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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]
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.
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.
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.
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
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.
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
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
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
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
REFERENCES
References to studies included in this review Nenna 2010 {published and unpublished data}
Corazzesi E, Nenna R, Tromba V, Tuccinardi R, Piacenti S,
Boogaard 2007 {published and unpublished data} Scalercio F, et al.Recombinant human deoxyribonuclease
Boogaard R, Hulsmann AR, Hop WCJ, Merkus PJF. treatment in hospital management of infants with moderate
Efficacy of recombinant human deoxyribonuclease (Rh- to severe bronchiolitis. European Respiratory Journal 2006;
DNase) in infants hospitalised with respiratory syncytial 28(Suppl 50):758s [4367].
virus bronchiolitis a multicentre randomised double blind ∗
Nenna R, Tromba V, Berardi R, De Angelis D, Papoff P,
clinical trial [Abstract]. European Respiratory Journal 2006; Sabbatino G, et al.Recombinant human deoxyribonuclease
28(Suppl 50):758s [4365]. treatment in hospital management of infants with moderate-
∗
Boogaard R, Hulsmann AR, Van Veen L, Vaessen- severe bronchiolitis. European Journal of Inflammation
Verberne AAPH, Yap YN, Sprij AJ, et al.Recombinant 2009;7(3):169–74.
human deoxyribonuclease in infants with respiratory
syncytial virus bronchiolitis. Chest 2007;131(3):788–95.
References to studies excluded from this review
Nasr 2001 {published data only (unpublished sought but not used)}
Nasr S, Strouse P, Soskolne E, Maxvold N, Garver K, Rubin
B, et al.Efficacy of recombinant human DNase I in the Merkus 2001 {published data only}
management of RSV bronchiolitis [abstract]. American Merkus PJFM, de Hoog M, van Gent R, de Jongste
Journal of Respiratory and Critical Care Medicine 2000;161 JC. DNase treatment for atelectasis in infants with
(3 Suppl):A339. severe respiratory syncytial virus bronchiolitis. European
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Nasr SZ, Strouse PJ, Soskolne E, Maxvold N, Garver Respiratory Journal 2001;18(4):734–7.
KA, Rubin BK, et al.Efficacy of recombinant human
deoxyribonuclease I in the hospital management of
respiratory syncytial virus bronchiolitis. Chest 2001;120: Additional references
203–8.
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Armstrong 1950 Hartling 2011
Armstrong JB, White JC. Liquefaction of viscous purulent Hartling L, Bialy LM, Vandermeer B, Tjosvold L, Johnson
exudate by deoxyribonuclease. Lancet 1950;256(6641): DW, Plint AC, et al.Epinephrine for bronchiolitis. Cochrane
739–42. Database of Systematic Reviews 2011, Issue 6. [DOI:
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Boogaard R, de Jongste JC, Merkus PJ. Pharmacotherapy of Hendriks 2005
impaired mucociliary clearance in non-CF pediatric lung Hendriks T, de Hoog M, Lequin MH, Devos AS, Merkus
disease. A review of the literature. Pediatric Pulmonology PJ. DNase and atelectasis in non-cystic fibrosis pediatric
2007;42(11):989–1001. [PUBMED: 17902149] patients. Critical Care 2005;9(4):341–2.
Boogaard 2007b Higgins 2011
Boogaard R, Hulsmann AR, Van Veen L, Vaessen-Verberne Higgins JPT, Green S (editors). Cochrane Handbook
AAPH, Yap YN, Sprij AJ, et al.Recombinant human for Systematic Reviews of Interventions Version 5.1.0
deoxyribonuclease in infants with respiratory syncytial virus [updated March 2011]. The Cochrane Collaboration,
bronchiolitis. Chest 2007;131(3):788–95. 2011. Available from www.cochrane-handbook.org.
Calogero 2007 Kupeli 2003
Calogero C, Sly PD. Acute viral bronchiolitis: to treat or Kupeli S, Teksam O, Dogru D, Yurdakok M. Use of
not to treat - that is the question. Journal of Pediatrics 2007; recombinant human DNase in a premature infant with
151(3):235–7. recurrent atelectasis. Pediatrics International 2003;45:
Corneli 2007 584–6.
Corneli HM, Zorc JJ, Mahajan P, Shaw KN, Holubkov R, Leader 2003
Reeves SD, et al.Bronchiolitis Study Group of the Pediatric Leader S, Kohlhase K. Recent trends in severe respiratory
Emergency Care Applied Research Network (PECARN). A syncytial virus (RSV) among US infants, 1997 to 2000.
multicenter, randomized, controlled trial of dexamethasone Journal of Pediatrics 2003;143(Suppl 5):127–32.
for bronchiolitis. New England Journal of Medicine 2007; Manoha 2007
357(4):331–9. [PUBMED: 17652648] Manoha C, Espinosa S, Aho SL, Huet F, Pothier P.
Deshpande 2003 Epidemiological and clinical features of hMPV, RSV and
Deshpande SA, Northern V. The clinical and health RVs infections in young children. Journal of Clinical
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among children under 2 years of age in a defined Nenna 2009
geographical area. Archives of Disease in Childhood 2003;88 Nenna R, Tromba V, Berardi R, De Angelis D, Papoff P,
(12):1065–9. [PUBMED: 14670770] Sabbatino G, et al.Recombinant human deoxyribonuclease
Erdeve 2007 treatment in hospital management of infants with moderate-
Erdeve O, Uras N, Atasay B, Arsan S. Efficacy and safety of severe bronchiolitis. European Journal of Inflammation
nebulized recombinant human DNase as rescue treatment 2009;7(3):169–74.
for persistent atelectasis in newborns: case-series. Croatian Patel 2000
Medical Journal 2007;48:234–9. Patel A, Harrison E, Durward A, Murdoch IA. Intratracheal
Fernandes 2010 recombinant human deoxyribonuclease in acute life-
Fernandes RM, Bialy LM, Vandermeer B, Tjosvold L, threatening asthma refractory to conventional treatment.
Plint AC, Patel H, et al.Glucocorticoids for acute viral British Journal of Anaesthesia 2000;84:505–7.
bronchiolitis in infants and young children. Cochrane Perrotta 2007
Database of Systematic Reviews 2010, Issue 10. [DOI: Perrotta C, Ortiz Z, Roque M. Chest physiotherapy for
10.1002/14651858.CD004878.pub2] acute bronchiolitis in paediatric patients between 0 and 24
Gadomski 2010 months old. Cochrane Database of Systematic Reviews 2007,
Gadomski AM, Brower M. Bronchodilators for Issue 1. [DOI: 10.1002/14651858.CD004873.pub3]
bronchiolitis. Cochrane Database of Systematic Reviews 2010, Puterman 1997
Issue 12. [DOI: 10.1002/14651858.CD001266.pub2] Puterman AS, Weinberg EG. rhDNase in acute asthma.
Greally 1995 Pediatric Pulmonology 1997;23:316–7.
Greally P. Human recombinant DNase for mucus plugging RevMan 2011
in status asthmaticus. Lancet 1995;346:1423–4. The Nordic Cochrane Centre, The Cochrane Collaboration.
Hall 2009 Review Manager (RevMan). 5.1. Copenhagen: The Nordic
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards Cochrane Centre, The Cochrane Collaboration, 2011.
KM, Staat MA, et al.The burden of respiratory syncytial Shak 1990
virus infection in young children. New England Journal of Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL.
Medicine 2009;360(6):588–98. [PUBMED: 19196675] Recombinant human DNase reduces the viscosity of cystic
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fibrosis sputum. Proceedings of the National Academy Wang 1992
of Sciences of the United States of America 1990;87(23): Wang EE, Milner RA, Navas L, Maj H. Observer agreement
9188–92. [PUBMED: 2251263] for respiratory signs and oximetry in infants hospitalized
Suri 2002 with lower respiratory infections. American Review of
Suri R, Grieve R, Normand C, Metcalfe C, Thompson S, Respiratory Disease 1992;145:106–9.
Wallis C, et al.Effects of hypertonic saline, alternate day and Wohl 2003
daily rhDNase on healthcare use, costs and outcomes in Wohl ME, Chernick V. Treatment of acute bronchiolitis.
children with cystic fibrosis. Thorax 2002;57(10):841–6. New England Journal of Medicine 2003;349:82–3.
[PUBMED: 12324668] Zhang 2011
ten Berge 1999 Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP.
ten Berge M, Brinkhorst G, Kroon AA, de Jongste JC. Nebulized hypertonic saline solution for acute bronchiolitis
DNase treatment in primary ciliary dyskinesia - assessment in infants. Cochrane Database of Systematic Reviews 2011,
by nocturnal pulse oximetry. Pediatric Pulmonology 1999; Issue 3. [DOI: 10.1002/14651858.CD006458.pub2]
27:59–61. ∗
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
Boogaard 2007
Notes
Risk of bias
Random sequence generation (selection Low risk Random table sample with blocks of 4
bias) numbers made by the study statistician
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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
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
Nasr 2001
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
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
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
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)
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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nenna 2010
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
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 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)
Incomplete outcome data (attrition bias) Low risk No participants interrupted the study
All outcomes
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
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]
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]
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]
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]
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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
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 ]
-2 -1 0 1 2
Favours rhDNase Favours control
Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 21
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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
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 ]
-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
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 ]
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
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 ]
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
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 ]
APPENDICES
HISTORY
Protocol first published: Issue 3, 2010
Review first published: Issue 11, 2012
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
INDEX TERMS
Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review) 26
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.