2.6 Sepsis and fever Flashcards

1
Q

The human body can only tolerate temperatures (core temperature) between ___________ (above which results in core protein destruction and death):
• Temperature is generated by biochemical reactions in all living cells (mitochondria)
• More than 50% of body heat is generated by inefficient biochemical processes converting food energy into free energy
• Body temperature is regulated by the nervous system → nervous input causes physiological adaptation

Physiological response to heat*

  • Sweating (evaporation of water in sweat produces a cooling effect)
  • Increased blood flow to the skin surface (allows increased heat loss)
  • Thermal set point: ______________ before any heat loss response is triggered

Physiological response to cold

  • Shivering/non-shivering thermogenesis (_____________ is main source of non-shivering form)
  • Diversion of blood from non-vital organs (e.g. skin) to the heart and brain
A

28°C - 41°C;

maximum temperature tolerated;

brown adipose tissue

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2
Q

THERMOREGULATION
The body detects core temperature via the thermoregulatory area (hypothalamus + limbic system + lower brainstem + reticular formation + stem cord + sympathetic ganglia):
• ___________ is the most important (situated near the rostral hypothalamus)
• Detects thermal input signals from the skin and core organs (including CNS)

Fever

  • Elevated core temperature in response to invading microorganisms or inanimate objects recognised as pathogenic/alien
  • ________ in early morning and ________ at any other time*

Hyperthermia

  • Unregulated rise in body temperature due to failure of _______________
  • Standard antipyretics (e.g. paracetamol) are generally ineffective
  • Diurnal variation in body temperature must be considered (lowest at 6am; highest at 4 – 6pm)
A

Pre-optic area (POA);

≥ 37.2°C; ≥ 37.8°C;

thermoregulatory homeostasis (not due to pyrogenic cytokines)

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3
Q

FEBRILE RESPONSE The febrile response is a complex physiological reaction to disease, accounting for concurrent physiological responses and components of the acute phase response:
• Exogenous pyrogens enter the body and activate __________, which produce various cytokines (e.g. IL-6, IL-1, TNF-α, IFN-γ) that act on the __________________
• Induces _________________, which mediates the febrile response (negative feedback loop induced to control core body temperature → reduce temperature-induced cell damage)

Exogenous pyrogens

  • Originate from outside the body
  • May be infectious agents/products or non-infectious agents (e.g. foreign products)
  • Usually microorganisms, toxins, other products (antigens)
  • Induce host cells (mainly ____________) to produce endogenous pyrogens
  • Bacterial liposaccharide (LPS) has a direct pyrogenic effect (binds ________ on macrophages)

Endogenous pyrogens

  • Originate from within host cells)
  • 4 main host cell-derived cytokines (____________________)
  • Produced in response to exogenous pyrogens or certain endogenous molecules (e.g. Ab-Ag complexes with complement, certain androgenic steroid metabolites, various lymphocyte-derived molecules)

Cryogens

  • Helps the body to lose heat (opposite effect to pyrogens):
  • α-MSH, glucocorticoids, GIP, __________ (stimulates gastric release), glucocorticoid inducers (CRH, corticotrophin → inhibit_______________, arginine vasopressin, TRH, NO, CO
A

leukocytes;

organum vasculosum of the lamina terminalis (OVLT);

prostaglandin E2 synthesis

macrophages;

TLR-4;

IL-1, TNF-α, IL-6, IFN;

bombesin ;

IL-6 & TNF-α

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4
Q

ACUTE PHASE RESPONSE
The acute phase response is a complex interplay between systems in response to a clinical insult (inflammatory response involving many changes):
• Patients develop a fever and other physiologic changes (severity is variable; depends on other factors like the pathogen and state of immunocompromise)

Neuroendocrine:

  • Fever, malaise, sleepiness (somnolence), loss of appetite (anorexia)
  • Rise in _____, _________, ____
  • Decrease in ______________

Haematopoietic

  • Increased WCC (predominantly neutrophilia; sometimes increased platelets → may decrease instead in very septic patients due to DIC)
  • Anaemia of chronic disease (not blood loss)

Metabolic
- Muscle breakdown, fat breakdown, reduced _____________________ → cachexia (wasting of the body; may occur in other syndromes like AIDS/malignancies)

Hepatic
- Changes in concentrations of various hepatic proteins

Non-protein plasma constituents
- Decreased total ___________, increased ______

A

catecholamines, cortisol, arginine vasopressin;

IGF-1 (insulin-like growth factor 1) ;

gluconeogenesis;

iron and zinc; copper

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5
Q

There are various proteins which are affected by the acute phase response (ceruloplasmin, haptoglobin, C-reactive protein, serum amyloid A, albumin, transferrin):
• Haptoglobin is useful in measuring the presence of haemolysis (decreased haptoglobin in ___________; increased haptoglobin ______________)

  • C-reactive protein (CRP) & Serum amyloid A: _______________
  • Haptoglobin & Fibrinogen: Rise gradually and falls gradually
  • _______________: Decrease during the acute phase response
  • Procalcitonin is another marker of inflammation which is more specific for sepsis (inflammation due to severe infection) and is generally used in the critical setting.
A

haemolysis;

in acute phase response;

Rapid rise (persists for a few days) before rapidly dropping;

Albumin &Transferrin

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6
Q

SEPSIS
Sepsis is the systemic response to severe infection, which is one form of systemic inflammatory response syndrome (SIRS) (severe inflammatory response to a wide variety of severe clinical insults):
• Occurs on a spectrum: _________ → _________ → __________ (if unchecked) → _______ → death
• Rate of progression depends on the nature of the pathogen and presence of any underlying comorbidities

A

infection → acute phase response → sepsis (if unchecked) → septic shock → death

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7
Q

INFECTION
Infection is the microbial phenomenon characterised by an _____________________ to the presence of microorganisms or invasion of normally sterile host tissues:
• Microorganisms are usually pathogenic (different from commensals) → commensals may become pathogenic occasionally when the immune system is compromised
• Inflammatory response in infection is initially localised, but may disseminate/invade
• Bacteraemia is the presence of ______________ in the blood (detected by blood cultures) → similar to fungaemia and parasitaemia

DIAGNOSIS
SIRS is diagnosed by at least 2 of the following parameters:
1. Temperature______________*
2. Heart rate > 90 beats/min
3. Respiratory rate > 20/min or PaCO2 < 32 mmHg
4. WBC count _______________ * or > 10% immature band forms
*The low temperature and WCC are paradoxical findings used as markers in certain situations (e.g. elderly).

A

inflammatory response;

viable bacteria;

> 38°C or < 36°C;

> 12000/mm3 or < 4000/mm3

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8
Q

COMPLICATIONS
If sepsis is not managed properly, it may lead to organ dysfunction, hypotension and hypoperfusion (inadequate blood supply to organ usually due to hypotension/thrombosis):
• Measurement of hypoperfusion:____________ (product of anaerobic metabolism) or urine output (oliguria: ___________)
• Cerebral hypoperfusion: causes altered mental states (e.g. delirium, drowsiness, agitation)

Septic shock is a type of severe sepsis which occurs when the patient remains hypotensive due to sepsis ___________________ (with signs of organ dysfunction):
• Sepsis-induced hypotension occurs before septic shock (defined as ______________________) → absence of other causes of hypotension
• If the low blood pressure responds to fluid resuscitation and there are no signs of organ dysfunction manifesting afterwards, it is unlikely to be septic shock

  • Multi-organ dysfunction syndrome (MODS) is on the spectrum of sepsis and refers to when _______________________.
A

lactic acid levels;

< 400 mL/day;

despite fluid resuscitation;

systolic < 90 mmHg or reduction of ≥ 40 mmHg from baseline;

1 or more organs are compromised due to severe sepsis

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9
Q

Diseases caused by Group A strep (S. ? pyogenes)

A

Streptococcal pharyngitis, erysipelas (large raised patches on skin), necrotising fasciitis, streptococcal toxic shock syndrome, impetigo (blisters/sores), scarlet fever, myositis

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10
Q

Virulence factors associated with Group A strep?

A

M-protein (associated with invasive infections), haemolysins (e.g. streptolysin O/S), exotoxins (e.g. pyrogenic toxin → scarlet fever, STSS), antiphagocytic properties of M-protein and hyaluronic acid capsule, serum opacity factor, adhesins

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11
Q

Host factors associated with Group A strep?

A

Poorly controlled diabetes
Excess alcohol
Renal failure

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12
Q

Disease caused by staphylococcus

A

Benign/deep infections, bacteraemia, endocarditis, necrotising fasciitis (in association with GAS), osteomyelitis

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13
Q

Virulence factors associated with staphylococcus?

A

Superantigens (TSST-1, enterotoxins), haemolysis, Panton-Valentine leukocidin (PVL), surface adhesins, protein A, biofilm (protects from immune system and antibiotic penetration)

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14
Q

Host factors associated with staphylococcus?

A
Diabetes
IV drug use
Solid organ transplantation
Dialysis
SLE
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15
Q

Diseases caused by clostridium perfringens?

A

Enteric disease (food poisoning, enteritis necroticans), gas gangrene (tissue necrosis, sepsis)

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16
Q

Virulence factors associated with Clostridium perfringens?

A

Exotoxins (e.g. phospholipase C, haemolysin, β-toxins)

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17
Q

Host factors associated with C. perfringens?

A

Wounds (trauma/surgery)
Vascular insufficiency (e.g. diabetes)
Poorly controlled diabetes

18
Q

disease caused by listeria?

A

Febrile gastroenteritis (often self-limiting), neonatal infection, CNS (meningitis)

19
Q

virulence factors associated with listeria?

A

Cell surface protein internalin, Listeriolysin O, iron

20
Q

host factors associated with listeria?

A

Pregnancy
Haematological malignancy
HIV/AIDS
Immunosuppressants (e.g. TNF-α)

21
Q

disease caused by salmonella?

A

Gastroenteritis, bacteraemia, abscesses, endocarditis

22
Q

virulence factors associated with salmonella

A

Bacteria-mediated endocytosis (e.g. type III secretion system), homocysteine secretion (NO antagonist), superoxide dismutase (inactivates ROS), PhoP/PhoQ (2-component regulatory system which modifies LPS including Lipid A)

23
Q

host factors affecting salmonella

A

HIV (low CD4)
Lymphoproliferative disorders
Post-transplant immunosuppression

24
Q

diseases caused by neisseria meningitis

A

Asymptomatic carriers

Meningitis, septicaemia

25
Q

virulence factors associated with n. meningitis

A

Encapsulation switching, pili, adhesion factors (e.g. Opc, OpaA), lipooligosaccharide

26
Q

host factors associated with n. meningitis?

A

Complement deficiency (especially C3)
Hyposplenism/
splenectomy

27
Q

*Neisseria meningitidis is an encapsulated organism (Gram-negative diplococcus) and has a variety of serotypes based on capsular polysaccharides (A, B, C, X, Y, Z, E, W-135, L) → meningococcal vaccine covers some, not all.
• Only ___________________ can invade epithelial cells
• Non-functional spleen results in the patient becoming prone to encapsulated organism infection (especially _______________________) → needs vaccination

A

unencapsulated meningococci;

influenza B, S. pneumoniae and N. meningitidis

28
Q

disease caused by vzv?

A
Chickenpox (skin, systemic)
Disseminated infection (pneumonia, meningoencephalitis)
29
Q

virulence factors caused by vzv

A

Glycoprotein C (skin tropism), downregulation of MHC-1

30
Q

host factors affecting vzv?

A

Old age, HIV, post-transplant immunosuppression, lymphoproliferative malignancies

31
Q

disease caused by cryptococcus neoformans?

A

Localised (lung/LN complex), disseminated (CNS, lung, skin, other organs in immunocompromised pts)

32
Q

virulence factors affecting cryptococcus neoformans?

A

Encapsulation (antiphagocytosis barrier, deplete complement, Ab unresponsiveness, interference with antigen presentation, decreased selectin and TNF receptors), melanin, high temperature growth

33
Q

host factors affecting cryptococcus neoformans: Kidney and liver transplant recipients, HIV/AIDS, immunosuppressive agents (e.g. infliximab), idiopathic CD4 T-cell lymphopenia

*Cryptococcus neoformans is an opportunistic infection (does not cause disease in normal hosts), and __________________ are not risk factors.

A

chronic alcoholism and diabetes

34
Q

The host-pathogen interaction determines the severity of the inflammation:
Pathogens activate immune cells via PAMPs binding to pattern recognition receptors (PRRs):
• Types of PRRs: toll-like receptors (TLRs), C-type lectin receptors (CLRs), retinoid acid-inducible gene I like receptors (RLRs), NOD-like receptors (NLRs)
• PAMPs: ___________ structures (across different microbial species) recognised by PRRs (part of the innate immune response driving inflammation and cell damage)

Upon PRR activation, several pro-inflammatory processes occur, including:
• Leukocyte activation causing the release of _____________
• Complement and coagulation are activated
• DAMPs (from necrotic cell death) feedback to the different PRRs in a negative feedback loop to reduce damage

The immune system has the ability to modify the immune response (anti-inflammatory response) via a combination of humoral and cellular responses and neural mechanisms:
• Phagocytes switch to the anti-inflammatory mode to promote tissue repair and reduce inflammation
• T cell inhibition and apoptosis of T and B cells occur
• Pro-inflammatory gene transcription is also inhibited

A

conserved;

ROS, proteases, and cytokines

35
Q

The inflammatory reaction to the pathogen causes a lot of damage, and the coagulation pathway is activated (via TF) and anticoagulation mechanisms are inhibited:
• Normally: thrombomodulin and activated protein C act as anticoagulants
• In sepsis: reduced levels of ___________ + excessive release of _______________) → impaired fibrinolysis
o Dying neutrophils release ______________ → massive coagulation with thrombus formation (blocks microvasculature and circulation)
o Loss of endothelial barrier function causes impaired tissue oxygenation, _________ and __________
o Vasodilation and reduced red-cell deformity also occurs
• Leads to _____________ and oxidative stress and damage to mitochondria, eventually resulting in organ damage

A

thrombomodulin and activated protein C;

plasminogen activated inhibitor (PAI-1;

neutrophil extracellular traps (NETs);

capillary leak;

interstitial oedema;

tissue hypoperfusion;

36
Q

Uncontrolled thrombosis causes the consumption of clotting factors and platelets more quickly than they can be replenished:
• Leads to dangerously low circulating platelet and clotting factor levels → spontaneous bleeding
• Lab results: low ___________, abnormal coagulation (raised INR), ________ D-dimers, __ fibrinogen
• May also occur in non-infective situations (e.g. malignancies)

A

platelet count;

elevated;

low

37
Q

*Necrotising fasciitis is caused by flesh-eating bacteria and may progress rapidly causing death; organisms spread from subcutaneous tissues (e.g. injury/surgery) & invade superficial/deep fascia:
• Aided by bacterial virulence factors (e.g. toxins and enzymes) → vascular occlusion, tissue hypoperfusion and ischaemia → tissue necrosis, septicaemia
• Example: Group A Streptococci have ________________ facilitating adhesion and protecting against phagocytosis, streptococcal pyrogenic exotoxins A, B, C and streptococcal superantigen
• Example: Staphylococcus aureus has __________________ which is a cytotoxin generating pores in the membranes of infected cells

A

M1 and M3 surface proteins;

staphylococcal Panton-Valentine leukocidin (PVL)

38
Q

SOURCES OF SEPSIS
The source of sepsis may be classified by the various systems including:

CNS” Meningitis, encephalitis, brain abscess (fluid-filled cavity full of _____________)

Cardiovascular: Endocarditis (signs: _______________________ etc.), myocarditis, infective pericarditis, Lemierre’s syndrome (thrombophlebitis of ________________)

Respiratory: Pneumonia, pulmonary abscess, empyema

Urinary tract: Pyelonephritis (kidney inflammation from ascending UTI), pyonephrosis (__________ in renal pelvis → distension), cystitis (bladder inflammation)

GI/hepatobiliary: Cholecystitis (_________ inflammation), cholangitis (____________ inflammation), abscesses (hepatic, pancreatic, intra-abdominal), colitis, ileitis, perforated diverticulum, toxic megacolon (e.g. C. difficile)

Musculoskeletal: Osteomyelitis, septic arthritis, ______ (bacterial infection of skeletal muscles → pus-filled abscess)

Skin and soft tissue: Cellulitis (________ infection), abscesses, necrotising fasciitis*

A

pus and inflammatory cells;

splinter haemorrhages, Osler’s nodes, Janeway lesion;

internal jugular vein;

pus collection;

gallbladder;

biliary tree;

pyomyositis;

skin

39
Q

[Sepsis]

Clinical examination
• Vital signs (BP, pulse, temperature, respiratory rate, O2 saturation)
• Full examination of all organ systems (including skin): identify initial source of infection (e.g. _______________ in possible endocarditis or trauma) and/or complications (e.g. DIC, ARDS, cardiac compromise, cerebral oedema)

Laboratory Diagnostics
1. Microscopy and cultures
• Blood (3 sets), urine, sputum
• ± CSF (if clinically indicated and no contraindications like _____________)

  1. General laboratory
    • FBC, U&E, LFT, glucose, CRP, ESR, procalcitonin, coagulation profile (D-dimers, fibrinogen if DIC suspected)
  2. Radiology
    • CXR, CT/MRI brain, targeted radiology (e.g. CT abdomen if intraabdominal source is suspected)
A

cellulitis/IV drug use;

cerebral oedema or space occupying lesion on CT/MRI, coagulopathy, significant thrombocytopenia

40
Q

MANAGEMENT
Survival in sepsis is dependent on early initiation of comprehensive support measures (e.g. fluid resuscitation, oxygen):
• Appropriate antimicrobial therapy should be given, and predisposing causes reversed after comprehensive supportive care

Strategy Measures Supportive measures
• Fluid resuscitation (__________ > colloids)
• Vasopressors (in septic shock)
• Hourly urine output measurement
• BP and cardiac monitoring
• Oxygen and continuous O2 saturation monitoring
• Renal dialysis
• Neurological observations
• DVT prophylaxis (anticoagulants) → infection and sepsis are procoagulant states (must balance against risk of spontaneous bleeding → patient with DIC must be given procoagulants and not anticoagulants like _____________________)

Antimicrobial therapy: Broad spectrum antibiotics per local hospital policy (e.g. non-neutropenic community-acquired: ___________________)

Other antimicrobials based on history/preliminary diagnostics:
• Antiparasitics: IV antimalarials (if malaria film positive) • Antifungals: if HIV+ (with low CD4 count), suspect cryptococcal meningitis or Pneumocystis jirovecii pneumonia; for BM transplant patients with prolonged neutropenia
• Antivirals: ________ (disseminated HSV/VZV), _______ (if pregnant/immunocompromised with pneumonia and sepsis)

Reversing predisposing causes: Supplements antimicrobial therapy (controls infection source and improves immune function):

  1. Necrotising fasciitis: urgent ____________ (definitive)
  2. Abscesses/collections: __________ (antibiotic absorption into abscesses is poor)
  3. Reverse/stop immunosuppressive therapy (e.g. post-chemo neutropenia GM-CSF, wean high-dose steroids, reduce post-transplant immunomodulators)
  4. Start ARV therapy (appropriate timing for opp. infections; liaise with HIV specialist team)
  5. Improve diabetes control
A

crystalloids;

platelet transfusions, FFP, cryoprecipitate;

IV co-amoxiclav & gentamicin;

IV acyclovir;

oseltamivir

surgical debridement ;

drainage