Archives of Pediatrics and Neonatology Volume 1, Issue 1, 2018, PP: 26-35

A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Illnesses other than Cystic Radha Patel , Tsz-Yin So*

[email protected] *CorrespondingDepartment Author: of Pharmacy,Tsz-Yin So, Moses Pediatric H. ClinicalCone Memorial Pharmacist, Hospital, Department Greensboro, of Pharmacy, NC 27401 Moses H. Cone Memorial Hospital, NC 27401, USA.

Abstract plugging is associated with several lower respiratory tract illnesses in the pediatric population. Majority of lower respiratory tract illnesses are treated with supportive care and lacks effective curative options. Dornase alfa, a mucolytic agent often used in patients with cystic fibrosis, was theorized to have benefits in other respiratory conditions such as , , and seen in mechanically-ventilated patients. Clinical studies performed thus far, however, did not show any clinical significance in using this regimen for majority of these indications. The only potential use of dornase alfa is in mechanically-ventilated patients who have developed atelectasis, but 3-7% hypertonic should be utilized first due to its reduced cost and its similar efficacy to dornase alfa. Keywords: Asthma; bronchiolitis; dornase alfa; pediatrics; pulmonary atelectasis

Abbreviations NICU-2 neonatal intensive care units; 2 CICU- cardiac intensive care unit; PaO - partial pressure of arterial ; CXR- chest radiographs; PCO - partial pressure of carbon dioxide; CF- cystic fibrosis; PIP- peak inspiratory pressure; DNA- deoxyribonucleic acids; PEEP- positive end-expiratory pressure; 2 ED- emergency department; PMN- polymorphonuclear neutrophils; 1 FiO - fraction of inspired oxygen; rhDNase- recombinant human dexoyribonuclease; FEV - forced expiratory volume in 1 second; RSV- respiratory syncytial virus IntroductionICU- intensive care unit; 4 The use of mucolytic agents is often seen in patients Respiratory illnesses are among the top 10 diagnoses beneficial in patients with mucus overproduction. of emergency department (ED) visits for pediatric 1-2 treatment options for severely-ill patients with other patients in the and Europe. Twenty with cystic fibrosis (CF). However, due to the lack of than 5 years of age was caused by lower respiratory agent beyond supportive care. respiratory conditions, this may be an alternative five percent of all3 hospitalization in children younger tract infections. Potential causes are due to mucus Agents that have been shown to aid in mucus clearance hypersecretions or the inability to clear mucus within alfa.5 include hypertonic saline, N-acetylcystine and dornase the respiratory tract in diseases such as cystic fibrosis, the mucus to help liquefy and clear the mucus. Dornase lead to the accumulation of mucus production within Each agent works on different components within airwaysasthma, andand the bronchiolitis. development This of respiratory problem may symptoms. in turn It has been proposed that mucolytic agents may be alfa (Pulmozyme®) is a mucolytic agent approved by Archives of Pediatrics and Neonatology V1 . I1 . 2018the Food and Drug Administration for the treatment26 A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis of cystic fibrosis. Dornase alfa is a recombinant human Two randomized controlled trials were performed deoxyribonuclease (rhDNase) that essentially works to assess the efficacy and safety of dornase alfa in by cleaving deoxyribonucleic acids (DNA) released patients hospitalized with RSV bronchiolitis. The first found within mucus secretions.6 controlled trial that included 225 patients younger from degenerating polymorphonuclear leukocytes study was a multicenter, randomized, double-blind, elasticity are directly correlated with the amount of than 12 months of age proven to have bronchiolitis Mucus viscosity and Dornase alfa can be administered via 14 They assessed 7 DNA content. and require supplemental oxygen. tube for patients who are on . nebulization or intratracheally down an endotracheal the efficacy of 2.5mg of rhDNase (2.5mL of 1mg/mL rhDNase) to placebo given twice daily until hospital Studies have shown that rhDNase has the ability discharge, discontinuation of supplemental oxygen for concentration-dependent manner.8 There has been to reduce viscosity of purulent CF- in a at least 12 hours, or until the need of transferring to an intensive care unit (ICU). Baseline characteristics much debate on whether rhDNase may be beneficial were mostly similar between groups except that to patients without cystic fibrosis. Depending on the there was a significantly lower birth weight in the indications, there are few trials performed thus far to rhDNase group compared to the control group. The in this patient population. The aim of this review is to help elucidate the efficacy and use of the medication primary objective was mean duration of hospital stay, and the difference was not statistically significant summarize the relevant literature for the use of dornase (rhDnase: 4.4 days vs Placebo: 3.8 days; p=0.11). alfa in pediatric patients with non-cystic fibrotic Also, no difference was found in the mean duration seen in mechanically ventilated patients. diseases, mainly bronchiolitis, asthma, and atelectasis of supplemental oxygen between the 2 groups (2.6 limitation of the study was that it did not include Bronchiolitis days vs 2.0 days respectively; p=0.053). One potential Bronchiolitis is one of the most common lower very sick patients with atelectasis who required ICU respiratory tract infections seen in infants younger admission, a population likely to have more mucus than 12 months of age.9 Bronchiolitis is usually caused mucolytic agents. Patients were also given additional production allowing for potential greater benefit from of the most common organisms seen during the winter by viruses, respiratory syncytial virus (RSV) being one treatments with and bronchodilators, months.10 which might have influenced the overall outcome. methods and potential suboptimal lung deposition of Each year, this clinical condition results in Other limitations included the lack of airway clearance and an estimated 500 deaths in the United States.9 approximately 3% of infants needing hospitalization rhDNase. Nevertheless, the authors concluded that the bronchiolitis increased substantially in Europe from length of hospital stay or duration of supplemental Similarly, the incidence of hospitalization due to use of rhDNase did not show a benefit in shortening 2000 to 2013.2 The infection causes damage to the 14 respiratory tract and sloughing of the oxygen in hypoxemic infants with RSV bronchiolitis. within the airways can occur.11 The second study was also a randomized double- lining and cilia. As a result, increase in mucus plugging blind, placebo-controlled trial that evaluated the effect First line therapy for of rhDNase in shortening length of hospitalization 12 It has been 15 This study included bronchiolitis is supportive care with oxygenation, and improvement in chest radiographs (CXR) in suggested that since bronchiolitis can lead to mucus hydration, and reduction of fever. hospitalized infants with RSV. 75 healthy full-term patients younger than 2 years patients’ improvement from admission to discharge plugging with DNA present, a logical approach in of age with proven RSV. The outcomes assessed this patient population.13 therapy is to use mucolytic agents like dornase alfa in 27 Archivesthrough of Pediatrics respiratory and symptoms, Neonatology CXR scoring V1 . I1 . system, 2018 A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis

chloride following the second dose of bronchodilator. and length of stay. The chest X-ray scores had shown dose of nebulized 5mg rhDNase or 5mg sodium the score (0.60) was worsened in the placebo group The primary objective was to assess the patients’ a significant improvement with rhDNase (0.46) while asthma score (scale range 5-15) 1 hour and 24 hours

(p<0.0001). However, there was not any significant difference in length of stay and respiratory symptoms after giving the study medication, and it was found unclear if the dose of medication or the route used between the groups. Similar to the last study, it was to be insignificant (p=0.23 & p=0.40, respectively). allow for good deposition and clearance of the mucus. Furthermore, the treatment did not prevent hospital admission. Overall, there was not any significant Even though there was a significant improvement difference in time until discharge or duration of oxygen in the CXR scores with rhDNase, there were not any supplementation between the two groups. Majority of significant differences in hospital length of stay and patients presented with mild disease, with only 4% analysis of patients with asthma scores of at least 12 oxygen saturation between the two groups. Thus,15 of patients requiring admission to the ICU. Subgroup these results challenge the clinical significance in the useAsthma of rhDNase for patients with RSV bronchiolitis. was performed; however, no significant improvement this group.19 in asthma score was seen with the use of rhDNase in The prevalence of asthma has increased at an 18-55 years old with acute asthma also did not show Of note, another study done in patients the prevalence of asthma in the United States was annual rate of 1.4% from 2001 to 2010. In 2010, 1 a difference in forced20 expiratory volume in 1 second It is postulated that patients 16 (FEV ), heart rate, and respiratory rate at any point The pathophysiological features of with more severe disease will have increased mucus 8.4%, affecting 7 million children from the age of post-randomization. 0 to 17 years. asthma include , edema of the bronchial plugging and hence more benefit from rhDNase mucosa, increased mucus production17 with airway treatment; however, this was not seen in this study. plugging, and bronchospasms. Unlike bronchiolitis, Due to the lack of evidence, it is concluded that use of and ß2-agonist. Patients with emergency department does not alleviate symptoms patients with asthma have more benefits from the nebulization with rhDNase given on arrival to the in children with moderate to severe acute asthma.19 for complications such as atelectasis and increased severe asthma exacerbation are also at a higher risk .18 Atelectasis in Mechanically-Ventilated Patients It is hypothesized that mucolytic Atelectasis can occur in patients on mechanical agents such as rhDNase can help patients who have 17 ventilation or with other severe respiratory moreThere severe is a limited asthma amount attacks. of evidence with the use of 21 mucolytic agents in pediatric patients with asthma. infections. are one of the common respiratory complications In addition, atelectasis and One randomized, double-blind, controlled clinical 19 on mechanical ventilation can develop atelectasis 10- in pediatric patients with asthma. seen after surgery, especially cardiac surgery. Children trial was performed to assess the efficacy of rhDNase 22 in this study were previously on short acting beta 54 percent of the time. These patients often have Patients (N=121) agonist (~30%), steroids (38%), no medications a greater risk of morbidity and increased length of (~25%), or combined steroids and short acting beta stay. Common physiological features of atelectasis agonist (10%). They included patient with symptoms include impaired gas exchange, increased pulmonary of mucus secretions.23 Potential treatment options of acute asthma whose asthma score was ≥8 and vascular resistance, lung injury and excess amount bronchodilators. Patients were given either a single who required at least two treatments with nebulized Archives of Pediatrics and Neonatology V1 . I1 . 2018include increasing ventilation parameters, regular28 A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis improvement in ventilation parameters.26 of this study included possible selection bias with the physiotherapy, position/proning, mucolytics, inhaled Limitation goal is to reduce recruitment of non-ventilated use of a matched subgroup to compare to the small bronchodilators, and/or antibiotics. The treatment pulmonary segments and to prevent respiratory 22 Some data suggested number of controlled patients. This study utilized a that the use of dornase alfa may shorten the duration by directly instilling the medication to the . It infections like pneumonia. different mode of administering the treatment drug

24 of mechanical ventilation, but it is not known if this is hypothesized29 that more lung deposition of drugs regimen can effectively reverse atelectasis. can be achieved with this mode compared to facemask nebulization. In conclusion, this study showed A single randomized placebo-controlled, double-blind therapy in children with atelectasis status post- who had undergone cardiac surgery.25 Dornase alfa that rhDNase is an effective adjunct to conservative study looked at 100 children (median age: 3 months) cardiac surgery. was dosed depending on the patients’ weight (<5kg: at 38 patients (median age: 3.5 months) in the cardiac 0.2mg/kg or ≥5kg:0.1mg/kg twice a day). Even The next study was also a retrospective study looking though there was not any significant difference in the The incidence of reintubation (p=1.0) between the groups, intensive care unit (CICU) who got ≤2 weeks27 of there was a significant decrease by 24% in the overall rhDNase while being mechanically ventilated. patients received 2.5mg of the rhDNase twice daily via ventilation time in the dornase alfa group (p=0.043). The treatment was stopped once their atelectasis had This study was powered for 80% with a sample size nebulization if their atelectasis persisted for 2 days. resulted in poor internal validity.25 Dornase alfa has set at 220 patients, which was not reached and likely of 28.9 days. The outcomes of this study were to improved. Patients were in the CICU for an average the potential benefit of decreasing time on ventilation post cardiac surgery, but it is not known if dornase assess gas exchange and ventilator parameters before population. alfa is effective at treating atelectasis in this patient and 2 hours after each dose of rhDNase up to the 2) concentration from 0.45 pre- Three other studies attempted to determine if fifth dose. There was a significant difference in the dornase alfa could help treat atelectasis.26-28 inspired oxygen (FiO was a retrospective observational study performed rhDNase compared to 0.40 post-rhDNase (p≤0.001). The first All other ventilator parameters (i.e. peak inspiratory in 46 patients (median age: 3.5 months) admitted to ]) pressure [PIP], positive end-expiratory pressure2 26 Three study groups were [PEEP], and partial pressure of arterial oxygen [PaO the pediatric intensive care unit with CXR evidence were not statistically significant. The patients’ CXR of atelectasis or infiltrates. atelectasis scores post rhDNase were significantly formed: patients with atelectasis, subgroup chosen to decreased compared to baseline (<5 doses: p≤0.05; patients with atelectasis given no treatment. Patients match for age and a diagnosis, and 17 cardiac surgery 5-10 doses: p≤0.01, 10-15 doses: p≤0.05). However, no significant improvement was noted beyond 15 were given rhDNase 0.1mg/kg intratracheally (via doses, indicating that short-term use of rhDNase endotracheal tube) twice a day until extubation. may suffice. A subgroup analysis also demonstrated a in patients who had greater than moderate amounts Among 35 patients in group 1 who received rhDNase significant improvement in the CXR atelectasis scores had a 76% significant improvement of atelectasis after present in the pre-therapy trachea aspirate. It is 24 hours of treatment (p=0.003). The subgroup that of polymorphonuclear neutrophils (PMN) or unclear as to what is considered a moderate amount was used to match with the historical data had a 100% improvement in atelectasis compared to 6% in the controlled group (p=0.0007). In addition, patients in of PMN in this study. Nonetheless, this was the first Archives of Pediatrics and Neonatology V1 . I1 . 2018 the29 subgroup treated with dornase alfa had significant study to show that atelectasis with bacteria or PMNs A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis had improved outcomes with the use of rhDNase, as An open label study evaluated the efficacy of beyond 15 doses. well as showing that rhDNase might not be as effective hypertonic saline in 40 newborn (38 preterms; 27 35 They included patients gestational age: 24-38 weeks and birth weight of 0.72 – 3.2 kg) with atelectasis. Finally, the last study was a prospective review of 22 with pulmonary atelectasis of ≥1 lobes. Patients neonatal intensive care unit (NICU) patients (term=10; distress syndrome on mechanical ventilation.28 These also had to fail conventional therapy, which included preterm=12) who were diagnosed with respiratory patients had previously tried conventional therapy for frequent position, , aspiration, atelectasis without any adequate response. This study elective endotracheal suction, and medical treatment alfa 1.25mg twice daily (2 hour dosing interval) for with N-. Patients were given dornase m2 twice daily for three days. If the patients did not utilized nebulized rhDNase initially at a dose of 1mg/ up to 3 days or 4 mL of 3% hypertonic saline every then every 6 hours until atelectasis disappeared. Both 2 hours for 3 doses, then every 4 hours for 5 doses, respond clinically after 3 days, they would recieve a treatment of rhDNase that was instilled through the groups showed complete resolution of atelectasis, endotracheal tube at the same dose. Overall, these and the 3% hypertonic saline group had significantly patients had significant improvements after three days improved CXR scores compared to rhDNase (p< 0.001). 2) (p<0.001). of treatment in CXR scores, respiratory rate, FiO2, and Furthermore, significant improvement in oxygen partial pressure of carbon dioxide (PCO saturation after treatment was observed with 3% Four patients relapsed and developed atelectasis hypertonic saline (98.4±1.4%) compared to rhDNase improved after the endotracheal administration of following nebulized therapy, but their atelectasis (97.1±2.1%;p<0.05). This was the only study35 that showed a beneficial effect in treating newborns with of how to potentially treat critically-ill patients with rhDNase. This study allows us to formulate an idea atelectasis with nebulized 3% hypertonic saline. controlled trials was performed in adults comparing A randomized, prospective, double-blind,36 placebo- atelectasis who have exhausted all other options by dornase alfa to hypertonic saline. endotracheal administration if needed.28 administering nebulized rhDNase and following with In this study, the Nebulized Hypertonic Saline Versus researchers utilized 7% hypertonic saline instead Dornase Alfa of the 3% used in the previous study. The thought is

that 7% saline may have higher mucolytic activity Thirty-three patients were included in this study and37 30 without the adverse effects of bronchospasm. Nebulized hypertonic saline like dornase alfa has well- documented efficacy in patients with cystic fibrosis. were divided into three groups: Group 1 received 4mL However, data on its efficacy for the treatment of of nebulized normal saline; group 2 received 4mL of atelectasis are only limited to newborns. Hypertonic 7% hypertonic saline; and group 3 utilized 2.5mg of saline primarily works by increasing hydration within administered twice daily. Patients were included if for the dilution of mucus and increasing respiratory nebulized dornase alfa. All of the above regimens were the to help liquefy the mucus, thus allowing they were intubated and admitted to the intensive care unit with new onset lobar or multilobar lung mucus.31 function regardless of DNA concentration within the There have been a few small randomized atelectasis. Baseline CXR scores were compared at hypertonic saline in patients with bronchiolitis by controlled trials that have shown the benefit of 3% 34, 48 and 73 hours and also at 7 days. The results reducing the length of hospital stay and relieving showed a decrease in CXR score from baseline to day 7 from 2.18±1.33 for rhDNase and 1.09±1.51 for 7% 32-34 symptoms in infants, and it is hypothesized that it may hypertonic saline compared to 1.00±1.79 for placebo Archives of Pediatrics and Neonatology V1 . I1 . 2018 be beneficial in patients with atelectasis. (p=NS). No other differences were observed 30among A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis

2 2 levels and time to Clinical Application 36 The author concluded that there was not all three groups for PaO /FiO Infants with moderate to severe bronchiolitis and any improvement in atelectasis with the use of either extubation. 36 Even though this moderate to severe asthma exacerbation do not benefit rhDNase or hypertonic saline. clinically from the use of rhDNase based on the lack of be initated for these 2 clinical conditions without other study was performed in adults, these results may be solid clinical evidence. Thus, dornase alfa should not extrapolated to the pediatric population since there with atelectasis while on mechanical ventilation has are not any pediatric studies comparing between 3% complications. The benefits of rhDNase in infants shown some relevant clinical outcomes. Even though andAnother 7% hypertonic retrospective saline study for atelectasis. evaluating the cost-

these patients may benefit from the use of rhDNase, effectiveness and efficacy of nebulized rhDNase and with unilateral or bilateral atelectasis who were on at present there is not any difference between the use hypertonic saline was performed in 87 newborns mechanical ventilation.38 The patients were placed into of rhDNase and 3-7% hypertonic saline therapy. After reviewing the literature, it may be prudent to use a more cost-effective agent like nebulized hypertonic hypertonic saline (12h intervals between doses) twice four groups: control with no medication (group 1), 7% saline prior to initiating rhDNase. appropriate dosing of this agent as well as the Further research is needed to determine the daily which was dosed based on weight (<2.5kg=3mL best mode of administration. Several studies have intervals between doses) twice daily (group 3) and & ≥2.5kg=4mL; group 2), rhDnase at 1.25mg (2h deter utilized different doses of dornase alfa without truly combination therapy of 7% hypertonic saline and mining if these doses were effective at reducing atelectasis. A greater percent recovery of atelectasis rhDNase twice daily (group 4) until resolution of the DNA concentrations within the patient’s respiratory was observed on day 3 with the combination tract. Few studies utilized similar dosing to cystic fibrosis patients (i.e. 2.5mg/day), while other studies suboptimal lung deposition in young children with utilized higher doses of 5mg/day in anticipation of therapy (27%, 70%, 81%, and 95% for placebo, 7% airway obstruction. hypertonic saline, rhDNase, and combination therapy, 39 Another study utilized dosing respectively; p=NS). A significantly shorter duration There have been a few case reports that describe the 38 by instilling 0.1mg/kg intratracheally twice daily. of treatment with was observed in group 2, A cost analysis was also performed on each treatment group 3, and group 4 compared to group 1 (p<0.05). successful utilization of intratracheally administered in the study. The additional cost per patient was divided into q24h or q12h) or based on body surface rhDNase at fixed2 doses (i.e. 2.5-5mg/day either regimen vary among the case reports). US$3.3 in group 2, approximately US$75 in group area (i.e. 1-4mg/m ; the duration and frequency of this there have not been any studies done thus29,39-41 far to assess 3 and US$65 in group 4. The cost of one day of 7% However, hypertonic saline treatment was approximately US$1, the intratracheal route of administration compared to while the cost of daily rhDNase was approximately improvement in outcomes for patients that utilized US$26. The authors concluded that in newborns, well-designed studies are needed to truly elucidate those that utilized the nebulized formulations. More monotherapy or combined treatment were effective and safe treatment options. The most efficient and cost administration to treat patient with mucus plugging. the most effective dose of rhDNase and route of effective of these methods is the co-administration of 7% hypertonic saline and rhDNase; though, the effect Figure 1 shows an algorithm on the potential use of treatment groups.38 on the current clinical data. was not statistically different compared to other dornase alfa in patients without cystic fibrosis based 31 Archives of Pediatrics and Neonatology V1 . I1 . 2018 A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis

Figure 1. Proposed algorithm for the use of dornase alfa in pediatric patients without cystic fibrosis.14—15, 19, 27-28, 38

*

For patients with asthma and RSV bronchiolitis, dornase alfa was not shown to be clinically effective. resolution on . †Failure = worsening hypoxemia, failure of oxygenation index to improve to <15, or failure of atelectasis

BID,Archives twice of daily; Pediatrics HS, hypertonic and Neonatology saline; PMN, V1 polymorphonuclear . I1 . 2018 neutrophils 32 A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis Conclusions [6] Cochrane Jones AP, Wallis CE. Recombinant human Database Syst Rev whose underlying disorder is related to an increase in deoxyribonucleas for cystic fibrosis. The use of dornase alfa can be beneficial for patients mucous production. Several clinical trials attempted . 2003;3:CD00127. and sputum viscosity. Thorax [7] Picot R, Das I, Reid L. Pus, deoxyribonucleic acid, 242. to determine the effect of this treatment for specific . 1978;33(2): 235- [8] indications other than cystic fibrosis; however, they important clinical endpoints such as mortality and were not able to show any significant differences in Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker Proc Natl Acad CL. Recombinant human DNase I reduces the trials should be performed to truly assess the cost Sci USA morbidity. Future larger randomized controlled viscosity of cystic fibrosis sputum. [9] . 1990;87(23): 9188-9192. in children. . effectiveness and efficacy of rhDNase in pediatric N Engl J Med this regimen should only be used in patients with Glezen P, Denny FW. Epidemiology of acute lower patients without cystic fibrosis. In the meantime, atelectasis who are on mechanical ventilation and who [10] 1973; 288(10): 498-505. virus and its role in acute bronchiolitis. Eur J saline. Everard ML, Milner AD. The respiratory syncytial have exhausted other therapy like 3-7% hypertonic Pediatr References [11] . 1992;151(9): 638-651. [1] Spencer H. Pathology of lung. Oxford, UK: common pediatric respiratory illnesses in United Knapp JF, Simon SD, Sharma V. Quality of care for [12] Pergamon press, 1985;131-165. States emergency departments: analysis of 2005 International variation in the management of national hospital ambulatory medical care survey Behrendt CE, Decker MD, Burch DJ, Watson PH. data. Pediatrics Eur J infants hospitalized with respiratory syncytial Pediatr [2] . 2008;122(6): 1165-1170. virus. International RSV Study Group. [13] . 1998;157(3): 215-220. Al-Mahtot M, Barwise-Munro R, Wilson P, admissions but not the children admitted – a Turner S. Changing characteristics of hospital Merkus PJ, de Hoog M, Van Gent R, de Jongste JC. whole population study between 2000 and 2013. severe respiratory syncytial virus bronchiolitis. DNase treatment for atelectasis in infants with Eur J Pediatr Eur Respir J

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Citation: Radha Patel , Tsz-Yin So. A Literature Review on the use of Dornase Alfa in Pediatric Patients with Lower Respiratory Tract Illnesses other than Cystic Fibrosis. Archives of Pediatrics and Neonatology. 2018; 1(1): 26-35. Copyright: © 2018 Radha Patel , Tsz-Yin So. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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