1. 1 Clinical Evaluation of ABS: Diagnostic Considerations Carl N. Kraus, M.D. Medical Officer Division of Special Pathogen and Immunologic Drug Product Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. 2 Although common, it is difficult to differentiate bacterial sinusitis from other causes of acute sinusitis

3. 3 (+) Imaging (+) Symptoms Which individuals have bacteria in their sinuses? Need for Population Definition Need for Population Definition Enriched population with greatest potential to benefit from antimicrobial therapy (+) Culture

4. What evidence is present in the literature correlating specific diagnostic criteria for individuals that have acute bacterial sinusitis (ABS)?

5. 5 Criteria Evaluated 1.Symptom Duration 2.Symptom Characteristics 3.Radiography 4.Endoscopy

6. 6 Search Strategy Sought studies that specified inclusion criteria and had a sinus puncture with culture as part of the initial evaluation. Illness duration at time of inclusion Illness duration at time of inclusion Antimicrobial use prior to study inclusion Antimicrobial use prior to study inclusion Percent of patients that underwent sinus puncture Percent of patients that underwent sinus puncture Study population Study population Use of a microbiologic cutoff Use of a microbiologic cutoff Specified inclusion criteria (signs, symptoms, radiography) Specified inclusion criteria (signs, symptoms, radiography)

7. 7 General Search Methodology MeSH Search 1966 to Present KeywordSearch Article References Abstract Evaluation Full Article Review

8. 8 Studies Identified  Symptom duration: 0 studies identified  Symptom character: 5 studies identified  Radiography:12 studies identified  Endoscopy:2 studies identified

9. 9 Approaches to Population Enrichment 1. Symptom Duration 2. Symptom Characteristics 3. Radiography 4. Endoscopy

10. 10 1. Symptom Duration Symptoms thought to be related to viral rhinosinusitis typically have a median duration of 1 week Gwaltney et.al., JAMA. 1967;202(6):494-500. 90% of patient with the common cold have (+) CT. Gwaltney et. al., NEJM, 1994; 330:25-30 Bacterial sinusitis is seen in only 20% of patients with symptoms less than 7 days Comments in Hickner JM et. al., Ann Intern Med. 2001;134(6):498-505 No studies evaluating the timing of sinus taps and microbiology identified in the literature.

11. 11 Approaches to Population Enrichment 1. Symptom Duration 2. Symptom Characteristics 3. Radiography 4. Endoscopy

12. 12 Reporting Variations Patient Based Reporting Sinus Based Reporting Sinus Based Reporting Aspirate Based Reporting 30 patients 15 with (+) cultures 50% (+) Culture Rate 30 patients 60 sinus punctures 40 (+) cultures 67% (+) Culture Rate 30 patients 80 sinus aspirates 60 (+) cultures 75% (+) Culture Rate

13. 13 Symptom Characteristics (2) 34% 1 60% 2 65% 3 1 van Buchem L, Eur J Gen Pract, 1995. 1: 155-60. 2 Hamory, B.H., et al., J Infect Dis, 1979. 139(2): 197-202. 3 Savolainen, S., et al., Acta Otolaryngol Suppl, 1997. 529: p. 148-52. 4 Berg O, et. al., Scand J Infect Dis 20: 511-516, 1988 87% 4 Inclusion: “clinical symptoms and signs of sinusitis indicating diagnostic and therapeutic puncture” and “prevailing antral secretion at aspiration” Headache Nasal Symptoms Purulence Facial Pain Post Nasal Drip Upper Jaw Pain Nasal Obstruction Impaired Smell (+) Sinus Cultures (N=113) (N=81) (N=132)

14. 14 Symptom Characteristics (4) 1 other study identified (24 adult pts, 17 with acute symptoms) Specific signs/symptoms not provided but: “ quality, radiation, intensity of facial pain, purulence of nasal discharge or presence of fever did not accurately predict the presence of infection as determined by aspiration” Evans FO et. al., NEJM 293: 735-739, 1975

15. 15 Symptom Characteristics (3) No maximum symptom duration cutoff No maximum symptom duration cutoff No minimum duration of symptoms No minimum duration of symptoms No exclusion secondary to antimicrobial use No exclusion secondary to antimicrobial use patient based reporting of data patient based reporting of data 4% patients enrolled but not punctured 4% patients enrolled but not punctured ----------------------------------------------------------------------------------------- (+) maximum symptom duration cutoff (+) maximum symptom duration cutoff No minimum duration of symptoms No minimum duration of symptoms Sinus based reporting of data Sinus based reporting of data 4% patients enrolled but not punctured 4% patients enrolled but not punctured ----------------------------------------------------------------------------------------- No maximum symptom duration cutoff No maximum symptom duration cutoff No minimum duration of symptoms No minimum duration of symptoms Patient based reporting of data Patient based reporting of data 18% patients enrolled but not punctured 18% patients enrolled but not punctured Van Buchem N=113 Hamory N=105 (81 subjects) SavolainenN=132

16. 16 Approaches to Population Enrichment 1. Symptom Duration 2. Symptom Characteristics 3. Radiography 4. Endoscopy

17. 17 Radiography (1) The percentage of subject with sinus puncture cultures ranged from 30- 77%.The percentage of subject with sinus puncture cultures ranged from 30- 77%. Extreme heterogeneity of clinical inclusions criteria.Extreme heterogeneity of clinical inclusions criteria.

18. 18 Radiography (2) No antibiotic exclusion No antibiotic exclusion many patients with confounding illnessesmany patients with confounding illnesses No duration cutoff No duration cutoff 4 studies (adult) 4 studies (adult) 2 sinus based reporting 2 sinus based reporting 2 patient based reporting 2 patient based reporting InclusionsReporting (+) Sinus Cultures: 30-54% Antila, J., J. Suonpaa, and O.P. Lehtonen,. Acta Otolaryngol Suppl, 1997. 529:162-4. Johnson, P.A., et al., J Otolaryngol, 1999. 28(1): p. 3-12 Pahor, A.L, Ear Nose Throat J, 1978. 57(10): p. 451-4. Talbot, G.H., et al., Clin Infect Dis, 2001. 33(10): p. 1668-75

19. 19 Radiography (2)  Facial Pain  (+) antibiotic exclusion  (+) purulence  No duration cutoff  3 studies (adult)  3 sinus based reporting  0 patient based reporting InclusionsReporting 60-66 (+) Sinus Cultures: 60-66 % Penttila, M., et al., Acta Otolaryngol Suppl, 1997. 529: p. 165-8. Camacho, A.E., et al., Am J Med, 1992. 93(3): p. 271-6. Hamory, B.H., et al., J Infect Dis, 1979. 139(2): 197-202.

20. 20 Radiography (2)  radiographic criteria  (+) antibiotic exclusion  (+) use of microbiologic cutoff  duration cutoff in 1 subgroup InclusionsReporting 70-77 (+) Sinus Cultures: 70-77 %  3 studies (2 pediatric)  2 patient based reporting  1 sinus based reporting Wald, E.R., et al.,. N Engl J Med, 1981. 304(13): p. 749-54. Wald, E.R., et al., J Pediatr, 1984. 104(2): p. 297-302 Rantanen, T, et al, Acta Otolaryngol, 1973. 76(1): p. 58-62

21. 21 Radiography (4) 34 culture positive sinuses: 16/34 (47%) Air Fluid Level 10/34 (29%)opacity 8/34 (24%)mucosal thickening Hamory, B.H., et al., J Infect Dis, 1979. 139(2): p. 197-202.

22. 22 Radiography (6) Only 1 study identified with sinus puncture data and CT: Requirments for study entry: Clinical Impression 174 subjects completed study 122 with abnormal CTs 92 subjects met CT criteria for Acute Sinusitis 61 found to have pathogenic bacteria (61/92; 66%) Hansen, J.G., et al., BMJ, 1995. 311(6999): p. 233-6.

23. 23 Approaches to Population Enrichment 1. Symptom Duration 2. Symptom Characteristics 3. Radiography 4. Endoscopy

24. 24 Endoscopy (1) Talbot, G.H., et al., Clin Infect Dis, 2001. 33(10): 1668-75 Vogan, J.C. et.al. Otolaryngol Head Neck Surg, 2000. 122(3): 370-3 ProcedurePopulation N Vogan, 2000endoscopyadult13* Talbot, 2001endoscopyadult53** *13 patients, 16 sinuses; 13 sinuses with previous antibiotic use, diagnositic criteria for acute sinusitis not stated, only patients with AFL on radiography included, no dilutions noted on semiquantitative microbiology **symptoms at time of inclusion well described, patients with >5mm or AFL included, (+) minimum symptom duration noted, (+) antimicrobial exclusion, (+) chronic sinusitis exclusion, (+) dilutions noted on semiquantative microbiology

25. 25 Endoscopy (2) No minimum duration of symptoms sinus punctures (+) in 14/16 sinuses only 4/16 sinuses (+) with more stringent micro cutoff Only 2 endoscopic cultures with > 1+ bacteria Overall, 8/16 (50%) sinuses studied had (+) endoscopic cultures with the same pathogen as the sinus puncture. (including any colony count and the pathogens S. pnemoniae, M. catarrhalis, and H. influenzae) No minimum duration of symptoms 23/46 (50%) with (+) sinus punctures 31/46 (67%) patients with (+) endoscopy Overall, 12/31 (39%) patients with (+) endoscopy had sinus puncture (+) cultures with the same pathogen. (including any colony count and the pathogens S. pnemoniae, M. catarrhalis, and H. influenzae) Vogan Talbot

26. 26Conclusions(1) Does the literature adequately describe specific criteria for the diagnosis of ABS ?  Symptom duration: 0 studies identified  Symptom character: 5 studies identified 60-65% (2 studies)  Radiography:12 studies identified 30-77% (12 studies)  Endoscopy:2 studies identified 39-50% (2 studies) 39-50% (2 studies)

27. 27 Symptoms Radiography Culture Symptoms are necessary, but not sufficient for ABS diagnosis.Symptoms are necessary, but not sufficient for ABS diagnosis. Radiography is not necessary or sufficient but may help enrich a population for ABS.Radiography is not necessary or sufficient but may help enrich a population for ABS. Given symptoms, cultures are sufficient and, since there is no validated, or reproducible, or standardized surrogate in the literature, necessary.Given symptoms, cultures are sufficient and, since there is no validated, or reproducible, or standardized surrogate in the literature, necessary. Conclusions (2)