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Dexamethasone for the Treatment of Sore Throat in
Children With Suspected Infectious Mononucleosis
A Randomized, Double-blind, Placebo-Controlled, Clinical Trial
Michel Roy, MD, FRCPC; Benoit Bailey, MD, MSc, FRCPC; Devendra K. Amre, MBBS, PhD;Jean-Bernard Girodias, MD; Jean-Franc¸ois Bussie`res, BPharm, MSc, MBA, FCSHP; Pierre Gaudreault, MD, FRCPC Objective: To evaluate the efficacy of a single oral dose
mean ± SD age was 13.5 ± 2.8 years. In comparison with of dexamethasone for pain relief in acute exudative phar- the placebo group, a significantly greater proportion of yngitis associated with infectious mononucleosis.
patients given dexamethasone achieved pain relief withinthe first 12 hours (12/20 vs 5/19; P = .03). On further fol- Methods: We conducted a randomized, double-blind,
low-up, the proportions achieving pain relief were simi- placebo-controlled pediatric emergency department– lar between groups: 11 of 20 vs 6 of 20 at 24 hours based clinical trial. Patients aged between 8 and 18 years (P = .10); 11 of 20 vs 11 of 20 at 48 hours (PϾ.99); 15 of with a sore throat from clinically suspected infectious 20 vs 15 of 19 at 72 hours (P = .93); and 18 of 19 vs 19 of mononucleosis were eligible. Patients were randomized 20 at day 7 (PϾ.99), with dexamethasone vs placebo, re- to receive either an oral dose of 0.3 mg/kg (maximum, 15 mg) of dexamethasone or a placebo. Patients com-pleted a diary of symptoms and rated their pain on a vi- Conclusions: The short-lived relief of pain in acute exu-
sual analog scale from 0 to 100 mm at 0 hours, 12 hours, dative pharyngitis in children with suspected infectious 24 hours, 48 hours, 72 hours, and on day 7. An improve- mononucleosis may suggest that a single oral dose of dexa- ment of 20 mm from baseline on the visual analog scale methasone may not be sufficient and that additional doses was evaluated as the primary end point.
may be necessary for ensuring lasting relief.
Results: Twenty patients were recruited in each group;
Arch Pediatr Adolesc Med. 2004;158:250-254 INFECTIOUSMONONUCLEOSIS(IM) dativepharyngitisassociatedwithIM,we
department (ED)–based clinical trial. Our hypothesis was that patients treated with dative pharyngitis is usually painful and a single oral dose of dexamethasone would have better relief of sore throat compared quent resolution within 7 to 14 days, al- though longer persistence has been re-ported.2,3 Severe sore throat is the symptomthat most frequently prompts patients to seek medical attention.3 Most patients who STUDY DESIGN AND ELIGIBILITY
consult physicians wish to obtain pain re-lief so that they may return to their nor- All patients aged 8 to 18 years with a sore throat mal daily activities. However, presently, evaluated for clinically suspected IM in one large, urban, tertiary pediatric hospital ED with acute exudative pharyngitis associated with a mean annual visit rate of 65 000 patients per IM despite the use of corticosteroids for year were candidates for inclusion in the study.
Because the monotest to confirm the diagno- sis of IM was only available during the day- time, all patients with clinical features suggest- ing IM according to the attending physician but their efficacy for the treatment of the were eligible. Patients were therefore in- pain associated with the pharyngitis is un- cluded in an intention-to-treat basis. Sore throat had to be present at enrollment but there was Hoˆpital Ste-Justine, Universite´ ticosteroids for pain relief in acute exu- cluded from the study if corticosteroids were (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 158, MAR 2004 2004 American Medical Association. All rights reserved.
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indicated for upper airway obstruction or if they had any of thefollowing conditions by history: pregnancy or suspected preg- nancy, cancer, liver disease, human immunodeficiency virus or AIDS, current or past peptic ulcer disease, hypertension, tu-berculosis, glaucoma, diabetes mellitus, immune deficiency, kid-ney disease, invasive bacterial infection, osteoporosis, vari- cella contact in patients without a history of chickenpox, active neurologic or psychiatric disease, malabsorption, immunosup- pressor treatment, and patients who received corticosteroids in the 7 days preceding the visit to the ED. All patients gave consent to the study, and one of their parents or legal guard-ian had to sign the consent form prior to randomization. Theethical review board at our institution approved the study.
PROCEDURE
After the initial clinical diagnosis of IM by the attending phy- sician, further confirmation was done by one of the investiga- tors (M.R. or B.B.). Clinical diagnosis was based on the pres-ence and duration of sore throat, odynophagia, respiratorydistress, fatigue, and fever. In addition, information on gen-eral appearance, temperature, weight, tonsil size, tonsil red- ness, tonsil exudates, cervical lymphadenopathy, and the size of the liver and spleen were also recorded. The investigator alsosubjectively evaluated the severity of the pharyngitis (light, mod- Participant flow in the study. VAS indicates visual analog scale.
erate, or severe). A bacterial throat culture, monotest, and Ep-stein-Barr virus were performed on each eligible patient to reach a 20-mm difference to be clinically important, a difference a final diagnosis of IM-induced acute exudative pharyngitis.
slightly higher than the 13-mm difference found to be clini- Participants were then asked to rate their sore throat pain cally significant in previous VAS studies.9 Thus, for an ␣ of .05, at time 0 on a standardized visual analog scale (VAS) from 0 to a ␤ of .80, and an SD of 20 mm, we would need 20 patients in 100 mm. Patients marked the VAS line with a pen, where 0 mm represents no pain and 100 mm represents the worst pain. Pa- Differences in categorical outcomes (for example, propor- tients were then randomized into 1 of 2 groups: treatment or tions achieving pain relief) between groups were examined us- placebo. A computer random number generator was used to ing the ␹2 test or Fisher exact test whenever appropriate. Sur- ensure unbiased allocation. The computer-generated list was vival analysis was done, and Kaplan-Meier survival curves were drawn up a priori by the statistician and given directly to the generated. Differences between groups in continuous vari- pharmacy department. An independent pharmacist prepared ables (for example, the dose of acetaminophen used) were evalu- either dexamethasone or a similar tasting and looking placebo ated by a t test or Mann-Whitney rank sum test, whenever ap- in small opaque bottles identified by a number according to the propriate. The level of significance was set at PՅ.05.
list. These bottles were kept in the ED at all times. The inves-tigator responsible for recruiting the patient allocated the nextavailable number on the list. A dose of 0.3 mg/kg of dexameth- asone (1 mg/mL; maximum, 15 mg) or an equivalent amountof placebo was administered orally with a syringe by an attend- A total of 40 patients were recruited from October 2001 ing nurse. All study personnel and participants were blinded to November 2002 (Figure). There was no significant
to treatment assignment for the duration of the study. The ran- difference in the baseline characteristics of both groups domization code was revealed to the researchers once recruit- (Table 1). Twenty-seven patients had a positive monotest
ment, data collection, and laboratory analyses were complete and serologic test at the initial examination. Two pa- tients had a positive monotest but negative serologic test When discharged from the ED, patients were provided with at the initial examination. The follow-up serologic test 5 copies of the visual analog scales, a chart for coanalgesia use was positive in those 2 cases. Two patients had a nega- (including type, timing, and dose), and a list of symptoms. Pa-tients were encouraged on the consent form to use acetamino- tive monotest and serologic test at the initial examina- phen for coanalgesia. Other analgesics were not contraindi- tion but a positive serologic test at the follow-up. One cated; patients were simply asked to write down type (ie, patient had a negative monotest but a positive serologic acetaminophen, ibuprofen, or codeine), time, and dose if coan- test at the initial examination. One patient had only a algesia was used. Telephone reminders were made for complet- monotest performed at the initial examination, and it was ing the VAS at times 12, 24, 48, and 72 hours, and on day 7. To assess blinding, one of the investigators (M.R.) tried to guess if Table 2 presents the critical 20-mm difference in
participants received dexamethasone or placebo once we had re- the VAS at different periods of time. In comparison with ceived the VAS. Patients were examined approximately 4 weeks those given the placebo (group 1), a significantly greater after enrollment by one of the investigators (M.R.).
proportion of patients given dexamethasone (group 2) MEASUREMENTS
achieved a 20-mm pain relief at 12 hours (12 [60%] of20 vs 5 [26%] of 19, (95% CI, ⌬ 3%-57%), but this dif- The main outcome with respect to the efficacy of dexametha- ference was not present at other times. The actual de- sone was assessed by comparing the proportion of patients who crease in pain achieved by dexamethasone or placebo at achieved at least a 20-mm improvement on the VAS. We chose different times is presented in Table 3. Again, dexa-
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tient hospitalized in group 1 was admitted for severe phar- Table 1. Baseline Characteristics of Patients
yngitis, decreased oral intake, and dehydration. The pa- Included in the Study
tient from group 2 who was hospitalized was a 15-year-old girl who initially came to the ED with a sore throat Dexamethasone Placebo
P
and fatigue. On day 3 of the study, the research nurse ad- Characteristic
(n = 20) Value
vised her to consult the ED for evaluation of dehydra- tion. Her physical examination demonstrated severe phar- yngitis and dehydration. She did not have respiratory symptoms. She was hospitalized and received intrave- nous erythromycin and methylprednisolone for severe pharyngitis on day 3. In the next days, she developed res- piratory distress and was later found to have pleural effu- sion and empyema. The culture was positive for Strepto- coccus constellatus. She later developed anemia and shock and was hospitalized in the pediatric intensive care unit for 2 weeks. She was seen in the infectious disease clinic 1 month after discharge. She was asymptomatic, and herhemoglobin level was normal.
Abbreviations: IM, infectious mononucleosis; VAS, visual analog scale.
The control physical examination was done in 39 *Data are given as number of patients unless otherwise indicated.
of 40 patients approximately 1 month after inclusion inthe study, and all physical examination findings were nor-mal. One patient did not return; he was asymptomatic Table 2. Number of Patients With a 20-mm Decrease in
at the telephone follow-up. Blinding appears to have been Pain at Various Times After a Single 0.3-mg/kg Oral Dose of
Dexamethasone or Placebo*
successful, as one of the investigators was only able tocorrectly identify 10 of 20 and 12 of 20 participants who Dexamethasone
P
received dexamethasone and placebo, respectively.
Difference, %
Therapeutic options for the pain relief of acute exuda- tive pharyngitis associated with IM are limited. Lympho- proliferative inflammation of the pharynx from the Ep-stein-Barr virus is responsible for the sore throat.
Abbreviation: CI, confidence interval.
*Data are given as number (percentage) of patients unless otherwise Compared with other viral pharyngitis, Epstein-Barr vi- rus exudative pharyngitis is more severe and lasts longer.3The goal of short-term corticosteroid therapy is to re- methasone only decreased pain at 12 hours (P = .007).
duce the acute inflammation and decrease the sore throat Kaplan-Meier survival curves did not reveal any signifi- symptoms. Secondarily, one can postulate that patients cant differences overall in time to pain relief between the with less pain can improve their oral intake and prevent dehydration and the need for hospitalization.
The frequency of use of acetaminophen was simi- The results of our study suggest that dexametha- lar between the comparison groups: 12 (60%) of 20 in sone is effective at providing greater relief of pain com- group 2 vs 16 (80%) of 20 in group 1 (P=.17). There were pared with a placebo at 12 hours. However, at 24 hours also no differences in the doses used (median, 12.4 in and later, there was no significant difference between dexa- group 2 vs 35.6 mg/kg per day in group 1; P = .24). The methasone and the placebo. Thus, more than 1 dose may overall frequency of use of any analgesic was similar be- be needed to achieve lasting relief of pain in IM-induced tween the 2 groups (16 [80%] of 20 for group 2 vs 17 pharyngitis. The dose of dexamethasone used, 0.3 mg/ [85%] of 20 for group 1; P = .68). Also, 11 patients used kg, is equivalent to a prednisone or prednisolone dose ibuprofen, 5 in group 2 and 6 in group 1 (P = .72). Two of 1.8 mg/kg, with a longer duration of action.12 A single patients used codeine, both in group 2 (P = .49).
oral dose of dexamethasone (0.6 mg/kg; maximum, 10 About 7 (44%) of 16 patients in the dexametha- mg) was recently found to have no effect on pain in- sone group had a fever (Ͼ38°C oral) after leaving the ED duced by group A ␤-hemolytic streptococcus and non– compared with 10 (67%) of 15 in the placebo group group A ␤-hemolytic streptococcus pharyngitis in chil- (P = .20). After 7 days, 9 (60%) of 15 of patients in group dren.13 In adults, a single dose of 10 mg of dexamethasone 2 had returned to their normal activities compared with has been found to be effective in group A ␤-hemolytic 7 (41%) of 17 in group 1 (P = .39).
streptococcus and viruses other than Epstein-Barr.14-16 Four patients were hospitalized during the course of Previous studies that evaluated the efficacy of corti- the study, all on subsequent visits to the ED, 3 patients in costeroids in IM are primarily based on data collected from group 1 (15%) and 1 (5%) in group 2 (P=.30). The first inpatient health infirmaries and were done mostly in the patient in group 1 was hospitalized for decreased oral in- 1960s. Schumacher et al4 found that oral prednisone, 60 take, vomiting, and dehydration. The second patient was mg/d for 5 days, had no effect on symptoms and signs of hospitalized for dehydration and pneumonia. The last pa- IM in a double-blind study of 13 patients with an average (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 158, MAR 2004 2004 American Medical Association. All rights reserved.
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Table 3. Difference of VAS Score of Pain at Different Times Compared With Baseline for Dexamethasone and Placebo
⌬ Dexamethasone vs Baseline,
⌬ Placebo vs Baseline,
⌬ Dexamethasone −
mm, Mean ± SD
mm, Mean ± SD
Placebo (95% CI), mm
P Value
Abbreviations: CI, confidence interval; VAS, visual analog scale.
age of 20 years. However, it is unclear how these symp- Three patients from the placebo group were hospi- toms were evaluated. Prout and Dalrymple8 conducted a talized, and only 1 patient from the dexamethasone group double-blind study in 82 college students with IM using was hospitalized. This might suggest that dexametha- oral paramethasone (dose equivalent to 40 mg of predni- sone could reduce the rate of hospitalization; however, sone that was tapered daily by an equivalent dose of 5 mg definite conclusions cannot be reached due to the lim- of prednisone) and demonstrated that corticosteroid ited sample size. The dexamethasone-treated patient who therapy was safe and significantly shortened the duration was hospitalized had a complicated case of IM. Intrave- of fever and infirmary stay but not the duration of sore nous methylprednisolone was also administered to this throat. Bender6 evaluated the efficacy of oral corticotro- patient because of the severe pharyngitis prior to the de- pin (80 units daily, tapered over 6 days) or oral predniso- velopment of respiratory distress. The assessment of dexa- lone (80 mg daily tapered over 6 days) to treat IM in 132 methasone’s role, if any, is complicated by the use of meth- patients aged between 17 and 32 years in a case-control ylprednisolone. However, empyema complicating IM was study. Fever duration was decreased from 5.6 to 1.4 days described in the literature in a patient who did not re- with corticosteroids (PϽ.001). The author also noted a less- ceive corticosteroids.21 It is a rare but known complica- ening in subjective throat distress. Klein et al5 evaluated tion of IM. Therefore, a causal relationship between the the efficacy of oral paramethasone (dose equivalent to 40 empyema and the use of oral dexamethasone and intra- mg of prednisone, tapered over 9 days) in a double-blind venous methylprednisolone cannot be made. The safety study of 24 college students with IM. More patients felt issue of corticosteroids in IM remains a subject for dis- that their throat symptoms had subjectively decreased 12 cussion. Future studies with larger sample sizes could hours after the beginning of the treatment (64% vs 8%; P=.01) and at 36 hours (73% vs 31%; P=.05) but not at The limitations of our study include the fact that all 60 hours (54% vs 69%). Collins et al7 reported on the ef- patients with or without (suspected) a confirmed diagno- ficacy of oral prednisone (60 mg daily, tapered over 6 days) sis of IM were enrolled. The inclusion of clinically sus- in a double-blind randomized trial in 47 college students pected IM pharyngitis in the study could have biased the with IM. No difference was found between the treatment study toward negative results since a single dose of dexa- and the placebo groups in the rapidity of resolution or im- methasone (0.6 mg/kg; maximum, 10 mg) was found to provement of symptoms at 1 or 4 weeks. Furthermore, have no effect in children with group A ␤-hemolytic strep- more recent studies of acyclovir alone or acyclovir and pred- tococcal pharyngitis and non–group A ␤-hemolytic strep- nisolone (0.7 mg/kg for 4 days tapered over the next 6 days tococcal pharyngitis.13 Another potential limitation of the by 0.1 mg/kg per day) were also found to be ineffective study is that the VAS has not been previously validated for the relief of sore throat in double-blind randomized for the assessment of sore throat in the ED. However, it clinical trials.17,18 Our study is the first one, to our knowl- has been used previously in similar studies14-16,22 and is likely edge, to assess the efficacy of corticosteroids in IM using to be quite accurate. This was also suggested by the ob- an objective measure (VAS) of sore throat.
servation that, in our study, there was a reasonable cor- Glucocorticoid administration is common in the ED.
relation between the subjective severity grading of the phar- Its use has been found to be safe and effective in the treat- yngitis done by the investigator and the initial pain intensity ment of asthma and laryngitis. In one study that evalu- obtained by the VAS (r=0.39; P=.002). It is important to ated the effect of corticosteroids on the serologic re- note that the study was not designed to have the power to sponse of IM, 10 days of corticosteroid treatment was not detect differences in outcomes other than the primary out- found to alter the serologic response of the Epstein-Barr come, which was pain associated with the sore throat.
virus to early antigens.19 Furthermore, corticosteroids In conclusion, the short-lived relief of pain in acute helped the lymphocytes, including B, total T, helper, and exudative pharyngitis in children with suspected IM may T-suppressor cell counts to return to normal values more suggest that a single oral dose of dexamethasone may not rapidly.19 Other studies that evaluated corticosteroids in be sufficient and that additional doses may be necessary IM found no risk associated with its short-term use.4,5,7,8,18 for insuring lasting relief. However, it remains unclear Also, it is interesting to note that for cases involving com- if the benefit of corticosteroids in the treatment of IM- plications of IM that are believed to be secondary immu- induced acute exudative pharyngitis can surpass the po- nopathologic reactions (such as hemolytic anemia, en- tential risk, if any, considering that 3 patients with sus- cephalitis, and myocarditis), the administration of pected IM would have to be treated to at least partly relieve the sore throat of 1 patient at 12 hours.
(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 158, MAR 2004 2004 American Medical Association. All rights reserved.
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8. Prout C, Dalrymple W. A double-blind study of eighty-two cases of IM treated Corticosteroids have been shown to reduce the upper air- with corticosteroids. J Am Coll Health Assoc. 1966;15:62-66.
way obstruction caused by IM but their efficacy for the 9. Todd KH, Funk KG, Funk JP, Bonacci PA. Clinical significance of reported changes treatment of the pain associated with pharyngitis is un- in pain severity. Ann Emerg Med. 1996;27:485-489.
clear. Previous studies have not objectively measured the 10. Browner WS, Newman TB, Hulley SB. Estimating sample size and power. In: Hul- effect of corticosteroids on pain and were mostly done ley SB, Cummings SR, eds. Designing Clinical Research. Baltimore, Md: Wil- in hospitalized patients. In this pediatric emergency de- 11. Riffenburgh RH. Statistics in Medicine. San Diego, Calif: Academic Press; 1999.
partment–based study, a single dose of dexamethasone 12. Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical ste- produced a short-lived reduction in the pain associated roids and their synthetic analogs; inhibitors of the synthesis and actions of ad- with IM-induced pharyngitis in adolescents. Additional renocortical hormones. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, doses may be necessary for ensuring lasting relief.
Goodman Gilman A, eds. Goodman and Gilman’s the Pharmacologic Basis ofTheraPeutics. New York, NY: McGraw-Hill; 1996:1459-1485.
13. Bulloch B, Kabani A, Tenenbein M. Oral dexamethasone for the treatment of pain Accepted for publication October 2, 2003. in children with acute pharyngitis: a randomized, double-blind, placebo-controlled trial. Ann Emerg Med. 2003;41:601-608.
This project was funded by a grant from the Cana- 14. Marvez-Valls EG, Stuckey A, Ernst AA. A randomized clinical trial of oral vs in- dian Association of Emergency Physicians. tramuscular delivery of steroids in acute exudative pharyngitis. Acad Emerg Med.
Corresponding author and reprints: Benoit Bailey, MD, MSc, FRCPC, Hoˆpital Ste-Justine, 3175 Chemin de la Coˆte- 15. Wei JL, Kasperbauer JL, Weaver AL, Boggust AJ. Efficacy of single-dose dexa- Ste-Catherine, Montre´al, Quebec, Canada, H3T 1C5 (e-mail: methasone as adjuvant therapy for acute pharyngitis. Laryngoscope. 2002;112:87-93.
16. O’Brien J, Meade J, Falk J. Dexamethasone as adjuvant therapy for severe acute pharyngitis. Ann Emerg Med. 1993;22:212-215.
17. van der Horst C, Joncas J, Ahronheim G, et al. Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis. J Infect Dis. 1991;164:788-792.
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