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Nebulised deoxyribonuclease for viral bronchiolitis in children

younger than 24 months (Review)

Enriquez A, Chu IW, Mellis C, Lin WY

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 11
http://www.thecochranelibrary.com

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Analysis 1.1. Comparison 1 Nebulised rhDNase versus control, Outcome 1 Duration of hospitalisation. . . . . . 21
Analysis 2.1. Comparison 2 Nebulised rhDNase versus control, Outcome 1 Change in clinical score. . . . . . . 22
Analysis 3.1. Comparison 3 Nebulised rhDNase versus control, Outcome 1 Change in respiratory rate score. . . . 22
Analysis 4.1. Comparison 4 Nebulised rhDNase versus control, Outcome 1 Change in wheezing score. . . . . . 23
Analysis 5.1. Comparison 5 Nebulised rhDNase versus control, Outcome 1 Change in retraction score. . . . . . 24
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 26
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) i
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Nebulised deoxyribonuclease for viral bronchiolitis in children


younger than 24 months

Annabelle Enriquez1 , I-Wen Chu2 , Craig Mellis3 , Wan-Yu Lin4

1 The Children’s Hospital at Westmead, Westmead, Australia. 2 Department of Medical Research and Academic-Industrial Collaboration

Office, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 3 Faculty of Medicine, Room 406, Blackburn Building, D06, The University
of Sydney, Sydney, Australia. 4 Department of Nuclear Medicine, Taichung General Veteran Hospital, Taichung City, Taiwan

Contact address: I-Wen Chu, Department of Medical Research and Academic-Industrial Collaboration Office, Chang Gung Memorial
Hospital, No.5, Fusing St., Gueishan Township, Taoyuan, 333, Taiwan. chui6172@gmail.com. chui@howrey.com.

Editorial group: Cochrane Acute Respiratory Infections Group.


Publication status and date: New, published in Issue 11, 2012.
Review content assessed as up-to-date: 3 August 2012.

Citation: Enriquez A, Chu IW, Mellis C, Lin WY. Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24
months. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD008395. DOI: 10.1002/14651858.CD008395.pub2.

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Bronchiolitis is one of the most common respiratory problems in the first year of life. The sputum of infants with bronchiolitis has
increased deoxyribonucleic acid (DNA) content, leading to mucous plugging and airway obstruction. Recombinant human deoxyri-
bonuclease (rhDNase), an enzyme that digests extracellular DNA, might aid the clearance of mucus and relieve peripheral airway
obstruction.

Objectives

To determine the effect of nebulised rhDNase on the severity and duration of viral bronchiolitis in children younger than 24 months
of age in the hospital setting.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 7 which includes the Acute Respiratory
Infections Group’s Specialised Register, MEDLINE (1966 to July Week 4, 2012), EMBASE (1974 to August 2012) and LILACS (1982
to August 2012).

Selection criteria

Randomised controlled trials (RCTs) using nebulised rhDNase alone or with concomitant therapy in children younger than 24 months
of age hospitalised with acute bronchiolitis.

Data collection and analysis

Two review authors independently performed literature searches, assessed trial quality and extracted data. We obtained unpublished
data from trial authors. We used Review Manager 5.1 to pool treatment effects expressed as the mean difference (MD) or standardised
mean difference (SMD) with 95% confidence intervals (CI).
Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 1
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results

Three RCTs (333 participants) were identified, two of which were multicentre trials comprising only participants positive for respiratory
syncytial virus (RSV). The other trial enrolled participants clinically diagnosed with bronchiolitis from a hospital in Italy. All studies
used 2.5 mL (1 mg/mL) of nebulised rhDNase compared with placebo either as a daily or a twice daily dose. Adjunctive therapy
included nebulised salbutamol, steroids, supplemental oxygen, intravenous fluids or tube feeding, nasal washing, nasal decongestants
and antibiotics.

Overall, nebulised rhDNase showed no benefit in clinically meaningful outcomes. Meta-analysis favoured the control group with a
shorter duration of hospital stay (MD 0.50; 95% CI 0.10 to 0.90, P = 0.01) and better clinical score improvement (SMD -0.24; 95%
CI -0.50 to 0.01, P = 0.06). The largest trial showed no difference in supplemental oxygen use or intensive care unit (ICU) admission.

In one RCT, four out of 11 patients in the treatment group had atelectasis. Two of these patients showed distinctive clinical improvement
after nebulised rhDNase.

There was no significant difference in adverse events. These included temporary desaturation, temporary coughing, increased coughing,
facial rash, hoarseness, dyspnoea and bad taste, reported in a total of 11 patients from both treatment groups.

Authors’ conclusions

The results based on the three included studies in this review did not support the use of nebulised rhDNase in children under 24
months of age hospitalised with acute bronchiolitis. In these patients, treatment did not shorten the length of hospitalisation or improve
clinical outcomes. It might have a role in severe bronchiolitis complicated by atelectasis, but further clinical studies would need to be
performed.

PLAIN LANGUAGE SUMMARY

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months

Bronchiolitis is the most common respiratory illness leading to hospitalisations in infants. Viral infections, particularly respiratory
syncytial virus, are the usual cause, which lead to blockage of the small airways of the lungs due to inflammation and increased mucus
production. Afflicted children have fever, cough, wheezing and difficulty breathing. Treatment is usually supportive. In bronchiolitis,
the mucus produced contains large amounts of DNA, which makes it thicker and stickier. Removal of this DNA facilitates clearance
of the mucus. RhDNase is an enzyme that breaks down DNA and hence may improve symptoms. We performed this review to assess
the effect of rhDNase delivered through a nebuliser in children under 24 months old hospitalised for bronchiolitis.

We identified three randomised controlled trials involving 333 children up to 24 months of age hospitalised with bronchiolitis. All
three studies compared nebulised rhDNase with placebo. Any additional treatments were given to both groups. Overall, the studies
did not show that nebulised rhDNase shortened the duration of hospital admission, or improved the severity of symptoms. No serious
side effects were reported by any of the studies.

One study showed that in patients suffering from atelectasis, a severe complication of bronchiolitis wherein the lung does not expand
completely, nebulised rhDNase treatment resulted in a distinct improvement within two days. To confirm this beneficial effect, further
clinical studies in patients with severe bronchiolitis are needed. Currently, the use of this treatment in young children hospitalised with
bronchiolitis is not recommended.

BACKGROUND
Bronchiolitis is one of the most common respiratory problems in
the first year of life. It is usually self limiting, with only a small
proportion of affected children needing hospital admission. De-
Description of the condition spite this, it is a major cause of morbidity and mortality in this age

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 2
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
group and is the leading cause of infant hospitalisation in the USA (Merkus 2001) have reported varying degrees of improvement
(Leader 2003). In Europe and the USA, up to 3% of infants under in lung function, sputum volume, oxygen need and chest X-ray
12 months of age are hospitalised with bronchiolitis (Deshpande (CXR) appearance.
2003; Hall 2009). Most cases are viral in origin, respiratory syncy-
tial virus (RSV) being the most common cause (Manoha 2007).
The predominant pathological feature of acute bronchiolitis is in- How the intervention might work
flammation of the respiratory and terminal bronchioles (Calogero
2007; Wohl 2003). Viral infection results in death of respiratory One of the predominant pathological features in bronchiolitis is
epithelial cells. The epithelium sloughs off and together with in- mucous plugging. The sputum of infants with bronchiolitis has
flammatory cells, produces cellular debris to form a thick mucous increased DNA content (Wohl 2003). RhDNase, by digesting
plug. Combined with oedema and cellular infiltration around the DNA, might aid the clearance of mucus and relieve peripheral
airway, the viscous mucus is responsible for obstructing the airway airway obstruction. Recent studies on rhDNase have shown im-
and disrupting normal airflow. Bronchiolitis is diagnosed clini- provement of radiologic abnormalities seen in RSV bronchiolitis
cally by fever, cough, increased respiratory rate, accessory muscle (Merkus 2001; Nasr 2001).
use, expiratory wheezing, inspiratory crackles and increased mu-
cus production.
Although much is known about the mechanism and manifesta- Why it is important to do this review
tion of bronchiolitis, treatment remains controversial. Currently
The mucolytic property of rhDNase has been well documented
the management of this condition is mainly supportive, includ-
in cystic fibrosis, and case reports have shown promising results
ing supplemental oxygen, nasal washing, adequate fluid intake, a
in other respiratory diseases such as bronchiolitis. Nevertheless, it
suitable thermal environment to minimise oxygen consumption
has not yet been established whether rhDNase improves clinical
and mechanical ventilation when necessary. Interventions aimed
outcomes in viral bronchiolitis.
at reducing mucus production and increasing clearance of air-
way secretions, such as bronchodilators, corticosteroids and chest
physiotherapy, are also widely used. However, recent reviews have
failed to show a consistently significant benefit in the routine use
of these symptomatic treatments (Corneli 2007; Gadomski 2010; OBJECTIVES
Fernandes 2010; Perrotta 2007). At present there are promising
To determine the effect of nebulised rhDNase on the severity and
reports that epinephrine (Hartling 2011) and nebulised hyper-
duration of viral bronchiolitis in children younger than 24 months
tonic saline (Zhang 2011) may be beneficial in reducing the length
of age in the hospital setting.
of hospital stay but further research is required to confirm these
findings.

METHODS
Description of the intervention
In bronchiolitis, degenerating leukocytes and epithelial cells re-
Criteria for considering studies for this review
lease large amounts of DNA (Merkus 2001). DNA has an inher-
ent tendency to form a viscous gel, contributing to increased vis-
cosity and adhesiveness of the mucus (Armstrong 1950). Removal
of this DNA facilitates clearance of the mucus. RhDNase is an Types of studies
enzyme that digests extracellular DNA. Initially developed for pa- Randomised controlled trials (RCTs).
tients with cystic fibrosis, rhDNase greatly reduces the viscosity
of purulent sputum (Shak 1990). It is delivered in the nebulised
form, wherein liquid rhDNase is converted to a fine mist for in- Types of participants
halation. Despite being expensive, rhDNase is now an established We included children younger than 24 months of age with doc-
treatment in cystic fibrosis (Suri 2002). umented bronchiolitis in the hospital setting. Acute bronchiolitis
In addition, nebulised rhDNase has been used in the treatment of was defined as the first episode of acute wheezing associated with
other lung diseases with significant mucous plugging or impaired rhinorrhoea, sneezing, cough, fever or tachypnoea. Confirmation
mucociliary clearance (Boogaard 2007a). Studies performed in of viral aetiology was not necessary for study inclusion.
children with asthma (Greally 1995; Patel 2000; Puterman 1997), We excluded participants who were born before 32 weeks of ges-
severe atelectasis (Erdeve 2007; Hendriks 2005; Kupeli 2003), tation, had low birth weight (< 2.5 kg), chronic lung disease or
primary ciliary dyskinesia (ten Berge 1999) and RSV bronchiolitis heart disease.

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 3
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of interventions 10. (influenza or flu).tw.
1. Nebulised rhDNase alone versus control. 11. exp Paramyxoviridae Infections/
2. Nebulised rhDNase plus any form of concomitant therapy 12. parainfluenza*.tw.
(intervention) versus the same form of concomitant therapy 13. or/1-12
alone (control). 14. exp Deoxyribonucleases/
15. exp Deoxyribonuclease I/
16. deoxyribonucleas*.tw.
Types of outcome measures 17. dna nucleas*.tw.
18. dnase.tw.
19. rhdnase.tw.
Primary outcomes 20. or/14-19
1. Duration of hospitalisation (days) 21. 20 and 13

Secondary outcomes Searching other resources


1. Clinical score We contacted experts in this field, checked conference abstracts
2. Respiratory rate and consulted www.clinicalstudyresults.org for unpublished stud-
3. Wheezing ies. We checked reference lists of all relevant articles to identify
4. Accessory muscle use other relevant studies. We contacted the authors of any identified
5. Oxygen saturation and duration of supplemental oxygen abstracts to ascertain the nature of the study design and outcome
6. Number of intensive care admissions measures. We only included abstracts with sufficient information
7. Radiological score and findings on the study design and outcome measures.
8. Adverse events

Data collection and analysis


Search methods for identification of studies

Selection of studies
Electronic searches Two review authors (IWC, AE) independently identified the stud-
We searched the Cochrane Central Register of Controlled Tri- ies and assessed whether they met the inclusion criteria. The third
als (CENTRAL) 2012, Issue 7, part of The Cochrane Library, review author (CM) was designated to resolve any discrepancies.
www.thecochranelibrary.com (accessed 3 August 2012), which We identified studies for the review based on their abstracts. We
contains the Acute Respiratory Infections Group’s Specialised Reg- retrieved the full-text articles if there was insufficient information
ister, MEDLINE (1966 to July Week 4, 2012), EMBASE (1974 in the abstract.
to August 2012) and LILACS (1982 to August 2012).
We used the following search terms to search CENTRAL and
MEDLINE. We adapted these terms to search EMBASE (see Data extraction and management
Appendix 1) and LILACS (see Appendix 2). There were no lan- Two review authors (IWC, AE) independently performed data
guage or publication restrictions. extraction. We collected the following data using a standardised
data extraction form for each included study.
1. Study characteristics: title of the study, names of authors,
MEDLINE (Ovid) publication status, setting.
1. Exp Bronchiolitis 2. Method: method of allocation, concealment of
2. bronchiolit*.tw. randomisation and specification of who was blinded (clinicians
3. respiratory syncytial viruses/ or respiratory syncytial virus, hu- caring for the patients, assessors, data managers or the care giver).
man/ 3. Participants: age, demographic factors, inclusion and
4. Respiratory Syncytial Virus Infections/ exclusion criteria, withdrawal or loss to follow-up.
5. (respiratory syncytial virus* or rsv).tw. 4. Disease: diagnostic criteria of bronchiolitis, duration of
6. adenoviridae/ or exp mastadenovirus/ illness, RSV status.
7. adenoviridae infections/ or adenovirus infections, human/ 5. Intervention: type, dose, duration, route and co-
8. adenovir*.tw. interventions.
9. Influenza, Human/ 6. Control: type, dose, duration, route and co-interventions.

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 4
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7. Outcome: we extracted the mean, standard deviation and blinding could have been broken, and the outcome is likely to be
the number of participants studied in each group for continuous influenced by lack of blinding.
outcomes. We extracted the total number of participants per
group and the number of participants experiencing the event for
dichotomous outcomes. 4. Incomplete outcome data addressed (attrition bias)
We entered the extracted data into RevMan 2011, The Cochrane
Low risk: no missing outcome data, reasons for missing outcome
Collaboration’s software program.
data unlikely to be related to true outcome, missing outcome data
balanced in numbers across intervention groups, with similar rea-
Assessment of risk of bias in included studies sons for missing data across groups, for dichotomous outcome
data, the proportion of missing outcomes compared with observed
Two review authors (IWC, AE) independently assessed the event risk not enough to have a clinically relevant impact on the
methodological quality of all included studies using the Cochrane intervention effect estimate, for continuous outcome data, plau-
Collaborations’ tool for assessing risk of bias (Higgins 2011). Two sible effect size (difference in means or standardised difference in
review authors (IWC, AE) independently assessed the following means) among missing outcomes not enough to have a clinically
six domains in each study. relevant impact on observed effect size or missing data have been
imputed using appropriate methods.
Unclear risk: insufficient or no reporting of missing outcome data.
1. Sequence generation (selection bias)
High risk: reason for missing outcome data likely to be related to
Low risk: sequence generated by random number table, computer true outcome, with either imbalance in numbers or reasons for
random number generator, coin tossing, shuffling cards or en- missing data across intervention groups. For dichotomous out-
velopes, throwing dice, drawing of lots or minimisation. come data, the proportion of missing outcomes compared with
Unclear risk: insufficient information about the sequence gener- observed event risk enough to induce clinically relevant bias in
ation process to permit judgement but did mention ’randomisa- intervention effect estimate; for continuous outcome data, plau-
tion’. sible effect size (difference in means or standardised difference in
High risk: sequence generated by odd or even dates of birth, date means) among missing outcomes enough to induce clinically rel-
of admission or hospital or clinic record number, judgement of evant bias in observed effect size, ’as-treated’ analysis done with
the clinician, availability of the intervention, results of laboratory substantial departure of the intervention received from that as-
tests or preference of the participant. signed at randomisation or potentially inappropriate application
of simple imputation.

2. Allocation concealment (selection bias)


Low risk: participant and investigators could not foresee assign- 5. Selective outcome reporting (reporting bias)
ment because of central allocation, drug container of identical ap-
pearance or sealed, opaque envelopes. Low risk: the study protocol may or may not be available but all
Unclear risk: insufficient information about the allocation con- of the study’s expected primary or secondary outcomes have been
cealment to permit judgement but did mention ’randomisation’. reported in the pre-specified way.
High risk: participant and investigators could foresee assignment Unclear risk: insufficient information to permit judgement about
because of open random allocation schedule, alteration or rota- outcome reporting.
tion of allocation, unsealed or non-opaque envelopes, or allocation High risk: not all of the study’s pre-specified primary outcomes
based on date of birth, case record number or any other explicitly have been reported, one or more of the reported outcomes were
unconcealed procedure. not pre-specified, one or more outcomes of interest in the review
are reported incompletely so that they cannot be entered in a meta-
analysis or the study report fails to include results for a key outcome
3. Blinding of outcome assessment (detection bias) that would be expected to have been reported for such a study.
Low risk: blinding of key study personnel and participants or no
blinding or incomplete blinding, but the review authors judge that
the outcome is not likely to be influenced by lack of blinding. 6. Other bias
Unclear risk: insufficient information to permit judgement of ’low Low risk: the study appears to be free of other sources of bias.
risk’ or ’high risk’ or the study did not address this outcome. Unclear risk: there may be a risk of bias but there is insufficient
High risk: no blinding or incomplete blinding, and the outcome information to assess whether an important risk of bias exists.
is likely to be influenced by lack of blinding or blinding of key High risk: there is at least one important risk of bias, has been
study participants and personnel attempted, but likely that the claimed to have been fraudulent or had some other problem.

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 5
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We defined high-quality trials as those with low risk in sequence RESULTS
generation, allocation concealment, blinding and loss to follow-
up.
Description of studies
Measures of treatment effect See: Characteristics of included studies; Characteristics of excluded
studies.
We measured the outcomes obtained as continuous variables. We
used RevMan 2011 to pool treatment effects. For continuous vari-
ables measured on the same scale, we calculated the mean differ-
Results of the search
ence (MD) with 95% confidence intervals (CI). We combined
clinical scores assessed with different scales using the standardised The electronic searches retrieved 1686 citations.
mean difference (SMD) with 95% CI. We identified three RCTs and three conference abstracts, which
were reviewed in full text. The three abstracts corresponded to the
three RCTs, which met all the criteria for study selection for this
Dealing with missing data review (see Characteristics of included studies table). No other
studies were identified from other resources.
We contacted the trial authors directly if there were missing data or
insufficient information was presented in the published trial. We
were able to obtain further information regarding the interventions
Included studies
used from two of the trials (Boogaard 2007b; Nenna 2009). To
enable us to combine study outcomes, we obtained raw data for
the duration of hospitalisation and for the separate components
of the clinical scores from one of the trials (Boogaard 2007b). Population
We then calculated the mean and SD for these variables prior to All three studies were randomised, double-blind, placebo-con-
performing the meta-analyses. trolled clinical trials involving inpatients with documented bron-
chiolitis. Two were multicentre trials, one from the Netherlands
(Boogaard 2007b: 10 hospitals) and one from the USA (Nasr
Assessment of heterogeneity 2001: two hospitals). The other trial enrolled inpatients from one
We measured heterogeneity by using the I2 statistic, with a value hospital in Rome (Nenna 2009). The multicentre trials only in-
greater than 50% considered to be substantial (Higgins 2011). cluded patients with RSV detected from nasopharyngeal samples;
the other trial used clinical diagnosis later supported with viral
studies. One study enrolled participants with gestational ages from
Assessment of reporting biases 32 weeks (Boogaard 2007b), while the remaining two studies en-
rolled subjects born after 37 weeks of gestation. The upper age
We would have used a funnel plot to detect any publication bias.
limits used were six months (Nenna 2009), 12 months (Boogaard
This was not necessary due to the small number of included trials.
2007b) and 24 months (Nasr 2001).

Data synthesis
Intervention
We calculated a weighted treatment effect across trials using
All studies used 2.5 mL (1 mg/mL) of rhDNAse delivered by jet
RevMan 2011 based on a fixed-effect model. For continuous out-
nebulisation. For the control participants, two of the studies gave
comes, we calculated the MD or the SMD, expressing the pooled
nebulised saline (Boogaard 2007b; Nenna 2009). The other study
treatment effects with 95% CIs.
gave rhDNase in a solution made with 150 mM sodium chloride
and 1.5 mM calcium chloride (Nasr 2001). This excipient was
given to the control group.
Subgroup analysis and investigation of heterogeneity
One trial (Nasr 2001) gave all participants nebulised salbutamol
We did not perform subgroup analysis. as part of their bronchiolitis protocol, with some of the partici-
pants also receiving steroids for three to five days. In the other two
studies additional treatment included supplemental oxygen, intra-
Sensitivity analysis venous fluids or tube feeding, nasal washing, nasal decongestants,
We performed sensitivity analysis for methodological quality. No antibiotics and bronchodilators. Two trials used a daily dose for
additional sensitivity analysis was conducted as no other issues up to five days (Nasr 2001; Nenna 2009) and the other gave the
were identified during the review process. dose twice daily until discharge (Boogaard 2007b).

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 6
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Outcome measures thus assigned a score of zero for each parameter. For the respiratory
rate score, there were 28 participants in the control group and
All the studies compared length of hospital stay (LOS). To report
28 participants in the treatment group with missing data; for the
their results, the largest trial (Boogaard 2007b) used geometric
wheezing score, there were 38 participants in the control group
means while the other two trials calculated arithmetic means. In
and 52 participants in the treatment group with missing data; and
order to combine the LOS results from all three studies, we ob-
for the retraction score, there were 39 participants in the control
tained the raw data from the authors of the largest trial and calcu-
group and 51 participants in the treatment group with missing
lated the arithmetic means.
data.
The same clinical scoring system was used in two trials (Boogaard
One trial (Nenna 2009) used a different scoring system. The total
2007b; Nasr 2001) on admission and at discharge. Initially de-
clinical score was based on oxygen saturation, retractions, respira-
scribed by Wang (Wang 1992), the score rated respiratory rate,
tory rate, feeding and chest X-ray findings.
wheezing, retraction and general condition from zero to three (the
Only one study reported adverse events (Boogaard 2007b).
higher score corresponding to increased severity). One of these
studies also compared CXRs taken during admission and at the
completion of the study (Nasr 2001). The other multicentre trial Excluded studies
compared duration of supplemental oxygen use and intensive care We excluded one case series (Merkus 2001) describing the effect of
unit (ICU) admission (Boogaard 2007b). nebulised rhDNase on five infants with severe RSV bronchiolitis
For one of the trials (Boogaard 2007b), we used the unpublished and atelectasis.
raw data provided by the trial authors to calculate the change in
clinical score between the day of admission (day one) and day
three; and also to determine individual scores (respiratory rate,
wheezing and retraction) on an intention-to-treat (ITT) basis. If
Risk of bias in included studies
a score was missing, we assumed complete patient recovery and The overall risk of bias is presented graphically in Figure 1.

Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Allocation
Blinding

All the studies clearly described randomisation and allocation con-


cealment methods. Each trial appropriately outlined blinding.
Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 7
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Incomplete outcome data Analysis from one of the studies was based on ITT (Boogaard
Descriptions of withdrawals were adequate in all the trials. In the 2007b) for all randomised participants and a separate per-protocol
largest study (Boogaard 2007b), two (one from each study arm) analysis was performed which excluded participants violating the
out of 224 participants were not included in the ITT analysis as study protocol. Results from both analyses were similar.
consent was withdrawn after the first dose. 30 participants were ex-
cluded from the per-protocol analysis for varying reasons as spec- Effects of interventions
ified in the study. A total of 333 inpatients were enrolled by the three randomised
Another trial had 11 out of 86 enrolled participants excluded from controlled trials (RCTs) and data from 319 participants were anal-
the study because of missing data (Nasr 2001) and the smallest ysed. The treatment was easy to administer.
trial (Nenna 2009) had no patient loss to follow-up with all 22
participants included.
Duration of hospital stay
Each individual trial reported that rhDNase treatment had no sta-
Selective reporting
tistically significant effect on the duration of hospital stay. Meta-
No reporting bias was identified. There were no statistically sig- analysis showed that the duration of hospital stay was significantly
nificant positive results reported by any of the published trials. shorter in the control group (Figure 2), with a pooled mean dif-
ference (MD) of 0.50 days (95% confidence interval (CI) 0.10 to
0.90, P = 0.01). There was no significant heterogeneity in results
Other potential sources of bias
between studies (I2 statistic = 0%).

Figure 2. Forest plot of comparison: duration of hospitalisation

Clinical score
None of the trials found any statistically significant difference in
clinical scores between the control and intervention groups. We
pooled data from two trials (Boogaard 2007b; Nenna 2009) com-
paring clinical scores on admission (assigned as day one) and day
three. Although not statistically significant, Figure 3 shows that the
control group overall had a higher improvement in clinical score
than the rhDNase group (standardised mean difference (SMD) -
0.24; 95% CI -0.50 to 0.01, P = 0.06, I2 statistic = 65%).

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 8
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 3. Forest plot of comparison: change in total clinical score

These studies used different overall scoring systems and had dif-
ferent lengths of stay. The smaller study (22 participants, Nenna chest retraction score) were combined from two studies (Boogaard
2009) evaluated clinical score differences between the study and 2007b; Nasr 2001), both of which used the same scoring system
placebo groups every day until day four only, while the larger study (Wang 1992). The differences between the individual scores in
recorded clinical scores until discharge. Nenna 2009 reported that the larger study (Boogaard 2007b) were derived from the raw data
two participants in the intervention group showed a worsening of on day of admission and day three. The differences between the
clinical scores, perhaps due to their young age (both one-month individual scores in the other study (Nasr 2001) were based on
old males). This may explain the apparent favouring of the control the scores on the day of admission and the day of discharge (the
group in this RCT, which may in turn account for the significant average length of stay being 3.34 days in the control group and
heterogeneity between the studies (in addition to the use of dif- 3.33 days in the intervention group).
ferent clinical scoring systems). Meta-analysis of the differences in respiratory rate score (MD 0.06;
95% CI -0.15 to 0.28, P = 0.55, I2 statistic = 0%), favoured the
Respiratory rate rhDNase group but not in a statistically significant manner (Figure
4).
The individual scores (respiratory rate score, wheezing score and

Figure 4. Forest plot of comparison: change in respiratory rate score

Wheezing
Meta-analysis of the differences in wheezing score (MD -0.03;
95% CI -0.21 to 0.16, P = 0.78, I2 statistic = 0%) favoured the
control group; but this was not statistically significant (Figure 5).

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 9
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 5. Forest plot of comparison: change in wheezing score

Accessory muscle use


The studies assessed accessory muscle use, with severity ranging
from none to severe chest retractions with nasal flare (Wang 1992).
Meta-analysis (Figure 6) showed that the differences in chest re-
traction score (MD -0.02; 95% CI -0.19 to 0.14, P = 0.77, I2
statistic = 0%) were higher in the control group is favoured; but
this was not statistically significant.

Figure 6. Forest plot of comparison: change in retraction score

In the same study (Boogaard 2007b), seven children (3.2%) re-


Oxygen saturation and duration of supplemental
quired transfer to the intensive care unit (ICU), five of whom re-
oxygen
ceived mechanical ventilation, with no significant differences ob-
One of the studies (Nenna 2009) incorporated oxygen saturation served between the control and intervention groups in terms of
in calculating the clinical severity score. A score of zero was given the proportion of individuals requiring intensive care (P = 1.0) or
for levels higher than 95%; one for saturations of 90% to 94%; mechanical ventilation (P = 0.43).
and two for levels below 89%. The actual data was not reported
individually.
In the largest trial (Boogaard 2007b), supplemental oxygen was Radiological score and findings
administered once oxygen saturation fell consistently below 93%, The trial by Nasr 2001 measured radiological changes before and
and was discontinued once it was consistently over 92%. There after treatment. Analysing the treatment and control arms sepa-
was no significant difference (expressed as a ratio of the geometric rately, they reported a significant improvement (chest X-ray differ-
means of rhDNase and placebo groups with 95% CI) in the du- ence score was 0.46, P = 0.02) in the intervention group, compared
ration of supplemental oxygen use (1.29; 95% CI 0.99 to 1.67, P with a significant deterioration (chest X-ray difference score was -
= 0.053). 0.60, P = 0.02) in the placebo group. The authors then performed
a one-way analysis of covariance using the hospital discharge chest
X-ray scores as the dependent variable and the hospital admission
Number of intensive care admissions score as the covariate. This revealed that there was a significant
Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 10
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
difference between the groups (P = 0.01) in spite of the fact that There was no significant heterogeneity among the trials, all of
group assignment was random: chest X-ray and respiratory rate which delivered the same amount of rhDNase by jet nebulisation
variables showed trends suggesting that the rhDNase group (40 using the corresponding excipient as control. One trial used twice
participants) was more severely affected than the placebo group daily dosing (Boogaard 2007b) rather than once daily. Another one
(35 participants) at the beginning of the trial. co-administered salbutamol as part of their protocol and notably
In another trial (Nenna 2009), chest X-ray showed atelectasis in did not report any adverse events (Nasr 2001).
four out of 11 children in the rhDNase group. The authors re- The two multicentre trials enrolled only patients with respiratory
ported a distinct reduction in clinical score for two of these pa- syncytial virus (RSV)-proven bronchiolitis (Boogaard 2007b; Nasr
tients (-80% and -67%) during the first two days of the trial. Both 2001), thus the results may not necessarily be applicable to non-
of these patients’ symptoms were due to respiratory syncytial virus RSV bronchiolitis.
(RSV). The outcomes measured across the three studies had similar re-
sults, making them relevant to children under 24 months of age
hospitalised with acute RSV bronchiolitis.
Adverse events In one study (Nasr 2001), the participants in the intervention
One study (Boogaard 2007b) described adverse events, which in- group were found to be more severely affected than those in the
cluded temporary desaturation, temporary coughing, increased control group, despite randomisation. This trial indicated radio-
coughing, increased mucus, facial rash, hoarseness, bad taste and logical improvement after nebulised rhDNase treatment. Chest X-
dyspnoea. However, no statistical difference was observed between ray changes are a surrogate endpoint and no significant benefit was
the intervention (eight events in total) and control (three events shown in clinically relevant outcomes such as symptom improve-
in total) groups. The other studies specified that no adverse events ment. Hence the clinical significance of chest X-ray improvement
were registered (Nasr 2001; Nenna 2009). In particular, no airway is unclear.
hyperactivity or bronchospasm were observed. The trials excluded children with risk factors for severe bronchi-
olitis and those who required intensive care at admission, so that
most of the patients enrolled only had mild airway obstruction.
The authors of the original studies suggested that this might help
DISCUSSION explain the lack of benefit seen after rhDNase treatment.
Indeed, the noticeable improvement observed in participants with
atelectasis suggests that nebulised rhDNase may be more beneficial
Summary of main results
in severe bronchiolitis. However, subgroup analysis performed in
The results based on the three included studies in this review did the largest trial (Boogaard 2007b) showed that even in patients
not show benefit with nebulised recombinant human deoxyri- with more severe symptoms, rhDNase treatment did not curtail
bonuclease (rhDNase) treatment. In these trials involving children hospital stay or improve clinical outcomes.
under 24 months of age hospitalised with bronchiolitis, the treat- In addition, none of the patients received airway clearance therapy,
ment did not shorten the length of hospital stay, improve clinical which is usually given concurrently to children with cystic fibrosis
scores, decrease supplemental oxygen use or reduce intensive care to help evacuate liquefied mucus (Boogaard 2007b). Especially in
unit (ICU) admission. Our analyses showed that children in the the much younger children who were unable to cough as effec-
control group had significantly shorter hospitalisation (mean dif- tively, this may have been a useful adjunct to potentiate the effect
ference (MD) 0.50; 95% confidence interval (CI) 0.10 to 0.90, of nebulised rhDNase.
P = 0.01) and better clinical outcomes (standardised mean differ-
ence (SMD) -0.24; 95% CI -0.50 to 0.01, P = 0.06).
One study found significant improvement in radiological appear-
ances in the intervention group compared to deterioration in the Quality of the evidence
control group. In another randomised controlled trial (RCT) four We assessed all trials included to be of high quality, scoring ’low
out of 11 patients in the treatment group had atelectasis. Two of risk’ in sequence generation, allocation concealment, blinding and
these patients with atelectasis showed distinctive clinical improve- loss to follow-up.
ment after nebulised rhDNase.
No statistically significant adverse events were reported with neb-
ulised rhDNase.
Potential biases in the review process
There was no disagreement between the two review authors re-
Overall completeness and applicability of garding any of the assessment parameters. There was 100% agree-
evidence ment regarding the trials included and excluded.

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 11
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Agreements and disagreements with other combinant human deoxyribonuclease (rhDNase) in complicated
studies or reviews bronchiolitis caused by non-RSV pathogens will need to be clari-
fied.
The beneficial effect of rhDNase on two patients with atelectasis
(Nenna 2009) is consistent with the improvement seen in an earlier Nebulised rhDNase is more likely to be of benefit in patients with
case series (Merkus 2001). They reported rapid and marked clin- atelectasis. Clinical studies on patients with severe bronchiolitis,
ical and radiological improvement after administration of nebu- such as those requiring mechanical ventilation or intensive care,
lised rhDNase in patients with atelectasis secondary to severe RSV are needed to establish any effects. Future studies could also de-
bronchiolitis. Mechanical ventilation was averted in two infants termine if in combination with airway clearance therapy, rhD-
and the three on artificial ventilation made a speedy recovery. Nase might decrease duration of ICU stay, artificial ventilation
and steroid dose, and reduce complications such as secondary bac-
terial infections (from retained mucus).

AUTHORS’ CONCLUSIONS

Implications for practice ACKNOWLEDGEMENTS


The results from the three included studies do not support the
The review authors wish to thank the following people. For
use of nebulised rhDNase in previously healthy children under
commenting on the draft protocol: Anne Lyddiatt, Carla Per-
the age of 24 months hospitalised with mild to moderately severe
rotta, Ruben Boogaard, Hema Patel, Nelcy Rodriguez and Anca
bronchiolitis. While safe and easy to administer, this intervention
Zalmanovici. For providing ongoing assistance regarding pro-
did not reduce the duration of hospital stay or accelerate the rate
tocol and review submissions: Liz Dooley (Managing Editor,
of clinical improvement in such patients.
Cochrane Acute Respiratory Infections Group). For assisting with
the electronic searches: Sarah Thorning (Trials Search Co-ordi-
Implications for research nator, Cochrane Acute Respiratory Infections Group). For com-
While respiratory syncytial virus (RSV) remains the most com- menting on the draft review: Manal Kassab, Carla Perrotta, Ruben
mon cause of bronchiolitis in infants, the efficacy of nebulised re- Boogaard, Elaine Beller and Anca Zalmanovici Trestioreanu.

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Indicates the major publication for the study

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 14
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Boogaard 2007

Methods Multicentre, randomised, double-blind, controlled clinical trial

Participants Age: < 12 months


Gender: male 109, female 113
Inclusion criteria: proven RSV bronchiolitis requiring supplemental oxygen admitted to
participating hospitals (10 in total)
Exclusion criteria: gestational age < 32/40; infants with cardiopulmonary disease or
immunodeficiency; systemic steroids at time of hospital admission; ICU admission before
parental consent for study
Diagnostic criteria (case definition): RSV by direct immunofluorescence of nasopharyn-
geal aspirate (NPA) sample
Duration of disorder: at admission: days sick 0 to > = 6

Interventions 1. Type: nebulised rhDNase


2. Dose: 2.5 mg twice daily (a 2.5 mL solution of 1 mg/mL rhDNase)
3. Duration: until discharge
4. Compared with: placebo (2.5 mL of sodium chloride 0.9%)
5. Additional treatment: supportive care according to the hospital guidelines. This in-
cluded nasal washings, nasal decongestants, supplemental oxygen and tube feeding or
IV fluids when necessary; antibiotics or bronchodilators

Outcomes Length of hospital stay


Secondary end points were
- duration of supplemental oxygen (supplemental oxygen was started when oxygen
saturation was consistently < 93% and stopped when saturation was consistently > 92%)
- improvement in symptom score
- number of intensive care admissions
Adverse events
The clinical assessment scoring described by Wang 1992 was utilised

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random table sample with blocks of 4
bias) numbers made by the study statistician

Allocation concealment (selection bias) Low risk

Blinding (performance bias and detection Low risk


bias)
All outcomes

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 15
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Boogaard 2007 (Continued)

Blinding of participants and personnel Low risk Physicians, nurses, parents and the trial co-
(performance bias) ordinator remained unaware of the inter-
All outcomes vention assignment

Blinding of outcome assessment (detection Low risk


bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk The data from all randomised participants
All outcomes were analysed on an intention-to-treat ba-
sis. A separate per-protocol analysis was
conducted in which participants who vio-
lated the study protocol were excluded
2 participants withdrew from the study af-
ter the first dose of study medication (1 in
each group) and consequently had no fol-
low-up data available

Selective reporting (reporting bias) Low risk

Nasr 2001

Methods Randomised, double-blind, placebo-controlled investigation

Participants 1. Age: < = 2 years of age


2. Gender: male 47, female 28
3. Inclusion criteria: < = 2 years of age; previously healthy full-term neonates; hospitalised
for proven RSV infection
4. Diagnostic criteria (case definition): specimens for viral isolation and quantitation were
obtained from a nasopharyngeal swab and assayed for antigen detection using indirect
immunofluorescent antibody staining technique. The criteria for hospitalisation of these
participants were decided by the emergency department attending physician at both
institutions

Interventions 1. Type: rhDNase was provided as a solution (1 mg/mL) in 2.5 mL of excipient (150
mM sodium chloride, 1.5 mM calcium chloride, pH 6.0)
2. Dose: 2.5 mg daily
3. Duration: for up to 5 days
4. Compared with: the placebo was excipient alone
Additional treatment: all participants in the 2 groups received albuterol nebulised treat-
ment as part of the RSV protocol in the 2 institutions. 19 (6 in control/13 in interven-
tion) participants received a steroid dose of 2 mg/kg/d for 3 to 5 days as a burst

Outcomes Length of stay


Difference measures between hospital admission and discharge:
- respiratory rate score
- wheezing score
- retraction score

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 16
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nasr 2001 (Continued)

- CXR score
The clinical assessment scoring described by Wang 1992 was utilised
No adverse events

Notes CXR and respiratory rate variables showed trends that suggest that the rhDNase group
was more ill than the placebo group in spite of the fact that group assignment was random
Significant CXR score improvement after rhDNase versus significant worsening with
placebo

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk The randomisation was conducted by
bias) the University of Michigan Investigational
Drug Service using a random table sample
with blocks of 4. All CXRs were coded and
randomised

Allocation concealment (selection bias) Low risk

Blinding (performance bias and detection Low risk


bias)
All outcomes

Blinding of participants and personnel Low risk Both physicians and parents were blinded
(performance bias) with respect to the treated and placebo
All outcomes groups. The statistician was unaware of
treatment status coding

Blinding of outcome assessment (detection Low risk Participants were examined twice daily by
bias) a paediatric pulmonologist or study co-or-
All outcomes dinator; all were blinded to the patient’s
assignment. 2 paediatric radiologists re-
viewed the CXRs and were blinded to each
patient’s study assignment, identity and
date of examination (hospital admission
versus discharge)

Incomplete outcome data (attrition bias) Unclear risk 11 participants were excluded from the
All outcomes analysis because of missing data (75 par-
ticipants were included in the analysis). 11
more participants did not receive hospital
admission or discharge CXRs and were ex-
cluded from the analysis of CXR scoring
(64 participants)

Selective reporting (reporting bias) Low risk

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 17
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nenna 2010

Methods Randomised, double-blind, placebo-controlled study

Participants 1. Age: < 6 months


2. Gender: 12 males, 10 females
3. Inclusion criteria: previously healthy full-term neonates; 6 months of age or less at the
time of the observation; clinical severity score > = 4; enrolled in a time span of 24 hours
from admission to hospital
4. Diagnostic criteria (case definition): clinical diagnosis of bronchiolitis; viral isolation
and quantification from NPA; PCR assays for viral detection
5. Duration of disorder: 1 to 4 days before hospitalisation

Interventions 1. Type: nebulised rhDNAse


2. Dose: 2.5 mL daily
3. Duration: 3 days
4. Compared with: placebo (saline)
5. Additional treatment: oxygen, intravenous fluids, nebulised salbutamol
All participants received the drug with the same nebulising equipment

Outcomes Length of hospital stay


Days until participants were ready for discharge
Days for weight recovery
Daily clinical score reduction
- SaO2
- Presence of retractions
- Respiratory rate
- Feeding evaluation
- Auscultatory rale presence
No adverse effects

Notes 4 out of 11 patients in the treatment group had atelectasis; 2 out of the 4 patients with
atelectasis showed rapid improvement after rhDNase

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random table sample with each number
bias) corresponding to a pack of 3 doses of the
drug/placebo

Allocation concealment (selection bias) Low risk The allocation codes were not opened until
the trial was completed

Blinding (performance bias and detection Low risk


bias)
All outcomes

Blinding of participants and personnel Low risk Throughout the study, both physicians/
(performance bias) nurses and parents were blinded in respect

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 18
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nenna 2010 (Continued)

All outcomes to the study or placebo groups

Blinding of outcome assessment (detection Low risk


bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk No participants interrupted the study
All outcomes

Selective reporting (reporting bias) Low risk

CXR: chest X-ray


d: day
ICU: intensive care unit
IV: intravenous
NPA: nasopharyngeal aspirate
PCR: polymerase chain reaction
RSV: respiratory syncytial virus
rhDNase: recombinant human deoxyribonuclease
SaO2: oxygen saturation

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Merkus 2001 Case series only

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 19
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Nebulised rhDNase versus control

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Duration of hospitalisation 3 319 Mean Difference (IV, Fixed, 95% CI) 0.50 [0.10, 0.90]

Comparison 2. Nebulised rhDNase versus control

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Change in clinical score 2 244 Std. Mean Difference (IV, Fixed, 95% CI) -0.24 [-0.50, 0.01]

Comparison 3. Nebulised rhDNase versus control

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Change in respiratory rate score 2 297 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.15, 0.28]

Comparison 4. Nebulised rhDNase versus control

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Change in wheezing score 2 297 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.21, 0.16]

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 20
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 5. Nebulised rhDNase versus control

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Change in retraction score 2 297 Mean Difference (IV, Fixed, 95% CI) -0.02 [-0.19, 0.14]

Analysis 1.1. Comparison 1 Nebulised rhDNase versus control, Outcome 1 Duration of hospitalisation.

Review: Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months

Comparison: 1 Nebulised rhDNase versus control

Outcome: 1 Duration of hospitalisation

Mean Mean
Study or subgroup rhDNase Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Boogaard 2007 111 4.38 (1.85) 111 3.84 (1.86) 68.0 % 0.54 [ 0.05, 1.03 ]

Nasr 2001 40 3.33 (2) 35 3.34 (2.3) 16.8 % -0.01 [ -0.99, 0.97 ]

Nenna 2010 11 3.6 (1.5) 11 2.7 (0.9) 15.2 % 0.90 [ -0.13, 1.93 ]

Total (95% CI) 162 157 100.0 % 0.50 [ 0.10, 0.90 ]


Heterogeneity: Chi2 = 1.64, df = 2 (P = 0.44); I2 =0.0%
Test for overall effect: Z = 2.45 (P = 0.014)
Test for subgroup differences: Not applicable

-2 -1 0 1 2
Favours rhDNase Favours control

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 21
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Nebulised rhDNase versus control, Outcome 1 Change in clinical score.

Review: Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months

Comparison: 2 Nebulised rhDNase versus control

Outcome: 1 Change in clinical score

Std. Std.
Mean Mean
Study or subgroup rhDNase Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Boogaard 2007 111 1.54 (1.87) 111 1.9 (1.92) 91.8 % -0.19 [ -0.45, 0.07 ]

Nenna 2010 11 2.36 (3.23) 11 4.55 (1.29) 8.2 % -0.86 [ -1.74, 0.02 ]

Total (95% CI) 122 122 100.0 % -0.24 [ -0.50, 0.01 ]


Heterogeneity: Chi2 = 2.02, df = 1 (P = 0.16); I2 =51%
Test for overall effect: Z = 1.89 (P = 0.058)
Test for subgroup differences: Not applicable

-2 -1 0 1 2
Favours control Favours rhDNase

Analysis 3.1. Comparison 3 Nebulised rhDNase versus control, Outcome 1 Change in respiratory rate
score.
Review: Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months

Comparison: 3 Nebulised rhDNase versus control

Outcome: 1 Change in respiratory rate score

Mean Mean
Study or subgroup rhDNase Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Boogaard 2007 111 0.99 (0.87) 111 0.95 (0.99) 77.3 % 0.04 [ -0.21, 0.29 ]

Nasr 2001 40 0.47 (1.19) 35 0.32 (0.79) 22.7 % 0.15 [ -0.30, 0.60 ]

Total (95% CI) 151 146 100.0 % 0.06 [ -0.15, 0.28 ]


Heterogeneity: Chi2 = 0.18, df = 1 (P = 0.68); I2 =0.0%
Test for overall effect: Z = 0.59 (P = 0.55)
Test for subgroup differences: Not applicable

-0.5 -0.25 0 0.25 0.5


Favours control Favours rhDNase

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 22
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.1. Comparison 4 Nebulised rhDNase versus control, Outcome 1 Change in wheezing score.

Review: Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months

Comparison: 4 Nebulised rhDNase versus control

Outcome: 1 Change in wheezing score

Mean Mean
Study or subgroup rhDNase Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Boogaard 2007 111 0.86 (0.88) 111 0.82 (0.87) 63.2 % 0.04 [ -0.19, 0.27 ]

Nasr 2001 40 0.53 (0.61) 35 0.67 (0.71) 36.8 % -0.14 [ -0.44, 0.16 ]

Total (95% CI) 151 146 100.0 % -0.03 [ -0.21, 0.16 ]


Heterogeneity: Chi2 = 0.86, df = 1 (P = 0.35); I2 =0.0%
Test for overall effect: Z = 0.28 (P = 0.78)
Test for subgroup differences: Not applicable

-0.2 -0.1 0 0.1 0.2


Favours control Favours rhDNase

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 23
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 5.1. Comparison 5 Nebulised rhDNase versus control, Outcome 1 Change in retraction score.

Review: Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months

Comparison: 5 Nebulised rhDNase versus control

Outcome: 1 Change in retraction score

Mean Mean
Study or subgroup rhDNase Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Boogaard 2007 111 1 (0.81) 111 1.05 (0.88) 57.9 % -0.05 [ -0.27, 0.17 ]

Nasr 2001 40 0.74 (0.57) 35 0.73 (0.58) 42.1 % 0.01 [ -0.25, 0.27 ]

Total (95% CI) 151 146 100.0 % -0.02 [ -0.19, 0.14 ]


Heterogeneity: Chi2 = 0.12, df = 1 (P = 0.73); I2 =0.0%
Test for overall effect: Z = 0.29 (P = 0.77)
Test for subgroup differences: Not applicable

-0.2 -0.1 0 0.1 0.2


Favours control Favours rhDNase

APPENDICES

Appendix 1. Embase.com search strategy


#22. #18 AND #21 9 4 Aug 2010
#21. #19 OR #20 795,476 4 Aug 2010
#20. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR ’cross-over’:ab,ti OR ’cross over’:ab,ti OR volunteer*:
ab,ti OR allocat*:ab,ti OR assign*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti AND [embase]/lim 757,735 4
Aug 2010
#19. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp
AND [embase]/lim 221,080 4 Aug 2010
#18. #13 AND #17 137 4 Aug 2010
#17. #14 OR #15 OR #16 8,858 4 Aug 2010
#16. deoxyribonucleas*:ab,ti OR ’dna nuclease’:ab,ti OR dnase:ab,ti AND rhdnase:ab,ti AND [embase]/lim 143 4 Aug 2010
#15. ’deoxyribonuclease i’/de AND [embase]/lim 3,853 4 Aug 2010
#14. ’deoxyribonuclease’/de AND [embase]/lim 5,016 4 Aug 2010
#13. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 116,105 4 Aug 2010
#12. paramyxovir*:ab,ti AND [embase]/lim 1,930 4 Aug 2010
#11. ’paramyxovirus infection’/exp AND [embase]/lim 1,615 4 Aug 2010
#10. influenza*:ab,ti OR flu:ab,ti OR parainfluenza*:ab,ti OR ’para-influenza’:ab,ti AND [embase]/lim 55,378 4 Aug 2010
#9. ’parainfluenza virus infection’/exp OR ’parainfluenza virus’/exp AND [embase]/lim 4,112 4 Aug 2010
#8. ’influenza’/de OR ’influenza virus’/de OR ’influenza virus a’/exp OR ’influenza virus b’/exp AND [embase]/lim 38,100 4 Aug 2010
#7. adenovir*:ab,ti AND [embase]/lim 31,327 4 Aug 2010
#6. ’adenovirus’/de OR ’mastadenovirus’/de AND [embase]/lim 17,385 4 Aug 2010
Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 24
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
#5. ’human adenovirus infection’/exp OR ’adenovirus infection’/de AND [embase]/lim 374 4 Aug 2010
#4. ’respiratory syncytial virus’:ab,ti OR ’respiratory syncytial viruses’:ab,ti OR rsv:ab,ti AND [embase]/lim 8,755 4 Aug 2010
#3. ’respiratory syncytial pneumovirus’/de OR ’respiratory syncytial virus infection’/exp AND [embase]/lim 8,450 4 Aug 2010
#2. bronchiolit*:ab,ti AND [embase]/lim 6,201 4 Aug 2010
#1. ’bronchiolitis’/exp AND [embase]/lim 8,370 4 Aug 2010

Appendix 2. LILACS (BIREME) search strategy


Mh Bronchiolitis OR Tw bronchiolit$ OR Tw bronquiolit$ OR Mh respiratory syncytial viruses OR Mh respiratory syncytial virus,
human OR Mh respiratory syncytial virus infections OR Tw respiratory syncytial virus$ OR Tw rsv OR Tw virus sincitiales respiratorios
OR Tw virus sinciciais respiratorios OR Mh adenoviridae OR Mh mastadenovirus OR Mh adenoviridae infections OR Mh adenovirus
infections, human OR Tw adenovir$ OR Mh influenza, human OR Tw influenza$ OR Tw flu OR Tw gripe humana OR Mh paramyx-
oviridae infections OR Tw parainfluenza OR Tw paramyxovirid$ [Words] and Mh deoxyribonuclease OR Mh deoxyribonuclease 1
OR Tw deoxyribonucleas$ OR Tw dna nucleas$ OR Tw dnase OR Tw rhdnase [Words]

HISTORY
Protocol first published: Issue 3, 2010
Review first published: Issue 11, 2012

Date Event Description

9 September 2010 Amended Contact details updated.

CONTRIBUTIONS OF AUTHORS
Annabelle Enriquez (AE) was responsible for writing the protocol background and review.
I-Wen Chu (IWC) was responsible for writing the protocol methods.
AE and IWC were responsible for study selection, quality assessment, data collection and data analysis.
Craig Mellis (CM), Wan-Yu Lin (WYL) and AE are responsible for providing general advice on the protocol.
CM was responsible for resolving any disagreements between AE and IWC and for providing general guidance on the review.
AE and WYL were responsible for the meta-analysis and statistical analysis of the raw data.
All review authors approved the final version of the review.

Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 25
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

External sources
• Rong Sing Medical Foundation, Taiwan.
Research Grant for Dr. I-Wen Chu

DIFFERENCES BETWEEN PROTOCOL AND REVIEW


We did not perform subgroup analyses according to patients’ age (children under 12 months of age versus children under 24 months
of age) and viral aetiology (RSV-positive versus RSV-negative). We did not assess any binary or dichotomous outcomes (for which we
would have calculated a risk ratio (RR)).

INDEX TERMS

Medical Subject Headings (MeSH)


Administration, Inhalation; Bronchiolitis, Viral [∗ drug therapy]; Deoxyribonucleases [∗ administration & dosage]; Nebulizers and
Vaporizers; Pulmonary Atelectasis [drug therapy]; Randomized Controlled Trials as Topic

MeSH check words


Humans; Infant

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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.