SasikarnSuesirisawad, MD<br />               J ALLERGY CLIN IMMUNOL AUGUST 2011<br />                           VOLUME 128...
Background<br />Chronic rhinosinusitis (CRS) defined as an inflammatory condition involving paranasalsinuses and linings o...
Background<br />Infrequently lead to serious suppurativecomplications (ophthalmitis, meningitis, brain abscess, osteomyeli...
Background<br />This is argument for use of corticosteroids to control inflammatory response. <br />Few studies: intranasa...
Background<br />Aim to examine efficacy and tolerability of oral MP in children and adolescents with CRS <br />Prospective...
Inclusion criteria<br />6-17 years<br />Diagnosis of CRS made on sinonasal S & S present for period of > 3 moin presence o...
Exclusion Criteria<br /> Used systemic steroids in last 2 mo before study or systemic ATB and inhaler or intranasal steroi...
Symptom scores<br />Visual analog scale (VAS) rating symptom from  0 (none) - 10(most severe). <br />6 symptoms scored: <b...
CT scanning<br />CT performed before and at endof treatment. <br />Lund-Mackay staging system <br />Sinus range from 0 -2 ...
Skin prick tests<br />Allergen skin tests performed with 30 most common aeroallergens. <br />Test positive if MWD ≥ 3 mm l...
Peripheral eosinophil count<br />CBC and differentials. <br />Baseline absolute eosinophil count calculated  before start ...
Interventions<br />Patients given either oral AMX/Cand methylprednisolone (MP gr) or AMX/C and placebo (placebo group) twi...
Interventions<br />Oral MP administered for the first 15 d: <br />  1 MKD(max,40 mg/d) for 10 d, 0.75 MKD for 2 d,  <br />...
Day 15<br />Day 30<br />Mean change in symptom & CT scores<br />2. Mean changes in individual symptom scores, relapse rate...
Compliance<br />Parental supervision of child while taking medication<br />Counting number of pills left at the second and...
Clinical recovery and relapse<br />VAS score of 0as complete clinical recovery.<br />Clinically significant improvement de...
Tolerability<br />Evaluated by medical history, physical examination, adverse events. <br />HT<br />Edema<br />Wt gain, In...
Outcome measures<br />Primary parameters: mean change in total symptom and coronal CT scores after treatment. <br />Second...
Statistical analysis<br />Paired t test <br />2 sample t testing. <br />Mann-Whitney test <br />x2or Fisher exact tests.<b...
RESULT<br />
48 patient<br />withdrawal<br />45 patient<br />22 pt.AMX/C + MP<br />23 pt.AMX/C + placebo<br />outcome<br />Total sympto...
RESULTS<br />Mean age: 8.2 ± 2.6 yrs(median,7 yrs), range 6 - 17 yr. <br />18 (40%) of 45 classified as atopic on basis of...
All parameters were insignificant <br />between groups.<br />
The most common symptoms<br />96%<br />93%<br />91%<br />78%<br />78%<br />64%<br />
P = 0.001<br />P = 0.001<br />P = 0.007<br />
Mean baseline total symptom score<br />symptom<br /> score<br />8<br />7<br />7<br />7<br />5<br />4<br />
86%<br />52%<br />Normal CT<br />P = .02<br />
Mean change from baseline in symptom and CT scan scores.<br />
Clinical recovery and clinical improvement<br />MP:17<br />Placebo: 7<br />(P = 0.005)<br />24(53%)<br />
clinical relapse<br />P = .137<br />25%<br />
Adverse event<br />
Mean weight change from baseline<br />Kg<br />P = 0.08<br />
CRITICAL APPRAISAL <br />
Study validity<br />
Study validity<br />
Study validity<br />
Applicability<br />Were all the important outcomes considered so the results can be applied?<br />   Yes, may be<br />
DISCUSSION<br />The first randomized, double-blind, placebo-controlled study evaluating efficacy and tolerability of oral ...
DISCUSSION<br />Objective (paranasal sinus CT scan scores) and subjective (VAS scores) to measure efficacy<br />CT scan is...
DISCUSSION<br />Presence of soft tissue abnormalities in children who have no symptoms of sinus disease is an important is...
DISCUSSION<br />CRS nasal mucosa culture, corticosteroids reduce production of many inflammatory molecules (IL-5, IL-8, GM...
DISCUSSION<br />A few RCT : intranasal steroids as adjunct to oral antibiotic  are effective in decreasing acute and CRS.<...
DISCUSSION<br />This study: no statistical differences between 2 gr concerning atopyor baseline eosinophil counts.<br />Ne...
DISCUSSION<br />Residual disease on CT after Tx in 48% of placebo group and 14% of MP group when cutoff point of score of ...
DISCUSSION<br />MP group nonatopic15-year old girl with very extensive chronic sinus disease (CT scan score, 15) showed in...
DISCUSSION<br />Both systemic corticosteroid and antibiotic treatments were well tolerated. <br />Although increase in app...
DISCUSSION<br />Limitations. <br />Not perform sinus puncture and microbial culture could not determine whether unresponsi...
summary<br />Treatment with oral methylprednisolone as adjunct to standard antibiotic treatment is well tolerated and help...
THANK YOU<br />
ostiomeatal complex is a collective term encompassing the maxillary sinus ostia, the ethmoidal infundibulum, the hiatus se...
paranasal sinuses divided into 2 groups<br />anterior group includes frontal, maxillary and anterior ethmoid sinuses.  The...
Ostiomeatal unit line drawing: inferior turbinate (1), middle turbinate (2), maxillary sinus (M), uncinate (U), ethmoidal ...
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Journal club: efficacy and tolerability of systemic methylprednisolone in children and adolescents with chronic rhinosinusitis

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  • Patients were recruited from the pediatric allergy and ear, nose, and throatoutpatient clinics of 2 university hospitals in the same countryDepartment of Pediatrics, Division of Pediatric Allergy and Clinical Immunology, OndokuzMayis University Faculty of Medicine, Samsun, and Department of Pediatrics, Division of Pediatric Allergy and Asthma, and Department of Otorhinolaryngology, Gazi University Faculty of Medicine, Ankara. Turkey
  • Rhinosinusitis symptoms were assessed by the patients and their parents
  • Each of the sinuses and ostiomeatal units were evaluated and scored separatelyAll CT scans were evaluated by an ear,nose, and throat specialist (F. I.) experienced in interpreting sinus CT scans.He was blind with respect to both treatment and sequence.
  • 48 pts (16 girls) randomized,45 (94%) completed study. Patients withdrew:Protocol deviation(2 (1 in MP gr &amp; 1 in placebo gr)) Unpalatability (1 in MP gr)All other patients were compliant to medications checked at the second and fourth weeks of treatment by counting the remaining pills
  • The mean 6 SD baseline total symptom score in MP gr was 35.1 6 8.2, and it was 36.5 6 6.5 in placebo group
  • Both MP and placebo group pts had significant improvement in mean total symptoms (P &lt; .001) and sinus CT scores (P &lt; .001) when comparing baseline values with end-of-treatment values.
  • MP was consistently and significantly more effective than placebo in reducing total (P = 0.001) and rhinosinusitis symptom scores of nasal obstruction (P = 0.001), postnasal discharge (P = 0.007), cough (P = 0.009) but not nasal discharge (P = 0.127), halitosis (P = 0.371), headache or facial pain (P = 0.953).
  • At the end of treatment, 19 (86%) of 22 methylprednisolonetreatedand 12 (52%) of 23 placebo-treated patients had no residual disease when a cutoff point of a Lund-Mackay score of 2or less was used to define a normal CT scan. This differencewas also statistically significant (P =.02).
  • FIG 1. Mean change from baseline in symptom and CT scan scores. Columnsand error bars represent means and 95% CIs. CS, Cough score (P 5.009); CTS, CT scan score (P 5 .004); H/FPS, headache or facial pain score(P &gt; .05); HS, halitosis score (P &gt; .05); MP, methylprednisolone; NDS, nasaldischarge score (P &gt; .05); NOS, nasal obstruction score (P 5 .001); P, placebo;PDS, postnasal discharge score (P 5 .007); TSS, total symptom score(P 5 .001).
  • Complete clinical recovery and clinically significant improvement found in 24 (53%) pt (17 in MP gr and 7 in placebo gr) and were significantly more frequent in MP group compared with placebo group (P = 0.005).
  • Therapy-related adverse events were not different between groupsTelephone follow-up, incidence of clinical relapse was also less in MP group, although differences were not significant (P = 0.137): 25% (4/16) of MP gr compared with 43% (3/7) of placebo gr.
  • No clinically significant adverse events were reported. 27 parents (16 in MP gr and 11 in placebo gr) reported that appetite and wt increased after treatment.
  • At the end of treatment, mean wts from baseline were 0.42 ± 0.26 kg in MP gr vs 0.27 ± 0.30 kg in placebo group.The difference was not significant (P = 0.08).
  • Oral MP as adjunct to antibiotic was significantly more effective than placebo not only in reducing total rhinosinusitis symptoms but also CT scores and the most bothersome individual symptoms of CRS, which are nasal obstruction, postnasal discharge, cough.No previously published placebo-controlled data showing efficacy of oral steroids in pts with CRS. (20 mg twice daily for 5 d followed by 20 mg once daily for 5 d)
  • CRS in children differs from that in adults histopathologically
  • Journal club: efficacy and tolerability of systemic methylprednisolone in children and adolescents with chronic rhinosinusitis

    1. 1. SasikarnSuesirisawad, MD<br /> J ALLERGY CLIN IMMUNOL AUGUST 2011<br /> VOLUME 128, NUMBER 2<br />
    2. 2. Background<br />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.<br />OtolaryngolHead Neck Surg. 1997;117<br />Pathophysiology is not clear<br />Various factors: microorganisms, allergic and nonallergicimmunologic inflammation, and noninfectious, nonimmunologic causes<br />
    3. 3. Background<br />Infrequently lead to serious suppurativecomplications (ophthalmitis, meningitis, brain abscess, osteomyelitis).<br />In children: generally medically treatable disease, because of small role of anatomic abnormalities, surgery is not often required.<br />Most ptswith ARS treated with antibiotics, they are only partially or transiently effective in CRS.<br />
    4. 4. Background<br />This is argument for use of corticosteroids to control inflammatory response. <br />Few studies: intranasal steroids as adjunct to oral antibiotic are effective in decreasing ARS and CRS.<br />Systemic steroids in treatment of CRS remains unclear. <br />Anti-inflammatory effects can be beneficial, their potential systemic side effects cause concern.<br />
    5. 5. Background<br />Aim to examine efficacy and tolerability of oral MP in children and adolescents with CRS <br />Prospective, randomized, double-blind, placebo-controlled study.<br />
    6. 6. Inclusion criteria<br />6-17 years<br />Diagnosis of CRS made on sinonasal S & S present for period of > 3 moin presence of abnormalities on CT scans.<br />S & S: nasal purulence, postnasal purulence, or both<br /> ≥ 1 symptoms: nasal obstruction, cough, halitosis, <br /> headache, or facial pain/pressure. <br />Multiple courses (10-14 d, >3 courses) of ATB with ≥ 2 of broad-spectrum ATB before entry into study: AMX/C, second generationcephalasporins, clarithromycin.<br />AR if showed purulent rhinorrhea, postnasal purulence, or both, signs unlikely to be caused by AR only<br />
    7. 7. Exclusion Criteria<br /> Used systemic steroids in last 2 mo before study or systemic ATB and inhaler or intranasal steroids in last 4 wkbefore study<br />Other RS disorders (CF, ciliary dyskinesia, nasal polyps, large adenoids, asthma), immune deficiency, systemic disease, GERD, aspirin sensitivity, sinonasal abnormalities <br />Contraindication to corticosteroid use.<br />Pollen induced rhinitis if during pollen season.<br />
    8. 8. Symptom scores<br />Visual analog scale (VAS) rating symptom from 0 (none) - 10(most severe). <br />6 symptoms scored: <br />Purulent nasal discharge<br />Nasal obstruction<br />Postnasal drainage<br />Halitosis<br />Cough<br />Facial pain or headache. <br />A total of score was 60 points.<br />
    9. 9. CT scanning<br />CT performed before and at endof treatment. <br />Lund-Mackay staging system <br />Sinus range from 0 -2 (0, no abnormality; 1, mucosal thickening; 2, opacification<br />Ostiomeatalunits 0-2(0, ostiomeatalcomplex unobstructed; and 2, ostiomeatal complex obstructed).<br />Total score 2 sides: max, 24 points<br />Sinus CT scan score of ≥ 5 points.<br />CT scans evaluated by ENT specialist who blinded.<br />
    10. 10. Skin prick tests<br />Allergen skin tests performed with 30 most common aeroallergens. <br />Test positive if MWD ≥ 3 mm larger than negative control.<br />
    11. 11. Peripheral eosinophil count<br />CBC and differentials. <br />Baseline absolute eosinophil count calculated before start of methylprednisolone treatment.<br />
    12. 12. Interventions<br />Patients given either oral AMX/Cand methylprednisolone (MP gr) or AMX/C and placebo (placebo group) twice daily<br />Random allocation chart based on table of random numbers. <br />Randomizationassignments kept in sealed envelopes. <br />Randomization code kept by nursing staff in pediatric allergy department. <br />Oral AMX/C administered at 45/6.4 mg/kg/d (max, 2000/285 mg/d) for 30 d for both groups. <br />
    13. 13. Interventions<br />Oral MP administered for the first 15 d: <br /> 1 MKD(max,40 mg/d) for 10 d, 0.75 MKD for 2 d, <br /> 0.5 MKD for 2 d, and 0.25 MKD for 1 d. <br />Placebo tablets contained lactose and same size and color as MP tablets (16 mg/tablet). <br />Placebo and MP tablets: identical packets containing 20 tablets each<br />
    14. 14. Day 15<br />Day 30<br />Mean change in symptom & CT scores<br />2. Mean changes in individual symptom scores, relapse rate, tolerability <br />AMX/C<br />MP<br />
    15. 15. Compliance<br />Parental supervision of child while taking medication<br />Counting number of pills left at the second and fourth weeks of treatment.<br />
    16. 16. Clinical recovery and relapse<br />VAS score of 0as complete clinical recovery.<br />Clinically significant improvement defined as total VAS score of ≤ 6, sinonasalVAS score was ≤ 2.<br />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.<br />Recurrence of symptoms monitored by telephone follow-up for 6 moafter the end of treatment.<br />
    17. 17. Tolerability<br />Evaluated by medical history, physical examination, adverse events. <br />HT<br />Edema<br />Wt gain, Increase in appetite<br />GI disturbances<br />Nervousness, Agitation, Psychosis, Headache, Mood swings, Delirium, Euphoria<br />Moon face, <br />Skin atrophy, bruising, hyperpigmentation, <br />Muscle weakness, jtpain,<br />Allergic reactions <br />
    18. 18. Outcome measures<br />Primary parameters: mean change in total symptom and coronal CT scores after treatment. <br />Secondary parameters: meanchanges in individual symptom scores after treatment, relapse rate, and tolerability.<br />
    19. 19. Statistical analysis<br />Paired t test <br />2 sample t testing. <br />Mann-Whitney test <br />x2or Fisher exact tests.<br />Statistical Package for Social Sciences, version 17.0 software.<br />P value of ≤ 0.05 statistically significant.<br />
    20. 20. RESULT<br />
    21. 21. 48 patient<br />withdrawal<br />45 patient<br />22 pt.AMX/C + MP<br />23 pt.AMX/C + placebo<br />outcome<br />Total symptom score<br />CT score<br />Change in symptom score<br />Relapse rate<br />Tolerability<br />
    22. 22. RESULTS<br />Mean age: 8.2 ± 2.6 yrs(median,7 yrs), range 6 - 17 yr. <br />18 (40%) of 45 classified as atopic on basis of SPT. <br />14: positive SPT for perennial aeroallergens (12 to HDM and 2 to HDM and cockroach)<br />3: seasonal aeroallergens (pollens)<br />1: for HDM and pollens.<br />
    23. 23. All parameters were insignificant <br />between groups.<br />
    24. 24. The most common symptoms<br />96%<br />93%<br />91%<br />78%<br />78%<br />64%<br />
    25. 25. P = 0.001<br />P = 0.001<br />P = 0.007<br />
    26. 26. Mean baseline total symptom score<br />symptom<br /> score<br />8<br />7<br />7<br />7<br />5<br />4<br />
    27. 27.
    28. 28. 86%<br />52%<br />Normal CT<br />P = .02<br />
    29. 29. Mean change from baseline in symptom and CT scan scores.<br />
    30. 30. Clinical recovery and clinical improvement<br />MP:17<br />Placebo: 7<br />(P = 0.005)<br />24(53%)<br />
    31. 31. clinical relapse<br />P = .137<br />25%<br />
    32. 32. Adverse event<br />
    33. 33. Mean weight change from baseline<br />Kg<br />P = 0.08<br />
    34. 34. CRITICAL APPRAISAL <br />
    35. 35. Study validity<br />
    36. 36. Study validity<br />
    37. 37. Study validity<br />
    38. 38. Applicability<br />Were all the important outcomes considered so the results can be applied?<br /> Yes, may be<br />
    39. 39. DISCUSSION<br />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. <br />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<br />
    40. 40. DISCUSSION<br />Objective (paranasal sinus CT scan scores) and subjective (VAS scores) to measure efficacy<br />CT scan is imaging of choice to study sinuses, demonstrates CRS with sensitivity > 80%.<br />Lund-Mackay system used for radiographic staging of CRS on CT. <br />
    41. 41. DISCUSSION<br />Presence of soft tissue abnormalities in children who have no symptoms of sinus disease is an important issue. <br />Children with no sinusitis symptoms but who had cranial CT scans for other reasons: score ≥ 4 is likely to represent true sinus disease. <br />For this reason, present study were required sinus CT scan score ≥5 and rhinosinusitissymptoms. <br />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.<br />
    42. 42. DISCUSSION<br />CRS nasal mucosa culture, corticosteroids reduce production of many inflammatory molecules (IL-5, IL-8, GM-CSF)<br />Well known that steroids are currently the most effective drugs in treatment of eosinophilic inflammation in airways mucosa as in asthma. <br />17 studies : mucosa in pediatric CRS shows increased eosinophil and lymphocyte counts. steroids might help to reduce eosinophilicinflammation in sinus tissues.<br />
    43. 43. DISCUSSION<br />A few RCT : intranasal steroids as adjunct to oral antibiotic are effective in decreasing acute and CRS.<br />Mechanism of intranasal steroids in CRS treatment is not fully understood.<br />No study that compared efficacy of intranasal and systemic steroids. <br />.<br />
    44. 44. DISCUSSION<br />This study: no statistical differences between 2 gr concerning atopyor baseline eosinophil counts.<br />Newman: presence of allergy and eosinophilia (>300/mL) in CRS indicates high likelihood of extensive disease, <br />This study does not find any correlation among atopy, eosinophil counts, and disease severity. <br />No study found correlation between response to CRS treatment and allergy parameters, such as atopic sensitization and eosinophil counts.<br />
    45. 45. DISCUSSION<br />Residual disease on CT after Tx in 48% of placebo group and 14% of MP group when cutoff point of score of ≤ 2 <br />Antibiotics alone were not sufficient to resolve mucosal inflammation in CRS.<br />
    46. 46. DISCUSSION<br />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<br />Might be irreversible inflammatory mucosal changes completely resistant to corticosteroids<br />
    47. 47. DISCUSSION<br />Both systemic corticosteroid and antibiotic treatments were well tolerated. <br />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.<br />
    48. 48. DISCUSSION<br />Limitations. <br />Not perform sinus puncture and microbial culture could not determine whether unresponsive cases infected by resistant strains. <br />This study was randomized, assume that if there were resistant strains, they were probably distributed alike in both placebo and MP groups. <br />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.<br />Monitored relapse of CRS only with recurrence of symptoms by telephone call and did not perform a follow-up paranasal CT scan.<br />
    49. 49. summary<br />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. <br />Oral MP given for 15 d in combination with standard antibiotic treatment might reduce probability of recurrence in medium term.<br />
    50. 50.
    51. 51. THANK YOU<br />
    52. 52.
    53. 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<br />
    54. 54. paranasal sinuses divided into 2 groups<br />anterior group includes frontal, maxillary and anterior ethmoid sinuses.  These drain near infundibulum. <br />posterior group includes sphenoid and posterior ethmoid sinuses.  These drain into ostia situated above attachment for the middle turbinate. <br />ostiomeatalcomplex represents relationship between middle meatus and ositaof anterior group of paranasal sinuses, in particular the anterior ethmoidal cells. <br />
    55. 55.
    56. 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 (*). <br />
    57. 57. At end of treatment: abnormal finding on CT scan<br />P = 0.013<br />

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