in southern Texas are of Hispanic
origin. Similar observations were also reported in studies from France and Taiwan, where only RSV was consistently found to be the most
common of all viruses [7,8].

Consistent with the prevalence reported in previous studies [18], our findings revealed that infection with multiple respiratory viruses
accounts for 10% and 22% of children admitted to the general ward and the PICU, respectively. Further, we found a significantly higher
percentage of multiple viral infections among

Table 3
a
Association between multiple viral infections and outcome of hospitalized bronchiolitis patients .

PICU admission

Unadjusted model Adjusted model

Predictor OR (95% CI) P OR (95% CI) P

<0.
Number of viral infections 3.57 (2.13–5.97) 01 2.42 (1.14–5.27) 0.03
<0.
b
Multiple viral infections 3.89 (2.28–6.64) 01 2.86 (1.28–6.42) 0.01
PICU: pediatric intensive care unit; OR: odds ratio; CI: confidence interval.
a Variables adjusted in multivariable logistic/linear regression: age categories, weight, bronchodilator use, feeding type, antibiotic use, systemic steroid use, heart rate at
admission.
b
Multiple viral infection: 2 strains.
P. Tsou et al. / Archives de Pe´diatrie 27 (2020) 39–44 43

9
the PICU cohort. Additionally, the results of multivariable analyses suggest that multiple respiratory viral infections were indepen-dently
associated with higher odds of severe bronchiolitis leading to PICU admission, while accounting for confounders. This finding is different
from the results reported by Nascimento et al., who suggested no significant association between multiple viral infections and PICU
admission for children admitted to hospital with bronchiolitis [12]. Several reasons might explain the difference. First, the study populations
might be different. Patient selection bias might exist in their study considering that the study was conducted in a neighborhood of residents
of high socioeco-nomic status. Secondly, their relatively small sample size (n = 77) might not afford adequate statistical power to determine
the significant association between multiple viral infections and PICU admission. In fact, our findings from multivariable analyses agree
with the results of a retrospective study by Richard et al. [8], in which multiple respiratory viral infections were found to associated with
higher odds of PICU admission (adjusted OR: 2.7, 95% CI: 1.2–6.2, P = 0.02) on multivariable analysis. In addition to having higher odds
of PICU admission, bronchiolitis with multiple viral infections was found to be associated with prolonged PICU stay in a British
retrospective cohort study enrolling children under 2 years of age admitted to the PICU for bronchiolitis [17]. The intriguing finding that
infection with multiple respiratory viruses is associated with more severe bronchiolitis is biologically plausible via several proposed
mechanisms, including virus-derived disruption of the epithelium and modification of the host immune system [19]. Taken together,
infection with multiple respiratory viruses is associated with more severe bronchiolitis and prolonged PICU stay.
Real-time multiplex PCR that detects the presence of nucleic acid from several viruses or bacteria from nasopharyngeal secretion in a
single test allows for timely recognition of pathogens with high sensitivity and specificity [20]. While the rapid recognition of pathogens
may help clinicians make decisions, one must be aware that the presence of viral nucleic acid based on PCR does not mean active viral
infection, as it could result from subclinical viral infection or prior viral infection since the viral nucleic acid remnant may last up to 4 weeks
after infection [21,22]. Therefore, the results of multiplex PCR must be interpreted together with the patients’ clinical presentation.
However, there is also evidence suggesting that subclinical viral infection leads to alteration of the host-microbe composition of the
respiratory tract, which might be linked to subsequent dysregulation in host immune function associated with development of asthma or
against bacterial infection [23,24]. The impact of altered micro-biota in the respiratory tract after viral infections awaits future studies.
There is no clear evidence that the use of real-time multiplex PCR could shorten the average length of hospital stay or the duration of
antibiotic use, but PCR might lead to reduced exposure to chest X-ray [25,26]. Furthermore, there is no consensus on when respiratory PCR
should be performed for pediatric patients. In general, respiratory PCR is recommended for neonates, immuno-suppressed patients, or
patients with chronic cardiopulmonary illness because a positive result might consequently lead to antiviral/antimicrobial treatments or
clinical interventions. Based on the findings of this study, we also recommend respiratory PCR for patients with a more severe presentation
of bronchiolitis as it may help clinicians decide on the patient’s condition and the level of care needed. This is because patients with a more
severe presentation of bronchiolitis with unremarkable chest X-rays but positive PCR results for co-infection with multiple viruses might
benefit from closer monitoring as they are more likely to experience a more severe course of bronchiolitis requiring PICU admission.
The results of this study should be interpreted in the context of its strength and limitations. Our study reconfirms the independent
association between multiple respiratory viral infections and severe bronchiolitis requiring PICU admission. However, this study has several
limitations. First, using PICU admission as a surrogate outcome for severe bronchiolitis might introduce bias. It might not reflect directly the
respiratory burden imposed by the multiple viral infections as accurately as respiratory rate or oxygen saturation level. Nevertheless, using
PICU admission as a surrogate outcome takes account of the cumulative impact of respiratory viral infections, not only on the respiratory
system but also on other organ systems, and of the interventions already adminis-tered. Therefore, it is reasonable to use of PICU admission
as a surrogate outcome. Second, as with other retrospective studies, our results might be confounded by non-measured variables, such as
exposure to cigarettes, duration of breastfeeding, number of siblings, socioeconomic status, personal or family history of atopy, or
undiagnosed asthma. As our study subjects were previously healthy full-term infants, the extent of the confounding effect would be to a
lesser degree. Further, adjustment for the use of steroids, inhaled corticosteroids, and antibiotics in the multivari-able analysis helps control
these confounding effects. Third, our study population is relatively selective as we only enrolled previously healthy full-term infants
hospitalized for bronchiolitis who had respiratory viral panel testing via PCR. Thus, the results might not be generalizable to other
populations (e.g., premature infants). Furthermore, the decision regarding admission to the PICU might not be entirely objective, as it was at
the discretion of clinicians who could not be entirely blinded to the patients’ clinical status. However, at our institution there were
established criteria that prevent unjustifiable admission to the PICU. Fourth, as with other clinical studies using ICD codes to ascertain
diseases from administrative databases, our study is also at risk of misclassifica-tion bias as the bronchiolitis might be erroneously
diagnosed or missed. Fifth, one must be aware that positive PCR results do not necessarily mean active infection, as there could be viral
residual shedding from previous infections. PCR should always be inter-preted along with the patients’ clinical presentation.

5. Conclusion
In summary, we identified the independent association between infection with multiple respiratory viruses and severe bronchiolitis
requiring PICU admission. Infants with bronchioli-tis due to multiple viruses may require PICU care more frequently than infants with
bronchiolitis due to a single or non-detectable viral infection. Bronchiolitis caused by multiple viruses is not associated with a higher need
for invasive mechanical ventilation. Establishing this association may help clinicians with early identification of high-risk patients who
might benefit from closer monitoring in the PICU and early institution of escalated care.
Ethical approval
This study was approved by the Driscoll Children’s Hospital Institutional Review Board.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgments We thank the staff at Driscoll Children’s Hospital for the contribution of technical support with the data.

P. Tsou et al. / Archives de Pe´diatrie 27 (2020) 39–44

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Richard N, Komurian-Pradel F, Javouhey E, et al. The impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis.
Pediatr Infect Dis J 2008;27:213–7.

Marguet C, Lubrano M, Gueudin M, et al. In very young infants severity of acute bronchiolitis depends on carried viruses. PLoS One 2009;4:e4596.

Brand HK, de Groot R, Galama JM, et al. Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol
2012;47:393–400.

Papadopoulos NG, Moustaki M, Tsolia M, et al. Association of rhinovirus infection with increased disease severity in acute bronchiolitis. Am J Respir Crit Care Med
2002;165:1285–9.

Nascimento MS, Souza AV, Ferreira AV, et al. High rate of viral identification and coinfections in infants with acute bronchiolitis. Clinics (Sao Paulo) 2010;65:1133–7.

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nasopharyngeal Swab samples. J Clin Microbiol 2018;56. http://dx.doi.org/ 10.1128/JCM.01945-17.

Jartti T, Lehtinen P, Vuorinen T, et al. Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics. Pediatr Infect Dis J
2009;28:311–7.

Oymar K, Skjerven HO, Mikalsen IB. Acute bronchiolitis in infants, a review. Scand J Trauma Resusc Emerg Med 2014;22:23.

Robinson RF. Impact of respiratory syncytial virus in the United States. Am J Health Syst Pharm 2008;65:S3–6.

Ghazaly M, Nadel S. Characteristics of children admitted to intensive care with acute bronchiolitis. Eur J Pediatr 2018;177:913–20.

Robledo-Aceves M, Moreno-Peregrina MJ, Velarde-Rivera F, et al. Risk factors for severe bronchiolitis caused by respiratory virus infections among Mexican children in an
emergency department. Medicine 2018;97:e0057.

Bosch AA, Biesbroek G, Trzcinski K, et al. Viral and bacterial interactions in the upper respiratory tract. PLoS Pathog 2013;9:e1003057.

Krause JC, Panning M, Hengel H, et al. The role of multiplex PCR in respiratory tract infections in children. Dtsch Arztebl Int 2014;111:639–45.

Loeffelholz MJ, Trujillo R, Pyles RB, et al. Duration of rhinovirus shedding in the upper respiratory tract in the first year of life. Pediatrics 2014;134:1144–50.

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Infect 2015;143:804–12.

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[CD006452].

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 Hubungan Multipel Infeksi Virus Pernapasan Dan Ruang Perawatan Intensif Anak
Pada Bayi Yang Masuk Dengan Bronkiolitis

Latar belakang: Tidak jelas apakah infeksi virus pernapasan multipel terkait dengan
bronkiolitis yang lebih parah membutuhkan untuk masuk ke unit perawatan intensif anak
(PICU). Kami bertujuan untuk mengidentifikasi hubungan antara infeksi virus pernapasan
multipel dan penerimaan PICU pada bayi dengan bronkiolitis.
Metode: Kami melakukan studi kontrol kasus 1: 1 yang mendaftarkan bayi cukup bulan yang
sebelumnya sehat (≤12 bulan) dengan bronkiolitis yang dirawat di PICU sebagai kasus dan
mereka yang ke bangsal anak umum sebagai kontrol dari 2015 hingga 2017. Reaksi berantai
polimerase multipleks ( PCR) digunakan untuk mendeteksi virus pernapasan. Kami
merangkum karakteristik bayi yang dirawat di PICU dan bangsal anak umum. Analisis
regresi logistik multivariabel digunakan untuk menyesuaikan hubungan antara infeksi virus
pernapasan ganda (2 strain) dan penerimaan PICU.
Hasil: Sebanyak 135 bayi yang dirawat di PICU dibandingkan dengan 135 bayi kontrol yang
dipilih secara acak yang dirawat di bangsal umum anak. Pasien PICU lebih muda (rata-rata
2,2 bulan, kisaran interkuartil: 1,3-4,2) dibandingkan pasien bangsal umum (median: 3,2
bulan, kisaran interkuartil: 1,6-6,4). Respiratory Synticial Virus (RSV)(74,1%), rhinovirus
(28,9%), dan coronavirus (5,9%) adalah virus yang paling umum untuk bronkiolitis yang
membutuhkan perawatan PICU. Pasien dengan bronkiolitis yang dirawat di PICU cenderung
mengalami beberapa infeksi virus dibandingkan dengan pasien di bangsal umum (23,0% vs
10,4%, P <0,001). Dalam analisis regresi logistik multivariabel, bronkiolitis dengan beberapa
infeksi virus dikaitkan dengan kemungkinan masuk PICU yang lebih tinggi (odds ratio yang
disesuaikan: 2,56, interval kepercayaan 95%: 1,17-5,57, P = 0,02).
Kesimpulan: Bayi dengan multiviral bronchiolitis memiliki kemungkinan masuk PICU lebih
tinggi dibandingkan dengan bayi dengan infeksi virus tunggal atau tidak terdeteksi.

1. Pengantar
Bronchiolitis adalah infeksi pernapasan virus akut ditandai dengan obstruksi bronkiolus
disertai edema, mukus, dan debris seluler pada anak di bawah usia 2 tahun. Anak-anak yang
terkena dampak, biasanya mengalami demam, batuk, dan gangguan pernapasan (misalnya,
retraksi, mengi). Bronkiolitis adalah masalah penting karena merupakan satu masalah
penyebab utama rawat inap di kalangan anak-anak. Jumlah seluruhnya biaya tahunan untuk
rawat inap terkait bronkiolitis di Amerika Serikat adalah $ 543 juta. Sekitar 2–3% dari anak-

12
anak yang terkena dampak, memerlukan rawat inap untuk tingkat perawatan yang lebih
tinggi, menyebabkan 149.000 rawat inap setiap tahun. Mayoritas dari anak-anak dengan
bronkiolitis memiliki penyakit ringan sampai sedang, tetapi 2-6% dari anak-anak yang
dirawat di rumah sakit membutuhkan unit perawatan intensif anak (PICU) masuk, dan 2-3%
dari anak-anak yang dirawat di rumah sakit membutuhkan aliran oksigenasi yang tinggi atau
ventilasi mekanis.
Faktor resiko yang pasti untuk masuk rumah sakit atau masuk PICU adalah prematuritas,
usia yang lebih muda, adanya penyakit penyerta, dan faktor lingkungan. Respiratory
Syncytial Virus (RSV) paling sering dikaitkan dengan bronkiolitis, presentasenya sekitar 43-
74% dari semua kasus. Baru- baru ini terkenal dan tersebar luas penggunaan metode berbasis
molekuler (Real-Time Multipleks Polymerase Chain Reaction [PCR]) telah membantu
mengidentifikasi peningkatan jumlah infeksi virus bersamaan (misalnya, metapneumovirus)
sebagai tambahan untuk RSV pada anak-anak dengan bronkiolitis akut. Virus lainnya yang
sering ditemukan pada anak-anak dengan bronkiolitis termasuk rhinovirus, coronavirus,
human metapneumovirus, virus parainfluenza, dan adenovirus. Infeksi virus bersamaan pada
anak-anak yang dirawat di rumah sakit dengan bronkiolitis berkisar dari 10% sampai 40%.
Namun, masih belum terjawab apakah beberapa infeksi virus pernapasan terkait dengan
bronkiolitis yang lebih parah. Penelitian sebelumnya dibatasi hanya untuk menyediakan
statistik deskriptif tanpa memperhitungkan perancu atau karena ukuran sampel yang tidak
memadai. Ini penting untuk diketahui apakah beberapa infeksi virus pernapasan terkait
dengan pernapasan yang lebih buruk, karena perawatan intensif dini yang diberikan kepada
populasi yang rentan ini mungkin dapat mengurangi kebutuhan akan respon cepat di bangsal
anak dan hasil yang berpotensi merugikan. Untuk mengatasi masalah ini, kami melakukan
studi kasus-kontrol dan melakukan analisis regresi multivariabel untuk menentukan
hubungan antara bronkiolitis parah yang mengakibatkan masuknya ke PICU dan jumlah
koinfeksi virus di antara bayi yang sebelumnya sehat yang dirawat di rumah sakit karena
bronkiolitis akut, sementara memperhitungkan untuk perancu

2. Bahan dan metode

2.1. Desain studi
Studi ini disetujui oleh Badan Peninjau Kelembagaan Rumah Sakit Anak Driscoll. Ini
adalah studi kasus kontrol 1: 1 pada bayi berusia 12 bulan atau lebih muda yang dirawat di
unit perawatan intensif anak (PICU) tersier 18 tempat tidur kami. Sampel penelitian dipilih
berdasarkan kode ICD untuk bronkiolitis selama masa penelitian. Bayi dengan bronkiolitis

13
yang dirawat di PICU diidentifikasi sebagai kasus dan dibandingkan dengan bayi dengan
bronkiolitis yang dirawat di unit perawatan umum anak sebagai kontrol. Sebagai kasus, kami
memasukkan semua pasien dengan bronkiolitis yang dirawat di PICU dari sampel usap
nasofaring yang telah dikumpulkan untuk PCR multipleks di institusi kami dari Januari 2015
hingga Desember 2017.
Analisis PCR dilakukan berdasarkan keputusan dokter mengenai perlunya pengujian
tambahan yang mungkin mengubah penanganan pasien. Sebagai kontrol, jumlah yang sama
dari neonatus (<28 hari; n = 20) dan bayi (n = 135) dipilih secara acak di antara 890 pasien
(usia ≤ 1 tahun) dengan bronkiolitis yang dirawat di unit pediatrik umum, dan untuk PCR
dilakukan selama periode penelitian yang sama, dengan menggunakan metode random
sampling. Analisis sensitivitas dilakukan untuk menentukan apakah ada perbedaan yang
signifikan antara pasien dengan bronkiolitis yang dirawat di unit perawatan umum anak yang
dilakukan PCR dan yang tidak dilakukan PCR. Kami secara retrospektif meninjau rekam
medis elektronik (EMR) pasien yang memenuhi syarat dan mendokumentasikan data
demografis, klinis, laboratorium, pencitraan, dan hasil. Pasien yang prematur atau memiliki
penyakit medis mendasar yang signifikan (misalnya, trakeostomi, kebutuhan oksigen awal,
penyakit jantung sianotik, gangguan kromosom, gangguan neurologis) dikeluarkan dari
penelitian.

2.2. Paparan minat: infeksi virus pernapasan

PCR multipleks waktu nyata yang digunakan di institusi kami adalah FilmArray
Respiratory Panel 2 (RP2) oleh BioFire yang memungkinkan deteksi cepat (sekitar 45 menit)
dari 22 patogen virus dan bakteri atipikal langsung dari sampel NPS. Patogen yang terdeteksi
antara lain adenovirus, coronavirus 229E, coronavirus HKU1, corona- virus NL63,
coronavirus OC43, human metapneumovirus, human rhinovirus / enterovirus, virus
influenza A, virus influenza A H1, virus influenza A H1-2009, virus influenza A H3, influenza
virus B, virus parainfluenza 1, virus parainfluenza 2, virus parainfluenza 3, virus
parainfluenza 4, virus pernapasan syncytial, Bordetella, pertusis, Chlamydia pneumoniae,
Mycoplasma pneumoniae, sindrom pernapasan Timur Tengah - coronavirus, dan Bordetella
parapertussis. FilmArray RP2 adalah pengujian yang andal dan akurat yang memiliki
persentase kesesuaian keseluruhan 99,2% dengan standar emas. Infeksi beberapa virus
didefinisikan sebagai adanya dua atau lebih strain virus.

14
2.3. Ukuran hasil
Hasil utama adalah masuk ke PICU, sebagai hasil pengganti untuk keparahan bronkiolitis.
Kriteria untuk masuk ke PICU di institusi kami termasuk, namun tidak terbatas pada,
hipoksia dengan kebutuhan oksigen 40% atau gangguan pernapasan yang membutuhkan
ventilasi mekanis dan nonmekanis (misalnya, oksigen aliran tinggi), ketidakstabilan
hemodinamik yang tidak merespons resusitasi cairan awal (yaitu, 60 mL / kg bolus saline
normal), atau kebijaksanaan dokter. Hasil sekunder kami adalah intubasi setelah masuk
rumah sakit.

2.4. Analisis statistik

Analisis data eksplorasi dilakukan untuk mendeskripsikan karakteristik bayi bronkiolitis
yang dirawat di bangsal umum anak dan PICU. Selanjutnya, jenis dan jumlah infeksi virus
pernafasan dibandingkan antara bayi yang dirawat di PICU dan yang dirawat di bangsal
umum anak. Variabel kategori disajikan sebagai frekuensi dan presentase, dan dibandingkan
dengan menggunakan uji Chi2. Variabel kontinu disajikan sebagai mean atau median dan
dibandingkan dengan uji t atau uji rank-sum Wilcoxon yang sesuai, untuk variabel kontinu
yang tidak terdistribusi normal dan variabel kontinu yang terdistribusi normal.
Untuk menilai hubungan antara jumlah infeksi virus pernapasan dan primer (yaitu, masuk
PICU) serta hasil sekunder (yaitu, intubasi), analisis regresi logistik multivariabel yang
mengendalikan perancu potensial dilakukan. Faktor-faktor berikut disesuaikan untuk:
kategori usia (neonatus, bayi), berat badan, penggunaan bronkodilator, jenis makan,
penggunaan antibiotik, penggunaan steroid sistemik, dan detak jantung saat masuk. Kovariat
awalnya ditentukan berdasarkan relevansi potensial yang dilaporkan dalam literatur dan pada
hubungannya dengan hasil dalam analisis bivariat pada tingkat signifikansi P <0,1. Analisis
statistik dilakukan dengan menggunakan Stata 12.0 (Stata Corp, College Station, TX, USA).

3. Hasil
3.1. Demografi pasien dan karakteristik klinis
Selama masa penelitian, ada 135 bayi di PICU yang dibandingkan dengan 135 bayi
kontrol yang dipilih secara acak dari 890 bayi yang dirawat di bangsal umum anak. Di
antara 135 pasien yang dirawat di PICU, 20 pasien (14,8%) adalah neonatus, 61 (45,2%) di
antaranya adalah perempuan, dengan usia rata-rata 2,2 bulan (kisaran interkuartil [IQR]: 1,3-
4,2 bulan). Sebagai perbandingan, di antara 135 pasien yang dirawat di bangsal umum anak
sebagai kontrol, 20 pasien (14,8%) adalah neonatus, di antaranya 54 (40,0%) adalah

15
perempuan, dengan usia rata-rata 3,2 bulan (IQR: 1,6-6,4 bulan). Karakteristik antara pasien
dengan bronkiolitis yang dirawat di PICU dan mereka yang dirawat di bangsal umum anak
dirangkum dalam tabel 1. Dibandingkan dengan pasien yang dirawat di bangsal anak umum,
pasien yang dirawat di PICU lebih muda, beratnya lebih sedikit, lebih mungkin telah
menerima bronkodilator, antibiotik, selang makanan (NG / ND), dan dirawat di rumah sakit
lebih lama. Tidak ada kematian di antara kasus atau kontrol.

Tabel 1
Karakteristik pasien bronkiolitis yang masuk PICU dan masuk non-PICU

Penerimaan non-PICU (n Masuk PICU (n = 135) P.

= 135)

Usia dalam bulan, median (IQR) 3.2 (1.6, 6.4) 2.2 (1.3, 4.2) 0,015

Neonatus, n (%) 20 (14.8) 20 (14.8) 1.00

Wanita, n (%) 61 (45.2) 0.39
54 (40.0)
Berat (kg), median (IQR) 7.1 (5.0, 11.5) 4.9 (3.9, 6.1) < 0,001

WBC (10 3 / m L), median (IQR) 10.5 (7.7, 13.9) 9.6 (7,3, 12,6) 0.31
Hgb (g / dL), median (IQR) 11.7 (10,8, 12,5) 11.1 (10.2, 12.0) 0,047
Penggunaan bronkodilator, n (%) 36 (26,7) 84 (62.2) < 0,001
Penggunaan ICS, n (%) 33 (24.4) 9 (6.7) < 0,001
Penggunaan steroid sistemik, n (%) 44 (32.6) 22 (16,3) 0,002
Penggunaan HTS, n (%) 115 (85.2) 125 (92.6) 0,053
Penggunaan antibiotik, n (%) 37 (27,4) 84 (62.2) < 0,001
HR di masuk rumah sakit, median 155.0 (137.0, 173.0) 166.0 (150.0, 180.0) < 0,001
(IQR)
RR saat masuk rumah sakit, median 46.0 (40.0, 55.0) 48.0 (39.0, 61.0) 0.14
(IQR)
Aliran O 2 saat masuk rumah sakit, 0.0 (0,0, 0,0) 3.0 (1.0, 8.0) < 0,001
median (IQR)
SpO 2 saat masuk rumah sakit, 98.0 (97.0, 100.0) 98.0 (95.0, 100.0) 0.45
median (IQR)
Durasi Abx, median (IQR) 48.0 (48.0, 72.0) 48.0 (24.0, 72.0) 0.15
Metode pemberian makan, n (%)
NG / ND 19 (14.1) 69 (51.1) < 0,001
PO 116 (85,9) 66 (48,9)
Lama tinggal di rumah sakit (h), 44.0 (30,0, 67,0) 130.0 (94.0, 214.0) < 0,001
median (IQR)

IQR: rentang interkuartil; PICU: unit perawatan intensif anak; ICS: kortikosteroid
inhalasi; HTS: larutan garam hipertonik; HR: detak jantung; RR: kecepatan
pernapasan; NG: nasogastrik; ND: nasoduodenal; PO: setiap os; h: jam.

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3.2 Profil virus pernapasan

Jenis dan jumlah virus pernapasan yang terdeteksi melalui PCR dirangkum
dalam Tabel 2 . Selama masa penelitian, 87,75% (781/890) pasien yang
didiagnosis bronkiolitis dan dirawat di bangsal umum menjalani tes PCR,
sedangkan 100% (135/135) pasien yang didiagnosis bronkiolitis yang
dirawat di PICU menjalani tes PCR. Tidak ada perbedaan yang signifikan
dalam usia, jenis kelamin, dan lama tinggal di rumah sakit antara mereka
yang dirawat di bangsal umum dengan dan tanpa tes PCR (P > 0,05).
Semua subjek penelitian (135 kasus dan 135 kontrol) dites untuk virus PCR
baik sebelum masuk atau selama mereka tinggal di rumah sakit. PCR
mendeteksi satu atau lebih virus pada 132 (97,8%) dan 100 (74,1%) bayi yang
dirawat di PICU dan bangsal umum, masing-masing. Infeksi dengan satu
virus dan beberapa virus ditemukan pada 101 (74,8%) dan 31 (23,0%) bayi
yang dirawat di PICU. Di sisi lain, infeksi dengan virus tunggal dan
beberapa virus ditemukan pada 86 (63,7%) dan 14 (10,4%) bayi yang
dirawat di bangsal umum. RSV, rhinovirus, dan coronavirus adalah tiga
penyebab utama bronkiolitis akut untuk pasien yang dirawat di bangsal
umum dan PICU. Dibandingkan dengan pasien dengan bronkiolitis yang
dirawat di bangsal umum, mereka yang dirawat di PICU lebih mungkin
memiliki koinfeksi RSV dan adenovirus (0% vs. 4,4%, P = 0,013), serta
RSV dan mikoplasma (3,7% vs. 11,9%, P = 0,012) ( Tabel 2 ). Gambar. 1
menunjukkan proporsi pasien PICU dengan bronkiolitis yang disebabkan oleh
setiap virus pernapasan periode 2015–2017. Dibandingkan dengan pasien yang dirawat
di bangsal umum, mereka yang dirawat di PICU lebih mungkin mengalami beberapa infeksi
virus dan jumlah rata-rata infeksi virus pernapasan yang tinggi tabel 2.

Tabel 2 Karakteristik dan tipe virus pernapasan berdasarkan status masuk PICU.
Penerimaan Masuk PICU (n = p
non-PICU (n = 135) 135)
Beberapa infeksi virus, n (%)
Tidak ada 35 (25.9) 3 (2.2) < 0,001
Tunggal 86 (63,7) 101 (74,8)
Banyak 14 (10.4) 31 (23.0)
Jumlah infeksi virus, rata-rata (SD) 0,9 (0,6) 1,2 (0,5) < 0,001
Jenis virus / organisme pernapasan
RSV, n (%) 79 (58,5) 100 (74.1) 0,007

17
 Coronavirus, n (%) 7 (5.2) 8 (5.9) 0.79
Metapneumovirus manusia, n (%) 2 (1,5) 6 (4.4) 0.15
Virus flu parain, n (%) 8 (5.9) 5 (3.7) 0.39
Adenovirus, n (%) 2 (1,5) 6 (4.4) 0.15
Mikoplasma, n (%) 0 (0,0) 1 (0,7) 0.32
Rhinovirus / enterovirus, n (%) 17 (12.6) 39 (28.9) < 0,001
Jenis koinfeksi virus / organisme
RSV + virus korona, n (%) 5 (3.7) 7 (5.2) 0,55
RSV + metapneumovirus manusia, n (%) 0 (0,0) 1 (0,7) 0.32
RSV + virus flu parain, n (%) 3 (2.2) 1 (0,7) 0.31
RSV + adenovirus, n (%) 0 (0,0) 6 (4.4) 0,013
RSV + mikoplasma, n (%) 5 (3.7) 16 (11.9) 0,012
Coronavirus + adenovirus, n (%) 1 (0,7) 1 (0,7) 1.00
Virus parain flu + mikoplasma, n (%) 0 (0,0) 1 (0,7) 0.32
Parain fl virus uenza + rhinovirus / 2 (1,5) 2 (1,5) 1.00
enterovirus, n (%)

Gambar 1. Kecenderungan virus / organisme pernafasan penyebab bronkiolitis terkait dengan

masuknya PICU periode 2015-2017. PICU: unit perawatan intensif anak.
3.3. Hubungan antara infeksi virus multipel dan penerimaan PICU serta intubasi endotrakeal

Dalam model regresi logistik multivariabel yang disesuaikan dengan kategori usia, jenis
kelamin, berat badan, penggunaan bronkodilator, jenis makan, penggunaan antibiotik,
penggunaan steroid sistemik, dan detak jantung saat masuk rumah sakit, bronkiolitis dengan
beberapa infeksi virus (2 strain) dikaitkan dengan kemungkinan PICU yang lebih tinggi

18
masuk (rasio odds yang disesuaikan [OR]: 2,42, 95% CI: 1,14-5,27, P = 0,03). Selanjutnya,
kemungkinan mengalami bronkiolitis terkait dengan masuk PICU meningkat dengan jumlah
infeksi virus saat masuk (OR: 2.86, 95% CI: 1.28–6.42, P = 0,01). Untuk hasil sekunder,
infeksi virus pernapasan ganda tidak terkait dengan peningkatan kemungkinan intubasi
endotrakeal dalam regresi logistik multivariabel (OR: 0,82, 95% CI: 0,19-3,44, P = 0,78) (
Tabel 3 ).

Tabel 3

Hubungan antara beberapa infeksi virus dan hasil akhir pasien bronkiolitis rawat inap
Model yang tidak
disesuaikan Model yang disesuaikan
Predictor ATAU (95% CI) P. ATAU (95% CI) P
Jumlah infeksi virus 3,57 (2,13–5,97) < 0,01 2.42 (1.14–5.27) 0,03
Infeksi virus multipel 3,89 (2,28–6,64) < 0,01 2,86 (1,28–6,42) 0,01

4. Diskusi

Studi kasus kontrol ini penting dari perspektif epidemiologi dan klinis. Ini merangkum
prevalensi infeksi virus pernapasan ganda dari satu kohort rumah sakit selama tiga tahun
berturut-turut. Selain itu, ini menegaskan dan mengukur hubungan independen antara
beberapa infeksi virus dan bronkiolitis parah yang menyebabkan masuknya PICU
menggunakan model regresi logistik multivariabel yang mengontrol pembaur potensial.
Temuan kami sangat penting karena dapat membantu dokter mengidentifikasi populasi rentan
yang lebih mungkin mengembangkan bronkiolitis parah yang mungkin memerlukan
perawatan PICU. Pemantauan ketat dan intervensi dini dapat diterapkan pada populasi ini
untuk menurunkan morbiditas dan mortalitas yang terkait dengan bronkiolitis.
RSV adalah virus yang paling sering terdeteksi baik untuk anak-anak dengan bronkiolitis
yang dirawat di PICU dan untuk mereka yang dirawat di bangsal anak umum. Tingkat deteksi
RSV sebesar 74% dan 59% untuk kasus dan kontrol, masing-masing, sesuai dengan angka
historis (60-80%) yang dilaporkan dalam berbagai penelitia . Demikian pula, rhinovirus
adalah virus paling umum kedua yang ditemukan pada 27% dan 12% anak yang dirawat di
PICU dan bangsal umum anak, sementara tingkat deteksi yang dilaporkan dalam literatur
adalah 20-40%. Menariknya, berbeda dari hasil yang dilaporkan dalam penelitian
sebelumnya, virus paling umum ketiga yang terdeteksi di antara anak-anak yang dirawat di
PICU dalam penelitian ini bervariasi menurut tahunnya. Alasan potensial bisa jadi variasi
tahunan dan geografis dalam prevalensi virus. Kedua, populasi penelitian yang berbeda

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mungkin menjelaskan sebagian variasi, karena sebagian besar pasien di Texas selatan berasal
dari Hispanik. Pengamatan serupa juga dilaporkan dalam penelitian dari Prancis dan Taiwan,
di mana hanya RSV yang secara konsisten ditemukan sebagai yang paling umum dari semua
virus.
Konsisten dengan prevalensi yang dilaporkan dalam penelitian sebelumnya, temuan kami
mengungkapkan bahwa infeksi dengan beberapa virus pernapasan menyumbang 10% dan
22% dari anak-anak yang dirawat di bangsal umum dan PICU. Lebih lanjut, kami
menemukan persentase infeksi virus multipel yang lebih tinggi secara signifikan kelompok
PICU. Selain itu, hasil analisis multivariable menunjukkan bahwa beberapa infeksi virus
pernapasan secara independen terkait dengan peluang yang lebih tinggi dari bronchiolitis
parah yang mengarah masuknya pasien ke PICU, sambil memperhitungkan perancu.
Temuan ini berbeda dengan hasil yang dilaporkan oleh Nascimento et al, yang tidak
menunjukkan adanya hubungan yang signifikan antara beberapa infeksi virus dan masuknya
anak-anak ke rumah sakit dengan bronchiolitis. Beberapa alasan mungkin bisa menjelaskan
perbedaannya. Pertama, studi populasi mungkin berbeda. Prasangka seleksi pasien mungkin
ada dalam penelitian mereka mengingat bahwa penelitian itu dilakukan di lingkungan
penduduk dengan status sosial ekonomi tinggi. Kedua, ukuran sampel mereka yang relatif
kecil (n-77) mungkin tidak mampu menyediakan kekuatan statistik yang memadai untuk
menentukan hubungan penularan virus yang banyak dan penerimaan langsung, pada
kenyataannya temuan kami dari analisis multivariable yang setuju dengan hasil dari studi
retrospektif oleh Richard et a, dimana beberapa infeksi virus pernapasan ditemukan terkait
dengan peluang lebih tinggi masuknya ke PICU (disesuaikan atau: 2,7.95% C: 12-6,2, P-
0.02) pada analisis multivariable. Selain memiliki kemungkinan lebih tinggi untuk masuk
PICU, bronkiolitis dengan beberapa infeksi virus ditemukan terkait dengan masa tinggal
PICU yang lama dalam studi kohort retrospektif Inggris yang mendaftarkan anak di bawah
usia 2 tahun yang dirawat di PICU untuk bronkiolitis. Penemuan yang menarik bahwa infeksi
dengan beberapa virus pernapasan berhubungan dengan lebih parah bronchiolitis dapat
diterima secara biologis melalui beberapa mekanisme yang diusulkan, termasuk gangguan
yang berasal dari virus dari epithelium dan modifikasi dari sistem kekebalan tubuh. Secara
bersama-sama, infeksi dengan beberapa virus pernapasan dikaitkan dengan bronchiolitis
yang lebih parah dan masa tinggal PICU yang berkepanjangan.
PCR multipleks waktu nyata yang mendeteksi keberadaan asam nukleat dari beberapa
virus atau bakteri dari sekresi nasofaring dalam satu tes memungkinkan pengenalan patogen
secara tepat waktu dengan sensitivitas dan spesifitas tinggi. Sementara pengenalan cepat

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patogen dapat membantu dokter membuat keputusan, kita harus menyadari bahwa
keberadaan asam nukleat virus berdasarkan PCR tidak berarti infeksi virus aktif, karena
dapat disebabkan oleh infeksi virus subklinis atau infeksi virus sebelumnya sejak asam
nukleat virus sisa dapat bertahan hingga 4 minggu setelah infeksi. Oleh karena itu, hasil PCR
multipleks harus diinterpretasikan bersama dengan gambaran klinis pasien. Namun, ada juga
bukti yang menunjukkan bahwa infeksi virus subklinis menyebabkan perubahan komposisi
mikroba inang saluran pernapasan, yang mungkin terkait dengan disregulasi berikutnya
dalam fungsi kekebalan tubuh yang terkait dengan perkembangan asma atau melawan infeksi
bakteri. Dampak mikrobiota yang berubah di saluran pernapasan setelah infeksi virus
menunggu penelitian selanjutnya.
Tidak ada bukti yang jelas bahwa penggunaan PCR multipleks waktu nyata dapat
mempersingkat rata-rata lama rawat inap di rumah sakit atau durasi penggunaan antibiotik,
tetapi PCR dapat mengurangi paparan sinar-X dada. Selain itu, tidak ada kesepakatan kapan
PCR pernapasan harus dilakukan untuk pasien anak. Secara umum, PCR pernapasan
direkomendasikan untuk neonatus, pasien dengan imunosupresi, atau pasien dengan penyakit
kardiopulmoner kronis karena hasil positif dapat mengarah pada pengobatan antivirus /
antimikroba atau intervensi klinis. Berdasarkan temuan penelitian ini, kami juga
merekomendasikan PCR pernafasan untuk pasien dengan presentasi bronkiolitis yang lebih
parah karena dapat membantu dokter memutuskan kondisi pasien dan tingkat perawatan
yang diperlukan.
Hasil penelitian ini harus diinterpretasikan dalam konteks kekuatan dan keterbatasannya.
Penelitian kami menegaskan hubungan independen antara infeksi virus pernapasan multipel
dan bronkiolitis berat yang membutuhkan perawatan PICU. Namun penelitian ini memiliki
beberapa keterbatasan. Pertama, menggunakan admisi PICU sebagai hasil pengganti untuk
bronkiolitis berat dapat menimbulkan bias. Ini mungkin tidak mencerminkan secara langsung
beban pernapasan yang ditimbulkan oleh berbagai infeksi virus seakurat laju pernapasan atau
tingkat saturasi oksigen. Namun demikian, menggunakan penerimaan PICU sebagai hasil
pengganti memperhitungkan dampak kumulatif infeksi virus pernapasan, tidak hanya pada
sistem pernapasan tetapi juga pada sistem organ lain, dan intervensi yang telah diberikan.
Oleh karena itu, masuk akal untuk menggunakan penerimaan PICU sebagai hasil pengganti.
Kedua, seperti penelitian retrospektif lainnya, hasil kami mungkin dibingungkan oleh
variabel yang tidak diukur, seperti paparan rokok, durasi menyusui, jumlah saudara kandung,
status sosial ekonomi, riwayat atopi pribadi atau keluarga, atau asma yang tidak terdiagnosis.
Karena subjek penelitian kami sebelumnya adalah bayi cukup bulan yang sehat, tingkat efek

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perancu akan lebih rendah. Selanjutnya, penyesuaian untuk penggunaan steroid,
kortikosteroid inhalasi, dan antibiotik dalam analisis multivariabel membantu mengontrol
efek perancu ini. Ketiga, populasi penelitian kami relatif selektif karena kami hanya
mendaftarkan bayi cukup bulan yang sebelumnya sehat yang dirawat di rumah sakit karena
bronkiolitis yang menjalani tes panel virus pernapasan melalui PCR. Dengan demikian,
hasilnya mungkin tidak dapat digeneralisasikan untuk populasi lain (misalnya, bayi
prematur). Selanjutnya, keputusan mengenai masuk ke PICU mungkin tidak sepenuhnya
objektif, karena itu adalah kebijaksanaan dokter yang tidak bisa sepenuhnya buta terhadap
status klinis pasien. Namun, di institusi kami ada kriteria yang ditetapkan yang mencegah
penerimaan yang tidak dapat diterima ke PICU. Keempat, seperti studi klinis lain yang
menggunakan kode ICD untuk memastikan penyakit dari database administratif, penelitian
kami juga berisiko bias kesalahan klasifikasi karena bronkiolitis mungkin salah didiagnosis
atau terlewatkan. Kelima, kita harus menyadari bahwa hasil PCR positif tidak selalu berarti
infeksi aktif, karena mungkin ada sisa virus yang keluar dari infeksi sebelumnya. PCR harus
selalu diinterpretasikan bersama dengan presentasi klinis pasien. karena itu adalah
kebijaksanaan dokter yang tidak bisa sepenuhnya dibutakan oleh status klinis pasien. Namun,
di lembaga kami ada kriteria yang ditetapkan yang mencegah masuknya izin ke PICU secara
tidak sah

5. Kesimpulan
Singkatnya, kami mengidentifikasi hubungan independen antara infeksi dengan beberapa
virus pernapasan dan bronkiolitis berat yang memerlukan perawatan PICU. Bayi dengan
bronkiolitis karena beberapa virus mungkin memerlukan perawatan PICU lebih sering
daripada bayi dengan bronkiolitis karena infeksi virus tunggal atau tidak terdeteksi.
Bronkiolitis yang disebabkan oleh beberapa virus tidak terkait dengan kebutuhan yang lebih
tinggi untuk ventilasi mekanis invasif. Membangun hubungan ini dapat membantu dokter
dengan identifikasi awal pasien berisiko tinggi yang mungkin mendapat manfaat dari
pemantauan lebih dekat di PICU dan institusi awal perawatan yang ditingkatkan.

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PPT

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