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doi:10.1378/chest.06-2282
(Chest. 2007; 131:788-795)
© 2007 American College of Chest Physicians
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Recombinant Human Deoxyribonuclease in Infants With Respiratory Syncytial Virus Bronchiolitis*

Ruben Boogaard, MD; Anthon R. Hulsmann, MD, PhD; Leoniek van Veen, MD; Anja A. P. H. Vaessen-Verberne, MD, PhD; Yen Ni Yap, MD; Arwen J. Sprij, MD; Govert Brinkhorst, MD; Barbara Sibbles, MD; Tom Hendriks, MD; Sander W. W. Feith, MD; Carsten R. Lincke, MD, PhD; Annelies E. Brandsma, MD, PhD; Paul L. P. Brand, MD, PhD; Wim C. J. Hop, PhD; Matthijs de Hoog, MD, PhD and Peter J. F. M. Merkus, MD, PhD

* From the Department of Pediatric Pulmonology (Drs. Boogaard and Merkus), Erasmus MC-Sophia Children’s Hospital, Rotterdam; Department of Pediatrics (Drs. Hulsmann and Vaessen-Verberne), Amphia Hospital, Breda; Reinier de Graaf Gasthuis (Dr. van Veen), Delft; Albert Schweitzer Hospital (Dr. Yap), Dordrecht; HagaTeaching Hospital/Juliana Children’s Hospital (Dr. Sprij), the Hague; Medisch Centrum Alkmaar (Dr. Brinkhorst), Alkmaar; Erasmus MC-Sophia Children’s Hospital (Drs. Sibbles and de Hoog), Rotterdam; Catharina Hospital (Dr. Hendricks), Eindhoven; Sint Franciscus Gasthuis (Dr. Feith), Rotterdam; Medisch Centrum Rijnmond Zuid (Drs. Lincke and Brandsma), Rotterdam; Isala Klinieken (Dr. Brand), Zwolle; and De-partment of Epidemiology and Biostatistics (Dr. Hop), Erasmus MC, Rotterdam, the Netherlands.

Correspondence to: Ruben Boogaard, MD, Room Sb-2666, Department of Pediatric Pulmonology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, PO Box 2060; 3000 CB Rotterdam, the Netherlands; e-mail: r.boogaard{at}erasmusmc.nl

Abstract

Background: Treatment of hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis is mainly supportive. Bronchodilators and systemic steroids are often used but do not reduce the length of hospital stay. Because hypoxia and airways obstruction develop secondary to viscous mucus in infants with RSV bronchiolitis, and because free DNA is present in RSV mucus, we tested the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase).

Methods: In a multicenter, randomized, double-blind, controlled clinical trial, 225 oxygen-dependent infants admitted to the hospital for RSV bronchiolitis were randomly assigned to receive 2.5 mg bid of nebulized rhDNase or placebo until discharge. The primary end point was length of hospital stay. Secondary end points were duration of supplemental oxygen, improvement in symptom score, and number of intensive care admissions.

Results: There were no significant differences between the groups with regard to the length of hospital stay (p = 0.19) or the duration of supplemental oxygen (p = 0.07). The ratio (rhDNase/placebo) of geometric means of length of stay was 1.12 (95% confidence interval, 0.96 to 1.33); for the duration of supplemental oxygen, the ratio was 1.28 (95% confidence interval, 0.97 to 1.68). There were no significant differences in the rate of improvement of the symptom score or in the number of intensive care admissions.

Conclusions: Administration of rhDNase did not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.

Key Words: controlled clinical trial • dornase alfa • pediatric respiratory syncytial virus bronchiolitis • treatment

Respiratory syncytial virus (RSV) is the most important cause of viral bronchiolitis in young children.1 In general, approximately 0.5 to 2% of children with RSV disease need to be hospitalized.23 It is estimated that each year approximately 50,000 to 80,000 children < 1 year old are hospitalized for RSV bronchiolitis in the United States,4 and consequently RSV bronchiolitis constitutes a significant burden on patients, parents, and the health-care system.

Treatment of hospitalized children with RSV bronchiolitis is mainly supportive, with supplemental oxygen, nasal washings, tube feeding, or IV fluids, and mechanical ventilation where necessary. ß2-Agonists and systemic steroids are frequently used,5 although their efficacy is disappointing. Several randomized studies678 have demonstrated that neither nebulized ß2-agonists, epinephrine, nor systemic steroids reduce the length of hospital stay.

It has been well recognized that RSV bronchiolitis is associated with severe airways obstruction due to the presence of intraluminal secretions, loss of epithelial cilia, sloughing of epithelial cells, and cellular debris from accumulated inflammatory cells within the airway.9 Because baseline airway resistance is high in infancy, even the presence of small amounts of mucus in the airways of infants can have a profound effect on the work of breathing.10 Since airway obstruction due to intraluminal mucus plugs is an important pathophysiologic feature of RSV bronchiolitis, a logical approach to therapy might be to use a mucolytic agent. The DNA present in mucous plugs following lysis of inflammatory cells contributes to increased viscosity and adhesiveness of the mucus.1112 Such mucus can be liquefied by recombinant human deoxyribonuclease (rhDNase [dornase alfa]), which cleaves the extracellular DNA released by degenerating leukocytes.1314 The efficacy of rhDNase has been well documented in patients with cystic fibrosis,15 and several publications suggest that rhDNase improves radiologic abnormalities in mild RSV bronchiolitis,12 and is effective in infants with severe RSV bronchiolitis,16 in pediatric patients with severe atelectasis or airways obstruction due to asthma,171819 and other respiratory diseases.2021222324

It is unknown whether infants with RSV bronchiolitis admitted to the hospital because of hypoxemia benefit from rhDNase treatment. Therefore, we conducted a randomized, placebo-controlled trial to examine the effect of nebulized rhDNase in oxygen-dependent infants hospitalized with RSV bronchiolitis. The primary outcome measure was length of hospital stay. Secondary outcome measures included duration of supplemental oxygen, change in symptom scores, number of admissions to the ICU, and use of bronchodilators and antibiotics. The study was approved by the ethics committees of all 10 centers. Written parental informed consent was obtained for each infant.

Materials and Methods

Setting and Participants
For entry into this study, we considered infants < 12 months of age with proven RSV bronchiolitis requiring supplemental oxygen, who were admitted to 1 of the 10 participating hospitals between November 2002 and February 2006: Erasmus MC-Sophia Children’s Hospital, Rotterdam; Amphia Hospital, Breda; Reinier de Graaf Gasthuis, Delft; Albert Schweitzer Hospital, Dordrecht; HagaTeaching Hospital/Juliana Children’s Hospital, the Hague; Medisch Centrum Alkmaar, Alkmaar; Catharina Hospital, Eindhoven; Sint Franciscus Gasthuis, Rotterdam; Medisch Centrum Rijnmond Zuid, Rotterdam; and Isala Klinieken, Zwolle, the Netherlands. RSV infection was confirmed by a direct immunofluorescence assay of a nasopharyngeal aspiration sample. We did not include infants born at a gestational age < 32 weeks, infants with cardiopulmonary disease or an immunodeficiency. We also did not include infants who received or had been prescribed systemic steroids at hospital admission, and infants who required intensive care admission before parents could give consent for the study.

Randomization
After parental consent was given, patients were randomly assigned to receive 2.5 mg of rhDNase or 2.5 mg of placebo bid until discharge, until oxygen supplementation could be stopped for at least 12 h, or until the patient had to be transferred to an ICU. Randomization was performed in the hospital pharmacy of each participating hospital using a random table sample with blocks of four numbers made by the study statistician. Throughout the study, physicians, nurses, parents, and the trial coordinator remained unaware of the treatment assignment.

Study Procedures and End Points
After hospital admission, the admitting physician recorded the clinical history of the patient, including duration of symptoms before admission, use of medication, parental smoking history, and family history of atopy. Vital signs and the use of supplemental oxygen were recorded three times daily by the nurse responsible. At inclusion and subsequently each morning, respiratory symptoms were scored by the attending physician using a scoring system described previously.25 The respiratory rate, presence of wheezing, and retractions were scored on a four-point scale (Table 1 ). A symptom score was calculated by adding up these three separate items, yielding a score ranging from 0 to 9.


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  		Table 1.. Symptom Score

 
During hospital admission, patients received supportive care according to the hospital guidelines. This included nasal washings, nasal decongestants, supplemental oxygen, and tube feeding or IV fluids when necessary. The decision to treat patients with antibiotics, bronchodilators, or systemic steroids was at the discretion of the attending physician, as was the decision on discharge. We calculated the length of hospital stay as the number of hours between the first dose of study medication and the moment of discharge. Because in real life, length of hospital stay can be affected by administrative and social factors unrelated to the clinical condition of a patient, we also assessed the duration that supplemental oxygen was required as a measure of efficacy. Supplemental oxygen was started when oxygen saturation was consistently < 93%, and stopped when saturation was consistently > 92%.

Twice daily, patients received either rhDNase (a 2.5-mL solution of 1 mg/mL rhDNase) or placebo (2.5 mL of sodium chloride 0.9%). A twice-daily dosing schedule was chosen to anticipate the poor lung deposition expected in young infants with airways obstruction due to bronchiolitis. Study medication was prepared by the hospital pharmacists. The first dose of study medication had to be administered within 32 h of hospital admission. Study medication was administered using a jet nebulizer through a firmly applied facemask with a constant oxygen supply of 6 to 8 L/min from a wall outlet. The same state-of-the-art nebulizing equipment (Sidestream; Romedic BV; Meersen, the Netherlands) was used in all participants.

Estimate of Sample Size
We aimed to detect a 25% difference in length of stay at the 5% significance level for a two-sided test with 80% power. Based on previous data,26 this would require 180 patients, with 90 infants in each group. To anticipate possible dropouts, we aimed to include 220 patients.

Statistical Analysis
The data from all randomized patients were analyzed on an intention-to-treat basis. A separate per-protocol analysis was conducted in which patients who violated the study protocol were excluded (Fig 1 ). The differences between the treatment groups with regard to the baseline characteristics were assessed by {chi}2 or Fisher exact test and the Mann-Whitney test. Main analyses of between-group comparisons regarding the length of hospital stay and duration of supplemental oxygen were performed by analysis of covariance (ANCOVA) after logarithmic transformation to obtain approximate normal distributions. The baseline covariates used in these analyses were the hospital of admission, the symptom score, sex and age. Birth weight was included as a covariate because it showed some imbalance between treatment groups. The analysis was performed using statistical software (SPSS version 11.5; SPSS; Chicago, IL). All reported p values are two sided.


Figure 1
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  		Figure 1.. Enrollment, random assignment, follow-up, and analysis.

 
After inclusion of the first 100 patients, an interim safety analysis was conducted by a committee of an independent statistician and two independent pediatricians, revealing no safety or ethical arguments to discontinue the study at that moment. Except for the interim safety analysis, the randomization code was not broken until the study was completed.

Results

A total of 225 infants were assigned to treatment: 113 infants to rhDNase and 112 infants to placebo (Fig 1). Two patients withdrew from the study after the first dose of study medication (one in each group) and consequently had no follow-up data available. During the first two RSV seasons of the study, patients were recruited in 4 hospitals; during the last two RSV seasons, patients were recruited from a total of 10 hospitals. In terms of demographic variables, there were no significant differences between the groups at randomization except for birth weight, which was slightly lower in the rhDNase group (Table 2 ). The duration of illness before hospital admission and the symptom score at randomization were comparable between the groups.


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  		Table 2.. Baseline Characteristics of the Infants at Admission to the Hospital*

 
Primary End Point
Overall, treatment with rhDNase had no significant effect on the length of hospital stay (Table 3 ). The duration of hospital stay is presented in Figure 2 . The length of hospital stay in the rhDNase group ranged from 1 to 32 days (interquartile range, 2.9 to 6.7 days); the range in the placebo group was 1 to 43 days (interquartile range, 2.7 to 5.7 days). ANCOVA, which allowed for center, age, sex, birth weight, and baseline symptom score, also showed that rhDNase had no significant effect on the length of hospital stay: the ratio of the length of hospital stay in the rhDNase group to that in the placebo group was 1.12 (95% confidence interval, 0.96 to 1.33; p = 0.19) [Table 4 ]. At baseline, approximately one half of the infants had a symptom score ≥ 4 and one half of the infants had a symptom score ≤ 3. Irrespective of the severity of symptoms at inclusion, the length of hospital stay did not differ between treatment groups (Table 3). The baseline symptom score and age were significantly related to the length of hospital stay (Table 4, Fig 3 ). Analysis of the primary end point according to the per-protocol analysis yielded similar results (data not shown). The first dose of study medication was administered after a median of 21 h after hospital admission in the placebo group and after 22 h in the rhDNase group (p = 0.35).


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  		Table 3.. Length of Hospital Stay and Time Supplemental Oxygen Was Required, According to the Baseline Symptom Score*

 

Figure 2
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  		Figure 2.. Percentage of participants in each group remaining in the hospital.

 

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  		Table 4.. Results of ANCOVA Regarding Length of Hospital Stay*

 

Figure 3
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  		Figure 3.. Geometric mean length of hospital stay, with SEs, according to the baseline symptom score for both treatment groups combined.

 
Secondary End Points
There were five children who did not receive supplemental oxygen at inclusion (three in the placebo group and two in the rhDNase group). For the remaining children, the duration of supplemental oxygen ranged from 0.2 to 24 days in the rhDNase group (interquartile range, 1.8 to 4.7 days) and from 0.04 to 17 days in the placebo group (interquartile range, 1.2 to 3.8 days).

Overall, treatment with rhDNase had no significant effect on the duration of supplemental oxygen, irrespective of the baseline symptom score (Table 3). ANCOVA also showed that rhDNase had no significant effect on the duration of supplemental oxygen: the ratio of the duration of supplemental oxygen in the rhDNase group to that in the placebo group was 1.28 (95% confidence interval, 0.97 to 1.68; p = 0.07). This analysis further showed that the duration of supplemental oxygen was negatively correlated with the age of the child (p = 0.02) and positively correlated with the symptom score at baseline (p = 0.004). The mean symptom score on each study day, as well as the rate of improvement of this score, were not significantly different in the rhDNase group compared with the placebo group (Fig 4 ).


Figure 4
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  		Figure 4.. Mean symptom score, with SEs, during hospital stay. Day 1 corresponds to the baseline symptom score. In calculating mean values, the individual symptom score after discharge was arbitrarily set at 0 points. • indicates RhDNase; {circ} indicates placebo.

 
Seven infants (3.2%) required transfer to the ICU, and five infants required mechanical ventilation. There were no significant differences between the groups in proportions requiring intensive care (p = 1.0) or mechanical ventilation (p = 0.43).

Twenty-four infants in the rhDNase group and 32 infants in the placebo group received antibiotics during hospital admission (p = 0.28). Fifty percent of the infants in the placebo group and 49% in the rhDNase group received bronchodilators on at least 1 day during hospital admission (p = 0.89). The number of adverse drug reactions (ie, adverse events that in the opinion of the treating physician were directly and temporally related to the inhalation of the trial solution) did not differ between treatment groups (p = 0.21) [Table 5 ].


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  		Table 5.. Adverse Reactions Considered To Be Related to Treatment*

 
Discussion

We report the first large, randomized, double-blind, controlled trial of rhDNase in infants with RSV bronchiolitis. This study demonstrates that the mucolytic rhDNase does not shorten length of hospital stay or duration of supplemental oxygen in hypoxemic infants with RSV bronchiolitis. Neither was the rate of clinical improvement better in infants treated with rhDNase than in those receiving a placebo.

Because mucus plugs play an important role in the pathophysiology of RSV bronchiolitis,27 and because the DNA content is increased in mucus of these infants,12 we hypothesized that rhDNase is an effective treatment for infants with RSV bronchiolitis. Anecdotal evidence indeed suggests that rhDNase treatment is effective in infants with severe RSV bronchiolitis.16 Furthermore, one randomized study12 in a small group of infants with mild bronchiolitis demonstrated that rhDNase improved radiologic abnormalities. In that study12 no differences in length of hospital stay and symptom scores were observed, but as many of these patients were not oxygen dependent, they may have had only mild airway obstruction. In addition, the efficacy of rhDNase has also been reported in observational studies of pediatric patients with atelectasis or severe airways obstruction due to asthma,171819 and other respiratory diseases2021222324; and a recent randomized study28 demonstrated that rhDNase effectively prevents the development of atelectasis in infants receiving postoperative mechanical ventilation.

There may be several explanations for the lack of effect of rhDNase in our study. One is that the infants probably had disease that was too mild, without large atelectasis, for rhDNase to be effective. Infants with risk factors for severe bronchiolitis, or who needed intensive care directly at hospital admission, were not included in this study. Although all infants required supplemental oxygen, reflecting the presence of clinically significant airways obstruction and mismatch of pulmonary ventilation and perfusion, only a small number required intensive care treatment. We cannot exclude that rhDNase could be effective in infants with more severe disease and/or atelectasis due to mucus plugging in the central airways that requires intensive care admission.

A second explanation could be a suboptimal lung deposition of rhDNase, resulting in deposition of rhDNase mainly in the more central airways, while in RSV bronchiolitis mucus predominantly blocks peripheral airways.9 A third explanation might be that the number of neutrophils, and hence the amount of DNA released in the mucus, was too low for rhDNase to be effective in our study population of infants with mild-to-moderately severe bronchiolitis.29

A fourth explanation might be that mucus was liquefied but that infants were not able to clear their airways effectively. While rhDNase is combined with airway clearance therapy in order to evacuate mucus in children with cystic fibrosis, the infants in our study did not receive airway clearance therapy. Moreover, as young infants cannot cough as forcefully as older children, especially during an illness, it might be difficult for them to expectorate liquefied mucus. Indeed, the observed trend toward a longer duration of supplemental oxygen in the rhDNase group is consistent with such a mechanism.

Treatment with study medication started after a median of 21 h and 22 h in the placebo and rhDNase groups, respectively. It could be argued that starting study medication within a few hours of hospital admission might change length of stay when waiting almost 24 h does not. However, a separate ANCOVA adjusting for the time between hospital admission and the first dose of study medication did not influence the results (data not shown). Moreover, the symptom score during hospital admission showed no difference between the treatment groups. We therefore think it is unlikely that initiating therapy earlier after hospital admission would have changed the outcome of this study.

One half of the patients in our study received bronchodilators during their hospital stay. Despite the fact that current evidence suggests that bronchodilators are not effective,6 the use of bronchodilators for hospitalized infants with RSV bronchiolitis is common practice.530

Although the risk of a secondary bacterial infection in infants with RSV bronchiolitis is minimal,31 antibiotics were also prescribed frequently; in approximately one fourth of all patients, a course of antibiotics was started at hospital admission or during hospital stay. This probably reflects the fact that it can be difficult to rule out a bacterial pneumonia or sepsis solely on the basis of clinical signs.

Because our study population reflects bronchiolitis patients in district and tertiary care hospitals, our results can be generalized to the large majority of hospitalized, oxygen-dependent infants with RSV bronchiolitis with no complications other than hypoxemia. Studies on the effect of rhDNase in infants with more severe bronchiolitis might still be warranted. Another implication of this study, which echoes that of a previous study8 with negative findings, is that we still have only supportive measures at our disposal. This emphasizes the need for effective and safe vaccination against RSV bronchiolitis. In conclusion, our study clearly shows that inhaled rhDNase does not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.

Footnotes

Abbreviations: ANCOVA = analysis of covariance; rhDNase = recombinant human deoxyribonuclease; RSV = respiratory syncytial virus

Roche BV, the Netherlands, provided an unrestricted grant for this study and financed the study medication. Romedic BV, the Netherlands, donated the nebulizing equipment. The study sponsors had no role in the study design, the collection, analysis or interpretation of data, the writing of the report, or the decision to submit for publication.

The principal investigators had full access to all study data and had final responsibility to submit for publication.

The authors have no conflicts of interest to disclose.

Received for publication September 15, 2006. Accepted for publication October 20, 2006.

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