J ALLERGY CLIN IMMUNOL AUGUST 2011 VOLUME 128, NUMBER 2

Sasikarn Suesirisawad, MD

BACKGROUND

Chronic rhinosinusitis (CRS) defined as an inflammatory condition involving paranasal sinuses and linings of nasal passages that lasts 12 weeks or longer, despite attempts at medical management.

Otolaryngol Head Neck Surg. 1997;117

Pathophysiology is not clear

Various factors: microorganisms, allergic and nonallergic immunologic inflammation, and noninfectious, nonimmunologic causes

BACKGROUND

Infrequently lead to serious suppurative complications (ophthalmitis, meningitis, brain abscess, osteomyelitis).

In children: generally medically treatable disease, because of small role of anatomic abnormalities, surgery is not often required.

Most pts with ARS treated with antibiotics, they are only partially or transiently effective in CRS.

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.

BACKGROUND

Aim to examine efficacy and tolerability of oral MP in children and adolescents with CRS

Prospective, randomized, double-blind, placebo-controlled study.

INCLUSION CRITERIA 6-17 years Diagnosis of CRS made on sinonasal S & S present for

period of > 3 mo in 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 generation cephalasporins, clarithromycin.

AR if showed purulent rhinorrhea, postnasal purulence, or both, signs unlikely to be caused by AR only

EXCLUSION CRITERIA

Used systemic steroids in last 2 mo before study or systemic ATB and inhaler or intranasal steroids in last 4 wk before 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.

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.

CT SCANNING CT performed before and at end of treatment.

Lund-Mackay staging system

Sinus range from 0 - 2 (0, no abnormality; 1, mucosal thickening; 2, opacification

Ostiomeatal units 0-2(0, ostiomeatal complex 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.

SKIN PRICK TESTS

Allergen skin tests performed with 30 most common aeroallergens.

Test positive if MWD ≥ 3 mm larger than negative control.

PERIPHERAL EOSINOPHIL COUNT

CBC and differentials.

Baseline absolute eosinophil count calculated before start of methylprednisolone treatment.

INTERVENTIONS Patients given either oral AMX/C and

methylprednisolone (MP gr) or AMX/C and placebo (placebo group) twice daily

Random allocation chart based on table of random numbers.

Randomization assignments 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.

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

AMX/C

MP

Day 15

Day 30

1. Mean change in symptom & CT scores

2. Mean changes in individual symptom scores, relapse rate, tolerability

COMPLIANCE

Parental supervision of child while taking medication

Counting number of pills left at the second and fourth weeks of treatment.

CLINICAL RECOVERY AND RELAPSE

VAS score of 0 as complete clinical recovery.

Clinically significant improvement defined as total VAS score of ≤ 6, sinonasal VAS 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 mo after the end of treatment.

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, jt pain, Allergic reactions

OUTCOME MEASURES

Primary parameters: mean change in total symptom and coronal CT scores after treatment.

Secondary parameters: mean changes in individual symptom scores after treatment, relapse rate, and tolerability.

STATISTICAL ANALYSIS

Paired t test 2 sample t testing. Mann-Whitney test x2 or Fisher exact tests. Statistical Package for Social Sciences,

version 17.0 software. P value of ≤ 0.05 statistically significant.

RESULT

48 patient

45 patient

withdrawal

22 pt.AMX/C + MP

23 pt.AMX/C + placebo

outcomeTotal symptom scoreCT score

Change in symptom scoreRelapse rateTolerability

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.

All parameters were insignificant

between groups.

THE MOST COMMON SYMPTOMS

post

nasa

l disch

arge

coug

h

nasa

l obs

truct

ion

puru

lent

rhin

orrh

ea

halit

osis

Heada

che

or fa

cial

pai

n 0%

20%

40%

60%

80%

100%

120%

common symptom

96%

93% 91%

78% 78%64%

P = 0.001

P = 0.001

P = 0.007

MEAN BASELINE TOTAL SYMPTOM SCORE

coug

h

puru

lent

nas

al d

isch

arge

nasa

l obs

truct

ion

puru

lent

pos

tnas

al d

isch

arge

halit

osis

facial

pai

n or

hea

dach

e

0

2

4

6

88 7 7 7 5 4

symptom

score

Normal CT

P = .02

86% 52%

MEAN CHANGE FROM BASELINE IN SYMPTOM AND CT SCAN SCORES.

CLINICAL RECOVERY AND CLINICAL IMPROVEMENT

significant improve no significant improve

21(47%) 24(53%)

MP:17Placebo: 7

(P = 0.005)

CLINICAL RELAPSE

MP Placebo

relapse 4 3

not relapse 12 4

5%15%25%35%45%55%65%75%85%95%

43%25%

P = .137

ADVERSE EVENT

MP Placebo

1611

612

increase appetite no increase appetite

MEAN WEIGHT CHANGE FROM BASELINE

MP Placebo0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.42 ± 0.26

0.27 ± 0.30

mean weight change

Kg

P = 0.08

CRITICAL APPRAISAL

STUDY VALIDITY

Study validity Result

Did the study ask clearly-focused question? Yes

Was this RCT and was that an appropriate design? Yes

Did the reviewers try to identify all relevant studies?Yes

Did the study have enough participants to minimise the play of chance?

Yes

STUDY VALIDITY

Study validity Result

Were the groups treated equally, apart from the experimental treatment? Yes

Were the groups similar at the start of the trial? Yes

Were the patients in all groups followed up and data collected in the same way? Yes

Were the outcome measured in a reasonable way _subjective / objective? Yes, subjective and objective

APPLICABILITY

Were all the important outcomes considered so the results can be applied?

Yes, may be

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

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.

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 rhinosinusitis symptoms.

10 (5 in MP gr and 5 in placebo gr) of 45 pt did not have pneumatized frontal sinuses, CT scan scores (12.0 ± 4.9) were compatible with severe sinus disease.

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 eosinophilic inflammation in sinus tissues.

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.

.

DISCUSSION

This study: no statistical differences between 2 gr concerning atopy or 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.

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.

DISCUSSION

MP group nonatopic 15-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

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 wt of pts between groups were not significant.

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 pts with 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.

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 nonatopic children with radiographically confirmed CRS.

Oral MP given for 15 d in combination with standard antibiotic treatment might reduce probability of recurrence in medium term.

THANK YOU

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

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.

ostiomeatal complex represents relationship between middle meatus and osita of anterior group of paranasal sinuses, in particular the anterior ethmoidal cells.

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 (*).

AT END OF TREATMENT: ABNORMAL FINDING ON CT SCAN

23%

77%

MPPlacebo

P = 0.013