Toxic Shock, Endotoxemia, and Meningococcus

Question 1

What causes Toxic Shock Syndrome?

Answer 1

Superantigen activates T-cells, bypassing the usual steps in an antigen-mediated response, leading to a…

CYTOKINE STORM

Question 2

Where does a superantigen bind?

Answer 2

Directly to the MHC II molecule and Vβ subunit of the TCR

Bypasses the MHC peptide binding groove

Question 3

How many CD4⁺ T cells are activated by a superantigen (compared to a normal response)?

Answer 3

Normally, a peptide presented by an APC will activate < 1% of all CD4⁺ T cells

Superantigens activate 20% of all CD4⁺ T cells

Question 4

What are the superantigens for S. aureus and S. Pyogenes?

Answer 4

S. aureus = TSST-1 (fever, shock, capillary leakage)

S. pyogenes = Exotoxin A (shock, capillary leakage, cardiotoxicity)

Question 5

CDC definition for Staph Dx

Answer 5

Fever > 102

Hypotension (SBP <90)

Diffuse rash

Desquamation at 1-2 wks

3 or more organ systems involved

Question 6

CDC definition for Strep Dx

Answer 6

Isolation of S. pyogenes from normally sterile site

Hypotension

≥ 2 of: renal insufficiency, coagulopathy, increased liver enzymes, ARDS, erthematous macular rash, soft tissue necrosis

Question 7

SIRS Criteria

(Systemic Inflammatory Response Syndrome)

Answer 7

≥2 of:

T > 38 or < 36 (100.4 and 96.8)

HR > 90

RR > 20, PaCO₂ < 32

WBC > 12,000 or < 4,000 (or > 10% bands)

Question 8

Sepsis Criteria

Answer 8

SIRS

+

Source of infection

Question 9

Severe Sepsis Criteria

Answer 9

Sepsis (SIRS + source)

+

Lactic acidosis, SBP <90 or a drop ≥ 40

Question 10

Septic Shock Criteria

Answer 10

Severe Sepsis

+

Hypotension despite fluid resuscitation

Question 11

Common causes of Staph (toxin-mediated)

Answer 11

Tampon

Nasal packing

Recent surgery

Wound

Post-partum

Question 12

What is the most likely cause of someone presenting w/ a skin infection that causes severe pain and bacteremia?

Answer 12

Strep

Question 13

What is the mortality rate of strep compared to staph?

Answer 13

Strep has a greater mortality rate (5-10%) than staph (3-5%)

Question 14

How do you distinguish staph from strep for toxin-mediated infections?

Answer 14

Remember, strep looks worse and is painful

Staph: think diffuse rash

(less likely to involve skin/soft tissue infection, severe pain at site of infection, or bacteremia)

Question 15

Endotoxin

Answer 15

Poisonous substance from within a pathogenic organism

Synonymous with LPS (only Gram - bacteria)

Question 16

What are the 3 components of LPS?

Answer 16

1. Lipid A portion (outermost) = toxic component that overactivates the immune system (similar to cytokine storm seen with superantigens)
2. Core component
3. O polysaccharide (innermost) = sugar used to distinguish b/w differenty types (i.e., E. Coli O157)

Question 17

TLR4

Answer 17

A PRR (pattern recognition receptor) that recognizes LPS immediately

Question 18

PAMP

Answer 18

Pathogen Associated Molecular Protein

Ex: LPS

Question 19

Where are PRRs expressed

Answer 19

Transmembrane proteins expressed by cells of the innate immune system and epithelial cells

Question 20

How many PRRs/TLRs are found in humans?

Answer 20

10

(13 in mice)

Question 21

Mechanism of LPS

Answer 21

Ligates TLR4, leading to:

activation of macrophages

the production of inflammatory cytokines (C5a, TNF-α, IL-1, and IL-6)

upregulation of co-stimulatory and adhesion molecules (coagulation)

= FEVER, HTN, and TISSUE DAMAGE

Question 22

Why do we have TLR4?

Answer 22

Without it, we would be markedly susceptible to

gram (-) infections

Question 23

What does an increased level of IL-6 correlate with?

Answer 23

Increased mortality

Unlike TNF-α and IL-1, IL-6 does not produce shock symptoms

Question 24

Tx of Septic Shock d/t gram (-) bacteria

Answer 24

IV fluids

Eradication of infection (broad sprectrum abx and consider surgery)

Vasopressor and Inotropes if needed

Question 25

“No other infection so quickly slays”

Gram (-), aerobic, diplococci

Metabolizes maltose and glucose

Grows on Thayer-Martin media

Answer 25

N. meningitidis

Question 26

How is neisseria meningitidis serotyped?

Answer 26

By capsule (13+ serogroups) = virulence factor

Capsule protects against dessication, phagocytosis, and complement-mediated lysis

Question 27

Which serotypes of neisseria meningitidis are virulent?

Answer 27

A, B, C, X, Y, and W135

(B, C, and Y are common in the U.S.)

(Africa = A and W135)

Question 28

Initial symptoms of neisseria meningitidis vs late symptoms

Answer 28

Initial symptoms are non-specific (fever, headache, and muscle pains)

Late symptoms are “classic”

• Hemorrhagic rash (petechiae under bra strap or belt line)
• Meningismus (stiff neck, photophobia)
• Impaired consciousness

Question 29

Why does neisseria meningitidis progress so quickly?

Answer 29

D/t high levels of endotoxin:

leads to dramatic increase in TNF-α, IL-1, IL-6, and IL-8

Note: IL-8 is a chemokine that induces phagocytosis, histamine release, and respiratory burst

Question 30

What is the reservoir for n. meningitidis?

Answer 30

Nasopharynx of humans

The invasive disease is uncommon b/c most meningococci are not very pathogenic

Question 31

Waterhouse-Friderichsen Syndrome

Answer 31

When meningococcemia (w/ petechial rash) becomes fulminant…overwhelming infection

Shock, Purpura, and acute hemorrhagic necrosis of the adrenals

Worry about DIC, multiple organ failure, and death

Question 32

Risk factors for contracting n. meningitidis

Answer 32

Terminal complement deficiency (C5-9)

Variants in mannose-binding lectin

Asplenia

Cigarette Smoking

Preceding URI

Question 33

Gold Standard method of diagnosis for neisseria meningitidis

Answer 33

Cx blood or CSF

HOWEVER, when facing meningococcal sepsis, a gram stain of a punch bx of skin is more sensitive than a CSF stain

Question 34

Which age group is most at risk for neisseria meningitidis?

Answer 34

The very young

(another peak during the 1st year of college, but not as many people comparatively)

Question 35

Tx for n. meningitidis

Answer 35

Abx for 10-14 days (penicillin or 3rd generation cephalosporin)

Chemoprophylaxis for close contacts = rifampin, ceftriaxone, or cipro

Question 36

Vaccine for n. meningitidis

Answer 36

MCV4 vaccine has antigens to serogroups A, C, Y, W-135 (not B)

New vaccines were approved that protect against serogroup B (which happens to be one of the most common in the U.S.)

Question 37

Meningitis Belt

Answer 37

In sub-Saharan Africa (may result from dust interference with IgA secretion in nasopharynx)

Serogroup A

During the dry season (Dec-Jun)

Every 8-12 years (cyclic)

Question 38

Ritter disease

Answer 38

aka Staphylcoccal Scalded Skin Syndrome

Occurs in children with S. aureus infection of the nasopharynx or skin. Bacteria produce exfoliative A and B toxins which cleave the protein desmoglein 1 (holds epidermal cells together). Results in a sunburn-like rash that spreads over the entire body

Question 39

Subcutaneous manifestations of S. aureus infections

Answer 39

Staph leads to neutrophilic inflammation

• Furuncle (boil)
• Carbuncle
• Hidradenitis (infection of apocrine glands, most often in the axilla)
• Paronychia and felons (painful infection at nail beds or palmar fingertips, respectively)

Question 40

How does Staph epidermidis differ from Staph aureus?

Answer 40

S. epidermidis (aka Coagulase negative Staph/CoNS)

Less virulent

Major cause of clinically significant infections in all age groups, largely due to its ability to grown on virtually all biomaterials composing indwelling medical devices (catheters and prosthetic cardiac valves)

Most common cause of nosocomial bacteremia