Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Prednisolone Treatment of Respiratory Syncytial Virus Infection: A Randomized Controlled Trial of 147 Infants

Bülow SM, Nir M, Levin E, et al.

Pediatrics 1999; 104: e77. [abstract] [full-text]

Reviewed by Joseph R. Hageman, MD, FAAP, FCCM, The Evanston Hospital, Northwestern University School of Medicine, Barry Markovitz, MD, FAAP, St. Louis Children's Hospital, Washington University School of Medicine

Review posted December 24, 2000

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I. What is being studied?:

The study objective:

To investigate the short and long term effects of the use of systemic corticosteroids in a large unselected group of infants hospitalized with Respiratory Syncytial Virus (RSV) infection.

The study design:

This is a prospective, randomized, double blind, placebo controlled multi-center trial.

The patients included:

Infants < 2 years of age who were hospitalized with RSV infection (defined as a respiratory tract infection with a positive RSV test-immunofluorescence in 2 centers and an ELISA test (Abbott Test Pack; Abbott Laboratories in the 3rd center.) during the time interval between November, 1995 and April, 1996 in one of the 3 participating medical centers providing care to the 34,000 infants < 2 years of age of the county of Copenhagen (and one other neighboring county). These data are summarized from Table 1:

Approximate number of RSV tests performed	1022
Infants < 2 years of age with positive RSV tests	372
Exclusion criterion #6 (doctor not present)	37
Approached	335
Randomized	147
Parents refused	131
Exclusion criteria 1-5	57

The patients excluded:

The exclusion criteria included the following:

• Disease in which corticosteroids are contraindicated
• Corticosteroid treatment within the last month (local or systemic)
• Forty eight hours has lapsed since the positive RSV test had been obtained
• Premature infants who, at the time of the randomization have a gestational age of < 40 weeks
• Communicative problems
• Parents are not approached because of absence of a doctor in charge

The interventions compared:

Oral prednisolone 2 mg/kg/day x 5 days with a placebo (quinine hydrochloride - to mimic the bitter taste of the active drug).

The outcomes evaluated:

Acute effect variables included duration of hospital stay, duration of illness and time for start in the day care center. Morbidity at one month and one year following discharge was assessed by the numbers of patients receiving treatment for asthma and having been admitted to the hospital for respiratory infections.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, by a computer-generated program

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Not quite. Of the 147 randomized, 11 patients could not be contacted at the one month and one year followup.

Were patients analyzed in the groups to which they were randomized?

Yes, they were. There was no crossovers between groups and all were analyzed by "intention to treat" despite 2 patients not receiving the assigned drug.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes.

4. Were the groups similar at the start of the trial?

Yes, the 2 groups were similar with respect to age, gender, duration of symptoms, exposure to tobacco smoke at home and other pertinent variables.

5. Aside from the experimental intervention, were the groups treated equally?

Probably. They report that patients received routine treatments, but they do not go into detail about other aspects of their care.

III. What were the results?

1. How large was the treatment effect?

Comparison of the effect variables during the 5 days of the treatment, at 1 month and at 1 year after discharge from the hospital failed to reveal any positive or negative effects of systemic corticosteroids during the acute state of RSV infection, at 1 month and 1 year after discharge from the hospital. However, there are salient data to review including the following:

• Of the total of 147 patients enrolled in the study, 134 completed the treatment course.
• The median hospital stay for both the experimental treatment group and the group taking placebo were 3.6 and 4.0 days respectively.
• Of note, a total of 27 patients (12%) were treated with supplemental oxygen and 16 (11%) were treated with nasal CPAP; there were no differences between the groups. One patient in the placebo group required assisted ventilation.
• Finally, hydration was provided by nasogastric tube and/or the intravenous route in a total of 40 patients (27%).

Assistance with respiration and hydration, are the two most frequent reasons for admission in patients with RSV bronchiolitis.

2. How precise was the estimate of the treatment effect?

The logistic regression showed an odds ratio for the treatment group of 1.26 for asthma treatment at 1 year and 0.83 for admission to the hospital with respiratory tract infection. This means that of the patients diagnosed with asthma by one year after discharge, they were 1.26 times as likely to have come from the treatment group compared to the control group. Similarly, of those admitted within the year for respiratory infection , they were 0.83 times as likely to have come from the treatment group. Although confidence intervals were not given, these were reported to be not significant.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

In general, yes. However, there were some differences that call into question the similarities of the study patients and ours. About 90+% of infants with RSV bronchiolitis managed in our institution require supplemental oxygen and about 10% receive some form of CPAP or assisted ventilation. These therapies were employed much less often in this study.

2. Were all clinically important outcomes considered?

Yes. The most important outcomes were duration of stay during the acute stage and numbers of patients seen in followup who are treated for reactive airway disease or asthmatic bronchitis (as the authors refer to in the manuscript).

3. Are the likely treatment benefits worth the potential harms and costs?

There was no demonstrable benefit and harms and costs were not evaluated.

Tang and Wang reviewed a total of 9 randomized control trials and concluded that there was inadequate evidence to establish whether corticosteroids were helpful or harmful in treatment of RSV infection in infants or children.(1)

However, Garrison and colleagues performed a meta-analysis and found that corticosteroids reduced hospital stay by about one half of a day. Although, not a large difference for an individual patient, given the thousands of patients admitted with RSV during each year, the total number of "one half days" might well add up. (2)

Finally, What is unique about Bülow and colleagues' paper is the long term followup. It is possible, that with larger numbers, a difference in short and/or long term outcome might have been seen with larger numbers and/or greater severity of illness.

References:

1. Tang N, Wang E: Bronchiolitis. Clinical Evidence. 2000; Issue 3. 173-181. BMJ Publishing Group
2. Garrison MM, Christakis DA, Harvey E, Cummings P, Davis RL. Systemic Corticosteroids in Infant Bronchiolitis: A Meta-analysis. Pediatrics. 2000;105:e44. [abstract] [full-text] [PedsCCM EB Journal Club Review]

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