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  • Act as superantigens capable of interacting simultaneously with MHC class II antigens on antigen-presenting cells and specific V-beta regions of T-lymphocyte receptors in the absence of classic antigen processing
    Result: massive release of cytokines including tumor necrosis factor-alpha, interleukin-beta, and interleukin-6
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    • 1. The sepsis syndrome:The sepsis syndrome: Differential diagnosis of the flu-likeDifferential diagnosis of the flu-like illnessillness Divya Ahuja, M.D. November , 2008 Med Micro 2008 Clinical Correlations #5
    • 2. Traditional definitionsTraditional definitions Bacteremia (or fungemia): presence of microorganisms in the blood Sepsis: Harmful consequences of microbes or their toxins in blood or tissues Septicemia (or bloodstream infection): bacteremia with clinical manifestations Septic shock: shock due to sepsis, often with bloodstream infection
    • 3. Revised definitionsRevised definitions Systemic inflammatory response syndrome (SIRS) Sepsis Severe sepsis Septic shock
    • 4. Systemic Inflammatory ResponseSystemic Inflammatory Response Syndrome (SIRS)Syndrome (SIRS) Two or more of the followingTwo or more of the following – temperature > 38 degrees C (100.4 F) – respirations > 20/minute – Heart rate > 90 beats per minute – leukocyte count > 12,000/cmm or < 4000/cmm or with > 10% band forms
    • 5. Sepsis and Severe SepsisSepsis and Severe Sepsis Sepsis: SIRS plus a documented infection (culture proven or identified by visual inspection) Severe sepsis: Sepsis associated with organ dysfunction, abnormalities due to hypoperfusion (such as lactic acidosis, oliguria, or acute alteration in mental status), ARDS, DIC, low platelets
    • 6. Septic shockSeptic shock Definition: Sepsis-induced hypotension despite fluid resuscitation and/or inotropic support, plus hypoperfusion abnormalities The hallmark of septic shock is low systemic vascular resistance, which distinguishes it from hemorrhagic shock and cardiogenic shock.
    • 7. Multiple Organ Failure Some physiologic descriptors – Serum creatinine – Platelet count – pO2/FiO2 ratio – Serum bilirubin – Glasgow coma score
    • 8. Sepsis Sepsis has a 20-50% mortality Severity has increased recently Hospital case-fatality has declined Incidence is greatest in winter Risk factors for sepsis – Bacteremia – Advanced age – Impaired immune system – Community acquired pneumonia
    • 9. Continuum of severity Incidence of positive blood cultures increases along the continuum Increased mortality rate Severe organ dysfunction manifested as – Acute respiratory distress syndrome – Acute renal failure – Disseminated intravascular coagulation
    • 10. Disseminated intravascular coagulopathy
    • 11. Case #1 20-year-old college student in ER General malaise, low-grade fever, and rapid development of purplish discoloration on his face. (from when he left his house to the time he arrived at the emergency room). Blood cultures were drawn and he was admitted to the intensive care unit
    • 12. Presentation Febrile, tachycardic, systolic BP-70 Creatinine- 3.6, poor urine output Platelets-46000 INR- 2.6 Obtunded mental status Needing maximum ventilatory support
    • 13. Case # 1 Meningococcemia with Waterhouse-Friderichsen Syndrome and DIC Treat with penicillin, ceftriaxone or chloramphenicol. Family members and hospital employees in contact with respiratory secretions should receive prophylaxis. Attack rates for household contacts is 0.3-1%, 300-1000 times the rate in the general population (rifampin x 4 doses or cipro x 1 dose)
    • 14. Epidemiology of meningococcal diseaseEpidemiology of meningococcal disease  About 1 to 2 cases/100,000 in temperate areas; occurs especially in the winter and spring  Serogroups A and C are known as “epidemic strains”; group B is major cause of sporadic disease in the U.S  Patients with deficiencies of late-acting complement components (C5 to C9) may repeat episodes of invasive meningococcal disease
    • 15. Correlation of traditional andCorrelation of traditional and revised definitionsrevised definitions Severe sepsis: Blood cultures are positive in 20% to 40% of cases Septic shock: Blood cultures are positive in 40% to 70% of cases
    • 16. Evaluation of blood culturesEvaluation of blood cultures True-positive versus false-positive (contamination; pseudobacteremia) Transient versus intermittent versus continuous Polymicrobial versus unimicrobial Primary versus secondary
    • 17. Clues to contaminationClues to contamination Microorganisms that are usually not pathogenic, unless isolated from multiple cultures (e.g., coagulase-negative staphylococci; Bacillus species) < 2 positive cultures and/or delayed growth and/or < 1 cfu/ml Doesn’t “fit” the clinical picture
    • 18. Patterns of bacteremiaPatterns of bacteremia Transient: caused by manipulation of a flora-containing body surface Intermittent: typical of most infections giving rise to positive blood cultures Sustained (or continuous): characteristic of intravascular infections--endocarditis, endarteritis, suppurative thrombophlebitis, infected AV fistula
    • 19. Number of microorganismsNumber of microorganisms Unimicrobial (or “monomicrobial”) bacteremia: one isolate Polymicrobial bacteremia: more than one microorganism; typical of complicated situations often with surgical implications
    • 20. Epidemiology of sepsisEpidemiology of sepsis Contributes to > 100,000 deaths in the United States each year. Annual incidence is probably between 300,000 and 500,000 cases. About 2/3rds of cases occur in patients hospitalized for another illness (nosocomial infection).
    • 21. Risk factors for nosocomial sepsisRisk factors for nosocomial sepsis Gram-negative bacilli: diabetes mellitus; tumors; cirrhosis; burns; invasive procedures; neutropenia Gram-positive cocci: vascular access lines, devices Fungi: immunosuppression; broad- spectrum antibiotic therapy
    • 22. Host factors in sepsisHost factors in sepsis Mortality is directly related to severity of underlying disease: rapidly-fatal> ultimately fatal (i.e., within 5 years)>nonfatal. Elderly have increased mortality. Mortality is higher in patients with subnormal temperatures than in those with fever.
    • 23. Clinical findings in sepsisClinical findings in sepsis Early: apprehension, hyperventilation, altered mental status Complications: hypotension, bleeding, leukopenia, thrombocytopenia, organ failure Lungs: cyanosis, acidosis, full-blown ARDS
    • 24. Clinical findings in sepsis (2)Clinical findings in sepsis (2) Kidneys: oliguria, anuria, tubular necrosis Liver: jaundice and transaminitis Heart: heart failure, stunned myocardium Gastrointestinal: nausea, vomiting, diarrhea, stress ulceration Systemic: lactic acidosis
    • 25. Clinical findings in sepsis (3)Clinical findings in sepsis (3)  Petechiae early in course: suspect especially meningococcemia, RMSF  Ecthyma gangrenosum: Ps. aeruginosa  Generalized erythroderma: Toxic Shock Syndrome
    • 26. Petechiae Ecthyema gangrenosum
    • 27. Skin lesions in septicemias (1)Skin lesions in septicemias (1) Neisseria meningitidis: erythematous macules or petechiae and purpura Rocky Mountain spotted fever: petechiae, purpura Staphylococcus aureus: “purulent purpura” Pseudomonas aeruginosa: ecthyma gangrenosum
    • 28. Skin lesions in septicemia (2)Skin lesions in septicemia (2)  Salmonella typhi: “Rose spots”  Hemophilus influenzae: cellulitis  Endocarditis: petechiae; Osler’s nodes (painful lesions of finger and toe pads); Janeway lesions (painless lesions of palms or soles)  Anthrax: papules-->vesicles-->eschar  Fungemias
    • 29. A 50 yo man presents to emergency room with severe painA 50 yo man presents to emergency room with severe pain and swelling of LLE. On exam, temperature is 40.0and swelling of LLE. On exam, temperature is 40.0 ºC,ºC, pulse rate is 135/min, respiration rate is 35/min, and bloodpulse rate is 135/min, respiration rate is 35/min, and blood pressure is 80/40pressure is 80/40
    • 30. Which of the following is the mostWhich of the following is the most appropriate initial therapy?appropriate initial therapy? 1. LLE elevation 2. X-ray of LLE 3. Surgical consultation 4. Oral antibiotics
    • 31. Necrotizing fasciitisNecrotizing fasciitis Necrotizing fasciitis usually results from an initial break in skin (trauma or surgery) It is deep: may involve the fascial and/or muscle compartments The initial presentation is that of cellulitis
    • 32. Necrotizing fasciitis: Red flagsNecrotizing fasciitis: Red flags 1. Severe pain (out of proportion of skin findings) 2. Bullae (due to occlusion of deep blood vessels) 3. Skin necrosis or ecchymosis 4. Gas in soft tissue (palpation or imaging) 5. Systemic toxicity 6. Rapid spread during antibiotic therapy
    • 33. Necrotizing fasciitisNecrotizing fasciitis Monomicrobial: S. pyogenes, S. aureus, anaerobic streptococci,…. Most are community acquired and present in the limbs in patients with DM or vascular insufficiency Polymicrobial: aerobic and anaerobic (bowel flora), Usually associated with abdominal surgical procedures, decubitus ulcer, perianal ulcer, bartholin abscess, IV drug injection
    • 34. Staphylococcal bacteremiaStaphylococcal bacteremia  Complications: endocarditis; metastatic infection; sepsis syndrome  Staphylococci adhere avidly to endothelial cells and bind through adhesin-receptor interactions  Fulminant onset; high fever, erythematous rash with subsequent desquamation, and multiorgan damage  DDx: Rocky Mountain spotted fever, streptococcal scarlet fever, leptospirosis
    • 35. Streptococcal toxic shock syndromeStreptococcal toxic shock syndrome  Early onset of shock and organ failure associated with isolation of group A streptococci  Necrotizing fasciitis present in about 50% of cases  Early symptoms: Myalgias, malaise, chills, fever, nausea, vomiting, diarrhea  Pain at minor trauma site may be first symptom
    • 36. Sepsis in the asplenic patientSepsis in the asplenic patient  Frequently fulminant with massive bacteremia  Streptococcus pneumoniae accounts for 50% to 90% of infections and 60% of deaths  Other pathogens: Haemophilus influenzae, Neisseria meningitidis, Capnocytophaga canimorsus (after dog bites), Babesia microti (babesiosis)
    • 37. 64 year old WM64 year old WM  Presents with fever, hypotension, cellulitis with bullous skin lesions  PMH: cirrhosis  SH: recently returned from New Orleans, likes oysters
    • 38. Vibrio vulnificusVibrio vulnificus sepsissepsis  Organism found in warm seawater and in shellfish (90% of deaths due to seafood in U.S.)  Cirrhosis a major risk factor to sepsis, with rapid onset  Chills, fever, characteristic skin lesions (bullae with hemorrhagic fluid; necrotizing fasciitis, other)  Also causes wound infection after exposure to salt water
    • 39. 41 year old WM41 year old WM  Fever, “worst headache ever,” myalgias, rash  Returned from family camping trip in Smoky Mountain National Park 1 week PTA
    • 40. Rocky Mountain spotted feverRocky Mountain spotted fever  Generalized infection of vascular endothelium  Headache typically severe. Fever may be low-grade and rash may be absent (“spotless fever”) when patient first seen  Suspect with flu-like illness and severe headache in endemic areas!
    • 41. 65 year old woman65 year old woman  PMH diabetes  During influenza epidemic, presents with fever, chills, aching all over (myalgia)  PE: bibasilar rales; no murmur  Admitted to hospital for treatment of heart failure
    • 42. Infective endocarditis: definitionsInfective endocarditis: definitions Septic vegetations of the endocardium usually involving the heart valves or other areas of turbulent flow Acute endocarditis occurs on normal heart valves, is caused by highly virulent bacteria and leads to death in < 6 weeks Subacute endocarditis is caused by less virulent bacteria and has a more indolent course.
    • 43. Pathogenesis of endocarditisPathogenesis of endocarditis Sterile vegetations arise downstream of high-flow areas of the heart Damaged endothelium and foreign bodies increase turbulent flow Microorganisms implant on the sterile vegetations during transient bacteremia Septic vegetations become a source of infection elsewhere
    • 44. Diagnosis of endocarditisDiagnosis of endocarditis Revised Duke Criteria : positive blood cultures plus echocardiography with or without minor criteria Heart murmurs (especially regurgitant) Splinter hemorrhages (nail beds) Osler nodes (finger pulps; painful) Petechiae; “pustular purpura” (Staph) Roth spots (fundi)
    • 45. Etiologies of endocarditisEtiologies of endocarditis Viridans streptococci most common (30-40%) Other streptococci include enterococci and Streptococcus bovis Staphylococci cause 20-30%) Less common: aerobic gram-negative rods; HACEK organisms; fungi; anaerobic bacteria; Brucella; Coxiella burnetti; Chlamydia psittaci “Culture-negative” (<5% to 24%)
    • 46. Case 42 year male Previously healthy, non smoker 2 week history of progressive cough, dyspnea, fever Intubated within 48 hours of admission
    • 47. Case
    • 48. Hamman-Rich syndrome Also known as acute interstitial pneumonia, is a rare, severe lung disease which usually affects otherwise healthy individuals Cough, fever, dyspnea Hamman-Rich syndrome progresses rapidly, with hospitalization and mechanical ventilation within days to weeks after initial symptoms
    • 49. Sepsis-summary Look at the host (age, immunedeficiency,-HIV, cancer, steroids, cirrhosis, dialysis, Clinical assessment for MOD (vitals, perfusion, mental status, urine output) Lab parameters-platelets, creatinine, coags, leukocytosis vs. leukopenia Hemodyanamic, ventilatory support, antibiotics Hit hard and hit early and then deescalate based on emerging microbiological data