Clinical trial NCT04221087
Conditions: Bronchiolitis, Viral
Keywords: bronchiolitis non-RSV bronchiolitis dexamethasone treatment steroid
Sponsor: Allison Williams
Start date: 2020-02-03; Completion date: 2022-12-31
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed study is a pilot randomized control trial to determine the efficacy of dexamethasone use in hospitalized children who are less than 2 years of age with non-respiratory syncytial virus (RSV) bronchiolitis admitted to the University of Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh from February 1 to May 31, 2022. It is hypothesized that the use of standard airway-dose steroids (0.6mg/kg dexamethasone) will improve the clinical outcome of children hospitalized for non-RSV bronchiolitis, which will be evident by decreased length of stay.

Detailed description:
The study will take place at UPMC Children's Hospital of Pittsburgh with patients admitted to the general pediatric service. The attending physician on the clinical service team will identify patients diagnosed with bronchiolitis. If the participant meets inclusion and exclusion criteria, a member from the study team will then meet with the participant's family to discuss the study and obtained informed consent. A participant may have had a rapid RSV/influenza testing already complete for clinical purposes. If this has been done, participants will be asked to obtain a secondary nasopharyngeal swab so that it may be tested for a full respiratory viral panel for statistical stratification. Once rapid testing is obtained and results are negative for both RSV and influenza, the participant will then be randomized to either the intervention (dexamethasone) or control (placebo) arm of the study. Study members will calculate a modified Tal score (MTS) at time of consent and then 12-24 hours after medication administration. Throughout admission, participants will also receive standard of care for bronchiolitis, which may include regular vital sign evaluation, supplemental oxygen, intravenous fluids or nasogastric tube feedings, and anti-pyretic therapy. Because this is a pilot study, the study will be underpowered, however, this study will provide data that will allow the investigators to estimate the sample size needed for a future study. The number of time points to be used for the generalized estimating equation can be determined ad hoc to include a reasonably balanced sample to make the comparison valid.

Arms: arm 1: Participants will be given a placebo of sugar water (0.6ml/kg/dose) in a single oral dose and standard of care for bronchiolitis (supplemental oxygen, antipyretics, suctioning etc.) arm 2: Participants will be given dexamethasone (0.6mg/kg/dose) in a single oral dose in addition to the standard of care for bronchiolitis (supplemental oxygen, antipyretics, suctioning etc.)
Interventions: intervention 1: Placebos intervention 2: Dexamethasone Oral
Intervention descriptions: intervention 1: Sugar water based on same ml dosing of intervention arm drug intervention 2: 0.6mg/kg/dose - single oral dose administration to intervention arm

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Study Protocol 
 
Steroid Use for the Treatment of Non-RSV Bronchiolitis 
NCT04221087 
11/9/2022 
 
 


Study Protocol: 
Scientific background: Bronchiolitis is the most common viral lower respiratory tract infection 
experienced by children < 24 months. The most common pathogen causing bronchiolitis is RSV, 
with the highest incidence of infection occurring throughout late winter/spring. Signs and 
symptoms include nasal congestion, cough, tachypnea, wheeze, and rales, and may progress to 
symptoms of respiratory distress (accessory muscle use, nasal flaring, head bobbing). While 
RSV is the predominant virus associated with bronchiolitis (up to 40% of cases), other viruses 
including rhinovirus, influenza, human metapneumovirus, and parainfluenza virus are also 
common causes. The second most common viral etiology of bronchiolitis is rhinovirus, which 
may account for up to 25%-40% of cases. 
Bronchiolitis is one of the leading causes of hospitalization for young children. In 2002, it was 
estimated that bronchiolitis hospitalization costs totaled $543 million, with a mean length of stay 
of 3.3 days. One study in 2013 indicated that although the incidence of hospitalizations for 
bronchiolitis decreased in the early 2000s, national healthcare utilization costs increased from 
$1.34 billion to $1.73 billion (a 30% increase). Due to the prevalence of bronchiolitis and high 
utilization cost, the American Academy of Pediatrics (AAP) issued an update in 2014 of the 
2006 guidelines for the diagnosis, management, and prevention of bronchiolitis. These guidelines 
indicate that bronchiolitis should be diagnosed clinically and treated with supportive care, such 
as nasal suctioning, intravenous fluid administration, and supplemental oxygen if required. These 
guidelines specifically recommend against the use of bronchodilators, nebulized hypertonic 
saline, systemic corticosteroids, and antibacterials. Since these guidelines have been published, 
studies show that there has been on overall decrease in both healthcare utilization costs and 
length of admission, but that there has not been a significant impact on all-cause 7-day 
readmission rates. 
While the treatment and management of RSV bronchiolitis has been extensively studied and 
validated, there is significantly less evidence to support similar management in children with 
non-RSV bronchiolitis. We conducted a literature review of over 120 articles related to the 
treatment of bronchiolitis with steroids. Many articles, including the AAP 2014 revised 
guidelines, discuss the limited use of steroids in the treatment of bronchiolitis. A 2007 PECARN 
multicenter study also showed no significant difference in hospitalization rate or re-admission 
rate with steroid use. These studies, however, do not differentiate between RSV and non-RSV 
bronchiolitis. 
Studies evaluating the immune response to different viral etiologies of bronchiolitis indicate that 
there may be a significant difference in the pathophysiology of disease. For example, RSV 
bronchiolitis causes an increased expression of β glucocorticoid receptors (GR) with no increase 
in α-GR, leading to a lower ratio of α/β receptors, which has been associated with an insensitivity 
response to glucocorticosteroids. In contrast, human rhinovirus-associated bronchiolitis has been 
associated with a higher Th2 helper cell response leading to more histamine release than RSV, 
which causes a Th1 predominant response. Additionally, a meta-analysis from 2017 suggested 
that infection with rhinovirus leading to wheezing before the age of 36 months is associated with 
increased risk of developing asthma later in life, possibly through airway remodeling, epithelial 
release of cytokines, and upregulated expression of genes predisposing to asthma. The 
mechanism of action of corticosteroids revolves around the inhibition of initial inflammatory 


responses such as vasodilation and chemotaxis of leukocytes to sites of inflammation. Since 
rhinovirus appears to have a different pathophysiology of immune response, it is possible that 
bronchiolitis secondary to other non-RSV viruses may respond to different immunomodulators, 
specifically steroids. This pilot study will contribute knowledge about the utility of steroid use in 
non-RSV bronchiolitis both clinically in terms of patient outcomes, and economically in terms of 
hospital utilization. If the proposed aims are achieved, this contribution will be significant 
because there may be reason to re-evaluate the current AAP Guidelines for diagnosis and 
management of bronchiolitis. We hypothesize that steroid use in this cohort will reduce length of 
stay, and subsequently reduce hospital costs through reduction of both 7-day same cause re-
admission rate and escalation of care (transfer to ICU). 
In the short term, our work will address the feasibility of conducting a clinical trial assessing the 
utility and safety of steroid use in non-RSV bronchiolitis in the inpatient setting. Moreover, the 
work proposed here will develop a platform for a larger, multi-center double-blinded randomized 
control trial addressing the same question. This pilot study will establish expected target 
enrollment rates, adherence and drop-out rates, expected length of stay, and expected severity of 
disease assessed with the Kristjansson score at time of discharge for use in sample size and 
power calculations for future phase II/III trials. Thus, this work will be a foundational resource 
providing a research strategy and protocol for a larger scale trial. 
Objectives: The long-term objective of this research is to improve the clinical course and 
outcomes of children diagnosed with non-RSV bronchiolitis. The objective of this proposal is to 
determine the efficacy of steroid use as a treatment modality in children < 24 months diagnosed 
with non-RSV bronchiolitis. The central hypothesis is that the use of standard airway- dose 
steroids (0.6mg/kg dexamethasone) will improve the clinical outcome of children hospitalized 
for non-RSV bronchiolitis, which will be evident by decreased length of stay. The central 
hypothesis was formulated based on data showing an interleukin response to rhinovirus that is 
dampened by steroid administration. The rationale underlying this proposal is that the 
completion of this research will identify a new treatment option for non-RSV bronchiolitis. The 
proposed work may change the currently accepted practice guidelines for diagnosis and 
management of bronchiolitis. The central hypothesis will be tested by pursuing these specific 
aims: 
1) To determine the extent to which steroid administration reduces hospital length of stay for 
clinical non-RSV bronchiolitis. 
Hypothesis: Steroid administration will decrease duration of admission from time of admission 
from the emergency department (ED) to time of discharge instructions being printed. 
2) To determine the extent to which steroid administration reduces the severity of bronchiolitis 
by using the Modified Tal Score to assess patients at admission, enrollment (if differs from 
admission time), 24 hours after administration of intervention, and discharge. 
Hypothesis: Steroid administration will reduce the severity of bronchiolitis, which will be 
evident by a lower Modified Tal Score at 24 hours after medication administration. 
Design/Methods: The study is a double-blind, randomized control trial. All participants will be 
treated with standard of care for viral bronchiolitis, including supportive care. All participants 
will also have had some form of viral testing confirming they do not have RSV or influenza. In 


addition, half the participants will receive standard airway dosing of dexamethasone (0.6mg/kg) 
orally, and the other half will received placebo (sugar water 0.6mL/kg). 
Eligibility Criteria: 
Inclusion criteria: 
1. Less than or equal to 24 months 
2. First episode of wheezing or a clinical diagnosis of bronchiolitis 
3. Admitted to the general pediatric service at UPMC Children's Hospital of Pittsburgh 
4. Between 2/1/20 and 12/31/22 
5. Ability of a parent or guardian to understand and comply with the study procedures 
6. Signed written informed consent by parent or guardian 
7. Respiratory viral testing obtained within 24 hours of admission 
Exclusion Criteria 
1. Preterm birth < 35 weeks 
2. Presence of underlying cardiopulmonary, neuromuscular, or other complex disease 
3. Admission to the PICU 
4. Coinfection with influenza infection, RSV, acute COVID-19, or concomitant bacterial 
infection (such as pneumonia) as documented within the past 72 hours (per chart review) 
5. History of allergy or reaction to steroids 
6. History of an underlying chronic medical condition -including chronic heart disease, chronic 
lung disease (except asthma),congenital anomalies of the airways or lung, cystic fibrosis, chronic 
renal disease including nephrotic syndrome, protein losing enteropathy of any cause, severe 
malnutrition, glaucoma, neurocognitive disorders, metabolic disorders (including 
phenylketonuria, diabetes mellitus), or genetic disorders (note: genetic syndromes such as Down 
syndrome and Edwards Syndrome are excluded; however, children with genetic disorders (e.g., 
hemophilia) but who do not have a genetic syndrome may not satisfy this particular exclusion 
criterion; it is important that children with such genetic disorders do not have symptoms and/or 
comorbidities that would pose additional risk to them nor jeopardize the adequacy of study 
assessments.”) 
7. History of a condition that compromises the immune system -HIV infection, primary 
immunodeficiency, anatomic or functional asplenia; receipt of a hematopoietic stem cell or solid 
organ transplant at any time; receipt of immunosuppressive therapy including chemotherapeutic 
agents, biologic agents, antimetabolites or radiation therapy during the past 12 months; or daily 
use of systemic corticosteroids for more than 7 consecutive days during the past 14 days. 
8. Any other condition that in the judgment of the investigator precludes participation because it 
could affect the safety of the subject 
9. Any patient admitted to the inpatient general pediatrics teams from 4pm-9pm, as patients are 
to be enrolled in the study within 10 hours of admission and medication distribution cannot be 
complete until 7am. 
10. Any patient who has previously received a dose of steroids medication in the emergency 
department within 24 hours prior to admission 
Statistical Considerations: We will compare mean duration of hospital stay in the two 
treatment groups using the student T-test. As a secondary outcome we will compare mean scores 
on the Kristjansson scale (range 0 to 9) at each time point using generalized estimating equations 


between the two treatment groups. Because this is a pilot study we will be underpowered, 
however, this study will provide data that will allow us to estimate the sample size needed for a 
future study. The number of time points to be used for the generalized estimating equation can be 
determined ad hoc to include a reasonably balanced sample to make the comparison valid.