W1P1 Flashcards
Covers first half of W1: 1. CBCs and WBCs 2. Barrier Defenses and Innate Immunity 3. Normal and Abnormal Hematopoiesis 4. Approach to RBCs 5. Fever 6. Anti Pyretics (161 cards)
1
Q
Difference between Antigen and Epitope
A
Antigen: something that induces an immune response
Epitope: the smallest component of an antigen that is recognized by the immune system
2
Q
What is an Antibody
- Where is it produced
A
aka: Immunoglobulin
It is a serum protein
Produced by: B cells, which become mature plasma cells that bind antigens and release Antibodies
3
Q
what are Chemokines
A
They are proteins released by cells that attract other cells (like neutrophils and macrophages) to the area (from the blood, bone marrow and surrounding tissues)
4
Q
The following symptoms are signs of what condition?
- High fever
- Headache
- Myalgia
- Nausea
- Skin Rash
- Hypotension
A
Cytokine Storm
5
Q
What are the three functions of the immune system?
A
- Fight infections
- Prevent Cancer (TNF)
- Develop a memory response
6
Q
What are examples of EARLY inflammatory mediators released by infected cells?
A
TNF: Tumour Necrosis Factor
CCL: chemokines, a type of cytokine
IFN: Interferons
7
Q
What makes up our First Line of Defence
A
Skin Hair/*CILIA* Saliva/tears Mucous Stomach acids Bile
8
Q
What are the four signs of inflammation
A
- Redness
- Swelling
- Heat
- Pain*
9
Q
What are the mediators of inflammation?
What are their functions?
A
Mediators include:
- Prostaglandins
- Leukotrienes
- Bradykinins
Functions:
- Vasodilation
- Vascular Permeability
- Recruitment of cells to the area of damage
10
Q
What are the two main cells lines formed from pluripotent hematopoietic stem cells in the bone marrow?
A
Common Lymphoid Progenitor (CLP) and
Common Myeloid Progenitor (CMP)
11
Q
What cells come from the CLP?
A
CLP: Common Lymphoid Progenitor
produce B cells, T cells, and NK cells released into the blood
which travel to the Lymph Nodes WHERE they would be activated and become Effector cells: Plasma cell
Activated T cell and
Activated NK cells
12
Q
What are the cells that come from the CMP
A
CMP: Common Myeloid Progenitor
In the bone marrow it produces: Granulocyte/macrophage progenitor cells which in the blood produces the granulocytes: Neutrophils, Basophils, Eosinophils, unknown precursor of mast cells and monocytes
The later two produce in mast cells and macrophages respectively in the tissues
In the bone marrow it also produces Megakaryocyte and erythrocyte progenitor cells from which comes platelets and RBCs respectively.
13
Q
Dendritic Cells (DC) Where would you find them What is their function What do they release
A
Found at the site of any skin interface
They release Defensins* which are protein mediators that reduce the acceptance of different microbes in the area (i.e. staph aureus is a common microbe found on our skin that our body protects us from)
Activated function: antigen uptake in peripheral sites and antigen presentation
14
Q
Neutrophils
A
These cells are apart of the innate immune system
Activated function: Phagocytosis and activation of bactericidal mechanisms
They are the FIRST to arrive at site of inflammation. And they release more cytokines to recruit more immune cells.
15
Q
Macrophages
A
similar to neutrophils except they are also: professional antigen presenting cells (APCs)
They reside in tissues
Activated function: phagocytosis and activation of bactericidal mechanisms + APC fnx
16
Q
Eosinophils
- What do they contain
- What are their main targets
A
Activated function: killing of antibody-coated parasites
- also involved in allergic and hypersensitivity reactions
part of the innate immune defense
Their granules contain large cyrstals called Major Basic Protein
17
Q
Mast Cell
A
Activated function: release of granules containing histamine* and active agents
18
Q
Basophil
- what do their granules contain?
A
rarest of leukocytes
granules: heparin, histamin and leukotrienes
play a role in hypersensitivity reactions.
19
Q
Natural Killer Cells
A
Activated function: Releases lytic granules that kill some virus-infected cells
it is an INNATE immune cells EVEN though it stems from CLP cells
because they do NOT have B/T cell markers
20
Q
What are the three different players in cell communication?
A
- Cell Surface Receptors (PRRs, TLRs)
- Cytokines (ILs)
- Chemokines (CXC, CC, C)
21
Q
Cell Surface Receptors
A
These are Pattern Recognition Receptors (PRRs) some of which are termed Toll-Like Receptors
When they bind to their ligand (e.g. bacterial cell wall protein) the innate response is activated immediately.
Bacteria, viruses and parasites have conserved common structures/components that can be recognized by these receptors
activations –> rapid response to perceived danger. This response includes phagocytosis, release of chemokines and cytokines.
22
Q
Examples of cell surface receptors on a macrophage
Activation of these receptors lead to the release of?
A
mannose receptor glucan receptor LPS receptor (CD14) TLR scavenger receptor
Activation releases:
- cytokines
- chemokines
- lipid mediators
Macrophages also phagocytose the infected cell.
23
Q
Examples of Ligands that bind to PPRs
A
Peptidoglycan Zymosan dsRNA LPS (gram neg bacteria) Flagellin ssRNA unmethylated DNA
24
Q
Cytokines
A
these are proteins, secreted by cells, that affect the behaviour of nearby cells - which have cytokine specific receptors
cytokine binding tells the cells what to do through intracellular signalling pathways.
some examples include interleukines: IL which are a family of cytokines involved in the activation of responding cells, cell growth and differentiation, and induction of fever.
25
What are three cytokines released by macrophages that systemic effects?
recall these are professional APCs.
The three main ones are IL-1B, TNFa, IL-6
IL-1B:
- activates vascular endothelium
- activates lymphocytes
- local tissue destruction
- increases access of effector cells
systemic effects: Fever + production of IL-6
TNFa:
- activates vascular endothelium and increases vascular permeability--> increase of IgG, complement and increased fluid drainage to lymph nodes.
systemic effects: Fever, Shock
IL-6:
- Lymphocyte activation
- increased antibody production
systemic effects: Fever + induces acute-phase protein production
26
The Complement System
Is a series of proteins, found in plasma, that are involved in:
- recognition of surface structures on pathogens,
- inflammation,
- activations of innate cells
- killing
- clearance of pathogens and products of inflammation from the body
ultimately preventing damage.
27
What are the three complement system pathways
1. Classical: Antigen-AB complexes (pathogen surfaces)
2. Lectin: Mannose-binding lectin or ficolin binding carbohydrates on pathogen surfaces
3. Alternative: Pathogen surfaces
They all ultimately lead to C3 convertase which produce C3a, C5a: peptide mediators of inflammation, phagocyte recruitment
and C3b: binds to compliment receptors on phagocytes, leading to opsonization of pathogens and removal of immune complexes
which then lead to terminal complement components: which form membrane-attack complex, lysis of certain pathogens and cells.
so the three outcomes of the complement system are:
- inflammation
- opsonization of pathogens, - MAC
28
Timing of
| innate vs early induced innate vs adaptive immune responses
Innate: 0-4 hours
Early induced Innate: 4-96 hours/4 days
Adaptive Immune: after 96 hours. leads to clonal expansion and differentiation to effector cells.
29
Systemic Inflammatory Response Syndrome (SIRS)
Uncontrolled inflammation leads to multiple organ involvement, especially lungs, kidneys, vasculature, liver and gut and a coagulopathy.
Diseases that show features of SIRS
- bacterial sepsis (meningococemia)
- pandemic influenza
- SARS, COVID
In these diseases, infectious agents use cytokine storm as a sort of smoke screen to prevent orderly activation of both the innate and adaptive responses thus prolonging the time for replication and increasing the mortality in the hosts.
30
Patient related factors that influence CBC results
- Activity
- Stress
- Altitude
- Time of day
- Medications
31
What does a total WBC count include?
all circulating, nucleated HEMATOPOIETIC cells with the exception of nucleated RBCs
WBC count used to diagnose and manage pts with hematologic and infectious diseases
also used to monitor pts using cytotoxic drugs, radiation therapy and some antimicrobial drugs.
32
WBC differential
the relative amounts of specific types of WBCs: neutrophils vs lymphocytes vs monocytes vs eosinophils vs basophils
too many or too little of a specific type of WBC can increase index of suspicion of infection, immune problem and conditions like leukemia.
33
Which is the most abundant WBC?
Neutrophils make up 50-60
34
Absolute vs Relative CBC
absolute count is considered more clinically valuable, it is a superior indicator of inflammation and infection.
35
Stages of Neutrophil development
1. Metamyelocyte: the youngest neutrophil. Large nucleus, round or bean-shaped. abundant cytoplasm, pale blue
2. Neutrophil band or stab: The nucleus is elongated and curved (horseshoe/S-shaped), cytoplasm is abundant, pink
3. Segmented neutrophil: is a mature neutrophil, nucleus is separated in 2-5segments or lobes. cytoplasm is pale red.
36
Which are the largest WBC circulating in peripheral blood
Monocytes
they become macrophages when they reside in tissues
macrophages have different names depending on their tissue, i.e. Kupffer cells = macrophages that live in the liver
37
Mononuclear Phagocyte System
This system is used to describe the monocytes and macrophages because of their complex connection to the blood stream and tissue
38
When do Macrophages arrive at the site of injury
within 48 hours
| usually the first cell to process and present antigen to lymphocytes
39
Lymphocytes
These are non-granulocytes responsible for immune responses to specific organisms
i.e. T cells and B cells
both produced in the bone marrow. T cell matures in thymus.
40
T cells
mature in the Thymus
responsible for cell-mediated immunity
it stimulates the B cell and triggers humoral/antibody mediated immunity
it has SEVERAL subtypes that can be divided into regulatory or effector cells!
41
B cells
Mature in the bone marrow
| Is responsible for humoral antibody-mediated immunity
42
Neutrophilia
- most common cause?
- timeframe
- type of disorder
- associated with which other conditions?
Most commonly caused by: Acute Bacterial Infection
Timeline: Neutrophil counts will rise 4-6 hours after an invasion by microorganisms
This is a type of myeloproliferative disorder, and this type of disorder includes polycythemia vera and chronic myelocytic leukemia
high neutrophil count is also associated with
- obesity
- smokin
- stress of surgery
43
Right vs left shift in neutrophils
Right shift: more mature neutrophils elevated
- pathologic conditions
Left shift: increased number of immature neutrophils released from the marrow
44
Neutropenia
- some causes
vs severe neutropenia
Count of less than 2,000 x 10e9/L
can occur with severe prolonged infections, or increased destruction of WBCs
consequence: inability to mount adequate defence when challenged
severe neutropenia: count less than 500 x 10e9/L
- predisposed to bacterial infection and opportunistic infections
45
Monocytosis
Absolute vs relative vs reactive absolute
Absolute Monocytosis: marker of myeloproliferative disorder (i.e. chronic myelomonocytic leukemia)
- requires bone marrow examination and cytogenetic studies
- hematology consultation needed
Relative Monocytosis: seen during recovery from drug-induced neutropenia
- does NOT require additional work-up
Reactive Absolute Monocytosis: Reflect chronic infectious, inflammatory, granulomatous processes, metastatic cancer, lymphoma, radiation therapy, and depression.
46
Lymphocytosis
Reactive Lymphocytosis vs B cell leukemia
Reactive Lymphocytosis with NORMAL appearing small lymphocyte morphology: viral etiology (e.g. mononucleosis, cytomegalovirus, measles)
B Cell Leukemia: (ALL or CLL)
merits a hematology consultation if clinical suspicion is present.
47
Eosinophilia
Triggers?
- an increase in the eosinophil count
Triggers
- occurs in response to parasitic infections
- bronchoallergic reactions: asthma, allergic rhinitis, and hay fever
- skin rashes
48
Basophilia
is the most uncommon cause of an elevated WBC
- Should be suspected in patient with hypersensitivities
49
What is a normal process of aging
Lymphopenia
however NOT normal in children obviously. this maybe the only early sign of immune deficiency
50
How many litres of blood is there in an average human body?
How much of it is water vs proteins?
5-6 litres
90% water
7% proteins
2% organic compounds
1% inorganic salts
51
What is the ration of plasma vs cellular elements in blood?
55% plasma
| 45% cellular elements
52
Plasma vs Serum
acellular components
serum = plasma WITHOUT clotting factors
recall plasma makes up 55%
53
Buffy coat
consists of WBC and platelets, this is the 1%
54
Hematocrite
the percentage of blood by volume that consists of RBC
usually expressed as a decimal percentage from 0.000 to 1.000
55
The Erythrocyte
- what is has vs lacks
- shape
RBC
It is acidophilic- stains red with eosin
Lacks
- Nucleus
- Organelles
DOES have
- membrane
- Cytoskeleton
- Enzymes
- Hgb
it is a biconcave disc = increases SA
56
What is the lifespan of RBC
- how many cells replaced daily ?
where are they broken down?
100-120 days
1% replaced daily
broken down in cells of spleen and liver
57
What is Anemia?
| What are the values to diagnose anemia?
Is when there is fewer than normal RBCs resulting in less Hgb
Men: Hgb less than 140 g/L
Women: Hgb less than 120 g/L
58
What is the entire structure of the RBC held together by?
the cytoskeleton*
depends on them to keep their shape
issues with cytoskeleton = diseases
59
List the 6 variations in RBCs
Microcytosis
Macrocytosis
Sickle cell shapes
Red cell fragments
Eccinocytes: spike cells, seens in renal insufficiency
Target cells: seen in hepatic insufficiency
60
What is Microcytosis
| - common causes
smaller RBC size
Causes:
Iron Deficiency
Disorders of Hgb synthesis (i.e. thalasemmias)
Lead poisoning
61
What is Macrocytosis
| - Common Causes
larger RBC size
Causes:
- Vit B12 deficiency
- Thyroid disease
- Drug and alcohol effect
- Disorders of the marrow (myelodysplasia)
62
The reticulocyte
- too few vs too many vs normal in marked anemia
this is a young RBC, still has it's nucleus/ribosomal TNA. they normally circulate in the peripheral blood. Often not included in the CBC, but important to check for RBC disorders.
too few: impaired production
too many: accelerated destructions
normal in anemia: impaired production (impaired compensation)
63
Which is the smallest cell in the blood?
Platelet.
| * not REALLY considered a proper cell because it too has no nucleus
64
Which two blood cells don't have a nucleus
RBC and platelets
65
Platelets
smallest "cell" in the blood
has no nucleus
comes from fragments of megakaryocytes of the bone marrow
filled with granules: serotonin and thromboxanes involved in clotting
it's membrane has SEVERAL proteins to enable interaction with each other and with clotting factors
66
What are the two leukocyte subtypes
Granulocytes
- polymorphonuclear cells
- neutrophils, eosinophils, basophils
Agranulocytes
- mononuclear cells
- monocytes and lymphocytes
67
What are the two kinds of granules in a neutrophil
specific granules vs azurophilic granules
recall main mission of neutrophil is to phagocytose
68
Where does hematopoeisis occur
| child vs adult?
occurs in the bone marrow
fetus: yolk sac
infancy to childhood: entire skeleton participates (distal bones too), + the liver and spleen
adult: axial skeleton
69
Two types of bone marrow
red: presense of blood and blood-forming cells
yellow: presence of a great number of adipose cells
70
List some key players in hematopoiesis
- Hematopoietic stem cell (HSC)
- Pluripotent stem cell
- bone marrow microenvironment
- stroma
- endothelial cells
fibroblastoid cells
miscroenvironment
71
What are the stromal cells
Bone marrow stromal cells (BMSCs) usually refers to a group of multipotential, heterogenous members within the bone marrow that act as stem/progenitor cells of the bone tissue and are indirectly responsible for hematopoiesis.
they can become for example:
Macrophages
Fibroblasts
Endothelial cells
72
Hematopoietic stem cells
| - identified by which cell markers
capable of self renewal
cell markers: CD34, sca-1
73
progenitor cells
some examples
not capable of indefinite self renewal
may not be capable of differentiating into ALL forms of blood cells as is the HSC
ex. Marrow progenitor cells: may differentiate into all forms of blood but cannot renew indefinitely
Common Myeloid progenitor (CMP)
- Common megakaryocytic/erythroid progenitor
- Common granulocyte/monocyte progenitor
Common Lymphoid Progenitor (CLP)
74
erythropoiesis
- controlled by which hormone?
- factors that regulate it
- timeframe
process of creating RBC/erythrocytes
hormone: erythropoetin [EPO] (made in the kidneys in response to low oxygen) which promotes it's differentiation form one stage onto the next
starts as proerythroblast then becomes reticulocyte before a full RBC
regulated by rate of RBC destruction and tissue oxygen needs
timeframe: takes up to ONE week for EPO to reach bone marrow receptor and produce an effect. thus won't be see in acute conditions.
75
Platelet Production
| - main player
Thrombopoietin (TPO)
produced in the liver (often seen thrombocytopenia in cirrhosis)
It is a megakaryocyte growth factor
76
Hemoglobin (Hgb)
- structure
- function
- production
- made up of 4 polypeptide chains, each containing a heme group
- each heme group can bind one oxygen molecule
Synthesis requires
- supply of iron
Normal production of protopophyrin and globin
77
RBC production
- lifespan
- rate of destruction
- How can you tell if RBC production is in a steady state?
lifespan: 100-120 days
destruction rate: 1%
Steady state: if normal erythroid/granulocytic ratio: 1/3 and based on the reticulocyte index
78
what on a CBC tells you if pt has micro/macrocytosis?
MCV: Mean RBC Volume*: average size of RBC
microcytosis: <80
macrocytosis: >100
79
Anemia
Occurs when there is an upset in the balance of RBC production and RBC destruction or loss (hemolysis)
80
Polycythemia
Case of there being TOO MANY RBCs
81
Approach to Anemia via CBC
| MCV Finding: Microcytic
1. Check Ferritin and Iron status
a. Low: Iron deficiency anemia
b. Normal: Thalassemia Hemoglobinopathy-> hemoglobin studies
c. High: Anemia of chronic disease, Sideroblastic Anemia -> Bone marrow ringed sideroblasts
82
Sideroblastic Anemia
Sideroblastic anemia is a group of blood disorders characterized by an impaired ability of the bone marrow to produce normal red blood cells . In this condition, the iron inside red blood cells is inadequately used to make hemoglobin, despite normal amounts of iron.
83
Approach to Anemia via CBC
| MCV Finding: Normocytic
Do Reticulocyte count
a. Low: aplasia anemia of chronic disease. Associated with high CRP and other cytokines
b. Normal: Acute blood loss
c. High: Hemolysis Chronic blood loss, associated with:
- high LDH
- high Bilirubin
- low haptoglobin
- can do a direct anti-globulin test
84
Approach to Anemia via CBC
| MCV Finding: Macrocytic
Do a blood smear morphology of neutrophils
a. No hypersegmented neutrophils
i. polychromasia -> reticulocytosis, associated with
- high LDH
- high bilirubin
- low haptoglobin
- direct anti globulin test
ii. Target cells -> Liver disease associated with
- high liver enzymes
b. Hypersegmented Neutrophils
Vit B12/Folate deficiency
85
what is a particular sign that signals someone may have VITB12 deficiency
any problems walking, especially in the dark
because this deficiency can lead to neurologic issues
physical exam:
- oral examination of the tongue
- abdominal exam, R/O hepatosplenomegaly
- Neurologic exam for loss of proprioception
86
What tests should be ordered for someone with macrocytic anemia?
- peripheral smear
- liver panel (elevated liver enzymes)
- reticulocyte count
- serum folate/RBC folate
- serum vit B12
87
Megaloblastic anemia
- investigative findings
- consequences
- either due to a. or b.
B12 or folic acid deficiency
results in defective hematopoiesis
Either due to
Pernicious Anemia: autoimmune destruction of parietal cells of the stomach. seen in up to 12% of the elderly population
( because parietal cells release instrinsic factor which is what enables absorption of b12)
other....
Nutritional
Malabsorption (due to conditions or diseases: celiac, crohn's, parasitic infestation)
88
Signs of Microcytic Anemia
deformed nail bed
| fatigue
89
Where is most of the total body iron stored?
Liver stores 70-90% of total body iron
so if you have liver issues, you may expect microcytic anemia maybe?
We did learn that cirrhosis is associated with thrombocytopenia because liver produces TPO
90
Thalassemias
Absent or reduced produciton of globin chain = imbalance =
Excess globin chains precipitate within RBC, which makes them small, unstable, and die rapidly
two types: alpha or beta thalassemia
91
Alpha Thalassemia Spectrum
you have different combinations of aa/aa
you can be missing one, two, three or all four
you can be missing 2, one on each side = trans, or 2, both from one side = cis
92
In what population is thalassemia more common?
It is common in individuals of Mediterranean, Middle Eastern, Aftrican, South and Southeast Asian
93
Alpha Thalassemia, diagnostic tests?
1. Exclusion of iron deficiency and other hemogloinopathies. recall that thalassemia is a microcytic anemia present when Iron levels are NORMAL.
2. Hb electropheresis is normal...
3. DNA investigation. Must be done for prenatal samples for parents with alpha thalassemia trait.
(can lead to fetal death from hypoxia)
94
Beta Thalassemia
- same principles as alpha thalassemia
- different spectrums: minor, intermedia or major [would need blood transfusions to survive]
DIFFERENCE with alpha:
diagnosis is easily made with an abnormal hemoglobin electropheresis (will show elevated Hb A2)
No need for PCR testing for diagnosis
95
What are the 4 etiologies of hemolytic anemia?
1. Extra-corpuscular
2. RBC membrane
3. Enzyme defects (along the ring)
4. Hemoglobin (in the biconcave center)
all these are relative to the RBC
96
Extra-corpuscular hemolytic anemias
Autoimmune hemolytic anemia (AIHA): Immunoglobulin (IgG) mediated
diagnostic test: positive direct coombs test (types of hypersensitivities)
ex. heart valves (?)
97
Red cell membrane hemolytic anemias
what are the two types?
There are two types:
Hereditary Elliptocytosis and
Hereditary spherocytosis
98
Enzyme Defect Hemolytic Anemia
these are congenital
examples:
G6PD deficiency
PK deficiency
99
Hemoglobinopathy and severe thalassemias Hemolytic Anemia
you'd have
- unstable hemoglobins
- congenital
- may have family history
- may have other clinical manifestations
100
Sickle Cell Disease
Hemoglobinopathy hemolytic anemia (type 4)
Mutation of B-globin gene in RBC
- diagnosed by a hemoglobin electropheresis
- present form birth, sickled shape of RBC causes hemolysis, anemia, and vaso-occlusive = organ damage and PAIN crisis [pt will complain of limb pain]
- this is the most common single gene disorder in the world
101
What is the most common single gene disorder in the world?
sickle cell anemia
102
What is polycythemia
Polycythemia refers to an increase in the number of red blood cells in the body. The extra cells cause the blood to be thicker, and this, in turn, increases the risk of other health issues, such as blood clots. Polycythemia can have different causes, each of which has its own treatment options
103
The following signs could be indications of which RBC illness.
- Facial plethora
- red/purplish mucous membranes
- no sign of cyanosis, normal O2 sat
- marks of pruritus
- spleen enlarged on exam
a lot of red, so think a lot of RBC = polycythemia
confirm that it is true polycythemia and not relative due to decrease in palsma volume (dehydration/diuretic invoked)
measure EPO level
104
Types of Erythrocytosis
Relative and Absolute erythrocytosis
relative: water losses
absolute:
primary or secondary
105
What are the two types of absolute erythrocytosis
Primary: independent of EPO
i.e. polycythemia (chronic erythroid leukemia)
Secondary: stimulated by EPO
a. appropriate: in cases of hypoxia
b. inappropriate: no hypoxia. indication of renal or liver cysts/tumours
106
Polycythemia Vera
- when to suspect
- how to investigate it
- treatment
suspect when: you have polycythemia INDEPENDENT of EPO
- it is compatible with a myeloprliferative disorder
investigate:
with JAK 2 blood tests
+/- Bone marrow aspirate and biopsy
refer to hematology
Treatment
- will need aspirin and phlebotomies to decrease his Hb back to normal and to avoid thrombotic risks
107
What is the opposite of anemia?
polycythemia: too many RBCs
108
In which anemia would occult bleeding be the cause?
microcytic anemia; presenting with Fe deficiency.
| important to check for occult bleeding in GI tract, or menses
109
Hemoglobin H disease
--/-a
on the severe spectrum of thalassemia disorders
presents as microcytic anemia with NORMAL iron levels.
110
What are cis and trans thalassemias
- a/-a = trans
- -/aa = cis
both present as mildly anemic, microcytic anemia with NORMAL iron values
111
-a/aa thalassemia means?
this person is only a carrier
| will have a normal MCV
112
What is the normal temperature range?
| - When is our temperature the lowest vs highest?
35.3 - 3.7.7
lowest at 6am, highest at 4-6pm
113
Average variation of body temperature is by how much?
| what about for females after ovulation?
variation: 0.5 degrees
| ovulating women: 0.6 degrees higher after ovulation
114
Where is temperature measured to receive the best approximate?
- how do oral readings compare?
Rectal and esophageal are the best approximations
oral temperature is about 0.6 degrees lower.
115
Where is the control centre for body temperature?
several nuclei in the anterior hypothalamus
116
What is the acute phase resposne?
It includes;
Fever
Neutrophilia
Change in serum proteins, hormones, intermediary metabolism
Sickness behaviour: lethargy, anorexia, loss of interest, hyperalgesia, sleep disturbance.
117
Fever vs Hyperthermia?
Fever: increase in core temperature due to a change of the hypothalamic set point.
rarely over 41.1 degrees
Hyperthermia: is due to an overriding of the set point, temperature can be >41.5 degrees
aka hyperpyrexia
118
What mechanisms do we use to increase our temperature to maintain core temperature in cold environments?
1. vasoconstriction
2. increased thermogenesis in brown fat. (important in new borns)
3. piloerection
4. shivering
5. behavioural changes
119
What mechanisms do we use to decrease our temperature to maintain core temperature in warm environments?
1. Vasodilation
2. Evaporation- insensible water loss, sweating
3. Behavioural changes
120
What are the different causes of fever?
1. Infections – parasitic, bacterial, fungal, viral
2. Tissue damage – myocardial infarction
3. Inflammatory conditions – Kawasaki disease, rheumatic fever,
4. Immune reactions eg transfusion reactions, drug fever
5. Malignancy (malignant tumour?)
121
What are the causes of hyperthermia?
Environmental heat and humidity
Exertion
Endocrine – thyrotoxicosis [too much thyroid hormone in you]
Drugs – anaesthetics
serotoninergic drugs 1e antidepressants
122
Exogenous vs Endogenous pyrogens
Fever is induced by CYTOKINES, here is the back story:
- It has been known for many years that bacterial products injected into animals produced fever., and they became known as EXOGENOUS pyrogens.
- In the 1940’s, a protein was isolated from infected macrophages that would induce fever in experimental animals, and it was labelled ENDOGENOUS PYROGEN
- Since then dozens of proteins that relay signals between cells of the immune system have been found and labelled CYTOKINES
123
What is the pathogenesis of Fever?
Our immune cells recognize PAMPs (pathogen-associated molecular patterns) or DAMPs (Damage associated molecule patterns)
They use TLR (1-10) found on the cell surfaces and endosomes, which bind to LPS and other bacterial substances.
binding to TLR sets off a cascade of intracellular events, which results in release of pro-inflammatory cytokines
124
What is secreted as a result of TLR activation?
pro-inflammatory mediators:
IL-1, TNFa which promotes secretion of IL6
these are the three systemic cytokines, as they lead to fever.
Knockout mice deficient in TNF or IL-1 have a decreased febrile response, those deficient in IL-6 lose the febrile response completely.
125
What are the actions of IL1B, IL6, TNFa?
1. Fever and malaise
2. Acute phase proteins – c-reactive protein – binds to bacteria improves activation, activates complement
- mannose-binding-lectin – also binds to pathogens and triggers complement
3. Pulmonary surfactant proteins SP-A and SP-D
4. Protein and energy mobilization
- Migration of dendritic cells to lymph nodes
126
Where do the three fever cytokines go and what do they trigger inorder to influence body temperature?
- IL-1 and TNF –alpha stimulate production of IL6
- These cytokines are carried in the bloodstream to the anterior hypothalamus, where they stimulate an increase in prostaglandins, especially PGE2.
Lesions in the hypothalamus will completely abrogate the response to LPS
- Substances such as ASA which block PGE2 synthesis decrease the febrile response to LPS
- Knockout mice which have lost the genes for PGE2 synthesizing enzymes or the PGE2 receptor do not produce fever with LPS
- PGE2 is also produced peripherally, and this may account for the muscle aches and malaise which accompany fever.
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What happens with the activation of CVO?
CVO = circumventricular organs
ACTIVATION leads to:
- Highly vascular
- Fenestrated endothelium
- Neural connections to other nuclei
- Histochemical evidence of activation after injection of LPS
- Damage to OVLT prevents fever after injection of LPS
- Some microglia in the CVO’s express TLR’s and respond directly to LPS, even before peripheral production of cytokines
- Endothelial cells throughout the brain can be activated by cytokines
128
Which substance is the FINAL MEDIATOR of fever in the brain?
PROSTAGLANDIN E2
PEG2 causes fever when injected into the ventricle and the anterior hypothalamus
PGE2 can cross the blood-brain barrier and acts on EP3 and perhaps EP1 receptors on thermosensitive neurons
This triggers the hypothalamus to elevate body temperature by promoting an increase in heat generation and a decrease in heat loss
The initial response thought to be mediated by ceramide release in neurons in the anterior hypothalamus
The late response is mediated by coordinate induction of COX-2 and microsomal PGE synthase-1 in the endothelium of blood vessels in the preoptic hypothalamic area to form PGE2GE2
129
What are the two methods of heat production?
1. Heat production
Obligatory – produced by metabolic processes
Facultative – produced by muscular activity
130
What are the methods of heat loss?
Radiation – about 60% at rest
Evaporation – about 20% not active if relative humidity over 75%
Convection – about 20%
131
How is heat lost during fever?
Increased blood flow to the skin.
Increased water loss through the skin and lungs
Behavioral changes
132
What are the evolutionary benefits of continuing to produce fever?
- Some bacteria and viruses reproduce more slowly at a temperature of 40
- Increased temperature decreases the availability of iron, required by bacteria for growth.
- Increased temperature may inhibit replication of some viruses
- Almost every aspect of the innate and adaptive immune system is enhanced by fever-range temperature
- “Sickness behavior” limits spread of infection
133
How does fever put metabolic stress on the body?
Fever puts a metabolic stress on the body
O2 requirement and CO2 production
Water loss
Cerebral injury
Discomfort
Seizure activity?
Each degree C of temperature increase increases O2 requirement 11-13 % and heart rate 5-10%
134
When should fever be treated?
Fever over 40 should be treated
Fever should be treated if the nervous system or cardiorespiratory system is compromised eg sepsis
Otherwise it should be treated to reduce discomfort.
135
Fever Phobia
caregivers, pediatricians, ER nurses, a significant proportion believe fever is dangerous and can lead to seizures/brain damage.
HOWEVER:
Fever is a part of the normal inflammatory response
Fever may be beneficial
It may be dangerous where CNS or cardiovascular systems are compromised
It causes anxiety out of all proportion to the damage it does.
Treating fever is important to decrease discomfort and anxiety
136
How would you respond to a toddler with fever?
why do new borns have fever more often?
```
Does the child look well?
History of travel?
Any underlying conditions?
Are immunizations up to date?
Is the physical exam normal?
```
If not, the illness is almost certainly viral and no investigation is needed
Newborns are less able to localize infection
Severe bacterial infections: E. coli
Group b streptococcus
Listeria
First month 7% to 12.5% of febrile infants have a serious bacterial illness vs 1 – 3% of children 3 – 36 months
Serious viral infections: Herpes virus
Varicella-zoster
RSV
137
Fever in old age
Infection is very likely because local defense mechanisms are impaired
Lungs
Urinary tract
Skin
However, fever can also be due to primary CNS damage
Pathogenesis poorly understood
hypoxia, ischemia
reperfusion
blood in the brain or CSF
Compression or damage to the anterior hypothalamus
138
Neurologic Damage and Fever
Where there is brain injury, fever can exacerbate the injury
Accelerates toxic neurotransmitter release
Increases oxygen free radical production
Disrupts the blood-brain barrier
Even a 1 degree temperature increase in experimental animals can increase the zone of injury and worsen outcome
139
At which temperature do you start to get irreversible damage?
Is this a fever?
This a heat stroke, a medical emergency
At temperatures > 42. irreversible damage begins to liver, brain, and vascular endothelium
Other scenarios: a child left in a car
elderly adult in a heat wave – estimated 8,000 excess deaths in the heat wave in Paris
140
What are the predisposing factors leading to Heat Stoke?
Other illnesses, esp affecting ability to lose heat
Dehydration
Poor acclimatization
Medications: atropine
serotonin syndrome
malignant hyperthermia
141
How do we conserve heat in fever?
1. Blood is shunted away from the skin and extremities. This can raise temperature
2. This leads to a sensation of cold which leads to behavioral changes – putting on more blankets, drinking hot liquids such as chicken soup
3. Shivering. This can raise temperature rapidly
4. Non-shivering thermogenesis takes place in brown fat, which is abundant in newborns but less important in adults.
142
What are some examples of anti-pyretic drugs?
Non-steroidal anti-inflammatory drugs (NSAIDs)
Aspirin
Acetaminophen
143
What are examples of endogenous pyrogens again?
Release of cytokines such as IL-1β, IL-6, TNF-α, and interferons acting as endogenous pyrogens
144
What is the effect of drugs that block PGE2/CO2
Drugs that block PEG2 decrease the febrile response.
Knockout mice deficient in COX-2 have a blunted febrile response.
COX-2 mRNA is increased in the hypothalamus during induced fever.
PEG2 activates neuronal circuits which activate the final response, but does not seem involved in normal thermoregulation
145
How do NSAIDs work?
| - what are their major actions?
They promote antipyretic effects by suppressing PGE2 synthesis
It is PGE3, that triggers the hypothalamus to elevate body temperatures
Major Actions:
- Analgesia (pain relief)
- Anti-pyretic
- Anti-inflammatory (except acetaminophen)
146
Production and actions of prostaglandins and thromboxane
1. membrane phopholipids - [phospholipase A2]-> arachidonic acid - [COX]->
a. Thromboxane: platelets, vascular SM cells
b. EP, prostaglandins: brain, kidney, vascular SM, platelets.
147
Aspirin Major Actions
1. Anti-pyretic action
Block the production of PGE2 to reset the hypothalamic temperature set point
2. Anti-platelet/anti-thrombotic
Decreases platelet production of TXA2 by COX-1 to limit platelet aggregation and vasoconstriction
Can lead to BLEEDING
148
Aspirin/NSAIDs
| What are some adverse reactions
- GASTROINTESTINAL
- BLEEDING
- EFFECTS ON
- PREGNANCY
- RENAL
- ASPIRIN/other NSAID SENSITIVITY
All due to alteration of normal prostaglandin physiology
USE IS AVOIDED IN CHILDREN with viral illness
149
What are sensitivity reactions?
```
Non-immunologicaly mediated (caused by NSAID inhibition of COX pathway)
Signs and symptoms
Rhinitis
Nasal polyps
Asthma
Urticaria (hives)
Laryngeal edema
Bronchospasm
AVOID SALICYLATES/NSAIDs (advil)
ACETAMINOPHEN (tylenol) IS OK TO USE
```
150
Over the counter names for the following drugs:
Salicylates
Acetaminophen
Ibuprophen
Salicylates: aspirin
Acetaminophen: tylenol
Ibuprophen: advil
151
What are the adverse GI effects of NSAIDs?
What is the mechanism?
BLEEDING
ULCERATION
OBSTRUCTION
aspirin = salicylic acid, is an example of NSAIDs
MECHANISM:
LOSS of CYTOPROTECTIVE ACTIONS of GASTRIC PROSTAGLANDINS
Acid secretion is unabated
Decrease in protective mucus
Decrease in mucosal blood flow
152
What are the risk factors for getting GI effects from NSAIDS/aspirin
```
Age > 65 years
History of peptic ulcer or bleeding
Multiple NSAID use
High dose use
Alcohol
Anti-coagulant use
```
153
NSAIDs on Gestation and Delivery
Antepartum and postpartum
Transfusion requirement is increased
Gestation is prolonged
Premature closure of the ductus
154
Renal Prostaglandins Function
ultimate affect of NSAIDS due to their impact on kidneys?
Modulate Na, K and water excretion
NSAIDs (ibuprofen) block the above to reduce Na & K excretion and may cause INCREASE in BP & WEIGHT
155
Aspiring Pharmacokinetics
| - What is it's half life?
It is DOSE DEPENDENT
Half life: 15 minutes
low dose: 2-3 hours
high dose: 12-15 hours
156
What can result from an aspiring overdose?
Combined metabolic acidosis & respiratory alkalosis
157
Compare Ibuprofen to aspirin
Also works through COX-1 and COX-2 inhibition HOWEVER,
COX inhibition is REVERSIBLE in ibuprophin. it is IRREVERSIBLE in aspiring.
and IBU is NOT used as an anti-platelet drug.
Adverse event profile is like aspirin
Great variability in individual response
Change to another NSAID
Not used as anti-platelet drugs
158
Why does aspirin distinguish itself from other NSAIDs?
aspiring inhibits COX irreversibly** so the effects (i.e. anti-platelet) last the life time of the platelet.
vs the other NSAIDS inhibit cox reversibly and can be overcome by competitive agonist.
159
Acetaminophen
Analgesic and anti-pyretic via inhibition of neuronal & vascular PGE2 generation
Weak anti-inflammatory & anti-platelet activity: failure to inhibit platelet TXA2 or inflammatory PGE2 synthesis
Little GI toxicity
Potentially hepatotoxic or nephrotoxic
160
Acetaminophen Toxcitity
acetaminophen = tylenol
```
Hepatotoxic when dose >4 gm/day
Hepatotoxicity may occur @ doses <4gm/d following binge drinking
Hepatic centrilobular necrosis
AST/ALT >1000 units
Treat with n-acetylcysteine orally
```
161
All NSAIDs (including selective COX2 inhibitors) are
- anti pyretic
- analgesic
- anti-inflammatory
EXCEPT:
Acetaminophen (tylenol)
| has anti-pyretic and analgesic but no anti-inflammatory activity
