Immune Flashcards
Innate/Natural Immune System
Limited specificity
immediate reaction
does not improve
no memory
Acquired/adaptive immune system
highly specific
develops in several days
Improves after exposure
has memory
cellular components of the natural immune system
granulocytes
monocytes/macrophages
natural killer cells
dendritic cells
mast cells
cellular components of the acquired immune system
CD4+ (helper) T cells
CD8+ (cytotoxic) T cells
B cells
plasma cells
Humoral components of the natural immune system
complement proteins
cytokines
acute phase proteins
antimicrobial proteins
Humoral components of the acquired immune system
antibodies
Possible modulators of immune competence during anesthesia and surgery
Volatile Anesthetics and Immune Response
Neutrophils
Fight bacterial and fungal infections
Most abundant type of WBC’s (60%)
Circulating neutrophils are rapidly primed to extravasate and migrate toward a site of inflammation/infection.
Monocytes
Circulating cells of the phagocyte system enter tissue and mature into macrophages
Phagocytosis
Release cytokines
Present pathogens to T-lymphocytes
Macrophages
Macrophages aretissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue.
Macrophage function is a sum of the local environment in which they reside, and the type of injuries or pathogen to which they are exposed
Often the first responders to infection, sending recruitment signals to other effector cells
Natural Killer Cells
Natural killer cellsprovide first line of defense against many viruses
Natural Killer (NK) Cells or large granular lymphocytes
____ develop in bone marrow and are potent killers of virus infected self cells
natural killer cells
____ are the main immune cells of the pregnant uterus, protects fetus against viral infections
natural killer cells
volatile anesthetics effect on immune cells (literature)
In vitrostudies revealed suppressive effects of volatile anesthetics on peripheral blood mononuclear cells(PBMCs) and macrophages
Sevoflurane and isoflurane at concentrations of 1.5 to 2.5 MAC suppressed the release of interleukin-1β and tumor necrosis factor(TNF)-α from human peripheral mononuclear cells stimulated by NK–sensitive tumor cells\
the role of platelets in fighting infection
Platelets have significant role in modulating clot formation
Additionally, they have considerable roles in inflammation and immune response
Gather at the damaged cite and adhere to white blood cells - release cytokines and chemokines which are chemotactic for neutrophils and monocytes.
Therefore, platelets are necessary for targeting lymphocytes, neutrophils and monocytes to inflammation site. Those interactions enhance inflammation
Serve as an immune cell by engulfing microbes
platelets and volatile anesthetics
Although the results of many studies have been conflicting, it appears that halothane, sevoflurane, and propofol inhibit platelet function in a reversible and dose-related manner at concentrations used clinically
Microglia
Resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair
Serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the CNS microenvironment
They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS
Microglia and anesthesia
Inhaled anesthetics have been demonstrated to cause neuroinflammation by activating microglia and may be involved in perioperative neurocognitive disorders
Etomidate induces PND attributed to hippocampal microglial activation during the early pathological stage
Propofol has no effects on neuroinflammation and cognition in the Alzheimer’s transgenic model
Development of B-cells begins in _____.
bone marrow and is completed in lymph tissue.
B cells
When a mature B cell encounters and binds antigen, it proliferates and differentiates into plasma cells that secrete soluble antibodies directed against the antigen
The secreted antibodies are Ig molecules and members of the gamma globulin fraction of serum proteins
Humoral Response to Antigen
B-cell binds to antigen
Secretes soluble antibodies directed against that antigen
The secreted antibodies are immunoglobulin (Ig) molecules
There are five main classes: IgA, IgD, IgE, IgG, and IgM
IgA
Found in mucous, saliva, tears, and breast milk. Protects against pathogens.
IgD
Part of the B cell receptor. Activates basophils an d mast cells.
IgE
Protects against parasitic worms. Responsible for allergic reactions.
IgG
Secreted by plasma cells in the blood. Able to cross the placenta into the fetus.
IgM
May be attached to the surface of a B cell or secreted into the blood. Responsible for the early stages of immunity.
The location of the different antibodies
IgG comprises 70% of serum immunoglobulin
IgA 20%
IgM 10%
Low levels of IgE found primarily on mast cells and circulating basophils
IgD located on B-cell surfaces where it binds antigens
Lymphocytes
Acquired immunity depends on lymphocytes
Two main families B Lymphocytes (B-cells)and T Lymphocytes (T-cells)
B-cells are responsible for humoral immunity, which is provided by soluble antibodies directed at a specific antigen
T-cells are responsible for cell mediated immunity directed at a specific antigen
Helper type 1 T cells (CD4)
Th1 promote function of mononuclear phagocytes, produce interferon, and promote cell mediated immune responses
Helper type 2 (CD4)
Th2 promote function of B-lymphocytes, produce specific interleukins (IL- 4 and 10) which suppress cell mediated immunity
Cytotoxic T cells (CD8)
Induction of apoptosis in infected or tumor cells
Human Leukocyte Antigen (HLA)
Major histocompatibility complex(MHC) is a group of polymorphic genes expressed in nearly all the vertebrates, which determines histocompatibility between different individuals.
In humans MHC is known as HLA
Genetic variability in HLA type influences susceptibility to infection and autoimmune disease and rejection of transplanted tissue.
Eosinophils
Provide defense against parasitic infections and phagocytosis of allergen-antibody complexes formed in an allergic response
Mast Cells and Basophils
Essential component of hypersensitivity reactions
Release histamine, leukotrienes, and prostaglandins
Epinephrine prevents degranulation by binding to beta 2 receptors on the cell membrane
Monoclonal Antibodies
Abciximab (RePro) against clotting receptor glycoprotein IIb-IIIa on platelets
Adalimumab (Humira) against TNF alpha for RA
Alemtuzumab against an antigen on T and B lymphocytes to treat CLL
Basiliximab (Simulect) Used for acute kidney transplant rejection
Daclizumab (Zinbryta) For the treatment of MS
Etanercept (Enbrel) TNF inhibitor for RA
Infliximab (Flixabi) used for crohns and RA
Omalizumab (Xolair) Binds to IgE receptor on the surface of mast cells used for treatment of asthma
Monoclonal Antibodies to treat COVID
Treatment pills: Paxlovid & Molnupiravir
Injections/Infusions: Remdesivir & Bebtelovimab
Sotrovimabis a monoclonal antibody that is specifically directed against the spike protein of SARS-CoV-2 and is designed to block the virus’ attachment and entry into human cells. FDA no longer authorized where BA.2 subvariantpredominates
Human Immunodeficiency Virus
Secondary immunosuppression can result from infection that causes depletion of immune cells
The primary target of HIV infection is CD4 lymphocytes Normal CD4 is 500-1500
Below 200 from advanced HIV infection is diagnosed with AIDS
Treatment of HIV
Highly Active Antiretroviral Therapy (HARRT) has been effective in stopping HIV replication and has changed HIV to a chronic manageable disease
Anesthesia Management of HIV
There is no conclusive evidence to support any recommendations
Protease inhibitors (amprenavir, indinavir ritonavir, saquinavir and tipranavir) decrease the metabolic pathways of opioids, nonsteroidal anti-inflammatory drugs, lidocaine and benzodiazepines
Careful titration of midazolam and fentanyl as the effects may be enhanced
Continue antiretroviral therapy
Different medications and their effect on patients with HIV
Midazolam - prolonged action after saquinavir
Fentanyl can have prolonged action as well
Prolonged effect after Non depolarizer muscle relaxants
Enhanced hypotensive effects after calcium channel blockers
Viral load and CD4 count for patients with HIV
Viral load and CD4+ count: mortality is inversely related to CD4+ count
Viral load is the term used to describe the amount of HIV in the patients blood, the higher your viral load, then the faster your CD4 cell count will fall, and the greater your risk of becoming ill because of HIV
Occupational Risk of caring for patients with HIV
Percutaneous injury with a hollow-bore needle is the most common mechanism of occupational HIV transmission
The average risk of HIV transmission associated with exposure to HIV infected blood is 0.3% after needle-stick injury and 0.09% after mucous membrane exposure
Post HIV Exposure Prophylaxis
The CDC recommends PrEP with antiretroviral medications soon after occupational exposure within hours and administered for 4 weeks
Four types of allergic reactions
Type I….Immediate
Type II….cytotoxic
Type III…..Immune complex
Type IV…..delayed cell mediated
Type I Reaction
Rapidly developing reaction that results from antigen-antibody interaction in an individual who has been previously exposed
Histamine stored in mast cells and basophils is released when an allergen interacts with membrane bound IgE
Anaphylactoid Reaction
Anaphylactoid reactions are caused by histamine release from basophils and mast cells in response to non-IgE mediated triggering event
Reactions are similar but less severe
No prior exposure is needed
Pathophysiology of anaphylaxis vs anaphylactoid reactions
anaphylaxis- IgE mediated reaction = urticaria, hypotension, bronchospasm and requires prior exposure
anaphylactoid- non-IgE mediated reaction, can appear identical to anaphylaxis but doesn’t require prior exposure (for example IV iodine contrast)
Defining an anaphylactic reaction (Qs to ask)
Is sensitization required? YES
Can reaction occur on first exposure? NO
How much exposure is needed to elicit a reaction? VERY LITTLE
Is reaction predicted by allergy skin tests? YES
Defining an anaphylactoid reaction (Qs to ask)
Is sensitization required? NO
Can reaction occur on first exposure? YES
How much exposure is needed to elicit a reaction? Usually more then for anaphylaxis
Is reaction predicted by allergy skin tests? NO
Histamine
Produces the symptoms of allergic reactions
H1 receptors
Vasodilation, Increased vascular permeability, and contraction of smooth muscle other than blood vessels
H2 receptors
Cardiac stimulation, Stimulation of gastric secretions
Arachidonic Acid Metabolites
Leukotrienes and Prostaglandins are proinflammatory mediators resulting from metabolic degradation of the arachidonic acid originating from membrane phospholipids
Bronchoconstriction and vasodilatation
Tryptase
Tryptase is a marker for an allergic reaction. It is released with histamine from the mast cells and has a peak blood level 15-120 minutes after exposure.
Grade I =
Cutaneous
Erythema Pruritus Urticaria with or without Angioedema
Grade II =
Cutaneous Grade I signs
Cardiovascular
Hypotension Tachycardia Pre-syncope
Respiratory
Dyspnea
Wheezing
Gastrointestinal
Nausea Vomiting Diarrhea Abdominal pain
Grade III =
Cardiovascular Grade II signs plus Cardiovascular collapse Profound hypotension Bradycardia Dysrhythmia
Respiratory
Bronchospasm
Hypoxia (Sao2 < 92%) Gastrointestinal
Grade II signs plus
Incontinence
Neurologic
Confused Unconscious
Grade IV =
Cardiovascular
Pulseless electrical activity Cardiac arrest
Treatment for anaphylaxis reactions
All drugs and surgery should be stopped
Airway patency must be maintained and 100% oxygen given
Titrate dose according to the severity of symptoms and patient response
Repeat dose every 1-2 minutes if necessary
Adults Children
Grade 2: 10-20 mcg 1-5mcg/kg
Grade 3: 100-200 mcg 1-5 mcg/kg
Grade 4: 1 mg 10mcg/kg
The β-adrenergic properties of epinephrine cause ______
bronchodilation, increase myocardial output and contractility, and suppress further mediator release from mast cells and basophils
What to do if the patient is refractory to epinephrine….
Vasopressin: IV doses 2-10 IU until response
Norepinephrine 0.05-0.1 mcg/kg/min
Diphenhydramine 0.5-1 mg/kg IV (H1 antagonist)
H2 receptor antagonist (Ranitidine)
Hydrocortisone adult 250mg IV, children 50-100mg
Bronchodilators Inhaled albuterol
Agents responsible for perioperative Allergic Reactions
Neuromuscular Blocking agents: 47.4%
Latex: 20%
Antibiotics: 18% (beta-lactems)
Hypnotics: 1%
Opioids: 2%
Colloids: 2%
Protamine, contrast media and others: 9%
Local Anesthetics: 0.6%
Neuromuscular blocking drugs
Common cause of perioperative allergic reactions
Antigenic quaternary ammonium groups
Rocuronium, vecuronium, and pancuronium have single quaternary ammonium group are less likely to cause anaphylaxis
Most common NMBD to cause anaphylaxis is succinylcholine
Agents responsible for perioperative Allergic Reactions
Neuromuscular Blocking agents: 47.4%
Latex: 20%
Antibiotics: 18% (beta-lactems)
Hypnotics: 1%
Opioids: 2%
Colloids: 2%
Protamine, contrast media and others: 9%
Local Anesthetics: 0.6%
List the neuromuscular blocking agents from highest to lowest incidence of allergy
Succinylcholine> atracurium> cisatracurium> rocuronium> vecuronium
Latex allergy
Latex allergy is recognized as a significant problem for healthcare workers and patients
Latex allergy is a IgE-mediated reaction
General population has a low incidence 1% to 2%
Who are high risk groups for latex allergies?
Healthcare workers with frequent latex glove use (8-16%)
Children with spina bifida, spinal cord trauma and urogenital malformations or any patient with repeated exposure to latex for any reason (24-64%)
Which food allergies increase the risk for latex allergy?
Avocado
Mango
Banana
Pineapple
Tomato
Papaya
Chestnuts
Kiwi
Symptoms of Latex Allergy
Immediate (Type I) hypersensitivity IgE mediated occurs 5-30 minutes after initial contact
Delayed (Type IV) hypersensitivity within 6-48 hours after initial contact
Contact dermatitis, non allergic occurring in frequent glove users
Biphasic Anaphylaxis
Delayed reaction (6 Hrs)
Theories of pathogenesis-The pathogenesis of biphasic anaphylaxis is not known, although several theories have been proposed
Influx of inflammatory cells
Second wave of mast cell degranulation
Late synthesis of platelet-activating factor
Effects of therapies “wearing off”
Uneven antigen absorption
Inadequate or delayed epinephrine
Type II Reactions
Cytotoxic Reactions also known as antibody-mediated cytotoxic hypersensitivity
Mediated by IgG or IgM
ABO incompatibility, autoimmune hemolytic anemia and myasthenia gravis, Goodpasture syndrome are examples of type II hypersensitivity reactions
Myasthenia Gravis
Autoimmune disorder
Fatigable skeletal muscle weakness
Antibody mediated attack of acetylcholine receptor in the post synaptic membrane of the neuromuscular junction
Difference between myasthenia gravis and Lambert Eaton synrome
Myasthenia Gravis:
antibody against AchR antibody
associated with thymic tumor
weakness worsens on prolonged exercise
normal deep tendon reflexes
autonomic dysfunction is present on repeated nerve stimulation, there is decremental response
Lambert Eaton Sydrome:
antibody against voltage gated calcium channel
associated with small lung cell CA
weakness improves with prolonged exercise
decreased or absent deep tendon reflexes
autonomic dysfunction is present
On repeated nerve stimulation, there is incremental response
Anesthesia considerations for myasthenia gravis
Continue anticholinesterase agents up to and including the am of surgery
Patients are sensitive to nondepolarizing and resistant to succinylcholine
Unpredictable response to NMBA reversal
Type III Reaction
Type III reactions represent immune complex diseases that result from antigen and antibodies that bind to insoluble complexes in the microvasculature
Complement is activated and neutrophils are localized to the site
Immune complex diseases include systemic lupus, rheumatoid arthritis, and glomerulonephritis are examples
Rheumatoid Arthritis
An autoimmune disease that targets the synovial joints. Systemic involvement due to infiltration of immune complexes into small arteries leading to vasculitis
Cytokines TNF and Interleukin-1 play a central role
2-3 times more common in women
Complications of Rheumatoid Arthritis
Airway:
TMJ synovitis-limited mouth opening
Cricoarytenoid arthritis- narrow glottis opening
AO instability- risk of spinal cord and vertebral artery compression
Anti-rheumatic drugs
Drugs inhibit TNF, IL 1 and 6 and inhibit T cells and B cells.
All drug suppress the immune system and risk infection and cancer
Methotrexate, cyclosporine and Enbrel (etanercept)
Methotrexate causes liver dysfunction and suppresses bone marrow function
Cyclosporine increases the duration of succinylcholine
Systemic Lupus Erythematosus
An autoimmune disorder characterized by proliferation of antinuclear antibodies
SLE affects every organ system as a result of antibody induced vasculitis
SLE is a disease that targets young women
Complications of lupus
Cricoarytenoiditis and recurrent laryngeal nerve palsy
Restrictive pulmonary defect, pleural effusion and PE
Pericarditis, Raynaud’s, Hypertension
Hypercoagulability, thrombocytopenia, anemia
Anesthetic considerations for lupus
Hoarseness and stridor could indicate cricoarytenoids arthritis, risk of post-extubation laryngeal swelling and airway obstruction. Consider smaller ETT
PTT may be prolonged but hypercoagulability increases risk of stroke DVT and PE
Cyclophosphamide inhibits plasma cholinesterase and increases duration of succinylcholine
Pregnancy, stress, infection and surgery can exacerbate symptoms
What exacerbates lupus?
PISSED CHIMP
Pregnancy, Infection, Surgery, Stress, Enalipril, D-penicillamine
Captopril, Hydralazine, Isoniazid, Methyldopa, Procainamide
Type IV Reactions
Delayed Hypersensitivity Reactions
Antigen specific lymphocyte binding produces cytokine release and a local inflammatory response
Manifest in 18-24 hours
Peak 40-80 hours
Duration of 72-96 hours
Graft verses host reactions and contact dermatitis
Types of Hypersensitivity Reactions
Surgery stimulates the stress response which causes the release of ____
cortisol and catecholamines
Perioperative ____ commonly occurs
lymphopenia
Stress reduces what ratio?
Stress reduces the Th1/Th2 ratio and predisposes patients to infection
Impaired lymphocyte proliferation may be caused by _____
circulating factors (stress hormones) and IV and inhalational agents
Tissue injury causes _____
a localized response by cells, innate system releases macrophages
IL-1 and TNF released from resident macrophages stimulate IL-6
IL-6 stimulates hepatocytes to release acute phase proteins (c-reactive proteins CRP)
Magnitude of this increase correlates with the intensity of the procedure
CRP may be predictive of perioperative mortality
Propofol does what to the immune system?
reduces inflammatory mediator levels, monocyte phagocytosis, oxidative burst, NOS production, and chemotaxis, neutrophil chemotaxis, release of superoxide and elastase
Dexmedetomidine does what to the immune system?
Reduces pro-inflammatory cytokine levels and neutrophil chemotaxis
Ketamine does what to the immune system?
Reduces systemic pro-inflammatory cytokine levels, and monocyte production of NO
Impairs neutrophil adhesion, degranulation, and antioxidant activity, as well as platelet aggregation
Increases Th1/Th2 ratio and improves immune function, but does not alter NK cell action
Sevoflurane does what to the immune system?
Decrease neutrophil oxidative burst, chemotaxis, and cytokine secretion
Desflurane does what to the immune system?
Genotoxic and pro-inflammatory effects in minor surgery
Benzodiazepine do what to the immune system?
Inhibit neutrophil and mast-cell activation
Reduce pro-inflammatory cytokine secretion
Induce an anti-inflammatory M2 monocyte/macrophage phenotype
Opioids do what to the immune system?
Block macrophage chemotaxis and phagocytosis
Decrease neutrophil bactericidal action
Direct T cells toward Th2 differentiation
Morphine suppresses NK cells
Regional anesthesia does what to the immune system?
Reduce neutrophil activation, decrease macrophages migration to the site of injury bactericidal effects, increase the integrity of endothelial barrier
Spinal and epidural anesthesia have been found to prevent postoperative leukopenia and adverse changes in lymphocyte sub-populations and NK-cell activity that occur in patients undergoing GA and surgery
Systemic Inflammatory Response Syndrome
SIRS Criteria, 2 or more signs
Temp > 38 C or < 36 C
HR > 90, RR > 20 or PaCO2 < 32 mmHg
WBC >12,000 or <4000 or >10% immature forms
Diagnosis: Based on confirmation of specific causative organism
Sepsis categories
Sepsis Criteria = suspected or present source of infection
Severe Sepsis Criteria = Lactic acidosis, SBP , 90 or > 40 mmHg drop from baseline
Septic shock = Severe sepsis with hypotension despite adequate fluid resuscitation
Treatment and Prognosis of Sepsis
Treatment Broad spectrum antibiotics and supportive care for failing organs
Prognosis: Depends on the virulence of the infecting organism, the time when therapy is started, the inflammatory response of the patient, the immune status of the patient, and the extent of organ system dysfunction
Management of Sepsis
Preoperative: Postpone surgery if possible surgery may be required for bowel perforation or to remove the infection source.
Antibiotics may be the intervention that can alter the course of the disease
Postoperative usually ICU after surgery intubated
Surviving Sepsis Campaign 2021
For patients with sepsis- induced hypoperfusion or septic shock at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hours of resuscitation.
For adults with sepsis or septic shock, balanced crystalloid instead of normal saline for resuscitation.
Guidelines for treating sepsis
Vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured.
Sepsis or septic shock we suggest against using IV vitamin C.
Septic shock and an ongoing requirement for vasopressor therapy followed by IV corticosteroids.
30 mL/kg IV crystalloid. This recommendation was downgraded from a strong recommendation to a weak recommendation based on the low quality of evidence.
Antimicrobials as soon as possible, ideally within 1 hour of sepsis recognition. (no Change)
For adult survivors of sepsis or septic shock, recommend assessment and follow-upfor physical, cognitive, and emotional problems after hospital discharge
