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Management of Streptococcal Pharyngitis: Role of the Laboratory and POC Testing

Management of Streptococcal Pharyngitis: Role of the Laboratory and POC Testing. Arthur E. Crist, Jr., Ph.D. Director, Clinical Microbiology York Hospital. Outline. Organism Nomenclature Pathogenesis & Spectrum of Disease Clinical Diagnosis Laboratory Diagnosis Culture

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Management of Streptococcal Pharyngitis: Role of the Laboratory and POC Testing

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  1. Management of Streptococcal Pharyngitis: Role of the Laboratory and POC Testing Arthur E. Crist, Jr., Ph.D. Director, Clinical Microbiology York Hospital

  2. Outline • Organism • Nomenclature • Pathogenesis & Spectrum of Disease • Clinical Diagnosis • Laboratory Diagnosis • Culture • Rapid Antigen Testing • Molecular Methods

  3. Gram Stain – Blood Culture

  4. Structure

  5. Extracellular products: Pyrogenicexotoxin = erythrogenic toxin scarlet fever, toxic shock lysogenic bacteriophage, Spe-A,B,C,F, Ssa. Hemolysins streptolysin O streptolysin S O2 sensitive O2 resistant antigenic (AST) non antigenic Enzymes DNases A-D Hyaluronidase Streptokinase NADase

  6. Classification

  7. Beta hemolysis on SBA

  8. Ignaz P. Semmelweiss

  9. Joseph Lister

  10. Why Diagnose Streptococcal Pharyngitis? • Treatment Prevents Sequelae -Rheumatic Fever - Scarlet Fever - Glomerulonephritis - Invasive Streptococcal Disease - (“Flesh-eating Strep”)

  11. Local Infections • Pharyngitis - Winter-Spring months - School aged child, esp. 3-10 years - Abrupt onset • Pyoderma (Impetigo) • Otitis Media • Sinusitis

  12. Streptococcal Sore Throat

  13. Impetigo

  14. Invasive Infections • Erysipelas • Cellulitis • Necrotizing Fasciitis • Puerperal Fever • Sepsis • Endocarditis • Scarlet Fever • Toxic Shock Syndrome

  15. Erysipelas

  16. Cellulitis

  17. Necrotizing Fasciitis

  18. Nonsuppurative Sequelae • Acute Rheumatic Fever • 1 to 5 weeks following acute pharyngitis • 6 to 15 years of age • Attack rate 0.4% (civilian) to 3% (military) • M types 1,3,5,6,12,18,19,24 • Inflammation of the heart (heart valves), joints, blood vessels, and subcutaneous tissues • Probably immunological (autoimmune?) • Recurrences are common

  19. Nonsuppurative Sequelae • Acute Glomerulonephritis • Approx. 10 days following acute pharyngitis; (3 weeks following pyoderma) • Winter/Spring (Summer/Fall-pyoderma) • 6 to 15 years of age (preschool-pyoderma) • Attack rate 10-15% with known neph. strain • Limited M types involved • Probably immunological (immune complex) • Recurrences are rare

  20. Which Streptococci Cause Sore Throat? • Group A streptococcus (S. pyogenes) • Group C streptococcus (S. dysgalactiae subsp. equisimilis) • Group G streptococcus (S. dysgalactiae subsp. equisimilis)

  21. Signs of Streptococcal Tonsillopharyngitis • Characteristic signs -Tonsillopharyngeal erythema -Tonsillopharyngeal exudate -Soft-palate petechiae (“doughnut” lesions) -Beefy red, swollen uvula -Anterior cervical lymphadenitis -Scarlatiniform rash • Uncharacteristic signs -Conjunctivitis -Anterior stomatitis -Discrete ulcerative lesions

  22. Symptoms of Streptococcal Tonsillopharyngitis • Characteristic symptoms -Sudden onset of sore throat -Headache -Pain on swallowing -Abdominal pain -Fever -Nausea and vomiting • Uncharacteristic symptoms -Coryza -Cough -Hoarseness -Diarrhea (Bisno, NEJM)

  23. Clinical Diagnosis of Streptococcal Pharyngitis • Based on signs and symptoms • Not very accurate • 50% of patients with pharyngitis will be treated but will not be infected with Group A Streptococci • 30% of patients with pharyngitis will not be treated but will be infected with Group A Streptococci

  24. Microbial Causes of Acute Pharyngitis (Bisno, NEJM) Estimated Pathogen Percentage of Cases Viral Rhinovirus (100 types and 1 subtype) 20 ³ Coronavirus (3 or more types) 5 Adenovirus (types 3, 4, 7, 14, and 21) 5 Herpes simplex virus (types 1 and 2) 4 Parainfluenza virus (types 1-4) 2 Influenzavirus (types A and B) 2 Coxsackievirus A (types 2, 4-6, 8, and 10) <1 Epstein-Barr virus <1 Cytomegalovirus <1 Human immunodeficiency virus type 1 <1

  25. Microbial Causes of Acute Pharyngitis (Bisno, NEJM) Estimated Pathogen Percentage of Cases Bacterial (Group A 15-30 Streptococcus pyogenes b -hemolytic streptococci) b 5 Group C -hemolytic streptococci <1 Neisseria gonnorrhoeae <1 Corynebacterium diphtheriae £ Arcanobacterium haemolyticum 1 Chlamydial Unknown Chlamydia pneumoniae Mycoplasmal <1 Mycoplasma pneumoniae

  26. Laboratory Diagnosis • Culture • Specimen Collection (10% FN) • “Gold Standard” ?? • Selective vs. non-selective medium • Aerobic, 5-10% CO2, anaerobic atmosphere • 1 or 2 day incubation • Broth enhancement

  27. Cockerill. 2002. Mayo Clinic Data. AACC Internet Presentation n=261 SXT plus blood agars n=187 n=189 Total positive cultures (%) Blood agar plate only n=151 n=106 Aggregate antigen detection tests Days CP1069709-1

  28. Culture Methods Roddey, et al. 1995. JAMA 274: 1863-1865

  29. Presumptive Identification

  30. Definitive Identification(Biochemical or Serological)

  31. Positive PYR Test

  32. Rapid Antigen Tests • Extract (acid) cell wall antigen from organism on throat swab • Detect presence of extracted antigen by • Latex agglutination (LA) • Enzyme immunoassay (EIA) • Optical immunoassay (OIA)

  33. Rapid Antigen Test

  34. FDA Approved Kits • 40 CLIA High Complexity (1993-1999) Effective Date • Abbott TestPack Plus Strep A 01-11-1999 • BD Directogen 1-2-3 Group A Strep 10-27-1995 • J & J CDI SureCell 10-06-1995 • Gen-Probe Group A Strep Direct 06-10-1994 • Almost all are used to type organisms from culture • Gen-Probe most frequently used direct specimen test in this group

  35. FDA Approved Kits • 77 CLIA Moderate Com. (1993-2002) Effective Date • Abbott Signify Strep A 03-08-2002 • Quidel Quickvue Strep A Test 03-05-2002 • Abbott TestPack Plus Strep A w/OBC II 01-11-1999 • Binax Strep A Test 04-19-1996 • J & J CDI SureCell 10-06-1995 • Abbott TestPack Plus Strep A 07-26-1993 • Baxter MicroScan Cards O.S. 07-26-1993 • BD Directogen 1-2-3 Grp A Strep 07-26-1993 • Binax Equate Strep A 07-26-1993 • BioStar Strep A OIA 07-26-1993 • Hybritech ICON Strep A 07-26-1993 • Meridian Diagnostics ImmunoCard 07-26-1993 • Quidel Group A Strep 07-26-1993 • Wampole Bactigen Group A Strep 07-26-1993

  36. FDA Approved Kits • 24 CLIA Waived (1996-2002) Effective Date • Genzyme OSOM Ultra Strep A Test 07-19-2002 • Quidel Quickvue In-Line Strep A 07-08-2002 • Acon Strep A Rapid Test Strip 12-18-2001 • Beckman Coulter ICON DS Strep A 12-18-2001 • Quidel Quickvue Dipstick Strep A 07-26-2001 • ICON DS Strep A 07-17-2001 • Beckman Coulter ICON FX Strep A 03-16-2001 • Wyntek Diagnostics OSOM Ultra Strep A 07-06-2000 • Fisher Sure -Vue Strep A 09-22-1999 • Meridian ImmunoCard STAT Strep A 05-19-1998 • Abbott Signify Strep A Test 09-22-1997 • Biostar Acceava Strep A Test 07-09-1997 • Binax NOW Strep A Test 01-10-1997

  37. Factors Affecting ADT Sensitivity • Culture methods selected in a study influence the calculated ADT sensitivities • Studies are likely to report higher ADT sensitivities when cultures are performed in physician offices • When culture methods result in identification of very small numbers of GABHS, the calculated sensitivity of an ADT will be lower than that calculated when a less rigorous culture method is used because ADTs are likely to fail to detect low numbers of GABHS

  38. Comparison of a CLIA Waived & Moderately Complex Test Mod. Complex ADT Sens. (%) Spec. (%) Waived ADT 91 93 Gold Standard Sens. (%) Spec. (%) Waived ADT 80 95 Gold Standard Sens. (%) Spec. (%) Mod. Com ADT 82 100

  39. Comparison of the Abbott Signify Group A Test to Culture – York Hospital Dec. 1999 to Mar. 2000(n=397) • Study Sens. (%) Spec. (%) PVP (%) PVN (%) __________________________________________________________________ • YH* 82.9 97.8 90.0 96.0 • PI** 96.0 97.8 ND ND • *York Hospital • ** Package Insert

  40. Sensitivity and Specificity of the OIA Sensitivity Specificity Study (%) (%) Harbeck 1993 97.4 95.6 Harbeck 1993 98.998.4 Dale 1994 81 97.5 Roe 1995 83 89 Heiter 1995 92.3 95.4 Fries 1995 94 98 Harris 1995 96 94 Baker 1995 78 90 Gerber 1997 84 93 Hart 1997 7762 Pitetti 1998 79.5 96.5 Kuhn 1999 89 96.5 Chapin 2002 86.1 97.1

  41. Comparison of Test Sensitivity Cockerill. 2002. Mayo Clinic Data. AACC Internet Presentation

  42. Conclusions: Rapid Antigen Kit Analytical Sensitivity Comparison • Detection of different isolates by different tests showed no differences • Analytical Sensitivities were best for the OIA (3.3 x 104 CFU) and worst for Directigen (5 x 105 CFU) Cockerill. 2002. Mayo Clinic Data. AACC Internet Presentation

  43. Molecular Tests for Detection of Group A Streptococcus from Throat Swabs - Not Point-of-Care • Group A Streptococcus Direct Test (Gen-Probe) • PCR – Conventional or Real Time

  44. Gen-Probe Group A Streptococcus Direct Test • Test detects rRNA sequences using a chemiluminescent single-stranded DNA probe • Enhanced sensitivity vs. Antigen detection methods

  45. Comparison Of The Gen-Probe Test and Culture Percent Positive Negative Test Sensitivity Specificity predictive predictive value value Heiter 1993 93.5 99.7 99.0 97.8 Pakorski 1994 85.7 97.8 83.9 98.1 Chapin 2002 94.8 100 100 96.9

  46. UnamplifiedDNA Cycle 3 Targeted sequence Cycle 0 Denatureand annealprimers Denatureand annealprimers Cycle 1 Primerextension Cycle 2 Primerextension Denatureand annealprimers Primerextension Cycles 4-25 At least 105-fold increase in DNA Polymerase Chain Reaction

  47. Comparison of PCR to Other Methods Test Sensitivity (%) Specificity (%) PVP (%) PVN (%) ____________________________________________________________________ OIA 76 92 85 87 Agar culture 79 100 100 90 Both-enhanced cult. 86 100 100 93 Combined cult. 89 100 100 94 OIA & agar cult. 89 92 86 94 PCR 96 100 100 98 Kaltwasser, et al. 1997. Pediatr. Infect. Dis. J. 16: 748-753

  48. Management of Streptococcal Pharyngitis Hofer, et al. 1997. Arch. Pediatr. Adolesc. Med. 151: 824-829.

  49. Management of Streptococcal Pharyngitis % Physicians Ordering Test_____________________________________________________________________ Private HMO Residents Total (n=50) (n=50) (n=50) (n=150)____________________________________________________________ Case A Throat culture 100 100 100 100 20-minute ADT 74 90 88 84 4-hour ADT 32 46 40 39 Case B Throat culture 80 64 66 70 20-minute ADT 54 54 54 54 4-hour ADT 18 30 20 23 Berwick, et al. 1987. Pediatr. Infect. Dis. J. 6: 1095-1102

  50. Management of Streptococcal Pharyngitis % of Physicians Who “Believe” ADT_____________________________________________________________________ Private HMO Residents Total (n=40) (n=43) (n=36) (n=119)____________________________________________________________ Case A Positive 98 93 94 95 Negative 42 42 50 45 (n=44) (n=45) (n=43) (n=132) Case B Positive 89 93 72 85 Negative 73 82 79 78 Berwick, et al. 1987. Pediatr. Infect. Dis. J. 6: 1095-1102

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