Chest ACCP Career Connection
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (23)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nasr, S. Z.
Right arrow Articles by Moler, F. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nasr, S. Z.
Right arrow Articles by Moler, F. W.
(Chest. 2001;120:203-208.)
© 2001 American College of Chest Physicians

Efficacy of Recombinant Human Deoxyribonuclease I in the Hospital Management of Respiratory Syncytial Virus Bronchiolitis*

Samya Z. Nasr, MD; Peter J. Strouse, MD; Errol Soskolne, MD; Norma J. Maxvold, MD; Kimberly A. Garver, MD; Bruce K. Rubin, MD, FCCP and Frank W. Moler, MD

* From the Divisions of Pediatric Pulmonology (Drs. Nasr and Maxvold), Radiology (Dr. Strouse), and Critical Care (Dr. Moler), University of Michigan Health System, Ann Arbor, MI; the Departments of Pediatrics (Dr. Soskolne) and Radiology (Dr. Garver), St. Joseph Mercy Hospital, Ann Arbor, MI; and Department of Pediatrics, Medicine, Physiology, and Pharmacology (Dr. Rubin), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to: Samya Z. Nasr, MD, Department of Pediatrics, University of Michigan Medical Center, 1500 E. Medical Center Dr, Ann Arbor, MI 48109-0212


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate the effect of recombinant human deoxyribonuclease I (rhDNase) in shortening the length of the hospitalization and improving the chest radiographs (CXRs) in hospitalized infants with respiratory syncytial virus (RSV) infection as a result of its mucolytic properties.

Methods: Randomized, double-blind, placebo-controlled investigation of 75 patients with RSV bronchiolitis. The study was conducted at the University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI.

Results: The respiratory rate, wheezing, and retraction difference scores, obtained by subtracting the hospital discharge score from the corresponding hospital admission score, show no difference between the two groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001). Analysis of covariance for the hospital discharge CXR score after adjusting for the hospital admission score for both groups was done. There was a difference in scores between the two groups, with adjusted mean for the study group of 2.03, and 2.76 for the placebo group (p < 0.001). Paired t test statistics in each of the two groups were computed. For the placebo group, the mean increase of 0.60 was significant (p = 0.02), and the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01).

Conclusion: In patients with RSV bronchiolitis, there was significant improvement in the CXRs with the use of rhDNase compared to significant worsening in the placebo group. To our knowledge, this is the first report of the use of rhDNase to treat RSV bronchiolitis.

Key Words: chest radiography • clinical score • length of stay • mucus • randomized clinical trial • respiratory syncytial virus


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children in the United States. It continues to be a major cause of hospitalization in children < 1 year old,1 leading to > 90,000 hospitalizations annually. A Canadian study2 has reported that nearly two thirds of societal costs related to annual RSV epidemics are the result of hospitalization in < 1% of those infected. Therapies that reduce hospital days could potentially reduce health-care expenditures for this condition. Currently, controversy exists related to the optimal treatment for bronchiolitis. Clinical trials3 4 using ß2-agonists to treat RSV bronchiolitis have in some cases shown short-term improvement, while others5 failed to show significant improvement. The use of glucocorticoids in the treatment of bronchiolitis has infrequently shown6 a positive therapeutic effect; more often, studies7 8 have demonstrated no clinical improvement in previously normal children with bronchiolitis. Immunoglobulin preparations to prevent hospitalization have not resulted in cost saving, improvement in mortality, or need for mechanical ventilation.

Pathophysiologically, bronchiolitis is an infectious inflammation of bronchioles from 75 to 300 µm in diameter.9 This invasion leads to necrosis of the respiratory epithelium and sloughing into the airway lumen. Tissue edema and mucus production occur resulting in thick mucous plugs within the airway lumen.9 This process leads to a disruption of the normal airflow. Some airways become partially or completely occluded, leading to air trapping and hyperinflation or atelectasis.10 Due to lysis of inflammatory cells, DNA is present in large amounts (3 to 14 mg/mL) in the mucous plugs. DNA is a polyanion molecular compound that contributes to the increased viscosity and adhesiveness of lung secretions.11 Recombinant human deoxyribonuclease I (rhDNase) has been used effectively as a mucolytic agent to liquefy the thick mucous plugs in patients with cystic fibrosis.12

We hypothesized that therapy with rhDNase may result in shorter length of hospitalization, improved clinical scores, and improved chest radiographs (CXRs) in hospitalized infants with RSV infection as a result of its mucolytic properties. A randomized, double-blind, placebo-controlled study was performed to assess this hypothesis.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design
This was a randomized, double-blind, placebo-controlled investigation conducted at two study sites (University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI). Patients were randomly assigned at entry to receive either rhDNase or placebo aerosol therapy at a dose of 2.5 mL once daily12 for up to 5 days while hospitalized for RSV bronchiolitis. The randomization was conducted by the University of Michigan Investigational Drug Service using a random table sample with block of fours. The criteria for hospitalization of these patients were decided by the emergency department attending physician at both institutions. The drug was administered on the enrollment day followed by daily morning administration until the patient was ready for hospital discharge or for 5 days of administration. Patients were examined at entry and observed twice daily by the investigator/study coordinator until hospital discharge. All patients were enrolled within 24 h of hospital admission.

Patients
Patients were eligible for this study if they met the following conditions: (1) <= 2 years of age, (2) previously healthy full-term neonates, and (3) proven RSV infection. All other patient-care management was decided by the attending physician. All patients in the two groups received albuterol nebulized treatment as part of the RSV protocol in the two institutions. No ipratropium bromide was administered. Written, informed consent was obtained from patient’s parent/guardian according to the guidelines of both institutional review boards. Early discontinuation of therapy was permitted if desired by parents/guardian or attending physician or if the patient required intubation and mechanical ventilation.

Clinical Assessment Scoring
Patients were examined twice daily by a pediatric pulmonologist (S.Z.N. and N.J.M.) or study coordinator; all were blinded to the patient’s assignment. The examinations were done once before and once after administration of the study drug. Each child was evaluated at each point by the same observer. The clinical assessment scoring described by Wang et al13 was utilized. A single point was given to patients with a respiratory rate of 31 to 45 breaths/min, wheezing at terminal expiration or only with stethoscope, intercostal retraction, and normal general condition. Two points were given to patients with a respiratory rate of 45 to 60 breaths/min, wheezing during the entire expiration or audible on expiration without stethoscope, tracheosternal retractions, and stable general condition. Three points were given to patients with a respiratory rate > 60 breaths/min, inspiratory and expiratory wheezing without stethoscope, severe retraction with nasal flaring, and general condition including irritability, lethargy, and poor feedings. Oxygen saturation and the need for supplemental oxygen were also recorded.

CXR Scoring
CXRs were obtained at the time of hospital admission and at completion of the study or prior to hospital discharge if it occurred prior to 5 days. Anteroposterior and lateral CXRs were obtained in most patients (64 of 75 patients). All CXRs were coded and randomized. Anteroposterior and lateral CXRs of the same patient were kept together. Two pediatric radiologists (P.J.S. and K.A.G.) reviewed the CXRs and were blinded to each patient’s study assignment, identity, and date of examination (hospital admission vs discharge). A CXR scoring system was developed based on review of the literature14 15 and personal experience of the radiologists. Each examination was graded for perihilar markings, hyperinflation, atelectasis or focal opacities, and generalized opacities. Each of these findings was graded on a 0- to 3-point scale, with 0 representing normal and 3 representing marked abnormality (Table 1 ). Hyperinflation was scored separately on the anteroposterior CXR and on the lateral CXR, with the two scores averaged. The anteroposterior CXR score was used if no lateral CXR was available. The other three findings were given a single score based on the radiologists’ assessment of both views. The scores for each examination finding (1 to 4) were then summed to generate an examination score. This score ranged from 0 (all findings normal) to 12 (all findings markedly abnormal).


View this table:
[in this window]
[in a new window]

  		Table 1. Description of Categories for Radiologic Assessment

 
Study Drug Administration
Patients were randomly assigned to receive either 2.5 mg of rhDNase or a placebo once a day. The dose was based on the results of a previous study.12 Both physicians and parents were blinded with respect to the treated and placebo groups. 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). The placebo was excipient alone. The study drug (rhDNase or control) was nebulized once a day. All patients received the study drug with the same nebulizing equipment (Vixone; West Med, Inc.; Tucson, AZ). A tight-fitting mask was used with the nebulized equipment for better delivery of the study drug. The first dose was given within 24 h after hospital admission; subsequent doses were administered between 7 AM and 8 AM each day. Patients received therapy for up to 5 days.

Virology Studies
Specimens for viral isolation and quantitation were obtained from a nasopharyngeal swab and assayed for antigen detection using indirect immunofluorescent antibody staining technique with the Bartels Viral Respiratory Screening and Identification Kit (Bartels Immunodiagnostic Supplies; Bellevue, WI). Sensitivity for this test is 94%, and specificity is 93%.

Statistical Analysis
The power of the study was 80% to be able to detect a 1-day difference in hospital length of stay. Data were analyzed using statistical software (SAS version 6.12; SAS Institute; Cary, NC). The statistician was unaware of treatment status coding. Two-sample t tests were used to compare the means of interval scale measures obtained from the drug and placebo samples at both hospital admission and discharge. {chi}2 and Fisher’s Exact Tests were used to compare frequency distributions obtained from the two groups. Ratings obtained from the two pediatric radiologists were analyzed using paired t tests and correlation coefficients. One-way analyses of covariance models were used to compare interval scale outcomes obtained at discharge controlling for hospital admission values.

Measurement of DNA Content
BAL fluid (BALF) was obtained from a subset of six patients with RSV bronchiolitis that required intubation and mechanical ventilation for management of their disease. Two patients who did not have RSV bronchiolitis and were intubated and received mechanical ventilation following elective surgery served as control subjects. BALF was obtained through flexible bronchoscopy. The suction catheter was "wedged" in the lower airway. Samples were obtained within 24 h from intubation and ventilation. BALF was lyophilized and resuspended to a standard volume of 1 mL. DNA content was measured by microfluorometry using 33258 Hoechst fluorochrome (Calbiochem; La Jolla, CA).16 Calf thymus DNA (Sigma Chemical; St. Louis, MO) was used as a standard. The supernatant was diluted 1:800 with saline-citrate solution (0.0154 M NaCl-0.015 M Na3-citrate, pH 7.0). One millimeter of the reagent solution (33258 Hoechst 1.5 x 10-6 M) was added to the sample, and fluorescence was measured by spectrophotofluorometry with an excitation wavelength at 360 nm and emission at 450 nm. DNA concentration was calculated by comparison with calf thymus DNA standard (0.25 to 10.0 µg/mL).17


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Eighty-six previously healthy, hospitalized infants with proven RSV bronchiolitis were enrolled in the study between February 1996 and May 1998. All patients completed the study. Eleven patients were excluded from the analysis because of missing data (75 patients were included in the analysis). Eleven more patients did not receive hospital admission or discharge CXRs and were excluded from the analysis of CXR scoring (64 patients). Table 2 represents patient demographics by treatment-group assignment. None of the patients received steroids prior to hospitalization. The steroid dose was 2 mg/kg/d for 3 to 5 days as a burst.


View this table:
[in this window]
[in a new window]

  		Table 2. Clinical Characteristics of the Patient Population*

 
Study aerosol treatments were administered daily to patients for 3.33 ± 2.00 days and 3.34 ± 2.30 days (mean ± SD) for the study and the placebo group, respectively. At hospital admission, the severity of illness based on clinical assessment scoring13 for the two groups was not statistically significant (Table 3 ). However, the 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. The two groups were also compared in terms of clinical measures obtained at hospital discharge. Descriptive statistics underlying these comparisons with associated significance levels are presented in Table 3 . These group comparisons also show no significant difference between the groups. Table 4 shows descriptive statistics for the difference scores obtained by subtracting the hospital discharge score from the corresponding hospital admission score, which are presented with significance levels from tests for group differences. The respiratory rate, wheezing, and retraction difference scores show no difference between the groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001).


View this table:
[in this window]
[in a new window]

  		Table 3. Summary of Results*

 

View this table:
[in this window]
[in a new window]

  		Table 4. Difference Measures Between Hospital Admission and Discharge*

 
Correlation analysis of the ratings obtained from the two pediatric radiologists showed that there was substantial agreement between the two observers. The correlation for ratings of CXRs obtained at the time of hospital admission was 0.76; the correlation at the time of hospital discharge was 0.73. However, the radiologists differed systematically as shown by paired t test analysis. For the hospital admission CXRs, the mean ratings for the two observers were 2.68 and 1.85 (p < 0.0001); for the hospital discharge CXRs, the means were 2.77 and 1.95 (p < 0.0001). Because of the high correlations between the radiologists, the average score of the two radiologists was used as our primary outcome variable.

When analysis of covariance for the CXR score was done for the two groups on hospital admission and discharge for each of the radiologists and for the average of the two radiologists, there was no statistical significance. However, when we looked at the hospital discharge score after adjusting for the admission score for both groups, there was a difference in scores between the two groups. This difference was also noted when we looked at each radiologist’s scores separately and for the average of the two radiologists, with adjusted mean for the study group of 2.03 and 2.76 for the placebo group (p < 0.001). This suggests that the study group was somewhat worse on hospital admission compared to the placebo group.

Having observed the significant group difference in CXR difference scores, we computed paired t test statistics in each of the two groups. For the placebo group, we observed that the mean increase of 0.60 was significant (p = 0.02) and that the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01)

Because of the observed differences between radiologists, to be sure that the radiologic results described were not an artifact attributable to the process of averaging the ratings, we carried out two sets of separate analyses, each of which used only data from one of the two pediatric radiologists. These analyses, which were parallel to the ones reported for the mean CXR scores, showed the same pattern of significance.

To evaluate our hypothesis and the literature,11 which indicates that the DNA content is increased in the mucus of RSV patients, we analyzed the content of BAL of a subset of six patients with RSV bronchiolitis and two patients who were RSV negative. All patients were intubated and received mechanical ventilation. The DNA content for the RSV group was 194.30 ± 213.48 µg/mL (mean ± SD), with a range of 59.7 to 611.0 µg/mL. The DNA content in the two RSV-negative patients (control group) was 43.8 µg/mL and 95.6 µg/mL, respectively.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This randomized, double-blind, controlled trial suggests that nebulized rhDNase may improve the CXR appearance of patients treated for acute bronchiolitis in infancy and may have the potential to improve the hospital course for these patients. Based on the observation that a significant improvement in the CXR score in the rhDNase group occurred, a significant worsening of the score in the placebo group indicates that this is not a chance occurrence.

The clinical assessment score and oxygen saturation were not statistically significant between the two groups at hospital discharge. These findings are probably due to the short hospital stay. The length of hospital stay between the two groups was not statistically significant as well. One explanation may be that patients with bronchiolitis are usually discharged from the hospital prior to complete resolution of symptoms, once their conditions are clinically stable. It is not known whether a different dosing schedule or frequency of rhDNase administration would result in improved outcomes such as length of hospitalization and clinical score. Additional studies will be required to assess such treatment outcome issues.

The aerosol therapy appeared safe and was easily administered. There were no adverse effects identified in either study group. There was no early withdrawal or termination of the study. The lack of side effects in this study as well as in another study12 when the drug was used for longer periods of time, the safety margin, and the ease of administration of this drug suggest that this drug therapy could be continued beyond 5 days, especially if the patients required longer hospitalization because of severity of illness. There was no airway hyperactivity or bronchospasm noted clinically with the use of the nebulized aerosol treatment in the study subjects.

This is the first study to our knowledge that was conducted to evaluate the usefulness of rhDNase, a mucolytic agent, in treating RSV bronchiolitis. Other treatment modalities have not proven effective to date. Of these, bronchodilators have been studied with conflicting results.3 4 5 Also, anti-inflammatory agents such as glucocorticoids have been studied and shown improvement in some studies6 and no clinical significance has been observed in the majority of studies.7 8 Ribavirin is the only antiviral agent approved for use in treating hospitalized children with RSV infection. Much controversy exists surrounding its use. It has been studied in healthy children and in high-risk groups with conflicting results.18 19 20 21 Moreover, potential side effects, costs, and the difficulty of administration have made its use problematic.

RSV infection is a very costly disease to the health system and economy, with > 90,000 hospitalizations in infants and young children annually. RSV may also lead to long-term problems with reactive airway disease. Thus far, attempts to develop an RSV vaccine have not been fruitful.22 Another approach to reduce hospitalization and long-term problems caused by RSV infection in the high-risk patient population has been to use a polyclonal RSV immune globulin product (RSV-immune globulin IV therapy),23 24 and more recently a humanized RSV monoclonal antibody (palivizumab).25 26 This prophylactic approach has limited success in high-risk patients. Thus far, therapeutic studies in hospitalized patients have not shown improved outcomes. Used for prophylaxis, these agents have high cost relative to benefits observed.27

We conclude that nebulized rhDNase may be an effective therapy for use in treating RSV infection in infants and young children; on the basis of the significant improvement in the CXR, it appears that rhDNase could be efficacious. However, further studies are warranted to confirm the results of this study and to investigate changes in clinical status and length of hospital stay by using this drug. Studies are needed to evaluate the usefulness of starting treatment with rhDNase once symptoms develop (eg, at the primary physician’s office or the emergency department) before the patient’s clinical condition warrants hospitalization. Treating RSV illness earlier may reduce the rate of hospitalization and other morbidities. This study revealed interesting findings that need to be examined further. It should be emphasized that the use of this drug to treat RSV bronchiolitis is not recommended without further studies.


   Acknowledgements
 
We thank Sharon Stetz, RN (study coordinator), and respiratory therapy staff, the nursing staff, and the housestaff at Mott Hospital, University of Michigan; and the nursing staff, the research council staff, and the staff physicians at St. Joseph Mercy Hospital. Statistical analyses were performed by Kenneth E. Guire, MS, at the Center for Statistical Consultant and Research, University of Michigan. We also thank Dr. Jung-Soo Kim for analysis of DNA in BALF and Jami L. Shaw for help with manuscript preparation.


   Footnotes
 
Abbreviations: BALF = BAL fluid; CXR = chest radiograph; rhDNase = recombinant human deoxyribonuclease I; RSV = respiratory syncytial virus

Supported in part by National Institutes of Health grant MO1-RR00042.

Presented in part at the International Conference for the American Thoracic Society, Toronto, Canada, May 8, 2000.

Presented in part at the Pediatric Academic Societies and American Academy of Pediatrics Joint Meeting, Boston, MA, May 12, 2000.

Received for publication June 7, 2000. Accepted for publication January 8, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hanvey, L, Avard, D, Graham, I, et al (1994) The health of Canada’s children: a CICH profile 2nd ed. Canadian Institute of Child Health Ottawa, Canada.
  2. Langley, JM, Wang, EEL, Law, BJ, et al (1997) Economic evaluation of respiratory syncytial virus infection in Canadian children: a Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study. J Pediatr 131,113-117[CrossRef][ISI][Medline]
  3. Alano, AJ, Lewander, WJ, Dennehy, P, et al (1992) The efficacy of nebulized metaproterenol in wheezing infants and young children. Am J Dis Child 146,412-418[Abstract]
  4. Klassen TP, Rower PC, Sutcliffe T, et al. Randomized trial of salbutamol in acute bronchiolitis [published erratum appears in J Pediatr 1991; 119:1010]. J Pediatr 1991; 118:807–811
  5. Gadomski, AM, Lichenstein, R, Horton, L, et al (1994) Efficacy of albuterol in the management of bronchiolitis. Pediatrics 93,907-912[Abstract/Free Full Text]
  6. Van Woensel, JB, Wolfs, TF, van Aalderen, WM, et al (1997) Randomized double blind placebo controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis. Thorax 52,634-637[Abstract]
  7. Connoly, JH, Filed, CMB, Glasgow, JFT, et al (1969) A double blind trial of prednisolone in epidemic bronchiolitis due to respiratory syncytial virus. Acta Pediatr Scand 58,116-120[ISI][Medline]
  8. Klassen, TP, Sutcliffe, T, Watters, LK, et al (1997) Dexamethasone in salbutamol treated patients with acute bronchiolitis: a randomized, controlled trial. J Pediatr 130,191-196[CrossRef][ISI][Medline]
  9. Spencer, H (1985) Pathology of the lung. ,131-165 Pergamon Press Oxford, UK.
  10. Cherry, JD (1987) Acute bronchitis. Feigen, R Cherry, J eds. Textbook of pediatric infectious disease 2nd ed. ,271-275 WB Saunders Philadelphia, PA.
  11. Picot, R, Das, I, Reid, L (1978) Pus, deoxyribonucleic acid, and sputum viscosity. Thorax 33,235-242[Abstract]
  12. Fuchs, HJ, Borowitz, DS, Christiansen, DH, et al (1994) Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 331,637-642[Abstract/Free Full Text]
  13. Wang, EEL, Milner, RA, Navas, L, et al (1992) Observer agreement for respiratory signs and oximetry in infants hospitalized with lower respiratory infections. Am Rev Respir Dis 145,106-109[ISI][Medline]
  14. Babcook, CJ, Norman, GR, Coblentz, CL (1993) Effect of clinical history on the interpretation of chest radiographs in childhood bronchiolitis. Invest Radiol 28,214-217[ISI][Medline]
  15. Friis, B, Eiken, M, Hornsleth, A, et al (1990) Chest radiograph appearances in pneumonia and bronchiolitis. Acta Pediatr Scand 79,219-225[ISI][Medline]
  16. Cesarone, CF, Bolognesi, C, Santi, L (1979) Improved microfluorometric DNA determination in biological material using 33258 Hoechst. Anal Biochem 100,188-197[CrossRef][ISI][Medline]
  17. Kim J-S, Hackley GH, Canache AT, et al. Inflammatory mediators in cystic fibrosis and chronic bronchitis sputum. Pediatr Pulmonol 2001 (in press)
  18. Moler, FW, Steinhart, CM, Ohmit, SE, et al (1996) Effectiveness of ribavirin in otherwise well infants with respiratory syncytial virus-associated respiratory failure. J Pediatr 128,442-448[CrossRef]
  19. Smith, DW, Frankel, LR, Mathers, LH, et al (1991) A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med 325,24-29[Abstract]
  20. Meert, KL, Sarnaik, AP, Gelmini, MJ, et al (1994) Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double blind, randomized trial. Crit Care Med 22,566-572[ISI][Medline]
  21. Guerguerian, A-M, Gauthier, M, Lebel, MH, et al (1999) Ribavirin in ventilated respiratory syncytial virus bronchiolitis: a randomized, placebo-controlled trial. Am J Respir Crit Care Med 160,829-834[Abstract/Free Full Text]
  22. Tristram, DA, Welliver, RC (1996) A vaccine for RSV: is it possible? Contemp Pediatr 13,47-63
  23. Rodriguez, WJ, Gruber, WC, Welliver, RC, et al (1997) Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infection. Pediatrics 99,454-461[Abstract/Free Full Text]
  24. Rodriguez, WJ, Gruber, WC, Groothius, JR, et al (1997) Respiratory syncytial virus immune globulin treatment of RSV lower respiratory tract infection in previously healthy children. Pediatrics 100,937-942[Abstract/Free Full Text]
  25. . The IMpact-RSV Study Group (1998) Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102,531-537[Abstract/Free Full Text]
  26. . The PREVENT Study Group. (1997) Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 99,93-99[Abstract/Free Full Text]
  27. Joffe, S, Ray, GT, Escobar, GJ, et al (1999) Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics 104,419-427[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 ChestHome page
R. Boogaard, A. R. Hulsmann, L. van Veen, A. A. P. H. Vaessen-Verberne, Y. N. Yap, A. J. Sprij, G. Brinkhorst, B. Sibbles, T. Hendriks, S. W. W. Feith, et al.
Recombinant Human Deoxyribonuclease in Infants With Respiratory Syncytial Virus Bronchiolitis
Chest, March 1, 2007; 131(3): 788 - 795.
[Abstract] [Full Text] [PDF]

Home page
 Arch Pediatr Adolesc MedHome page
W. C. Bordley, M. Viswanathan, V. J. King, S. F. Sutton, A. M. Jackman, L. Sterling, and K. N. Lohr
Diagnosis and Testing in Bronchiolitis: A Systematic Review
Arch Pediatr Adolesc Med, February 1, 2004; 158(2): 119 - 126.
[Abstract] [Full Text] [PDF]

Home page
 Arch Pediatr Adolesc MedHome page
V. J. King, M. Viswanathan, W. C. Bordley, A. M. Jackman, S. F. Sutton, K. N. Lohr, and T. S. Carey
Pharmacologic Treatment of Bronchiolitis in Infants and Children: A Systematic Review
Arch Pediatr Adolesc Med, February 1, 2004; 158(2): 127 - 137.
[Abstract] [Full Text] [PDF]

Home page
 Pediatr. Rev.Home page
C. A. McCarthy and C. B. Hall
Respiratory Syncytial Virus: Concerns and Control
Pediatr. Rev., September 1, 2003; 24(9): 301 - 309.
[Full Text] [PDF]

Home page
 ChestHome page
A. Mandelberg, G. Tal, M. Witzling, E. Someck, S. Houri, A. Balin, and I. E. Priel
Nebulized 3% Hypertonic Saline Solution Treatment in Hospitalized Infants With Viral Bronchiolitis
Chest, February 1, 2003; 123(2): 481 - 487.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
E. M. Sarrell, G. Tal, M. Witzling, E. Someck, S. Houri, H. A. Cohen, and A. Mandelberg
Nebulized 3% Hypertonic Saline Solution Treatment in Ambulatory Children With Viral Bronchiolitis Decreases Symptoms
Chest, December 1, 2002; 122(6): 2015 - 2020.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (23)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nasr, S. Z.
Right arrow Articles by Moler, F. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nasr, S. Z.
Right arrow Articles by Moler, F. W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS