Hindawi

Evidence-Based Complementary and Alternative Medicine

Volume 2022, Article ID 2229735, 12 pages
https://doi.org/10.1155/2022/2229735

Research Article
Safety and Effectiveness of Inhaling Different Dosage
Recombinant Human Interferon α1B for Bronchiolitis in
Children: a Systematic Review and Meta-Analysis

Jiefeng Luo ,1,2,3,4 Mengting Yang,2,3,4,5 Linan Zeng,2,3,4 Xiangcheng Pan ,1,2,3,4
Dan Liu ,1,2,3,4 Sha Diao,2,3,4 Liang Huang,2,3,4 Ting Chen,6 Zhi-Jun Jia ,1,2,3,4
Guo Cheng,4,6,7 Qin Yu,4,8 and Lingli Zhang 2,3,4
1
West China School of Pharmacy, Sichuan University, Chengdu, China
2
Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China
3
Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
4
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education,
Chengdu, China
5
West China School of Medicine, Sichuan University, Chengdu, China
6
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, China
7
Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu, China
8
National Drug Clinical Trial Institute, West China Second University Hospital, Sichuan University, Chengdu, China

Correspondence should be addressed to Lingli Zhang; zhanglingli1306@163.com

Received 10 January 2022; Revised 30 March 2022; Accepted 4 April 2022; Published 27 April 2022

Academic Editor: Roberto Miniero

Copyright © 2022 Jiefeng Luo et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To systematically evaluate the safety and effectiveness of different dosages of recombinant human interferon α1b
(IFNα1b) inhaled for bronchiolitis in children. Methods. 7 databases, including PubMed, EMBASE, Cochrane Library, Web
of Science, CNKI, Wanfang Database, and VIP, were searched. The search time was from their inception dates to March 28,
2022. A randomized controlled trial (RCT) of 2 μg/kg IFNα1b (low dosage group) monotherapy or in combination with
other drugs vs. 4 μg/kg IFNα1b (high dosage group) monotherapy or in combination with the other drugs was included. The
risk of bias 2.0 evaluated the RCT’s quality, and the grading of recommendations assessment, development and evaluation
(GRADE) tool was used for evaluating the overall quality of the evidence. Then, a meta-analysis was performed by RevMan
5.4. Results. A total of 13 RCTs with 1719 children were included. The meta-analysis results showed that the high dosage
group was significantly shorter than the low dosage group of the duration of hospital stays (MD  −0.40, 95%CI (−0.73,
−0.07), P  0.02) (low quality), three depressions sign disappearing time (MD  −0.60, 95%CI (−1.05, −0.14), P  0.010) (low
quality), and wheeze disappearing time (MD  −0.62, 95%CI (−1.17, −0.06),  0.03) (low quality). There was no significant
difference between the two groups in coughing disappearing time, pulmonary rales disappearing time, wheezing sound
disappearing time, or adverse event rates. Conclusions. Compared with low dosage IFNα1b, high dosage IFNα1b reduces the
duration of hospital stays, the disappearance time of the three depression signs, and the disappearance time of wheeze in the
treatment of bronchiolitis in children. Limited by the low quality of the evidence, the conclusions still need to be supported
by high-quality studies.

1. Introduction ranges from 2 months to 6 months. The incidence of infants

in the first year after birth is approximately 11%, and
Bronchiolitis is a lower respiratory tract disease that mainly bronchiolitis is one of the leading causes of illness and
occurs in children under 24 months. The peak age of onset hospitalization in children under one year old [1, 2]. The
2 Evidence-Based Complementary and Alternative Medicine
most common etiology of bronchiolitis is respiratory syn-
cytial virus (RSV) infection. Other viruses include the
parainfluenza virus, influenza virus, and rhinovirus [2, 3].
Unfortunately, a causative treatment of acute viral bron-
chiolitis does not exist due to its special pathophysiology
[4, 5]. In clinical practice, oxygen and fluid supplementation
are usually used for symptomatic treatment [6].
Interferon (IFN) plays an essential role during bron-
chiolitis, particularly for children infected with RSV [7].
IFNs are a group of signaling proteins synthesized and
released by host cells in response to pathogens. Normally,
virus-infected cells release IFNs to enable surrounding cells
to improve their anti-viral defenses [8]. This early response
can influence the clinical course of RSV bronchiolitis,
thereby affecting the duration of the disease and damage to
the lungs [9]. However, it has been considered that common
respiratory viruses, including RSV, may disrupt the host
antiviral IFN response [9–12]. Based on the importance of
IFN in bronchiolitis, many researchers in China have used
exogenous IFN as a supplementary treatment for
bronchiolitis.
Recombinant human interferon α1B (IFNα1B), as a
major antiviral subtype in the Chinese population, has
attracted the attention of Chinese researchers [5]. As the
lesion site of bronchiolitis is located in the bronchioles,
administration by nebulized has the advantages of rapid-
onset, fewer adverse reactions, and high compliance [5].
Therefore, aerosol inhalation IFNα1B for bronchiolitis in
children has been recommended by the Chinese National
Formulary [13] and the Standardized Management Guide-
lines for Children’s Nebulization Center [14]. At present, the
guidelines or expert consensus recommended dosage of
nebulized IFNα1b for bronchiolitis in children is 2–4 μg/kg
[15, 16]. However, there is still controversy about 2 μg/kg or
4 μg/kg in clinical practice. Some researchers believe that
4 μg/kg of IFNα1b has better efficacy [17, 18]. Others believe
that 2 μg/kg and 4 μg/kg of IFNα1b have equivalent efficacy.
Considering the safety and economic effects, 2 μg/kg IFNα1b
should be promoted [19, 20].
Therefore, this study aims to evaluate the safety and
effectiveness of inhaling 2 μg/kg and 4 μg/kg of IFNα1b for
bronchiolitis in children, providing evidence-based evidence
for clinical practice.
2. Methods
This review was conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines [21].
2.1. Search Strategy. A total of 7 databases, including
PubMed, Embase (Ovid), Cochrane Library (Ovid), Web of
Science, CNKI, Wanfang Database, and VIP, were searched.
Additionally, we used a manual search strategy to retrieve
the relevant articles cited by the retrieved publications. The
search time was from their inception dates to March 28,
2022. Medical subject headings combined with free text
terms were used to search for eligible articles. Two clinical
trial registration sites, including clinicaltrials.gov (https://
clinicaltrials.gov/) and the WHO International Clinical
Trials Registry Platform (ICTRP) (http://apps.who.int/
trialsearch/), were searched for unpublished but eligible
articles.
2.2. Inclusion and Exclusion Criteria
2.2.1. The Inclusion Criteria
Population: infants under 2 years old and hospitalized
with a diagnosis of bronchiolitis.
Intervention/control: the high dosage group was given
4 μg/kg IFNα1b, and the low dosage group was given 2 μg/kg
IFNα1b, and both were treated with nebulization. IFNα1b
monotherapy or in combination with other drugs (e.g.,
budesonide, albuterol, and hypertonic saline) were included.
Outcomes: the primary outcome is the duration of
hospital stays. The secondary outcome is based on the main
clinical symptoms described in the “Expert consensus on the
diagnosis, treatment and prevention of bronchiolitis (2014),”
including cough disappearance time, pulmonary rales dis-
appearance time, wheeze disappearance time, and wheezing
sound disappearance time, three depression sign disap-
pearance times, and adverse event rates.
2.2.2. The Exclusion Criteria.
(1) Non-Chinese and Non-English studies
(2) Inaccessible studies
(3) No information about the child
(4) Duplicate publication
2.3. Data Extraction and Risk-of-Bias Assessments. Two re-
searchers selected the included RCTs back-to-back according
to the inclusion and exclusion criteria and extracted the data.
Cochrane risk of bias assessment tool (ROB 2.0) was used to
evaluate the RCT’s quality, and the grading of recommen-
dations assessment, development and evaluation (GRADE)
tool was used to evaluate the overall quality of evidence. When
two researchers had opposite opinions, disputes were decided
by the third researcher. The content of the literature ex-
traction includes basic information about the literature (such
as first author and year of publication); basic information
about the child (such as age and course of the disease); basic
information about intervention (such as course of treatment,
frequency of administration, and combined therapy); and
research results (data of outcomes).
2.4. Statistical Analysis. RevMan 5.4 statistical software
provided by the Cochrane Collaboration Network was
performed for meta-analysis. Relative risk (RR) and risk
difference (RD) were used for dichotomous data, mean
difference (MD) was used for continuous data, and 95%
CIs were calculated using the Mantel–Haenszel method
and the inverse variance statistical method, respectively.
Heterogeneity was tested by χ 2 test and I2 statistics, and
the random effect model was performed for meta-
Evidence-Based Complementary and Alternative Medicine
Records from the databases including Pubmed,
Embase (Ovid), The Cochran Library, Web of Science, CNKI,
Wanfang and VIP (n=2129)
Remove duplication studies
Screening titles and abstracts
Screening full texts
Included studies (n=13)
Figure 1: Literature screening flow diagram.
analysis. Subgroup analysis was performed by mono-
therapy or combined therapy. Sensitivity analysis was
performed by eliminating included RCTs one by one in
each outcome.
3. Results
The initial searches included 2129 RCTs. After dedupli-
cation, 927 RCTs were removed. After screening titles and
abstracts, 1013 RCTs were removed. Ultimately, 13 RCTs
remained after screening full texts [17–20, 22–30]
(Figure 1).
3.1. Characteristics of the Included Studies. The basic infor-
mation of the included RCT is presented in Table 1. Among
the included RCTs, 5 RCTs adopted a random number table
for randomization [17, 24, 26–28], 1 RCT adopted the en-
velope method for randomization [18], and the rest did not
describe the method or used the wrong method. 1 RCT
adopted a central randomization system for concealed al-
location [17], and the rest did not mention the method for
concealed allocation. Only 1 RCT risk-of-bias assessment
result was “Some concerns” [17], and the results of the other
RCTs were “High risk”(Figures 2 and 3); GRADE results
were “low” and “very low” (Table 2).
Chen 2018 [18] subdivided the drug administration into
the early high dosage group, the early low dosage group, the
late high dosage group, and the late low dosage group. Since
there were no overlap children between early and late, the
early and late were independently analyzed. Additionally,
Zhao 2018 [17] subdivided the low dosage group into the qid
group and the tid group. Since there were no overlap
3
Exclude studies (n=927)
Exclude studies (n=1013)
Exclude studies (n=174) :
Not a1b or subtype not mentioned (n=16)
Non-dose comparison (n=97)
Non 4 ug vs 2 ug comparison (n=16)
Non-children (n=2)
Non-bronchiolitis (n=12)
Non-atomization (n=1)
Reviews or summary (n=6)
unaccessible (n=20)
Duplicate publication (n=4)
children between the qid group and the tid group, the qid
group and the tid group were combined into the low dosage
group.
3.2. Primary Outcome. The duration of hospital stays: 8
RCTs included 733 children [18–20, 22, 23, 26, 27, 29]. The
duration of hospital stays in the high dosage group was
significantly shorter than that in the low dosage group
(MD � −0.40, 95%CI (−0.73,−0.07), P � 0.02; I2 � 68%) (low
quality) (Figure 4).
3.3. Secondary Outcomes. Three depression signs dis-
appearing time: 4 RCTs included 487 children
[17, 18, 22, 28]. Three depressions sign disappearing time in
the high dosage group was significantly shorter than that in
the low dosage group (MD � −0.60, 95%CI (−1.05,−0.14),
P � 0.010; I2 � 75%) (low quality) (Figure 5).
Cough disappearance time: 8 RCTs included 797 chil-
dren [17–19, 23, 27–30]. There was no significant difference
in coughing disappearance time between the high dosage
group and the low dosage group (MD � −0.13, 95%CI
(−0.43, 0.16), P � 0.38; I2 � 63%) (very low quality)
(Figure 6).
Pulmonary rales disappearing time: 4 RCTs included 303
children [18, 22, 25, 29]. There was no significant difference
in pulmonary rales disappearance time between the high
dosage group and the low dosage group (MD � −0.25, 95%CI
(−0.94, 0.43), P � 0.47; I2 � 83%) (very low quality)
(Figure 7).
Wheeze disappearing time: 3 RCTs included 381 children
[17, 18, 28]. Wheeze disappearing time in the high dosage
 4
Table 1: Basic information of included RCTs.
Number Interventions
Course of High Low
Study ID Age (months) High dosage Low dosage Outcome
disease (days) dosage dosage Combination with other drugs Combination with other drugs
group group
group group
IFNα1b IFNα1b
Huang T: 9.23 ± 0.53 C: T: 6.08 ± 1.24 C:
80 80 4 μg/kg qid, Albuterol + budesonide 2 μg/kg, qid, Albuterol + budesonide ①③⑦
2015 [12] 9.45 ± 0.62 6.10 ± 1.28
5–7d 5–7d
IFNα1b IFNα1b
Shang
— — 110 110 4 μg/kg, qid, Albuterol + budesonide 2 μg/kg, qid, Albuterol + budesonide ②③⑤⑦
2014 [10]
5–7d 5–7d
IFNα1b IFNα1b
Li 2019 T: 11.83 ± 2.53 T: 0.90 ± 0.34
30 30 4 μg/kg, qid, Albuterol + budesonide 2 μg/kg, qid, Albuterol + budesonide ①②③④⑤⑦
[11] C: 11.63 ± 2.17 C: 0.92 ± 0.35
5–7d 5–7d
IFNα1b IFNα1b
Cai 2020
6.54 ± 3.10 — 53 53 4 μg/kg, qid, Albuterol + budesonide 2 μg/kg, Albuterol + budesonide ①②④⑦
[14]
5–7d qid,5–7d
IFNα1b IFNα1b
Hu 2014
— — 17 20 4 μg/kg, qid, Albuterol + budesonide 2 μg/kg, Albuterol + budesonide ③⑥⑦
[22]
5–7d qid,5–7d
IFNα1b IFNα1b
Dai 2019 T: 13.52 ± 3.87 T: (5.36 ± 0.74)
50 50 4 μg/kg, qid, Albuterol + budesonide 2 μg/kg, Albuterol + budesonide ⑦
[16] C: 13.63 ± 3.84 C: (5.11 ± 0.77)
7d qid,7d
IFNα1b IFNα1b
Wang T: 10.42 ± 0.56 T: (2.46 ± 0.68)
41 41 4 μg/kg, qid, — 2 μg/kg, qid, — ①⑦
2018 [13] C: 10.31 ± 0.77 C: (2.29 ± 0.77)
5–7d 5–7d
Liao 2017 T: 9.4 ± 0.5 IFNα1b IFNα1b
— 47 54 Budesonide + ipratropium bromide Budesonide + ipratropium bromide ②③⑤⑦
[20] C: 9.6 ± 0.6 4 μg/kg, qid 2 μg/kg, qid
T1: 6.69 ± 0.6 IFNα1b IFNα1b
Zhao
T2: 7.44 ± 0.96 — 20 40 4 μg/kg, qid, Albuterol + budesonide 2 μg/kg, qid, Albuterol + budesonide ④⑦
2018 [17]
C: 7.2 ± 0.84 5–7d 5–7d
IFNα1b IFNα1b
Xu 2017 T: 12.21 ± 3.32 T: 2.57 ± 0.42
40 40 4 μg/kg, qid, Budesonide + ambroxol 2 μg/kg, qid, Budesonide + ambroxol ①③⑥⑦
[19] C: 13.23 ± 3.45 C: 2.51 ± 0.52
7d 7d
IFNα1b IFNα1b
Liu 2018 T: 17.16 ± 6.12 T: 2.57 ± 0.42
31 31 4 μg/kg, qid, Budesonide + ambroxol 2 μg/kg, qid, Budesonide + ambroxol ①③⑥⑦
[15] C: 18 ± 2.76 C: 2.51 ± 0.52
7d 7d
IFNα1b IFNα1b
Chao 40 (tid 20; Budesonide + terbutaline + normal Budesonide + terbutaline + normal
— 1–7 37 4 μg/kg, qid, 2 μg/kg, qid, ①③④⑦
2016 [21] qid 20) saline saline
5–7d 5–7d
T (early):
6.0 ± 1.8
54 (early 52 (early IFNα1b IFNα1b
Chen C (early):
— 27; late 26; late 4 μg/kg, qid, Budesonide + terbutaline 2 μg/kg, qid, Budesonide + terbutaline ①⑦
2018 [18] 5.5 ± 2.1
27) 26) 5–7d 5–7d
T (late):6.9 ± 3.6
C (late):6.8 ± 2.9
①Qid: twice a day; tid: three times a day; ①the duration of hospital stays; ② three depression sign disappearing times; ③ cough disappearance time; ④ pulmonary rales disappearing time; ⑤ wheeze disappearing
time; ⑥ wheezing sound disappearing time; ⑦ adverse event rates. T: high dosage group; C: low dosage group.
Evidence-Based Complementary and Alternative Medicine
Evidence-Based Complementary and Alternative Medicine 5

Deviations from intended

Randomization process

Missing outcome data

Measurement of the

Selection of the
reported result
interventions

outcome

Overall
Unique ID

Huang 2015 ? ? + ? ? ?

Cai 2020 ? ? + ? ? ?

Hu 2014 ? ? + ? ? ?

Dai 2019 ? ? + ? ? ?

Wang 2018 ? ? + ? ? ?

Liao 2017 ? ? + ? ? ?

Zhao 2018 ? ? + ? ? ?

Xu 2017 ? ? + ? ? ?

Chen 2018 ? ? + + + ?

Shang 2014 + ? + + + ?

Li 2019 ? ? + + + ?

Chao 2016 ? ? + ? ? ?

Liu 2019 ? ? + + ? ?

+ Low risk

? Some concerns

? High risk

Figure 2: Risk of bias summary.

As percentage (intention-to-treat)

Overall Bias

Selection of the reported result

Measurement of the outcome

Mising outcome data

Deviations from intended interventions

Randomization process

0 10 20 30 40 50 60 70 80 90 100

Low risk
Some concerns
High risk
Figure 3: Risk of bias graph.

group was significantly shorter than that in the low dosage disappearance time (MD � 0.01, 95%CI (−0.37, 0.39),
group (MD � −0.62, 95%CI (−1.17,−0.06), P � 0.03; I2 � 73%) P � 0.96; I2 � 0%) (low quality) (Figure 9).
(low quality) (Figure 8). Adverse event rates: 13 RCTs included 1251 children
Wheezing sound disappearing time: 3 RCTs included [17–20, 22–30]. The high dosage group and the low dosage
179 children. The high dosage group and the low dosage group had no significant difference in adverse event rates
group had no significant difference in wheezing sound (RR � 1.20, 95%CI (0.61, 2.39), P � 0.59; RD � 0.00, 95%CI
6 Evidence-Based Complementary and Alternative Medicine

Table 2: GRADE evidence profile.

Certainty assessment No of patients
Effect
Relative
Study Risk of Other 2ug/kg 4ug/kg Absolute Certainty
Outcome Inconsistency Indirectness Imprecision (95%
design bias considerations IFNα1b IFNα1b (95% CI)
CI)
MD 0.40
lower
Very
(0.73 ⊕⊕○○
① RCT serious Not serious Not serious Not serious None 366 367 —
lower to LOW
a
0.07
lower)
MD 0.60
lower
Very
(1.05 ⊕⊕○○
② RCT serious Not serious Not serious Not serious None 240 247 —
lower to LOW
a
0.14
lower)
MD 0.13
lower
Very ⊕○○○
(0.43
③ RCT serious Serious b Not serious Not serious None 392 405 — VERY
lower to
a LOW
0.16
higher)
MD 0.25
lower
Very ⊕○○○
(0.94
④ RCT serious Serious b Not serious Not serious None 140 163 — VERY
lower to
a LOW
0.43
higher)
MD 0.62
lower
Very
(1.17 ⊕⊕○○
⑤ RCT serious Not serious Not serious Not serious None 187 194 —
lower to LOW
a
0.06
lower)
MD 0.01
higher
Very
(0.37 ⊕⊕○○
⑥ RCT serious Not serious Not serious Not serious None 88 91 —
lower to LOW
a
0.39
higher)
2 more
RR 1.07
Very per 1,000
18/610 17/641 (0.58 ⊕⊕○○
⑦ RCT serious Not serious Not serious Not serious None (from 11
(3.0%) (2.7%) TO 1 LOW
a fewer to
.98)
26 more)
CI: confidence interval; SMD: standardized mean difference; RR: risk ratio; RD: risk difference. a. Using a wrong method for randomization or did not
perform allocation conceal; b. Included RCTs were distributed on both side of the invalidity line. ① The duration of hospital stays; ② three depressions sign
disappearing time; ③ cough disappearance time; ④ pulmonary rales disappearing time; ⑤ wheeze disappearing time; ⑥ wheezing sound disappearing time;
⑦ adverse event rates.

(−0.01, 0.02), P � 0.77; I2 � 0%) (low quality) (Figures 10 and when IFNα1b was treated with monotherapy, there was no
11). statistically significant difference in hospital stay between the
two groups (MD � −0.21, 95%CI (−0.51, 0.09), P � 0.17)
(Figure 12).
3.4. Subgroup Analysis

3.4.1. The Duration of Hospital Stays. The results of sub-
group analysis showed that when IFNα1b was combined
with other drugs, the hospital stay in the high dosage group
was significantly shorter than that in the low dosage group
(MD � −0.44, 95%CI (−0.84, −0.03), P � 0.04; I2 � 71%);
3.4.2. Adverse Event Rates. The results of subgroup analysis
showed that regardless of IFNα1b combined therapy or
monotherapy, there was no statistically significant difference
in adverse event rates between the two groups (Figures 13
and 14).
Evidence-Based Complementary and Alternative Medicine 7

4 ug/kg 2 ug/kg Mean Difference Mean Difference

Study or Subgroup Weight (%)
Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

Cai 2020 6.03 1.37 53 6.62 1.31 53 12.5 –0.59 [–1.10, –0.08]
Chao 2016 7.84 1.57 37 7.86 1.54 40 10.0 –0.02 [–0.72, 0.68]
Chen (early) 2018 6.36 2.14 27 6.95 1.17 26 7.4 –0.59 [–1.51, 0.33]
Chen (Late) 2018 6.93 2.57 27 7.21 1.21 26 6.2 –0.28 [–1.36, 0.80]
Huang 2015 6.1 1.28 80 6.08 1.24 80 14.3 0.02 [–0.37, 0.41]
Li 2019 5.57 1.34 30 7.23 1.01 30 11.2 –1.66 [–2.26, –1.06]
Liu 2018 5.42 1.22 31 5.6 1.27 31 11.0 –0.18 [–0.80, 0.44]
Wang 2018 5.23 0.68 41 5.44 0.71 41 15.6 –0.21 [–0.51, 0.09]
Xu 2017 5.41 1.23 40 5.62 1.29 40 11.9 –0.21 [–0.76, 0.34]

Total (95% CI) 366 367 100.0 –0.40 [–0.73, –0.07]

Heterogeneity: Tau2 = 0.16; Chi2 = 25.02, df = 8 (P = 0.002); I2 = 68%
Test for overall effect: Z = 2.37 (P = 0.02) –2 –1 0 1 2
4 ug/kg 2 ug/kg

Figure 4: The duration of hospital stays.

Experimental Control Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight (%) IV, Random, 95% CI IV, Random, 95% CI
Cai 2020 1.53 1.09 53 2.11 1.54 53 24.0 –0.58 [–1.09, –0.07]
Li 2019 3.8 1.03 30 5.03 1.54 30 19.8 –1.23 [–1.89, –0.57]
Liao 2017 1.8 0.9 47 1.9 0.6 54 29.8 –0.10 [–0.40, 0.20]
Shang 2014 2.8 1.5 110 3.5 1.7 110 26.4 –0.70 [–1.12, –0.28]

Total (95% CI) 240 247 100.0 –0.60 [–1.05, –0.14]

Heterogeneity: Tau2 = 0.16; Chi2 = 12.03, df = 3 (P = 0.007); I2 = 75%
Test for overall effect: Z = 2.58 (P = 0.010) –2 –1 0 1 2
Favours [experimental] Favours [control]

Figure 5: Three depression signs disappearing time.

4 ug/kg 2 ug/kg Mean Difference Mean Difference

Study or Subgroup Weight (%)
Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

Chao 2016 5.85 1.34 37 5.63 1.17 40 11.9 0.22 [–0.34, 0.78]
Hu 2014 5.62 1.23 17 5.31 1.16 20 8.7 0.31 [–0.46, 1.08]
Huang 2015 5.87 1.42 80 5.51 1.35 80 14.6 0.36 [–0.07, 0.79]
Li 2019 5.83 0.87 30 6.73 1.14 30 12.9 –0.90 [–1.41, –0.39]
Liao 2017 6.1 1.2 47 6.3 1.1 54 14.1 –0.20 [–0.65, 0.25]
Liu 2018 6.2 1.31 31 6.33 1.39 31 10.1 –0.13 [–0.80, –0.54]
Shang 2014 6 1.3 110 6.4 1.3 110 16.3 –0.40 [–0.74, –0.06]
Xu 2017 6.21 1.32 40 6.36 1.4 40 11.4 –0.15 [–0.75, 0.45]

Total (95% CI) 392 405 100.0 –0.13 [–0.43, 0.16]

Heterogeneity: Tau2 = 0.11; Chi2 = 18.69, df = 7 (P = 0.009); I2 = 63%
Test for overall effect: Z = 0.88 (P = 0.38) –2 –1 0 1 2
4 ug/kg 2 ug/kg

Figure 6: Coughing disappearing time.

Study or Subgroup 4 ug/kg 2 ug/kg Weight (%) Mean Difference Mean Difference
Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

Cai 2020 3.47 1.41 53 4.36 1.68 53 24.8 –0.89 [–1.48, –0.30]
Chao 2016 5.3 1.53 37 5.3 1.36 40 23.9 0.00 [–0.65, 0.65]
Li 2019 4.37 1 30 5.07 1.23 30 25.1 –0.70 [–1.27, –0.13]
Zhao 2018 7.25 0.92 20 6.71 0.92 40 26.2 0.54 [0.05, 1.03]

Total (95% CI) 140 163 100.0 –0.25 [–0.94, 0.43]

Heterogeneity: Tau2 = 0.40; Chi2 = 17.22, df = 3 (P = 0.0006); I2 = 83%
Test for overall effect: Z = 0.73 (P = 0.47) –2 –1 0 1 2
4 ug/kg 2 ug/kg

Figure 7: Pulmonary rales disappearing time.

3.5. Sensitivity Analysis. When eliminating Li 2019, the significantly. The meta-analysis results of the duration of
heterogeneity of the duration of hospital stays, cough dis- hospital stays, cough disappearance time, three depression
appearance time, and wheeze disappearance time decreased sign disappearance times, wheezing sound disappearance
8 Evidence-Based Complementary and Alternative Medicine

4 ug/kg 2 ug/kg Mean Difference Mean Difference

Study or Subgroup Weight (%)
Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

Li 2019 3.77 1.36 30 4.97 0.96 30 29.8 –1.20 [–1.80, –0.60]

Liao 2017 5.2 1.4 47 5.3 1.2 54 32.8 –0.10 [–0.61, 0.41]
Shang 2014 5.1 1.4 110 5.7 1.5 110 37.4 –0.60 [–0.98, –0.22]

Total (95% CI) 187 194 100.0 –0.62 [–1.17, –0.06]

Heterogeneity: Tau2 = 0.17; Chi2 = 7.54, df = 2 (P = 0.02); I2 = 73%
Test for overall effect: Z = 2.18 (P = 0.03) –2 –1 0 1 2
4 ug/kg 2 ug/kg

Figure 8: Wheeze disappearing time.

Study or Subgroup 4 ug/kg 2 ug/kg Weight (%) Mean Difference Mean Difference
Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

Hu 2014 5.36 1.35 17 5.3 1.08 20 22.5 0.06 [–0.74, 0.86]

Liu 2018 5.4 1.33 31 5.35 1.27 31 34.1 0.05 [–0.60, 0.70]
Xu 2017 5.37 1.28 40 5.42 1.34 40 43.4 –0.05 [–0.62, 0.52]

Total (95% CI) 88 91 100.0 0.01 [–0.37, 0.39]

Heterogeneity: Tau2 = 0.00; Chi2 = 0.07, df = 2 (P = 0.96); I2 = 0%
Test for overall effect: Z = 0.05 (P = 0.96) –1 –0.5 0 0.5 1
4 ug/kg 2 ug/kg

Figure 9: Wheezing sound disappearing time.

4 ug/kg 2 ug/kg Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight (%) M-H, Random, 95% CI M-H, Random, 95% CI

Cai 2020 2 53 3 53 15.4 0.67 [0.12, 3.83]

Chao 2016 1 37 0 40 4.7 3.24 [0.14, 77.06]
Chen (early) 2018 2 27 1 26 8.6 1.93 [0.19, 19.98]
Chen (Late) 2018 1 27 0 26 4.7 2.89 [0.12, 67.96]
Dai 2019 3 50 2 50 15.5 1.50 [0.26, 8.60]
Hu 2014 2 17 0 20 5.3 5.83 [0.30, 113.75]
Huang 2015 1 80 1 80 6.2 1.00 [0.06, 15.71]
Li 2019 0 30 0 30 Not estimable
Liao 2017 1 47 1 54 6.3 1.15 [0.07, 17.87]
Liu 2018 2 31 1 31 8.6 2.00 [0.19, 20.93]
Shang 2014 3 110 3 110 18.9 1.00 [0.21, 4.85]
Wang 2018 0 41 5 41 5.8 0.09 [0.01, 1.59]
Xu 2017 0 40 0 40 Not estimable
Zhao 2018 0 20 0 40 Not estimable

Total (95% CI) 610 641 100.0 1.20 [0.61, 2.39]

Total events 18 17
Heterogeneity: Tau2 = 0.00; Chi2 = 5.90, df = 10 (P = 0.82); I2 = 0%
Test for overall effect: Z = 0.53 (P = 0.59) 0.005 0.1 1 10 200
4 ug/kg 2 ug/kg

Figure 10: Adverse event rates (RRs).

times, and adverse event rates showed no change after
eliminating including RCTs one by one. The meta-analysis
results of pulmonary rales disappearing time turned into
statistically significant differences (MD � −0.55, 95%CI
(−1.06,−0.04)) when eliminating Zhao 2018. The meta-
analysis results of wheeze disappearing time turned into no
statistically significant difference (MD � −0.38, 95%CI
(−0.87, 0.11)) when eliminating Li 2019.
4. Discussions
4.1. Summary. Bronchiolitis is a lower respiratory tract
infection mainly involving small airways (bronchioles). It is
a common cause of illness and hospitalization in infants and
young children. Severe bronchiolitis may also increase the
risk of children developing asthma and continue to adult-
hood [6, 31, 32]. Therefore, the etiological treatment of
bronchiolitis is of great importance.
This study included 13 RCTs with 1719 children to study
the safety and effectiveness of different dosages of IFNα1b
inhalation for bronchiolitis. The results showed that in the
duration of hospital stays, wheeze disappearing time, and
three depressions sign disappearing time, the high-dosage
group is significantly shorter than the low-dosage group
(P ≤ 0.05), but there was no difference between the two
groups in cough disappearance time, pulmonary rales dis-
appearing time, wheezing sound disappearing time, and
adverse event rates (P > 0.05).
Evidence-Based Complementary and Alternative Medicine 9

4 ug/kg 2 ug/kg Risk Difference Risk Difference

Study or Subgroup Events Total Events Total Weight (%) M-H, Random, 95% CI M-H, Random, 95% CI

Cai 2020 2 53 3 53 4.4 –0.02 [–0.10, 0.06]

Chao 2016 1 37 0 40 5.8 0.03 [–0.04, 0.10]
Chen (early) 2018 2 27 1 26 1.9 0.04 [–0.09, 0.16]
Chen (Late) 2018 1 27 0 26 3.0 0.04 [–0.06, 0.13]
Dai 2019 3 50 2 50 4.0 0.02 [–0.07, 0.11]
Hu 2014 2 17 0 20 1.0 0.12 [–0.05, 0.29]
Huang 2015 1 80 1 80 24.3 0.00 [–0.03, 0.03]
Li 2019 0 30 0 30 7.3 0.00 [–0.06, 0.06]
Liao 2017 1 47 1 54 9.6 0.00 [–0.05, 0.06 ]
Liu 2018 2 31 1 31 2.5 0.03 [–0.07, 0.14]
Shang 2014 3 110 3 110 15.5 0.00 [–0.04, 0.04]
Wang 2018 0 41 5 41 2.5 –0.12 [–0.23, –0.01]
Xu 2017 0 40 0 40 12.8 0.00 [–0.05, 0.05 ]
Zhao 2018 0 20 0 40 5.4 0.00 [–0.07, 0.07]

Total (95% CI) 610 641 100.0 0.00 [–0.01, 0.02]

Total events 18 17
Heterogeneity: Tau2 = 0.00; Chi2 = 8.90, df = 13 (P = 0.78); I2 = 0%
Test for overall effect: Z = 0.29 (P = 0.77) –0.2 –0.1 0 0.1 0.2
4 ug/kg 2 ug/kg

Figure 11: Adverse event rates (RDs).

4 ug/kg 2 ug/kg Mean Difference Mean Difference

Study or Subgroup Weight (%)
Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

6.1.1 combination therapy

Cai 2020 6.03 1.37 53 6.62 1.31 53 12.5 –0.59 [–1.10, –0.08]
Chao 2016 7.84 1.57 37 7.86 1.54 40 10.0 –0.02 [–0.72, 0.68]
Chen (early) 2018 6.36 2.14 27 6.95 1.17 26 7.4 –0.59 [–1.51, 0.33]
Chen (Late) 2018 6.93 2.57 27 7.21 1.21 26 6.2 –0.28 [–1.36, 0.80]
Huang 2015 6.1 1.28 80 6.08 1.24 80 14.3 0.02 [–0.37, 0.41]
Li 2019 5.57 1.34 30 7.23 1.01 30 11.2 –1.66 [–2.26, –1.06]
Liu 2018 5.42 1.22 31 5.6 1.27 31 11.0 –0.18 [–0.80, 0.44]
Xu 2017 5.41 1.23 40 5.62 1.29 40 11.9 –0.21 [–0.76, 0.34]
Subtotal (95% CI) 325 326 84.4 –0.44 [–0.84, –0.03]
Heterogeneity: Tau2 = 0.23; Chi2 = 24.16, df = 7 (P = 0.001); I2 = 71%
Test for overall effect: Z = 2.10 (P = 0.04)

6.1.2 monotherapy
Wang 2018 5.23 0.68 41 5.44 0.71 41 15.6 –0.21 [–0.51, 0.09]
Subtotal (95% CI) 41 41 15.6 –0.21 [–0.51, 0.09]
Heterogeneity: Not applicable
Test for overall effect: Z = 1.37 (P = 0.17)

Total (95% CI) 366 367 100.0 –0.40 [–0.73, –0.07]

Heterogeneity: Tau2 = 0.16; Chi2 = 25.02, df = 8 (P = 0.002); I2 = 68%
Test for overall effect: Z = 2.37 (P = 0.02) –2 –1 0 1 2
Test for subgroup differences: Chi2 = 0.76, df = 1 (P = 0.38); I2 = 0%
4 ug/kg 2 ug/kg

Figure 12: Subgroup analysis (the duration of hospital stays).

4.2. Comparison with Similar Research. Chen Can [33]
conducted a meta-analysis on the effectiveness and safety of
IFNα1b nebulized inhalation for bronchiolitis based on 24
RCTs. The study results concluded that IFNα1b nebulized
inhalation is safe and effective for bronchiolitis. However,
there are still some problems in this study. The first is the
high heterogeneity, such as the outcome of the duration of
hospital stays (P＜0.01, I2 � 98%), and the subgroup analysis
of different doses of IFNα1b did not reduce the heteroge-
neity. In addition, only 3 RCTs compared different dosages
of IFNα1b [17, 19, 30], and different dosages of IFNα1b were
not further studied.
4.3. Sensitivity Analysis. When eliminating Li 2019 [18], the
heterogeneity of each outcome has decreased, and the meta-
analysis results of wheeze disappearance time have changed.
The possible reason is that the disease course of children in
this RCT (both groups are ＜24 hours) is significantly
shorter than in other RCTs (1–6 days). Another cause may be
that the children have a high proportion of fever. The
proportion of children with a temperature ≥39°C in the high
and low dosage groups is 30% and 43%, respectively.
However, the consensus points out that the temperature of
children with bronchiolitis generally does not exceed 39°C
[3]. When eliminating Zhao (2018), the meta-analysis results
10 Evidence-Based Complementary and Alternative Medicine

4 ug/kg 2 ug/kg Risk Ratio Risk Ratio

Study or Subgroup Weight (%)
Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI

5.1.1 combination therapy

Cai 2020 2 53 3 53 15.4 0.67 [0.12, 3.83]
Chao 2016 1 37 0 40 4.7 3.24 [0.14, 77.06]
Chen (early) 2018 2 27 1 26 8.6 1.93 [0.19, 19.98]
Chen (Late) 2018 1 27 0 26 4.7 2.89 [0.12, 67.96]
Dai 2019 3 50 2 50 15.5 1.50 [0.26, 8.60]
Hu 2014 2 17 0 20 5.3 5.83 [0.30, 113.75]
Huang 2015 1 80 1 80 6.2 1.00 [0.06, 15.71]
Li 2019 0 30 0 30 Not estimable
Liao 2017 1 47 1 54 6.3 1.15 [0.07, 17.87]
Liu 2018 2 31 1 31 8.6 2.00 [0.19, 20.93]
Shang 2014 3 110 3 110 18.9 1.00 [0.21, 4.85]
Xu 2017 0 40 0 40 Not estimable
Zhao 2018 0 20 0 40 Not estimable
Subtotal (95% CI) 569 600 94.2 1.41 [0.70, 2.86]
Total events 18 17
Heterogeneity: Tau2 = 0.00; Chi2 = 2.48, df = 9 (P = 0.98); I2 = 0%
Test for overall effect: Z = 0.95 (P = 0.34)

5.1.2 monotherapy
Wang 2018 0 41 5 41 5.8 0.09 [0.01, 1.59]
Subtotal (95% CI) 41 41 5.8 0.09 [0.01, 1.59]
Total events 0 5
Heterogeneity: Not applicable
Test for overall effect: Z = 1.64 (P = 0.10)

Total (95% CI) 610 641 100.0 1.20 [0.61, 2.39]

Total events 18 17
2 2 2
Heterogeneity: Tau = 0.00; Chi = 5.90, df = 10 (P = 0.82); I = 0%
Test for overall effect: Z = 0.53 (P = 0.59) 0.002 0.1 1 10 500
Test for subgroup differences: Chi2 = 3.32, df = 1 (P = 0.07); I2 = 69.9%
4 ug/kg 2 ug/kg

Figure 13: Subgroup analysis (adverse event rates (RRs)).

Study or Subgroup 4 ug/kg 2 ug/kg Weight (%) Risk Difference Risk Difference
Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI

5.1.1 combination therapy

Cai 2020 2 53 3 53 4.4 –0.02 [–0.10, 0.06]
Chao 2016 1 37 0 40 5.8 0.03 [–0.04, 0.10]
Chen (early) 2018 2 27 1 26 1.9 0.04 [–0.09, 0.16]
Chen (Late) 2018 1 27 0 26 3.0 0.04 [–0.06, 0.13]
Dai 2019 3 50 2 50 4.0 0.02 [–0.07, 0.11]
Hu 2014 2 17 0 20 1.0 0.12 [–0.05, 0.29]
Huang 2015 1 80 1 80 24.3 0.00 [–0.03, 0.03]
Li 2019 0 30 0 30 7.3 0.00 [–0.06, 0.06]
Liao 2017 1 47 1 54 9.6 0.00 [–0.05, 0.06]
Liu 2018 2 31 1 31 2.5 0.03 [–0.07, 0.14]
Shang 2014 3 110 3 110 15.5 0.00 [–0.04, 0.04]
Xu 2017 0 40 0 40 12.8 0.00 [–0.05, 0.05]
Zhao 2018 0 20 0 40 5.4 0.00 [–0.07, 0.07]
Subtotal (95% CI) 569 600 97.5 0.01 [–0.01, 0.02]
Total events 18 12
Heterogeneity: Tau2 = 0.00; Chi2 = 3.93, df = 12 (P = 0.98); I2 = 0%
Test for overall effect: Z = 0.65 (P = 0.52)

5.1.2 monotherapy
Wang 2018 0 41 5 41 2.5 –0.12 [–0.23, –0.01]
Subtotal (95% CI) 41 41 2.5 –0.12 [–0.23, –0.01]
Total events 0 5
Heterogeneity: Not applicable
Test for overall effect: Z = 2.23 (P = 0.03)

Total (95% CI) 610 641 100.0 0.00 [–0.01, 0.02]

Total events 18 17
Heterogeneity: Tau2 = 0.00; Chi2 = 8.90, df = 13 (P = 0.78); I2 = 0%
Test for overall effect: Z = 0.29 (P = 0.77) –0.2 –0.1 1 0.1 0.2
Test for subgroup differences: Chi2 = 5.31, df = 1 (P = 0.02); I2 = 81.2%
4 ug/kg 2 ug/kg

Figure 14: Subgroup analysis (adverse event rates (RDs)).

Evidence-Based Complementary and Alternative Medicine
of pulmonary rales disappearing time have changed. The
possible reason is that Zhao (2018) [25] subdivides the low
dosage group into three times a day and two times a day.
However, it is unified into the low dosage group for sta-
tistical analysis in this study, which may lead to a change in
baseline comparability. The difference in sample size be-
tween the high dosage group and the low dosage group may
also be one of the reasons.
4.4. Subgroup Analysis. Subgroup analysis showed no sig-
nificant difference between the high dosage group and the
low dosage group in the duration of hospital stays and
adverse event rates when IFNα1b was treated with mono-
therapy. In terms of the duration of hospital stays, the
conclusions of monotherapy and when combined with other
drugs are inconsistent. However, considering that there is
only 1 RCT on monotherapy, it cannot be concluded that
there is no statistically significant difference in the duration
of hospital stays between the high dosage group and the low
dosage group when IFNα1b was treated with monotherapy.
A large sample, multicenter clinical research is needed to
support these results.
4.5. Risk-of-Bias Assessments. The areas of lower quality are
“Randomization process” and “Randomization process,”
53.85% of the RCTs did not use or used the wrong method
for randomization, such as according to the order of ad-
mission, which may lead to incomparable baselines between
the two groups. In addition, 92.31% of the RCTs did not use
blinding or concealed allocation, which may lead to bias
when giving interventions or measuring outcome data.
5. Advantages and Limitations
5.1. Advantage. There has been controversy about the dif-
ferent dosages of IFNα1b inhaling for bronchiolitis in
clinical practice. However, there is not any evidence-based
medical evidence. This study uses systematic reviews and
meta-analysis methods to provide a reference for clinical
practice.
5.2. Limitation. There are some limitations to this study.
First, the quality of the included RCTs is low. Only 1 RCT has
a result of “Some concerns,” and the others are “High risk.”
Second, most of the outcomes of this study adopt the dis-
appearance time of disease symptoms, and the judgment
criteria are subjective. Third, since none of the included
RCTs mentioned the symptom classification of bronchiolitis,
the disease severity was not considered in this study.
6. Conclusions
Compared with the low dosage IFNα1b, the high dosage
IFNα1b reduces the duration of hospital stays, the disap-
pearance time of the three depression signs, and the dis-
appearance time of wheeze in the treatment of bronchiolitis
in children. Limited by the quality of the included RCTs, the
11
above conclusions still need to be supported by large samples
and high-quality studies.
Data Availability
The RevMan data used to support the findings of this study
are available from the corresponding author upon request.
Conflicts of Interest
The author reports no conflicts of interest in this work.
Acknowledgments
This study was supported by the Sichuan Province Science
and Technology Plan Project (No.2020YFS0035) and Sub-
project of Science and Technology Plan Project of Sichuan
Province (20ZDYF3101).
Supplementary Materials
Search strategies for all databases can be seen in the sup-
plementary material. (Supplementary Materials)
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