1. Sepsis In A Young Physician March 31, 2004 Edward L. Goodman, MD

2. Outline Case Presentation Differential Diagnosis Hospital Course Epidemiology Adjunctive Therapy

3. History CC: Fever and myalgias HPI: 40 year old neurologist –Six days of progressive large muscle myalgias –Three days of mild cough mildly productive –Mild dyspnea, no pleurisy –Self administered amantadine for presumed influenza

4. History 2 ROS: no recent sore throat, no CNS symptoms, no GI or GU sx PMH: unremarkable except for frequent flu like illnesses for which he takes amantadine and NSAIDs Epidemiology: twins age 15 month, not in daycare, recent travel to California where exposed to two other young children

5. Exam Very ill and toxic appearing Temp very elevated, HR 120, BP 115/73 Injected conjunctivae without petechiae Supple neck Diffuse erythema on trunk Few petechiae on legs Few rales LLL, gallop rhythm Tender muscles

6. Initial Chest X Ray

7. Initial Lab pH 7.4, pCO2 33.8, pO2 58 on RA –Mixed acid base disorder WBC 8500, 53% bands Platelets 158,000 INR 1.7, PTT 48.7, d dimer 537 Creat 1.0, Alk ptase 173, AST/ALT 48/121, Bili 3.7 (direct 2.6), CRP 23.1

8. Differential Diagnosis Focal infiltrates - Community Acquired Pneumonia, post influenza pneumonia Severe Myalgias –Influenza: proper season –Dengue: no travel to tropics –Leptospirosis: no exposure to rats, cattle, dogs Petechiae, septic, infiltrate: – meningococci

9. Hospital Course Started on Ceftriaxone and Moxifloxacin for possible CAP, meningococcemia Transfer to ICU for deteriorating BP, pulmonary status Blood cultures positive at 12 hours for GPC in pairs and chains = likely Strept pneumo?

10. Next Day: 2/23/04 0600 blood cultures are beta hemolytic –Not Strept pneumo! One dose Vancomycin Added Clindamycin Started Xigris On vent 100% FiO2 Multiple pressors Survival seems unlikely

11. Third Day: 2/24/04 Group A Strept confirmed Added IVIG Multiple pressors and 100% FiO2 still Cardiac arrest – resuscitated Hung crepe with family

12. Subsequent CXR 2/26/04

13. Subsequent Course Blisters on leg develop and evolve Vascular surgeon recommends against debridement Gradually rallies –Pressors tapered –Vent tapered MOF reversed Discharged to Rehab 3/15/04 Home 3/22/04!

14. Initial Lab pH 7.4, pCO2 33.8, pO2 58 on RA –Mixed acid base disorder WBC 8500, 53% bands Platelets 158,000 INR 1.7, PTT 48.7, d dimer 537 Creat 1.0, Alk ptase 173, AST/ALT 48/121, Bili 3.7 (direct 2.6), CRP 23.1

15. Peak Lab Abnormalities TestResultDate WBC32,6003/01/04 Platelets62,0002/27/04 PTT120.92/24/04 Creat3.62/28/04 Bili6.42/27/04 AST3093/11/04 ALT5023/12/04 Alk phos5233/12/04

16. Skin Lesions First Day

17. Evolving Lesions

20. Desquamation Day 16

21. Recent Film: 3/8/04

24. Epidemiology of Invasive GSS

25. Epidemiology

26. Discussion Antibiotics –Penicillin –Clindamycin Role of IVIG

27. Penicillin’s ineffectiveness High mortality in invasive GAS when Penicillin used –81% mortality in myositis –Animal data on inoculum effect High concentrations of GAS in deep sites –Stationary phase reached quickly –PBPs not expressed in stationary phase

28. Clindamycin No inoculum effect Suppresses toxin synthesis Facilitates phagocytosis by inhibiting M protein synthesis Suppresses proteins involved in cell wall synthesis Longer post antibiotic effect (PAE) Suppress LPS induced monocyte synthesis of TNF-alpha

29. TSS and IVIG Shock from gram positive toxins –Superantigens Enterotoxins TSST-1 SPEA –Superantigens bind to MHC II ß chain of T cell receptor –Resulting in T cell proliferation Cytokine production

30. IVIG Blocks in vitro T cell activation Contains superantigen neutralizing antibodies

34. Effects of IVIG Kaul et al, CID 1999;28:800

39. Conclusion Severe pain and fever – think of GAS Know the epidemiology of your institution Consult a surgeon promptly if skin or muscle involvement Add Clindamycin to beta lactam therapy for necrotizing or serious GAS infections Consider IVIG for TSS Consider Xigris

40. References Bisno AL, Stevens DL. Streptococcal Infections of Skin and Soft Tissues. New Eng J Med 1996; 334:240-245. Case Records of the MGH. New Eng J Med 1995; 333: 113-119. Case Records of the MGH. New Eng J Med 2002; 347:831-837. Disease Prevention News. TDH. March 27, 2000;60: No.7. Kaul R, McGeer A et al. Intravenous Immunoglobulin Therapy for Streptococcal Toxic Shock Syndrome – A Comparative Observational Study. Clin Infect Dis 1999; 28:800-807.

41. References - continued Kazatchkine MD, Kaveri, SV. Immunomodulation of Autoimmune and Inflammatory Diseases with Intravenous Immune Globulin. New Eng J Med 2001; 345: 747-755. Stevens DL. The Flesh-Eating Bacterium: What’s Next. J Infect Dis 1999;179(Suppl 2): S366-374