1. SasikarnSuesirisawad, MD J ALLERGY CLIN IMMUNOL AUGUST 2011 VOLUME 128, NUMBER 2

2. Background Chronic rhinosinusitis (CRS) defined as an inflammatory condition involving paranasalsinuses and linings of nasal passages that lasts 12 weeks or longer, despite attempts at medical management. OtolaryngolHead Neck Surg. 1997;117 Pathophysiology is not clear Various factors: microorganisms, allergic and nonallergicimmunologic inflammation, and noninfectious, nonimmunologic causes

3. Background Infrequently lead to serious suppurativecomplications (ophthalmitis, meningitis, brain abscess, osteomyelitis). In children: generally medically treatable disease, because of small role of anatomic abnormalities, surgery is not often required. Most ptswith ARS treated with antibiotics, they are only partially or transiently effective in CRS.

4. Background This is argument for use of corticosteroids to control inflammatory response. Few studies: intranasal steroids as adjunct to oral antibiotic are effective in decreasing ARS and CRS. Systemic steroids in treatment of CRS remains unclear. Anti-inflammatory effects can be beneficial, their potential systemic side effects cause concern.

5. Background Aim to examine efficacy and tolerability of oral MP in children and adolescents with CRS Prospective, randomized, double-blind, placebo-controlled study.

6. Inclusion criteria 6-17 years Diagnosis of CRS made on sinonasal S & S present for period of > 3 moin presence of abnormalities on CT scans. S & S: nasal purulence, postnasal purulence, or both ≥ 1 symptoms: nasal obstruction, cough, halitosis, headache, or facial pain/pressure. Multiple courses (10-14 d, >3 courses) of ATB with ≥ 2 of broad-spectrum ATB before entry into study: AMX/C, second generationcephalasporins, clarithromycin. AR if showed purulent rhinorrhea, postnasal purulence, or both, signs unlikely to be caused by AR only

7. Exclusion Criteria Used systemic steroids in last 2 mo before study or systemic ATB and inhaler or intranasal steroids in last 4 wkbefore study Other RS disorders (CF, ciliary dyskinesia, nasal polyps, large adenoids, asthma), immune deficiency, systemic disease, GERD, aspirin sensitivity, sinonasal abnormalities Contraindication to corticosteroid use. Pollen induced rhinitis if during pollen season.

8. Symptom scores Visual analog scale (VAS) rating symptom from 0 (none) - 10(most severe). 6 symptoms scored: Purulent nasal discharge Nasal obstruction Postnasal drainage Halitosis Cough Facial pain or headache. A total of score was 60 points.

9. CT scanning CT performed before and at endof treatment. Lund-Mackay staging system Sinus range from 0 -2 (0, no abnormality; 1, mucosal thickening; 2, opacification Ostiomeatalunits 0-2(0, ostiomeatalcomplex unobstructed; and 2, ostiomeatal complex obstructed). Total score 2 sides: max, 24 points Sinus CT scan score of ≥ 5 points. CT scans evaluated by ENT specialist who blinded.

10. Skin prick tests Allergen skin tests performed with 30 most common aeroallergens. Test positive if MWD ≥ 3 mm larger than negative control.

11. Peripheral eosinophil count CBC and differentials. Baseline absolute eosinophil count calculated before start of methylprednisolone treatment.

12. Interventions Patients given either oral AMX/Cand methylprednisolone (MP gr) or AMX/C and placebo (placebo group) twice daily Random allocation chart based on table of random numbers. Randomizationassignments kept in sealed envelopes. Randomization code kept by nursing staff in pediatric allergy department. Oral AMX/C administered at 45/6.4 mg/kg/d (max, 2000/285 mg/d) for 30 d for both groups.

13. Interventions Oral MP administered for the first 15 d: 1 MKD(max,40 mg/d) for 10 d, 0.75 MKD for 2 d, 0.5 MKD for 2 d, and 0.25 MKD for 1 d. Placebo tablets contained lactose and same size and color as MP tablets (16 mg/tablet). Placebo and MP tablets: identical packets containing 20 tablets each

14. Day 15 Day 30 Mean change in symptom & CT scores 2. Mean changes in individual symptom scores, relapse rate, tolerability AMX/C MP

15. Compliance Parental supervision of child while taking medication Counting number of pills left at the second and fourth weeks of treatment.

16. Clinical recovery and relapse VAS score of 0as complete clinical recovery. Clinically significant improvement defined as total VAS score of ≤ 6, sinonasalVAS score was ≤ 2. Relapse defined as recurrence of sinonasal symptoms (nasal purulence, postnasal purulence, or both and >1 symptoms: nasal obstruction, cough, halitosis, headache, facial pain/pressure) for ≥2 mo. Recurrence of symptoms monitored by telephone follow-up for 6 moafter the end of treatment.

17. Tolerability Evaluated by medical history, physical examination, adverse events. HT Edema Wt gain, Increase in appetite GI disturbances Nervousness, Agitation, Psychosis, Headache, Mood swings, Delirium, Euphoria Moon face, Skin atrophy, bruising, hyperpigmentation, Muscle weakness, jtpain, Allergic reactions

18. Outcome measures Primary parameters: mean change in total symptom and coronal CT scores after treatment. Secondary parameters: meanchanges in individual symptom scores after treatment, relapse rate, and tolerability.

19. Statistical analysis Paired t test 2 sample t testing. Mann-Whitney test x2or Fisher exact tests. Statistical Package for Social Sciences, version 17.0 software. P value of ≤ 0.05 statistically significant.

20. RESULT

21. 48 patient withdrawal 45 patient 22 pt.AMX/C + MP 23 pt.AMX/C + placebo outcome Total symptom score CT score Change in symptom score Relapse rate Tolerability

22. RESULTS Mean age: 8.2 ± 2.6 yrs(median,7 yrs), range 6 - 17 yr. 18 (40%) of 45 classified as atopic on basis of SPT. 14: positive SPT for perennial aeroallergens (12 to HDM and 2 to HDM and cockroach) 3: seasonal aeroallergens (pollens) 1: for HDM and pollens.

23. All parameters were insignificant between groups.

24. The most common symptoms 96% 93% 91% 78% 78% 64%

25. P = 0.001 P = 0.001 P = 0.007

26. Mean baseline total symptom score symptom score 8 7 7 7 5 4

28. 86% 52% Normal CT P = .02

29. Mean change from baseline in symptom and CT scan scores.

30. Clinical recovery and clinical improvement MP:17 Placebo: 7 (P = 0.005) 24(53%)

31. clinical relapse P = .137 25%

32. Adverse event

33. Mean weight change from baseline Kg P = 0.08

34. CRITICAL APPRAISAL

35. Study validity

36. Study validity

37. Study validity

38. Applicability Were all the important outcomes considered so the results can be applied? Yes, may be

39. DISCUSSION The first randomized, double-blind, placebo-controlled study evaluating efficacy and tolerability of oral steroid in combination with antibiotics in children and adolescents with CRS without nasal polyposis. 1 retrospective study: adult 40 pts with CRS treated with oral prednisone for 10 d. Antibiotics 4 – 8 wk showed that oral steroid was effective in improving both symptom and CT scores of CRS

40. DISCUSSION Objective (paranasal sinus CT scan scores) and subjective (VAS scores) to measure efficacy CT scan is imaging of choice to study sinuses, demonstrates CRS with sensitivity > 80%. Lund-Mackay system used for radiographic staging of CRS on CT.

41. DISCUSSION Presence of soft tissue abnormalities in children who have no symptoms of sinus disease is an important issue. Children with no sinusitis symptoms but who had cranial CT scans for other reasons: score ≥ 4 is likely to represent true sinus disease. For this reason, present study were required sinus CT scan score ≥5 and rhinosinusitissymptoms. 10 (5 in MP gr and 5 in placebo gr) of 45 ptdid not have pneumatized frontal sinuses, CT scan scores (12.0 ± 4.9) were compatible with severe sinus disease.

42. DISCUSSION CRS nasal mucosa culture, corticosteroids reduce production of many inflammatory molecules (IL-5, IL-8, GM-CSF) Well known that steroids are currently the most effective drugs in treatment of eosinophilic inflammation in airways mucosa as in asthma. 17 studies : mucosa in pediatric CRS shows increased eosinophil and lymphocyte counts. steroids might help to reduce eosinophilicinflammation in sinus tissues.

43. DISCUSSION A few RCT : intranasal steroids as adjunct to oral antibiotic are effective in decreasing acute and CRS. Mechanism of intranasal steroids in CRS treatment is not fully understood. No study that compared efficacy of intranasal and systemic steroids. .

44. DISCUSSION This study: no statistical differences between 2 gr concerning atopyor baseline eosinophil counts. Newman: presence of allergy and eosinophilia (>300/mL) in CRS indicates high likelihood of extensive disease, This study does not find any correlation among atopy, eosinophil counts, and disease severity. No study found correlation between response to CRS treatment and allergy parameters, such as atopic sensitization and eosinophil counts.

45. DISCUSSION Residual disease on CT after Tx in 48% of placebo group and 14% of MP group when cutoff point of score of ≤ 2 Antibiotics alone were not sufficient to resolve mucosal inflammation in CRS.

46. DISCUSSION MP group nonatopic15-year old girl with very extensive chronic sinus disease (CT scan score, 15) showed insignificant improvement both CT scan score and clinically after Tx with oral MP Might be irreversible inflammatory mucosal changes completely resistant to corticosteroids

47. DISCUSSION Both systemic corticosteroid and antibiotic treatments were well tolerated. Although increase in appetite and wt gain, only reported adverse event, was more common in MP gr (73% vs 48%), mean changes from baseline in wtof ptsbetween groups were not significant.

48. DISCUSSION Limitations. Not perform sinus puncture and microbial culture could not determine whether unresponsive cases infected by resistant strains. This study was randomized, assume that if there were resistant strains, they were probably distributed alike in both placebo and MP groups. Treated all ptswith 45/6.4 mg/kg/d oral AMX/C (max, 2000/285 mg/d), which is less than recommended by some experts, but this is standard recommended ATB and dose CRS. Monitored relapse of CRS only with recurrence of symptoms by telephone call and did not perform a follow-up paranasal CT scan.

49. summary Treatment with oral methylprednisolone as adjunct to standard antibiotic treatment is well tolerated and helpful in improving symptom and CT scores in both atopic and nonatopicchildren with radiographically confirmed CRS. Oral MP given for 15 d in combination with standard antibiotic treatment might reduce probability of recurrence in medium term.

51. THANK YOU

53. ostiomeatal complex is a collective term encompassing the maxillary sinus ostia, the ethmoidal infundibulum, the hiatus semilunaris, the middle meatus, the frontal recess, the uncinate process and the bulla ethmoidalis

54. paranasal sinuses divided into 2 groups anterior group includes frontal, maxillary and anterior ethmoid sinuses. These drain near infundibulum. posterior group includes sphenoid and posterior ethmoid sinuses. These drain into ostia situated above attachment for the middle turbinate. ostiomeatalcomplex represents relationship between middle meatus and ositaof anterior group of paranasal sinuses, in particular the anterior ethmoidal cells.

56. Ostiomeatal unit line drawing: inferior turbinate (1), middle turbinate (2), maxillary sinus (M), uncinate (U), ethmoidal bulla (B), frontal sinus (F), ethmoidal infundibulum (INF), nasal septum (NS), and middle meatus (*).

57. At end of treatment: abnormal finding on CT scan P = 0.013