How do superantigens activate the immune system?
Super antigens produced (by S. aureus or S. pyogenes) directly bind to the MHC II molecule AND the Vß subunit of the CD4+ T Cell Receptor.
They don't activate traditionally, they bind to the SIDES of the receptors (outside MHC peptide groove).
What's the difference between traditional CD4+ activation and superantigen activation?
Traditional activation by some foreign peptide will only activate 1/100,000 CD4+ cells on a good day.
Superantigen activation will activate 20% OF ALL YOUR CD4+ CELLS. Hence the big reaction.
What's the pathophysiology of a superantigen mediated toxic shock syndrome?
The superantigens made link up with a CD4+ cell and antigen presenting cell, binding to the MHC II complex and TCR. This turbo charges the CD4+ cell.
Macrophages make IL-1, IL-6, and TNF, which sounds the alarm. IL-8 is made to recruit other WBCs.
The liver starts making acute phase reaction proteins to protect the body, the blood vessel's endothelium gets really permeable, allowing WBCs to get into tissue.
The endothelial cells make IL-8 as well, which tells WBCs to get into tissue and phagocytose.
Temperature is increased to stop any would-be invaders from growing well (like turning up the AC to get in-laws out of your house), PMNs are activated, recruited, and start carpet bombing, damaging tissue along with anything foreign (not how you would get in-laws out of your house).
The response is excessive, leading to a cytokine storm, causing capillary leak, tissue damage, multi organ failure and death.
How does one diagnose Staphylococcal Toxic Shock Syndrome?
Fever > 102°F
Hypotension (systolic BP < 90 mmHg)
Diffuse macular erythroderma (rash)
Desquamation at 1-2 weeks
3 or more organ systems involved (GI, renal, liver, muscular, CNS, mucus membranes and/or thrombocytopenia)
What must be ruled in/out for diagnosis of Staph TSS?
measles, leptospirosis, rocky mountain spotted fever (serology)
other organisms (negative blood cultures)
S. aureus by isolation -- NOT REQUIRED
Risk factors for Staph TSS?
THE CRIMSON TIDE:
tampon in for greater than 8 hours (the hunt for red october)
packing your nose to stop bleeding (shouldn't have let them punch you in the nose in the first place...)
Signs and symptoms of Staph TSS?
That headache, confusion, sunburn like rash (hands, feet especially), photophobia, myalgias, pelvic pain, sore throat, hypotension, fever, vomiting, diarrhea so you can rest medicine.
Actually, considering the symptoms, it sounds more like a mix between a bad date and and alien abduction...
How does one diagnose Streptococcal Toxic Shock Syndrome?
Isolation of Streptococcus pyogenes from a normally sterile site (tissue biopsy, surgical wound, CSF, pleura, peritoneal fluid, blood)
Hypotension (systolic BP < 90 mmHg)
2 or more of the following:
renal insufficiency, coagulopathy, increased liver enzymes, adult respiratory distress syndrome, soft tissue necrosis, and/or erythematous macular rash (may desquamate). It's beginning to look a lot like Christmaaaaaas...
Risk factors for Strep TSS?
any disease compromising skin or mucosal surfaces
use of NSAIDS
(sounds like a step-by-step list for 19th century family making)
Strep TSS associated with?
MO: invasive, skin/soft tissue infections (necrotizing fasciitis, myositis)
patients will frequently have pain at the site of the skin infection.
Types of Staph TSS?
Menstrual (super absorbant tampons become a FOB for S. aureus as it produces TSST-1)
post surgery, skin infections, abscess, wounds (usually burn victims), post influenza staph pneumonia
A superabsorbant tampon??? Why???
Their theory: increased intravaginal O2 from tampons, high protein, neutral pH
My theory: don't we culture Staph on blood agar plates?...
In Staph TSS, is there usually pain at the site of infection?
Staph vs Strep TSS
Skin/soft tissue infection
Severe pain at skin
Staph: VERY COMMON
Treatment of Toxic Shock Syndrome?
Thorough search for site of infection (tampon? foreign bodies? abscess drainage, wound debridement)
Antibiotics (MSSA-nafcillin, MRSA-vancomycin, GAS-penicillin G)
Clindamycin to block toxin production
Maybe IVIG therapy
The word endotoxin is associated with
LPS/Lipopolysaccharide, found in outer membrane of Gram negative bacteria
How do our cells recognize LPS?
LPS is recognized by TLR4, a Pattern Recognition Receptor (PRR) • PRRs recognize PAMPS (pathogen associated molecular patterns)
• PAMPS are molecules associated with pathogens (but not humans) that are recognized by the innate immune system
• Many PAMPS are recognized by PRRs in the Toll-like receptor (TLR) family
Does LPS just bind to TLR4 and cause normal genetic signaling like with other receptor?
Nope. LPS ligates the TLR4 and causes a cascade of inflammation via TNF and other cytokines.
How do we treat Septic Shock due to Gram Negative bacteria?
• IV fluids
• Eradication of the infection broad spectrum abx +/- surgery
• Vasopressors and inotropes if needed (optimize perfusion)
For reference, despite the known pathophysiology, the following do not help clinical course of pts in septic shock
- anti-endotoxin Ab
- TLR-4 antagonist
- TNF inhibitors
- IL-1 antagonists
- bradykinin antagonists
- nitric oxide inhibitors
Discuss the symptoms of Neisseria Meningitidis
Sx: Petechial rash from Thrombocytopenia that typically first occurs in areas where pressure is applied tothe skin such as belts --> risk for DIC.
Waterhouse Fredrichsen Syndrome characterized by hemorrhage of adrenals and also known as Purpura fulminans --> acute cutaneous hemorrhage due to vascular necrosis/vasculitis and DIC.
Discuss the pathophys behind how Neisseria Meningitidis spreads and causes systemic issues
Pathophys: LOS envelope proteins cause inflammatory response (very dramatic increases in proinflammatory cytokines like TNF-a, IL-1, IL-6, IL-8) → Capillaries begin to leak → Hypovolemia and shock
Virulence factors for Ne. Meningitidis
Virulence: IgA protease that cleaves IgA at hinge region. Polysaccharide capsule to stop phagocytosis
Labs for N. Meningitidis
Labs: Ferments maltose and glucose.
Dx: Culture from blood or CSF, Latex Agglutination on CSF or urine
In meningococcal sepsis, Gram stain of a punch bx of skin lesions is more sensitive (72%) than Gram stain of CSF (22%)
Discuss thevaccine for N. Meningitidis
Vaccine: Contains polysaccharide capsule, no type B capsule in vaccine
Who is at risk for N. Meningitidis
At risk: Sickle Cell patients and those that are asplenic. Spreads in close areas like college dorms.
How do we treat N. Meningitidis
Tx: Rifampin prophylaxis for close contacts. Treat with Ceftriaxone if it is PCN resistant. You can use Chloramphenicol if you want to be sued by your patients.
Do we even get N. Meningitidis in the U.S.?
U.S. 2500-3500 cases per year (esp serogroups B, C and Y) somewhat seasonal, with attack rates highest in Feb/March case fatality rate: 10% (without Rx up to 70% mortality) sequelae in 10-20% of survivors