Nebulised deoxyribonuclease

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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.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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[Intervention Review]

Nebulised deoxyribonuclease for viral bronchiolitis in childrenyounger than 24 months

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

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

Office,Chang Gung Memorial Hospital, Taoyuan, Taiwan. 3Faculty of Medicine, Room 406, Blackburn Building, D06, The University

of Sydney, Sydney, Australia. 4Department 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. [email protected]. [email protected] .

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 Reviews2012, Issue 11. Art. No.: CD008395. DOI: 10.1002/14651858.CD008395.pub2.


A B S T R A C T

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 Groups 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).

1Nebulised deoxyribonuclease for viral bronchiolitis in children younger than 24 months (Review)

mailto:[email protected]:[email protected]:[email protected]:[email protected]


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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 oneRCT, four outof 11 patients in thetreatment group hadatelectasis.Two of these patients showeddistinctive 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.

P L A I N L A N G U A G E S U M M A R Y

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.

B A C K G R O U N D

Description of the condition

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-

spite this, it is a major cause of morbidity and mortality in this age




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group and is the leading cause of infant hospitalisation in the USA

(Leader 2003). In Europe and theUSA,up to 3% of infants under

12 months of age are hospitalised with bronchiolitis (Deshpande

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-flammation of the respiratory and terminal bronchioles (Calogero

2007; Wohl 2003). Viral infection results in death of respiratory

epithelial cells. The epithelium sloughs off and together with in-

flammatory cells, produces cellular debris to form a thick mucous

plug. Combined with oedema and cellular infiltration around the

airway, the viscous mucus is responsible for obstructing the airway

and disrupting normal airflow. Bronchiolitis is diagnosed clini-

cally by fever, cough, increased respiratory rate, accessory muscle

use, expiratory wheezing, inspiratory crackles and increased mu-

cus production.

Although much is known about the mechanism and manifesta-

tion of bronchiolitis, treatment remains controversial. Currently

the management of this condition is mainly supportive, includ-ing supplemental oxygen, nasal washing, adequate fluid intake, a

suitable thermal environment to minimise oxygen consumption

and mechanical ventilation when necessary. Interventions aimed

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;

Fernandes 2010; Perrotta 2007). At present there are promising

reports that epinephrine (Hartling 2011) and nebulised hyper-

tonic saline (Zhang 2011) maybe beneficial in reducing thelength

of hospital stay but further research is required to confirm these

findings.

Description of the intervention

In bronchiolitis, degenerating leukocytes and epithelial cells re-

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

enzyme that digests extracellular DNA. Initially developed for pa-

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-

halation. Despite being expensive, rhDNase is now an established

treatment in cystic fibrosis (Suri 2002).

In addition, nebulised rhDNase has been used in the treatment of

other lung diseases with significant mucous plugging or impaired

mucociliary clearance (Boogaard 2007a). Studies performed in

children with asthma (Greally 1995; Patel 2000; Puterman 1997),

severe atelectasis (Erdeve 2007; Hendriks 2005; Kupeli 2003),

primary ciliary dyskinesia (ten Berge 1999) and RSV bronchiolitis

(Merkus 2001) have reported varying degrees of improvement

in lung function, sputum volume, oxygen need and chest X-ray

(CXR) appearance.

How the intervention might workOne of the predominant pathological features in bronchiolitis is

mucous plugging. The sputum of infants with bronchiolitis has

increased DNA content (Wohl 2003). RhDNase, by digesting

DNA, might aid the clearance of mucus and relieve peripheral

airway obstruction. Recent studies on rhDNase have shown im-

provement of radiologic abnormalities seen in RSV bronchiolitis

(Merkus 2001; Nasr 2001).

Why it is important to do this review

The mucolytic property of rhDNase has been well documented

in cystic fibrosis, and case reports have shown promising resultsin other respiratory diseases such as bronchiolitis. Nevertheless, it

has not yet been established whether rhDNase improves clinical

outcomes in viral bronchiolitis.

O B J E C T I V E S

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.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

We included children younger than 24 months of age with doc-

umented bronchiolitis in the hospital setting. Acute bronchiolitis

was defined as the first episode of acute wheezing associated with

rhinorrhoea, sneezing, cough, fever or tachypnoea. Confirmation

of viral aetiology was not necessary for study inclusion.

We excluded participants who were born before 32 weeks of ges-

tation, had low birth weight (< 2.5 kg), chronic lung disease or

heart disease.




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Types of interventions

1. Nebulised rhDNase alone versus control.

2. Nebulised rhDNase plus any form of concomitant therapy

(intervention) versus the same form of concomitant therapy

alone (control).

Types of outcome measures

Primary outcomes

1. Duration of hospitalisation (days)

Secondary outcomes

1. Clinical score

2. Respiratory rate

3. Wheezing

4. Accessory muscle use5. Oxygen saturation and duration of supplemental oxygen

6. Number of intensive care admissions

7. Radiological score and findings

8. Adverse events

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Tri-

als (CENTRAL) 2012, Issue 7, part of The Cochrane Library,

www.thecochranelibrary.com (accessed 3 August 2012), which

contains the AcuteRespiratory Infections Groups Specialised Reg-

ister, MEDLINE (1966 to July Week 4, 2012), EMBASE (1974

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

Appendix 1) and LILACS (see Appendix 2). There were no lan-

guage or publication restrictions.

MEDLINE (Ovid)

1. Exp Bronchiolitis

2. bronchiolit*.tw.

3. respiratory syncytial viruses/ or respiratory syncytial virus, hu-

man/

4. Respiratory Syncytial Virus Infections/

5. (respiratory syncytial virus* or rsv).tw.

6. adenoviridae/ or exp mastadenovirus/

7. adenoviridae infections/ or adenovirus infections, human/

8. adenovir*.tw.

9. Influenza, Human/

10. (influenza or flu).tw.

11. exp Paramyxoviridae Infections/

12. parainfluenza*.tw.

13. or/1-12

14. exp Deoxyribonucleases/

15. exp Deoxyribonuclease I/16. deoxyribonucleas*.tw.

17. dna nucleas*.tw.

18. dnase.tw.

19. rhdnase.tw.

20. or/14-19

21. 20 and 13

Searching other resources

We contacted experts in this field, checked conference abstracts

and consulted www.clinicalstudyresults.orgfor unpublished stud-

ies. We checked reference lists of all relevant articles to identify

other relevant studies. We contacted the authors of any identifiedabstracts to ascertain the nature of the study design and outcome

measures. We only included abstracts with sufficient information

on the study design and outcome measures.

Data collection and analysis

Selection of studies

Two review authors (IWC, AE) independently identified the stud-

ies and assessed whether they met the inclusion criteria. The third

review author (CM) was designated to resolve any discrepancies.

We identified studies for the review based on their abstracts. We

retrieved the full-text articles if there was insufficient information

in the abstract.

Data extraction and management

Two review authors (IWC, AE) independently performed data

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,

publication status, setting.

2. Method: method of allocation, concealment of

randomisation and specification of who was blinded (clinicians

caring for the patients, assessors, data managers or the care giver).

3. Participants: age, demographic factors, inclusion and

exclusion criteria, withdrawal or loss to follow-up.

4. Disease: diagnostic criteria of bronchiolitis, duration of

illness, RSV status.

5. Intervention: type, dose, duration, route and co-

interventions.

6. Control: type, dose, duration, route and co-interventions.


http://www.clinicalstudyresults.org/http://www.clinicalstudyresults.org/


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7. Outcome: we extracted the mean, standard deviation and

the number of participants studied in each group for continuous

outcomes. We extracted the total number of participants per

group and the number of participants experiencing the event for

dichotomous outcomes.

We entered the extracted data into RevMan 2011, The CochraneCollaborations software program.

Assessment of risk of bias in included studies

Two review authors (IWC, AE) independently assessed the

methodological quality of all included studies using the Cochrane

Collaborations tool for assessing risk of bias (Higgins 2011). Two

review authors (IWC, AE) independently assessed the following

six domains in each study.

1. Sequence generation (selection bias)

Low risk: sequence generated by random number table, computerrandom number generator, coin tossing, shuffling cards or en-

velopes, throwing dice, drawing of lots or minimisation.

Unclear risk: insufficient information about the sequence gener-

ation process to permit judgement but did mention randomisa-

tion.

High risk: sequence generated by odd or even dates of birth, date

of admission or hospital or clinic record number, judgement of

the clinician, availability of the intervention, results of laboratory

tests or preference of the participant.

2. Allocation concealment (selection bias)

Low risk: participant and investigators could not foresee assign-ment because of central allocation, drug container of identical ap-

pearance or sealed, opaque envelopes.

Unclear risk: insufficient information about the allocation con-

cealment to permit judgement but did mention randomisation.

High risk: participant and investigators could foresee assignment

because of open random allocation schedule, alteration or rota-

tionof allocation, unsealed or non-opaqueenvelopes, or allocation

based on date of birth, case record number or any other explicitly

unconcealed procedure.

3. Blinding of outcome assessment (detection bias)

Low risk: blinding of key study personnel and participants or no

blinding or incomplete blinding, but thereview authors judge that

the outcome is not likely to be influenced by lack of blinding.

Unclear risk: insufficient information to permit judgement of low

risk or high risk or the study did not address this outcome.

High risk: no blinding or incomplete blinding, and the outcome

is likely to be influenced by lack of blinding or blinding of key

study participants and personnel attempted, but likely that the

blinding could have been broken, and the outcome is likely to be

influenced by lack of blinding.

4. Incomplete outcome data addressed (attrition bias)

Low risk: no missing outcome data, reasons for missing outcomedata unlikely to be related to true outcome, missing outcome data

balanced in numbers across intervention groups, with similar rea-

sons for missing data across groups, for dichotomous outcome

data, the proportion of missing outcomes compared with observed

event risk not enough to have a clinically relevant impact on the

intervention effect estimate, for continuous outcome data, plau-

sible effect size (difference in means or standardised difference in

means) among missing outcomes not enough to have a clinically

relevant impact on observed effect size or missing data have been

imputed using appropriate methods.

Unclear risk: insufficient or no reportingof missing outcome data.

High risk: reason for missing outcome data likely to be related to

true outcome, with either imbalance in numbers or reasons formissing data across intervention groups. For dichotomous out-

come data, the proportion of missing outcomes compared with

observed event risk enough to induce clinically relevant bias in

intervention effect estimate; for continuous outcome data, plau-

sible effect size (difference in means or standardised difference in

means) among missing outcomes enough to induce clinically rel-

evant bias in observed effect size, as-treated analysis done with

substantial departure of the intervention received from that as-

signed at randomisation or potentially inappropriate application

of simple imputation.

5. Selective outcome reporting (reporting bias)

Low risk: the study protocol may or may not be available but all

of the studys expected primary or secondary outcomes have been

reported in the pre-specified way.

Unclear risk: insufficient information to permit judgement about

outcome reporting.

High risk: not all of the studys pre-specified primary outcomes

have been reported, one or more of the reported outcomes were

not pre-specified, one or more outcomes of interest in the review

are reported incompletely so that theycannot be entered in a meta-

analysis orthe study reportfailsto include results fora keyoutcome

that would be expected to have been reported for such a study.

6. Other bias

Low risk: the study appears to be free of other sources of bias.

Unclear risk: there may be a risk of bias but there is insufficient

information to assess whether an important risk of bias exists.

High risk: there is at least one important risk of bias, has been

claimed to have been fraudulent or had some other problem.




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We defined high-quality trials as those with low risk in sequence

generation, allocation concealment, blinding and loss to follow-

up.

Measures of treatment effect

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-

ence (MD) with 95% confidence intervals (CI). We combined

clinical scores assessed with different scales using the standardised

mean difference (SMD) with 95% CI.

Dealing with missing data

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 informationregarding the interventions

used from two of the trials (Boogaard 2007b; Nenna 2009). Toenable 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).

We then calculated the mean and SD for these variables prior to

performing the meta-analyses.

Assessment of heterogeneity

We measured heterogeneity by using the I2 statistic, with a value

greater than 50% considered to be substantial (Higgins 2011).

Assessment of reporting biases

We would have used a funnel plot to detect any publication bias.

This was not necessary due to the small number of included trials.

Data synthesis

We calculated a weighted treatment effect across trials using

RevMan 2011 based on a fixed-effect model. For continuous out-

comes, we calculated the MD or the SMD, expressing the pooled

treatment effects with 95% CIs.

Subgroup analysis and investigation of heterogeneityWe did not perform subgroup analysis.

Sensitivity analysis

We performed sensitivity analysis for methodological quality. No

additional sensitivity analysis was conducted as no other issues

were identified during the review process.

R E S U L T S

Description of studies

See: Characteristicsof included studies; Characteristicsof excluded

studies.

Results of the search

The electronic searches retrieved 1686 citations.

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

review (see Characteristics of included studies table). No other

studies were identified from other resources.

Included studies

Population

All three studies were randomised, double-blind, placebo-con-

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

2001: two hospitals). The other trial enrolled inpatients from one

hospital in Rome (Nenna 2009). The multicentre trials only in-

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

32 weeks (Boogaard 2007b), while the remaining two studies en-rolled subjects born after 37 weeks of gestation. The upper age

limits used were six months (Nenna 2009), 12 months (Boogaard

2007b) and 24 months (Nasr 2001).

Intervention

All studies used 2.5 mL (1 mg/mL) of rhDNAse delivered by jet

nebulisation. For the control participants, two of the studies gave

nebulised saline (Boogaard 2007b; Nenna 2009). The other study

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.

One trial (Nasr 2001) gave all participants nebulised salbutamol

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-

venous fluids or tube feeding, nasal washing, nasal decongestants,

antibiotics and bronchodilators. Two trials used a daily dose for

up to five days (Nasr 2001; Nenna 2009) and the other gave the

dose twice daily until discharge (Boogaard 2007b).




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Outcome measures

All the studies compared length of hospital stay (LOS). To report

their results, the largest trial (Boogaard 2007b) used geometric

means while the other two trials calculated arithmetic means. In

order to combine the LOS results from all three studies, we ob-

tained the raw data from the authors of the largest trial and calcu-lated the arithmetic means.

The same clinical scoring system was used in two trials (Boogaard

2007b; Nasr 2001) on admission and at discharge. Initially de-

scribed by Wang (Wang 1992), the score rated respiratory rate,

wheezing, retraction and general condition from zero to three (the

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

compared duration of supplemental oxygen use and intensive care

unit (ICU) admission (Boogaard 2007b).

For one of the trials (Boogaard 2007b), we used the unpublished

raw data provided by the trial authors to calculate the change in

clinical score between the day of admission (day one) and daythree; and also to determine individual scores (respiratory rate,

wheezing and retraction) on an intention-to-treat (ITT) basis. If

a score was missing, we assumed complete patient recovery and

thus assigned a score of zero for each parameter. For the respiratory

rate score, there were 28 participants in the control group and

28 participants in the treatment group with missing data; for the

wheezing score, there were 38 participants in the control group

and 52 participants in the treatment group with missing data; and

for the retraction score, there were 39 participants in the controlgroup and 51 participants in the treatment group with missing

data.

One trial (Nenna 2009) used a different scoring system. The total

clinical score was based on oxygen saturation, retractions, respira-

tory rate, feeding and chest X-ray findings.

Only one study reported adverse events (Boogaard 2007b).

Excluded studies

We excluded one case series (Merkus 2001) describing the effect of

nebulised rhDNase on five infants with severe RSV bronchiolitis

and atelectasis.

Risk of bias in included studies

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

All the studies clearly described randomisation and allocation con-

cealment methods.

Blinding

Each trial appropriately outlined blinding.




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Incomplete outcome data

Descriptions of withdrawals were adequate in all the trials. In the

largest study (Boogaard 2007b), two (one from each study arm)

out of 224 participants were not included in the ITT analysis as

consent was withdrawn after the first dose. 30 participantswere ex-

cluded from the per-protocol analysis for varying reasons as spec-ified in the study.

Another trial had 11 out of 86 enrolled participants excluded from

the study because of missing data (Nasr 2001) and the smallest

trial (Nenna 2009) had no patient loss to follow-up with all 22

participants included.

Selective reporting

No reporting bias was identified. There were no statistically sig-

nificant positive results reported by any of the published trials.

Other potential sources of bias

Analysis from one of the studies was based on ITT (Boogaard

2007b) forall randomised participants anda separate per-protocol

analysis was performed which excluded participants violating the

study protocol. Results from both analyses were similar.

Effects of interventionsA total of 333 inpatients were enrolled by the three randomised

controlled trials (RCTs) and data from 319 participants were anal-

ysed. The treatment was easy to administer.

Duration of hospital stay

Each individual trial reported that rhDNase treatment had no sta-

tistically significant effect on the duration of hospital stay. Meta-

analysis showed that the duration of hospital stay was significantly

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

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 daythree.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%).




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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

2009) evaluated clinical score differences between the study and

placebo groups every dayuntil dayfour only, while the largerstudy

recorded clinical scores until discharge. Nenna 2009 reported that

two participants in the intervention group showed a worsening of

clinical scores, perhaps due to their young age (both one-month

old males). This may explain the apparent favouring of the control

group in this RCT, which may in turn account for the significantheterogeneity between the studies (in addition to the use of dif-

ferent clinical scoring systems).

Respiratory rate

The individual scores (respiratory rate score, wheezing score and

chest retraction score) were combined from two studies (Boogaard

2007b; Nasr 2001), both of which used the same scoring system

(Wang 1992). The differences between the individual scores in

the larger study (Boogaard 2007b) were derived from the raw data

on day of admission and day three. The differences between the

individual scores in the other study (Nasr 2001) were based on

the scores on the day of admission and the day of discharge (the

average length of stay being 3.34 days in the control group and

3.33 days in the intervention group).

Meta-analysisof the differences in respiratory rate score (MD 0.06;

95% CI -0.15 to 0.28, P = 0.55, I2 statistic = 0%), favoured the

rhDNase group butnot in a statistically significant manner(Figure

4).

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

WheezingMeta-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).




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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 severechest 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, I 2

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

Oxygen saturation and duration of supplemental

oxygen

One of the studies (Nenna 2009) incorporated oxygen saturation

in calculating the clinical severity score. A score of zero was given

for levels higher than 95%; one for saturations of 90% to 94%;

and two for levels below 89%. The actual data was not reported

individually.

In the largest trial (Boogaard 2007b), supplemental oxygen was

administered once oxygen saturation fell consistently below 93%,and was discontinued once it was consistently over 92%. There

was no significant difference (expressed as a ratio of the geometric

means of rhDNase and placebo groups with 95% CI) in the du-

ration of supplemental oxygen use (1.29; 95% CI 0.99 to 1.67, P

= 0.053).

Number of intensive care admissions

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

quired transfer to the intensive care unit (ICU), five of whom re-

ceived mechanical ventilation, with no significant differences ob-

served between the control and intervention groups in terms of

the proportion of individuals requiring intensive care (P = 1.0) or

mechanical ventilation (P = 0.43).

Radiological score and findings

The trial byNasr 2001 measured radiological changes before andafter treatment. Analysing the treatment and control arms sepa-

rately, they reported a significant improvement (chest X-raydiffer-

ence score was0.46,P = 0.02) in theinterventiongroup, compared

with a significant deterioration (chest X-ray difference score was -

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

score as the covariate. This revealed that there was a significant




13/28

difference between the groups (P = 0.01) in spite of the fact that

group assignment was random: chest X-ray and respiratory rate

variables showed trends suggesting that the rhDNase group (40

participants) was more severely affected than the placebo group

(35 participants) at the beginning of the trial.

In another trial (Nenna 2009), chest X-ray showed atelectasis infour out of 11 children in the rhDNase group. The authors re-

ported a distinct reduction in clinical score for two of these pa-

tients (-80% and -67%) during the first two days of the trial. Both

of these patients symptoms were due to respiratory syncytial virus

(RSV).

Adverse events

One study (Boogaard 2007b) described adverse events, which in-

cluded temporary desaturation, temporary coughing, increased

coughing, increased mucus, facial rash, hoarseness, bad taste and

dyspnoea. However, no statistical difference was observed between

the intervention (eight events in total) and control (three eventsin total) groups. The other studies specified that no adverse events

were registered (Nasr 2001; Nenna 2009). In particular, no airway

hyperactivity or bronchospasm were observed.

D I S C U S S I O N

Summary of main results

The results based on the three included studies in this review did

not show benefit with nebulised recombinant human deoxyri-

bonuclease (rhDNase) treatment. In these trials involving childrenunder 24 months of age hospitalised with bronchiolitis, the treat-

ment did not shorten the length of hospital stay, improve clinical

scores, decrease supplemental oxygen use or reduce intensive care

unit (ICU) admission. Our analyses showed that children in the

control group had significantly shorter hospitalisation (mean dif-

ference (MD) 0.50; 95% confidence interval (CI) 0.10 to 0.90,

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

control group. In another randomised controlled trial (RCT) four

out of 11 patients in the treatment group had atelectasis. Two of

these patients with atelectasis showed distinctive clinical improve-ment after nebulised rhDNase.

No statistically significant adverse events were reported with neb-

ulised rhDNase.

Overall completeness and applicability ofevidence

There was no significant heterogeneity among the trials, all of

which delivered the same amount of rhDNase by jet nebulisation

using the corresponding excipient as control. One trial used twice

daily dosing(Boogaard 2007b) ratherthanonce daily. Anotherone

co-administered salbutamol as part of their protocol and notably

did not report any adverse events (Nasr 2001).The two multicentre trials enrolled only patients with respiratory

syncytial virus(RSV)-proven bronchiolitis (Boogaard 2007b; Nasr

2001), thus the results may not necessarily be applicable to non-

RSV bronchiolitis.

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.

In one study (Nasr 2001), the participants in the intervention

group were found to be more severely affected than those in the

control group, despite randomisation. This trial indicated radio-

logical improvement after nebulised rhDNase treatment. Chest X-

ray changes area surrogate endpointand no significant benefit was

shown in clinically relevant outcomes such as symptom improve-ment. Hence the clinical significance of chest X-ray improvement

is unclear.

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

explain the lack of benefit seen after rhDNase treatment.

Indeed, the noticeable improvement observed in participants with

atelectasissuggests that nebulised rhDNase may be morebeneficial

in severe bronchiolitis. However, subgroup analysis performed in

the largest trial (Boogaard 2007b) showed that even in patients

with more severe symptoms, rhDNase treatment did not curtail

hospital stay or improve clinical outcomes.In addition, none of the patients received airway clearance therapy,

which is usually given concurrently to children with cystic fibrosis

to help evacuate liquefied mucus (Boogaard 2007b). Especially in

the much younger children who were unable to cough as effec-

tively, this may have been a useful adjunct to potentiate the effect

of nebulised rhDNase.

Quality of the evidence

We assessed all trials included to be of high quality, scoring low

risk in sequence generation, allocation concealment, blinding and

loss to follow-up.

Potential biases in the review process

There was no disagreement between the two review authors re-

garding any of the assessment parameters. There was 100% agree-

ment regarding the trials included and excluded.




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Agreements and disagreements with otherstudies or reviews

The beneficial effect of rhDNase on two patients with atelectasis

(Nenna 2009)isconsistentwiththeimprovementseeninanearlier

case series (Merkus 2001). They reported rapid and marked clin-

ical and radiological improvement after administration of nebu-lised rhDNase in patients with atelectasis secondary to severe RSV

bronchiolitis. Mechanical ventilation was averted in two infants

and the three on artificial ventilation made a speedy recovery.

A U T H O R S C O N C L U S I O N S

Implications for practice

The results from the three included studies do not support the

use of nebulised rhDNase in previously healthy children under

the age of 24 months hospitalised with mild to moderately severebronchiolitis. While safe and easy to administer, this intervention

did not reduce the duration of hospital stay or accelerate the rate

of clinical improvement in such patients.

Implications for research

While respiratory syncytial virus (RSV) remains the most com-

mon cause of bronchiolitis in infants, the efficacy of nebulised re-

combinant human deoxyribonuclease (rhDNase) in complicated

bronchiolitis caused by non-RSV pathogens will need to be clari-

fied.

Nebulised rhDNase is more likely to be of benefit in patients with

atelectasis. Clinical studies on patients with severe bronchiolitis,

such as those requiring mechanical ventilation or intensive care,are needed to establish any effects. Future studies could also de-

termine if in combination with airway clearance therapy, rhD-

Nase might decrease duration of ICU stay, artificial ventilation

and steroid dose, and reduce complications such as secondary bac-

terial infections (from retained mucus).

A C K N O W L E D G E M E N T S

The review authors wish to thank the following people. For

commenting on the draft protocol: Anne Lyddiatt, Carla Per-

rotta, Ruben Boogaard, Hema Patel, Nelcy Rodriguez and AncaZalmanovici. For providing ongoing assistance regarding pro-

tocol and review submissions: Liz Dooley (Managing Editor,

Cochrane Acute Respiratory Infections Group). For assisting with

the electronic searches: Sarah Thorning (Trials Search Co-ordi-

nator, Cochrane Acute Respiratory Infections Group). For com-

menting on the draft review: Manal Kassab, Carla Perrotta, Ruben

Boogaard, Elaine Beller and Anca Zalmanovici Trestioreanu.

R E F E R E N C E S

References to studies included in this reviewBoogaard 2007 {published and unpublished data}

Boogaard R, Hulsmann AR, Hop WCJ, Merkus PJF.

Efficacy of recombinant human deoxyribonuclease (Rh-

DNase) in infants hospitalised with respiratory syncytial

virus bronchiolitis a multicentre randomised double blind

clinical trial [Abstract]. European Respiratory Journal2006;

28(Suppl 50):758s [4365]. Boogaard R, Hulsmann AR, Van Veen L, Vaessen-

Verberne AAPH, Yap YN, Sprij AJ, et al.Recombinant

human deoxyribonuclease in infants with respiratory

syncytial virus bronchiolitis. Chest2007;131(3):78895.

Nasr 2001 {published data only (unpublished sought but not used)}

Nasr S, Strouse P, Soskolne E, Maxvold N, Garver K, RubinB, et al.Efficacy of recombinant human DNase I in the

management of RSV bronchiolitis [abstract]. American

Journal of Respiratory and Critical Care Medicine2000;161

(3 Suppl):A339. Nasr SZ, Strouse PJ, Soskolne E, Maxvold N, Garver

KA, Rubin BK, et al.Efficacy of recombinant human

deoxyribonuclease I in the hospital management of

respiratory syncytial virus bronchiolitis. Chest2001;120:

2038.

Nenna 2010 {published and unpublished data}Corazzesi E, Nenna R, Tromba V, Tuccinardi R, Piacenti S,

Scalercio F, et al.Recombinant human deoxyribonuclease

treatment in hospital management of infants with moderate

to severe bronchiolitis. European Respiratory Journal2006;

28(Suppl 50):758s [4367]. Nenna R, Tromba V, Berardi R, De Angelis D, Papoff P,

Sabbatino G, et al.Recombinant human deoxyribonuclease

treatment in hospital management of infants with moderate-

severe bronchiolitis. European Journal of Inflammation

2009;7(3):16974.

References to studies excluded from this review

Merkus 2001 {published data only}

Merkus PJFM, de Hoog M, van Gent R, de Jongste

JC. DNase treatment for atelectasis in infants with

severe respiratory syncytial virus bronchiolitis. European

Respiratory Journal2001;18(4):7347.

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Armstrong JB, White JC. Liquefaction of viscous purulent

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Boogaard 2007a

Boogaard R, de Jongste JC, Merkus PJ. Pharmacotherapy of

impaired mucociliary clearance in non-CF pediatric lung

disease. A review of the literature. Pediatric Pulmonology

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Boogaard 2007b

Boogaard R, Hulsmann AR, Van Veen L, Vaessen-Verberne

AAPH, Yap YN, Sprij AJ, et al.Recombinant human

deoxyribonuclease in infants with respiratory syncytial virus

bronchiolitis. Chest2007;131(3):78895.

Calogero 2007

Calogero C, Sly PD. Acute viral bronchiolitis: to treat or

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Corneli 2007

Corneli HM, Zorc JJ, Mahajan P, Shaw KN, Holubkov R,Reeves SD, et al.Bronchiolitis Study Group of the Pediatric

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Deshpande SA, Northern V. The clinical and health

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Fernandes 2010

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C H A R A C T E R I S T I C S O F S T U D I E S

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;systemicsteroidsat timeof hospital admission; ICU admissionbefore

parental consent for study

Diagnostic criteria (case definition): RSV by direct immunofluorescence of nasopharyn-

geal aspirate (NPA) sampleDuration 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 oxygensaturation 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 byWang 1992 was utilised

Notes

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Random table sample with blocks of 4numbers made by the study statistician

Allocation concealment (selection bias) Low risk

Blinding (performance bias and detection

bias)

All outcomes

Low risk




18/28

Boogaard 2007 (Continued)

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Physicians, nurses, parents and the trial co-

ordinator remained unaware of the inter-

vention assignment

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk

Incomplete outcome data (attrition bias)

All outcomes

Low risk The data from all randomised participants

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 healthyfull-term neonates; hospitalised

for proven RSV infection4. Diagnostic criteria (casedefinition): specimens for viral isolationand 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




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Nasr 2001 (Continued)

- CXR score

The clinical assessment scoring described byWang 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

bias)

Low risk The randomisation was conducted by

the University of Michigan Investigational

Drug Service using a random table samplewith blocks of 4. All CXRs were coded and

randomised

Allocation concealment (selection bias) Low risk


bias)

All outcomes

Low risk


(performance bias)

All outcomes

Low risk Both physicians and parents were blinded

with respect to the treated and placebo

groups. The statistician was unaware of

treatment status coding


bias)

All outcomes

Low risk Participants were examined twice daily by

a paediatric pulmonologist or study co-or-

dinator; all were blinded to the patients

assignment. 2 paediatric radiologists re-

viewed the CXRs and were blinded to each

patients study assignment, identity and

date of examination (hospital admission

versus discharge)


All outcomes

Unclear risk 11 participants were excluded from the

analysis because of missing data (75 par-

ticipants were included in the analysis). 11more participants did not receive hospital

admission or discharge CXRs and were ex-

cluded from the analysis of CXR scoring

(64 participants)





20/28

Nenna 2010

Methods Randomised, double-blind, placebo-controlled study

Participants 1. Age: < 6 months

2. Gender: 12 males, 10 females3. 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


Random sequence generation (selection

bias)

Low risk Random table sample with each number

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


bias)

All outcomes

Low risk


(performance bias)

Low risk Throughout the study, both physicians/

nurses and parents were blinded in respect




21/28

Nenna 2010 (Continued)

All outcomes to the study or placebo groups


bias)

All outcomes

Low risk


All outcomes

Low risk No participants interrupted the study


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




22/28

D A T A A N D A N A L Y S E S

Comparison 1. Nebulised rhDNase versus control

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

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



studies

No. of


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



studies

No. of


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



studies

No. of


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




23/28



studies

No. of


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

Study or subgroup rhDNase ControlMean

Difference WeightMean

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




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Analysis 2.1. Comparison 2 Nebulised rhDNase versus control, Outcome 1 Change in clinical score.



Outcome: 1 Change in clinical score

Study or subgroup rhDNase Control

Std.Mean

Difference Weight

Std.Mean

Difference


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%



-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.



Outcome: 1 Change in respiratory rate score



Difference


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 ]




-0.5 -0.25 0 0.25 0.5





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Analysis 4.1. Comparison 4 Nebulised rhDNase versus control, Outcome 1 Change in wheezing score.



Outcome: 1 Change in wheezing score



Difference


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 ]




-0.2 -0.1 0 0.1 0.2





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Analysis 5.1. Comparison 5 Nebulised rhDNase versus control, Outcome 1 Change in retraction score.



Outcome: 1 Change in retraction score



Difference


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 ]




-0.2 -0.1 0 0.1 0.2


A P P E N D I C E S

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




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#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]

H I S T O R Y

Protocol first published: Issue 3, 2010

Review first published: Issue 11, 2012

Date Event Description

9 September 2010 Amended Contact details updated.

C O N T R I B U T I O N S O F A U T H O R S

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.




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D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

No sources of support supplied

External sources

Rong Sing Medical Foundation, Taiwan.

Research Grant for Dr. I-Wen Chu

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We did not perform subgroup analyses according to patients age (children under 12 months of age versus children under 24 monthsof 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)).



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Nebulised deoxyribonuclease