INTEGRATION
TERMINOLOGY
 Cancer naming: tissue/organ of origin +
carcinoma, sarcoma, or blastoma as suffix
o Carcinoma = epithelial cells
o Sarcoma = connective tissue (bone,
cartilage, fat, nerve)
o Blastoma = immature precursor cells or
embryonic tissue
o Germ cell tumor = pluripotent cells, testicle
or ovary most common
 Anaplasia: loss of morphological features of
malignant cells so resemblance to normal cells lost
 Local/ized: organ where started and not spread
 Regionally and locally advanced: around organ
 Distant, advanced, metastatic: farther from organ
 PET scan: nuclear medicine. Radiotracers labelled
with radioactive material; accumulate in tumors or
regions of inflammation. Camera detects gamma
ray emissions from radiotracer
o Most commonly F-18 fluorodeoxyglucose
(FDG), cancer cells more metabolically
active and absorb glucose at higher rate
o Receive as injection, swallow, or inhale as
gas
o Disadvantages: slow-growing, less active
tumors; small tumors; confused with high
blood sugar, very expensive
 Image fusion: combine nuclear medicine images
(functional) with CT or MRI (anatomic)
o Interpret two sources of info at once 
more precise
o Advantages: differentiate malignancy vs.
benign, stage cancer, assess treatment
response and disease progression
 Paraneoplastic syndromes: rare disorders
triggered by abnormal immune response to
neoplasm
 Prevention:
o Primary: prevent from getting disease
o Secondary: catch when asymptomatic and
prevent disease from worsening
o Tertiary: improve QOL and reduce
symptoms of disease
 Biofilms
o Biofilms are communities of
microorganisms, form protective matrix 1)
adhere to surface and 2) better resist
antimicrobial agents and host clearance
mechanisms
o Induce inflammatory reaction in host, and
upregulate genes linked to matrix
metalloproteinases, and decrease tissue
inhibitors of MMPs
 Surgical site infection
o Endogenous: skin, mucous membranes, and
hollow viscera
 S. aureus, coagulase-negative
staphylococci, enterococcus, and E.
coli are most common
o Exogenous: air, instruments, materials
Staphylococci and streptococci
most common
 Hormone-sensitive cancer: hormones help tumors
grow
o Breast: estrogen and progesterone
o Ovarian: estrogen
o Uterine or endometrial: estrogen and
progesterone
o Prostate: androgens
IMMUNE SYSTEM PATH
 Pathogens expresses PAMPs
 Innate immune cells recognize and engulf
o Mast cells secrete histamine 
inflammation
o Macrophages secrete cytokines
 CXCL8 attract leukocytes
 IL-6 activates lymphocytes,
stimulates liver to make more
proteins (fibrinogen for wound
healing, CRP for inflammation,
mannose binding-lectin for
complement)
 IL-1B increases vascular
permeability
 IL-12 activates NK and
differentiation of naive to Th1
helper
 TNF-a stimulates inflammatory
response. Also dendritic cells to
migrate to lymph nodes
o Together allow leukocytes to enter
(neutrophils are fast)
 Complement proteins enter tissue and help destroy
pathogen, also stimulate phagocytosis
 Phagocytosis by macrophage
o By complement protein or toll-like receptor
o Then phagolysosome  small antigens 
express on cell surface
 Activated dendritic cell expresses CCR7, attracted
to CCL21 produced by lymph node, allow to travel
to lymph node
ANTIBIOTICS
 Penicillin first– now good against syphilis only
 Gram+ don’t have outer lipid membrane, they only
can use beta-lactamase
o Beta lactamase-resistant penicillin to fight
methicillin-sensitive staph aureus (MMSA)
o E.g. nafcillin, dicloxacillin (oral)
o Vancomycin to treat methicillin-resistant
staph aureus (MRSA) ONLY
o Above, daptomycin (bloodstream but not
pneumonia) and linezolid (lung but not
bloodstream)
 Gram- have outer lipid membrane, need small
antibiotics to get through membrane
o Aminopenicillins but beta lactamase-
sensitive
 o E.g. amoxicillin, ampicillin
o Can add on b-lactamase inhibitor – will
extend spectrum to gram+, strep
o E.g. amox-clav, amp-sulb
o Pseudomonas virulent and not sensitive to
typical penicillin  antipseudomonal
penicillin also has the inhibitor
o E.g. pip-tazo, tic-sulb
o Above, carbapenems (meropenem) and
monobactams (aztreonam)
 Foundation of ladder is cephalosporins
o First-gen do gram+ (strep and MSSA)
o E.g. cephalexin, cephazolin
o Third-gen do gram- and strep
o E.g. ceftriaxone
o Fourth-gen do antipseudomonal and gram-
o E.g. cefepime
 Fluoroquinolone baseball diamond because pick up
as you go
o Ciprofloxacin can only fight gram-
o Levo not useful unless specific sensitivity
o Moxifloxacin can fight gram+
 Anaerobic coverage
o Metronidazole in gut and vagina
o Clindamycin everywhere else
 Higher on ladder = newer. Choosing wisely means
choosing lower on ladder to prevent antimicrobial
resistance
 Vancomycin and pip-tazo are ‘broad-spectrum’
antibiotics. Mean don’t know what infection is. If
they’re really ill, only then you should
RULES OF MANAGEMENT
1. If sick, go broad (more upfront)
2. Escalate quickly if deteriorating (add a bunch at
once)
3. De-escalate slowly (remove one a day)
a. Start on pip-tazo and vancomycin
b. Sure it’s not antipseudomonal 
downgrade to amp-sulb (strep, gram-,
anaerobes)  next remove vancomycin if
not suspect staph
4. Target cultures and sensitivities that is the lowest on
the ladder
5. Empiric therapy lowest on ladder, balance vs.
illness level
EMPIRIC ANTIBIOTIC THERAPY
 Community-acquired pneumonia
o If into hospital, ceftriaxone and
azithromycin
o If not into hospital, azithromycin
o Moxifloxacin only if beta-lactam allergy
 MRSA and pseudomonas
o Vancomycin (linezolid if can’t) and piptazo
(meropenem if can’t)
 Meningitis
o Vancomycin, ceftriaxone,
methylprednisolone, +/- ampicillin if
immuno compromised
 Outpatient UTI
o Amoxicillin best choice overall outpatient
o If beta-lactam allergic, nitrofurantoin
o TMP-SMX another option but less effective
 Inpatient UTI (including pyelonephritis)
o Ceftriaxone
 Cellulitis
o Strep – in-patient ceftriaxone, out-patient
amoxicillin
o Staph –in-patient vancomycin or
clindomycin
CANCER IN CANADA
 Nearly ½ Canadians have cancer in lifetime, ¼ die
from cancer
 In 2020, ~110,000 men and women each diagnosed
with cancer and ~40,000 would die
 Lung, breast, colorectal, and prostate cancer are
most commonly diagnosed types of cancer ~50%
cases
o Prostate ~20% in men, 5yr survival 93%
o Breast ~25% in women, 5yr survival 88%
o Lung ~14% total, 5yr survival 19%
o Colorectal ~12% total, 5yr survival 65%
TUMOR GRADING
 Classify tumors based on histologic appearance
(degree of cell differentiation)
 Poor differentiation = high-proliferation index,
presence of nucleoli, giant cells with multiple
nuclei, abnormal shape cell or nucleus, different
cell polarity, different orientation of nuclei,
increased mitotic figures, hyperchromasia,
heterogenous chromatin distribution
 AJCC most commonly for nonhematologic
o G1: well-differentiated (low)
o G2: moderately differentiated
(intermediate)
o G3: poorly differentiated (high)
o G4: undifferentiated/anaplastic (high)
o Gx: differentiation cannot be assessed
TUMOR STAGING
 Classify tumors by spread through body (correlates
with prognosis)
 TNM system
 Tumor: size or direct extent of primary tumor
o Tcis: carcinoma in situ – no BM
penetration
o T1-4: increasing size, T4 refers to
infiltration of neighboring organs
 Node: involvement of regional lymph nodes
o N0: no lymph node involvement
o N1-3: number, size, location of nodes
 Metastasis: presence of metastasis
o M0: no distant metastasis
o M1: present distant metastasis
o Mx: unknown if distant or not
 Certainty: certainty of diagnosis
o C1 : routine procedure (e.g. X-ray)
o C2 : special procedure (e.g. CT)
o C3 : biopsy, cytology, or surgical
exploration
o C4: surgery and histopathologic workup
o C5: autopsy and histopathologic workup
 cTNM = clinical criteria
 pTNM = histopathological criteria
  Overall: based on specific type of cancer, but rule
of thumb is higher stage = more spread
 Stage 0: carcinoma in situ, precancerous, abnormal
cells have not yet invaded surrounding tissue
 Stage 1: tumor small and hasn’t grown outside
organ it started in
 Stage 2/3: larger or has grown outside organ it
started in to nearby tissue, including lymph nodes
 Stage 4: has spread through blood or lymphatic
system to distant site in body
 Factors affecting stage: grade, cancer cell type,
tumor markers, genetic underpinning, age
 Note: stage doesn’t change, important because
diagnostic stage used to study survival statistics and
treatments. Restaged indicated with ‘r’
CANCER SCREENING IN ONTARIO
BREAST CANCER
 Average risk: 50-74 screened by mammography
every 2 years
 High risk: 30-69 get screened every year with both
mammography and breast MRI
o Known gene mutation
o First-degree relative has gene mutation
o Personal or family history of breast or
ovarian
o Radiation to chest for another condition
before 30 and at least 8 years ago
CERVICAL CANCER
 Sexually active: Pap test every 3 years starting 21
until at least age 70 and 3 or more normal tests in
previous 10 years
COLON CANCER
 No family history: 50-74, fecal immunochemical
test every 2 years
 Family history before 60: colonoscopy every 5
years
 Family history after 60: colonoscopy every 10
years
LUNG CANCER
 Must meet following criteria
o 55-74
o Smoked cigarettes every day for at least 20
years (does not have to be consecutive)
 Low-dose computed tomography
COMPARISON OF SCREENING
 Pros: indication of cancer before symptoms
develop, may find cancer at early stage when
treatment curative/more likely to be successful
 Cons: not completely accurate (false negatives),
sometimes indeterminable significance,
unnecessary worry and investigations when no
cancer present and slow-growing that will not cause
symptoms, cannot do anything/change management
despite result
WILSON AND JUNGNER’S PRINCIPLES OF
SCREENING
 Important health problem
 Natural history of condition adequately understood
 Recognizable latent or early symptomatic stage
 Suitable test or exam
 Test acceptable to population
 Agreed policy on whom to treat as patients
 Accepted treatment for patients with recognized
disease
 Facilities for diagnosis and treatment available
 Cost of case-finding should be economically
balanced
 Case-finding should be continuing process and not
‘once and for all’ project
METASTASIS
 Development of secondary malignant growths at
distance from primary site of cancer
 Lymphatic: lymphatic vessels and nodes. Most
common for most carcinomas
 Hematogenous: blood vessels; venous more than
arterial because thin walls facilitate invasion. Most
common for most sarcomas
 Seeding: spillage of malignant cells to neighboring
structures (e.g. implant along biopsy canal)
 Transcoelomic: spread into body cavities via
penetration of surfaces such as pleura, pericardium,
peritoneum
 Canalicular: canalicular system (bile ducts,
lactiferous ducts, urinary tract, subarachnoid space)
MECHANISMS
 1) Invasion of extracellular tissue
o Loss of adhesion to basement membrane 
invasion through basement membrane 
passage through extracellular tissue
o Loss of E-cadherin expression associated
with metastatic potential
o Overproduction of proteases such as
collagenase and matrix metalloproteinase
degrade BM and interstitial matrix
o Autocrine signalling (cytokines) and
paracrine signaling (cleaved matrix
components and extracellular chemotactic
and growth factors)  tumor cell
locomotion blood or lymph
 2) Dissemination and colonization
o Host defenses destroy majority of
circulating cancer cells, but mechanisms
avoid include cell aggregation, platelet-
tumor complexes, and binding of active
coagulation factors to form malignant
emboli  implantation
COMMON SITES OF CANCER METASTASIS
 Target organ usually first capillary bed encountered
by neoplastic cells
 Some cancers have organ tropism: tendency to
spread to particular organs
 Liver
o Second most common site following
regional lymph nodes
o Colon, stomach, pancreas
 Bone
o Majority from metastases
o Usually involve axial skeleton
o Lytic: NSCLC, kidney, multiple myeloma,
thyroid
o Blastic: prostate, SCLC
o Mixed: breast
 o Prostate, breast, kidney, thyroid, lung,
multiple myeloma
 Brain
o ~50% from metastases
o White-grey matter junction as multiple
well-circumscribed lesions
o Lung, breast, melanoma, colon, kidney
MECHANISMS OF ORGAN TROPISM
 Discrepancy between anatomy and metastasis:
‘seed and soil’ hypothesis
 Extrinsic factors
o Circulation patterns and supply
o Vascular wall accessibility
 Intrinsic factors
o Interact with microenvironment  cross
barriers, survive, engage with organ-
specific cell types
o Growth factors, hormones, protein
receptors that promote growth in that
location
 General mechanisms: genes that support invasion,
survival, immune evasion  multiple organs
CARCINOGENS
CLASSES
 Initiator: irreversible changes to DNA, exposed
before promoter
 Promoter: reversible increase in cell proliferation,
after initiator (e.g. hormones, alcohol, chronic
irritation and wound healing)
CHEMICAL
 Benzene, benzol in gasoline, tobacco
 Vinyl chloride in PVC-related manufacturing
 Nitrosamines in cured meats, cold-smoked foods
 Aromatic amines in tobacco, dyes
 Asbestos in insulation material, certain cements
 Ethanol in alcohol
 Alkylating agents in chemotherapeutic agents
 Radon in basements, highest Southwestern Ontario
 Aflatoxin in stored nuts and grains
 Arsenic in pesticides, herbicides, metal smelting
 Beryllium in certain occupations (smelting,
welding, manufacturing)
 Silica in certain occupations (quartz, sand, granite
e.g. sandblasting, glass manufacturing)
 Chromium in galvanization, pain and glass
manufacturing, tanning leather, building materials
 Nickel in mining, smelting, welding, casting of
alloys
RADIATION
 Nonionizing: UV-B
 Ionizing: X-rays, gamma rays
ONCOGENIC INFECTIONS
 EBV (Burkitt and Hodgkin lymphoma,
nasopharyngeal carcinoma, oral hairy leukoplakia,
primary CNS lymphoma, gastric carcinoma)
 HBV (hepatocellular carcinoma)
 HHV-8 (Kaposi sarcoma)
 HPV16, 18 (squamous cell carcinoma of vulva,
vagina, cervix, anus, penis, oropharynx, larynx)
 HTLV-1 (T-cell leukemia)
 HCV (hepatocellular carcinoma)
NONVIRAL PATHOGENS
 Schistosoma haematobium (squamous cell
carcinoma of bladder)
 Clonorchis sinensis (cholangiocarcinoma)
 H. pylori (gastric adenocarcinoma, MALT
lymphoma)
 Streptococcus bovis (colorectal cancer)
FEVER PATHOPHYSIOLOGY
 Inflammation and/or infection  release of
endogenous pyrogens (cytokines) induced by
exogenous pyrogens (proteins, lipopolysaccharides)
 hypothalamic receptors  release of
prostaglandins  increase set point of
hypothalamic thermoregulatory centre  elevation
in body temperatures  increased immune system
activity and decreased pathogen growth
 Hyperthermia: exogenously increased
temperature, body unable to lower temperature
BACTERIOLOGY
COMMENSALS
 Organisms living on or within humans that do not
harm host normally and may even be beneficial
 Flora in each part
o Skin: staphylococcus epidermis
o Nasal: staphylococcus epidermis
o Oropharyngeal: viridans group streptococci
o Dental plaques: streptococcus mutans
o Gut flora: E. coli and bacteroides
o Vaginal flora: lactobacillus acidophilus
o Lung flora: nesisseria catarrhalis, alpha-
hemolytic streptococci, staphylococci,
nonpathogenic corynebacterial, Candida
albicans
TYPES OF PATHOGENS
 Facultative: can survive outside of host,
opportunistic – usually benign but disease in
immunocompromised
o For bacteria, can produce ATP outside cell,
e.g. mycobacterium, salmonella, Neisseria,
 listeria, francisella, legionella, yersinia,
brucella
 Obligate: can only replicate inside cells of host
o For bacteria, cannot produce ATP outside
host cell, e.g. rickettsia, chlamydia,
Coxiella
 Anaerobic:
o Obligate: grows only in absence of oxygen
o Occur in gut flora, pathogenic other places
o Often produce small foul due to SCFA and
gases in tissue
o E.g. clostridium, actinomyces israelii,
bacteroides, fusobacterium
o Facultative: can use oxygen for ATP
generation but may switch to anaerobic
o e.g. staphylococcus, streptococcus, gram-
negative bacteria in gut
 Aerobic: require oxygen to produce ATP and grow
optimally in atsmopheric oxygen levels
o E.g. P. aerouginosa, M. tuberculosis, B
pertussis, Nocardia
 Immunocompromise, disruption of resident flora
balance (e.g. due to antibiotics), or spread of
resident flora to otherwise sterile areas (e.g. E. coli
enter urethra) can facilitate multiplication
CHARACTERISTICS
 Bacilli: rod-shaped
 Cocci: sphere-shaped with different arrangements
o Staphylococci: grape-like clusters
o Streptococci: chains
o Diplococci: pairs
 Coccobacilli: very short rods almost resembling
cocci
 Spirochetes: spiral-shaped organisms
o Contain axial filaments (endoflagella)
o Poorly visible on Gram stain
o Include Treponema pallidum, Borrelia
burgdorferi, Leptospira interrogans
o Usually diagnosed by dark-field
microscopy and serologic studies
CELL WALL
 Thick in gram+, thin in gram-
 Composed of peptidoglycan
o Muramic acid: alternating amino sugar acid
occurring as N-acetylmuramic acid
o Peptide side chains crosslinked by
transpeptidase
o Mycolic acid in acid-fast bacteria
 In gram+, also contains lipoteichoic acid extending
from membrane to exterior
 Functions
o Structural strength, protects against osmotic
pressure damage, mycolic provides
chemical and aridity resistance, lipoteichoic
stimulates release of TNF-α, IL-1, IL-6
CAPSULE
 Polysaccharide structure outside cell membranes of
certain bacteria
 Function
o Antiphagocytic by impeding opsonization,
adherence to surfaces, protect from free
radicals and heavy metal irons
 Important bacteria
o Group B streptococcus, strep pneumoniae,
haemophilus influenzae type b, Neisseria
meningitidis, E. coli, salmonella, klebsiella
pneumoniae, pseudomonas aeruginosa
GRAM STAINING
 Application of crystal violet to previously heat-
fixed smear of bacterial culture  addition of
iodine to trap dye  wash out dye with acetone or
ethanol  counterstain with safranin
 Gram+: traps crystal violet so violet-to-blue
 Gram-: does not trap crystal violet but retains
counterstain (safranin) so pink
 Atypical: very thin or lack of cell wall, atypical
composition, or intracellular bacteria so colorless
ACID-FAST STAINING
 Stains mycolic acid, in cell wall of acid-fast
bacteria (e.g. mycobacteria, nocardia)
 Auramine-rhodamine stain (yellow-red) more
sensitive than Ziehl-Neelsen stain (red)
CLASSIFICATION
GRAM-POSITIVE
 Staphylococci (catalase +)
o Coagulase +: staph aureus
o Coagulase -: staph epidermidis, staph
saprophyticus
 Streptococci (catalase -)
o a-hemolysis: strep pneumoniae, viridans str.
o B-hemolysis: strep pyrogenes, strep
agalactiae
o y-hemolysis: enterococcus
 Rods
o Clostridium difficile, botulinum, tetani,
perfringens
o Listeria monocytogenes
o Cornyebacteria diphtheria
o Bacillus anthracis, cereus
o Actinomyces
o Nocardia
GRAM-NEGATIVE
 Diploccoci
o Neisseria meningitidis, gonorrhea
 Rods
o Enterobacteria: escheria coli, klebsiella
pneumoniae, salmonella typhi, shigella
dysenteriae, yersinia pestis and
enterocolitica, proteus mirabilis,
Citrobacter, serratia
o Coccobacilli: haemophilus influenzae,
bortedella pertussis, brucella, Pasteurella
o Other: helicobacter pylori, vibrio cholerae,
campylobacter jejuni, pseudomonas
aeruginosa, legionella pneumophila,
bartonella henselae
ATYPICAL GRAM-STAINING
 Mycobacteria tuberculosis, leprae, NTM
 Mycoplasma pneumoniae
 Chlamydia trachomatis, pneumoniae, psittaci
 Ricketsia
 Borella burgdorferi
 Leptospira
 Treponema pallidum

INNATE IMMUNE SYSTEM
OVERVIEW
 Immune cells
o Granulocytes: neutrophils, eosinophils,
basophils
o Mast cells
o NK cells
o APCs
 Mononuclear phagocyte system:
monocytes and macrophages
 Dendritic cells
 Physical barriers
o Coughing and sneezing after irritation of
receptors in nose, sinuses, airways
o Skin and mucous membranes
 Tight junctions between epithelial
cells
 Ciliary function of ciliated
epithelium in respiratory
 Symbiosis with microorganisms
 Biochemical barriers
o Mucus and secretions contain nonspecific
and specific protective substances
o Enzymes: lysozyme (neutrophils,
granulocytes, macrophages) lyses bonds in
peptidoglycan; lactoferrin (neutrophils and
secretory fluids) iron chelation to prevent
microbial growth; acid hydrolases; RNases
o Peptides: defensins
o Acids: gastric acid and vaginal florid with
acidic pH
o Major basic protein: by eosinophils, esp.
against parasites; in response to antibody
coating on pathogens  destruction of
pathogens
o Toxic products of respiratory burst:
superoxide, hypochlorite, H peroxide,
hydroxyl radicals, NO
 Humoral defenses
o Acute phase proteins
o Complement system
CELLULAR MECHANISMS
HLA SYSTEM
 MHC I
o HLA-A, B, and C
o Two polypeptide chains of different
lengths; long-chain contains alpha domains;
short-chain contains B2 domain
o Surface of all nucleated cells, platelets, and
APCs but not RBCs
o Intracellular pathway: cytotoxic T-cell
reaction kills cells infected with pathogens
and/or produce atypical proteins (e.g.
malignant)
o Absence of MHC I receptors on infected or
malignant recognized by NK cells
o A3: hemochromatosis
o B8: Addison disease, myasthenia gravis,
Graves disease
o B27: psoriatic arthritis, ankylosing
spondylitis, IBD-associated arthritis,
reactive arthritis
o C: psoriasis
 MHC II
o HLA-DP, DQ, DR
o Two polypeptide chains of equal length;
each contains two domains (a1, a2 and
b1,b2)
o Surface of APCs only: dendritic cells,
monocytes/macrophages, B cells
o Extracellular pathway: helper T cell
activate B cells
o DQ2/DQ8: celiac disease
o DR2: MS, SLE, Goodpasture syndrome,
Hay fever
o DR3: DM1, SLE, Graves, Hashimoto,
Addison disease
o D4: RA, DM1, Addison
o DR5: Hashimoto
PATTERN RECOGNITION RECEPTORS
 Types of PRRs
o TLRs: bind to PAMPs and activate NF-kB
pathway
o Nucleotide-binding oligomerization
domain-like receptors (NLRs):
intracellular PRR recognize both PAMPs
and DAMPs
 Activation of NOD-like receptors
 upregulate NF-kB  increased
transcription of proinflammatory
cytokines
 Recognize:
o Pathogen-associated molecular patterns
 Viral nucleic acids
 LPS of gram-negative bacteria
 Bacterial flagellin
o Damage-associated molecular patterns
released from damaged host cells
RESPIRATORY BURST (OXIDATIVE BURST)
 Phagocytes ingest pathogens  activation of
NADPH oxidase complex  release ROS that
destroy pathogens in phagosomes
HUMORAL MECHANISMS
 Vasodilation and increased vascular permeability
 increased blood flow
 Activation, proliferation, and attraction T CELL DEVELOPMENT
(chemotaxis) of immune cells
COMPLEMENT SYSTEM
 Group of plasma proteins synthesized in liver as
inactive precursors
 Activation triggers amplifying cascade of reactions
that leads to inflammation, activation of MAC, and
enhanced phagocytosis
 Classical pathway
o Activated by IgM or IgG complexes
binding to pathogen
o Assessed via CH50 test
 Alternate pathway
o Activated directly by pathogen surface
molecules
o Assessed via AH50 test T CELL ACTIVATION
 Lectin pathway
o Activated by mannose or other sugars on
pathogen surface
 Common end phase
o C3-convertase cleaves complement C3 to
C3a (chemotaxin)  creation of C5-
convertase which can cleave C5
o C5a acts as anaphylatoxin, along with
others e.g. C3a and C4a, that cause
inflammation: cytokine release, neutrophil
and macrophage activation, platelet
activation
o C5b binds C6-9 to form MAC
 Effect
o Opsonization: increases susceptibility of
target particles to phagocytosis (structural
changes facilitate interaction with immune
cells); C3b and IgG two main opsonins for
bacteria
o MAC: lysis of target through cell wall
perforation
o Anaphylaxis: activation of mast cells and
granulocytes via C3a/C4a/C5a
o Chemotaxis: attraction of neutrophils via
C5a
DIFERENTIATE INNATE FROM ADAPTIVE
 Inherited vs. not inherited
 Within minutes to hours vs. days
 Recognition of PRRs rather than specific antigens
ADAPTIVE IMMUNE SYSTEM
T CELLS
 Cell-mediated immunity
o Directly involves cytotoxic T cells and
other phagocytes
o Recognition and destruction of intracellular
pathogens
 Surface proteins distinguish from other
lymphocytes and recognize antigens presented by
APCs
o General: CD3, CD28, TCR
 TCRs complex of proteins of Ig superfamily
B CELLS
oEach expresses variant that binds to one
specific antigen on MHC  activation
 Lymphoid progenitor in BM and mature in thymus,
dysfunctional undergo apoptosis
 Positive selection in thymic cortex
o Cortical cells have MHC class I and class II
antigens  test binds appropriately
 Negative selection in thymic medulla
o Medullary cells have tissue-restricted self-
antigens  test if doesn’t bind
 Cluster of differentiation: type of CD has higher
affinity for is kept (CD4 to MHC II, CD8 to MHC
I)
 Competent but naïve T cells leave thymus and
migrate within peripheral, BV, secondary lymphoid
organs (e.g. nodes, spleen, MALT)
 1. Antigens processed by APCs (macrophages,
monocytes, B cells, Langerhans, dendritic)
o Exogenous = MHC II (helper); endogenous
= MHC I (cytotoxic)
 2. Costimulatory signal required for activation 
survival and proliferation of T cells
o B7 protein (CD80 or CD86) on dendritic
cell interacts with CD28 on naïve T cell
 3. Effects are all cell-mediated immunity except
Th2
o Th1: cellular immune response to
intracellular pathogens (viruses, bacteria)
 release cytokines (IFN-y, IL-2, TNF) 
stimulate macrophages and cytotoxic T
cells AND induce granuloma formation
against foreign bodies that cannot be
eliminated by cells AND B cells to produce
IgG
o Th2: humoral immune response to
extracellular pathogens (bacteria, parasites)
 release cytokines (IL-4, IL-5, IL-13) 
stimulate eosinophils, basophils, mast cells
AND B cells to produce IgG
o Th17: extracellular pathogens, regulate
tissue inflammation with both anti and
proinflammatory effects  activate
neutrophils
o Tfh: T follicular helper cells support B cell
activation and maturation in lymphoid
tissues
 CD4, CD40L
o Regulatory T cells/suppressor T cells:
protect against excessive immune response;
promote immune self-tolerance; prevent
formation of autoantibodies  stimulate or
suppress CD4 and CD8 effector cells
 CD4, CD25
o Cytotoxic: direct cell lysis or induction of
apoptosis of infected or neoplastic cells via
perforin and proteases; release cytokines
(IFN-y, TNF) to activate macrophages
 CD8
 T cell activation/”priming” mainly in secondary
lymphoid organs, such as lymph nodes
  Humoral immunity
o Mainly B cells and antibodies
 Numerous surface proteins
o CD19, CD20, CD21, CD40, MHC II, B7,
BCR with Ig component
 BCR: type 1 transmembrane protein composed of
Igs and signal-transmitting subunits
 Ig parts of mature BCRs highly specific to certain
antigens
B CELL DEVELOPMENT
 Originate and mature in bone marrow
 Diversity
o Random recombination of genes: V, D, J
genes; and random recombination of light
chains with heavy chains
o Terminal deoxynucleotidyl transferase
randomly adds nucleotides to DNA
 Mature but naïve circulate between blood and
secondary lymphatic organs
 After activation, differentiate into plasma cells that
produce and secrete antibodies
B CELL ACTIVATION
 T cell-dependent
o Protein antigens
o BCR-mediated endocytosis of BCR/antigen
complex  breakdown of antigen by
lysosomal proteases  presentation of
antigen via MHC II to Th cells AND
costimulation CD40 receptor by Th cell
CD40L
 T cell-independent
o Non-protein antigens
o Leads to production of IgM antibodies
o Thymus-independent antigens are weakly
immunogenic, why vaccines containing
nonprotein antigens need adjuvants
 Affinity maturation
o B cells interact with Th cells within
germinal center of secondary lymphoid to
secrete Igs with higher affinity for specific
antigens
o Somatic hypermutation: point mutations
creating random alterations in variable
region of Ab gene
o Clonal selection: higher affinity B cells
survival advantage through positive
selection so predominate within follicle
 Isotype switching
o Cytokine release from
activation/costimulation stage  gene
rearrangement  class switching
o IgM, primary Ab on B cell before
activation, switched to IgA, IgE, or IgG
irreversibly
 IL-4, IL-13: IgE
 IL-5, TGF-B: IgA
 IFN-y, IL-4, IL-21: IgG
IMMUNOGLOBULIN
 Fc region
o Constant region formed by heavy chains
o Determines antibody isotype (IgA, IgG,
IgM)
o Binds complement (IgG, IgM), and various
immunological cells (opsonization) to
stimulate phagocytic/cytotoxic
 Fab region
o Variable region formed by heavy/light
chains
o Determines idiotype (one antigenic
specific)
o Binds to antigens on epitope
 Two halves are connected by disulfide bridges
 Specificity increases with affinity maturation;
alterations take place in variable region
TYPES
 IgM: pentamer, largest antibody. Formed early
(early reaction antibodies). Pentameric = strong
antigen binding (can bind multiple pathogens, helps
agglutinate, and strong complement fixing) while
humoral response initiated
 IgG: monomer, most abundant in serum. Delayed
formation (late reaction antibodies). Only Ig that
can cross placenta (actively transported). Mediates
type II and type III hypersensitivity
 IgA: monomer or dimer, most abundant in body but
low serum. Especially in mucosal surfaces and in
bodily fluids; prevents binding of pathogens to
mucous membranes. No complement fixation.
 IgE: monomer. Binds to mast cells  cross-linking
upon allergen exposure  histamines. Binds to
basophils. Type I hypersensitivity
 IgD: monomer. function incompletely understood
FUNCTIONS
 Activates complement
 Opsonization of bacteria
 Neutralization of pathogens
MEMORY
 Recognize antigens after initial exposure to quickly
and efficiently mount response subsequently
 Formation of memory B and T cells
 Memory B: plasma cells ability to persist for
decades and produce high-affinity antibodies
throughout
 Memory T: elicit immediate and more potent
immune response; can be CD4 or CD8
o Effector: persist in circulation and
peripheral tissue
o Central: persist in secondary lymphoid
tissue and able to differentiate into effector
upon activation
PRIMARY LYMPHOID ORGANS
 Location where lymphocytes become
immunocompetent (able to recognize pathogens)
RED BONE MARROW
 Medullary cavity of long bones
o In children, located in almost all bones
o In adults, restricted to axial skeleton, pelvic
and pectoral girdles, and heads at proximal
limb heads
 Site of hematopoiesis, for lymphoids B (BM-
derived) + NK cells but not T cells
THYMUS
  Above heart in mediastinum
 When first born, large
o But does not grow, other organs become
larger
 Secretes hormones to regulate T cell maturation
 Blood thymus barrier prevents programming of T
cells to self antigens
SECONDARY LYMPHOID ORGANS
 Immunocompetent migrates to these
SPLEEN
 Filter blood vs. nodes filter lymph
 Soft-walled, capsulated organ conforms to
surrounding organs. Intraperitoneal organ
 Splenic artery of celiac trunk. Splenic vein drains
into inferior mesenteric  superior mesenteric 
portal vein
 Hilum: BV, nerves
 Two sets of tissue
o Red pulp ~75%: artery  central
arterioles  end capillaries. Venous
sinuses around end capillaries  collecting
veins  splenic. Cords between capillaries
and sinuses; contain many macrophages.
Sinuses have endothelial slits that filter out
old, dead, damaged RBCs  phagocytosed
by cords
o White pulp ~25%: lymphocytes and
macrophages aggregated on reticular fibers.
Periarteriole lymphatic sheath (T and
macrophage) and follicles (B) surrounded
by marginal zone (macrophages)
 Also monitor for foreign antigens
 Sequestration of platelets
o 1/3 of platelets are sequestered in spleen
LYMPH NODES
 Fibrous capsule surrounds kidney shape
 Multiple afferent lymph vessels on cortex
 Hilum: BV, nerves, one efferent lymph vessel
o More lymph enters than exits
o Stagnation of lymph to ensure all pathogens
have been identified and destroyed
 Cortex: lymph nodules and germinal centres, where
B cells multiply and differentiate. Paracortex beside
germinal centres for T cells.
 Medulla: looser network of lymphocytes, plasma
cells, macrophages, reticular cells, and reticular
fibers
 Fibrous extension of capsule create trabeculae that
partially divide interior
 Lymphocyte proliferation  increase in volume 
lymphadenitis
MUCOSA-ASSOCIATED TISSUE (MALT)
TONSILS
 Pharyngeal tonsil in nasopharynx (1)
 Palatine tonsils at end of soft palate (2)
 Lingual tonsils underlying tongue (numerous)
 Guard against inhaled and ingested pathogens
INTESTINAL MALT
 E.g. Peyer patch in ileum
ANTIBIOTICS
DEFINITIONS
 Antibiotics: antimicrobial drugs against bacteria
 Bactericidal: kills
o Some only effective if in combination,
against certain pathogens, in higher
concentrations
 Bacteriostatic: slows bacterial growth or stops
bacterial reproduction
o Some only against certain, can be both
bactericidal and bacteriostatic
 Rule of thumb: agents that inhibit cell wall
synthesis bactericidal (except ethambutol), while
those that inhibit protein synthesis are bacteriostatic
(except tigecycline, rifamycins, aminoglycosides)
OVERVIEW OF CLASSES
 Inhibition of cell wall synthesis
 B-lactams:
o Penicillin: natural (G and V), anti-
staphylococcal (oxacillin, nafcillin,
dicloxacillin), aminopenicillins
(amoxicillin, ampicillin), antipseudomonal
(piperacillin, ticarcillin)
o Cephalosporins: 1st (cephalexin), 2nd
(cefaclor), 3rd (cefixime), 4th (cefepime), 5th
(ceftraloline) generation
o Carbapenems (imipenem, meropenem,
ertapenem, doripenem)
o Monobactams (aztreonam)
o MOA: bind to penicillin-binding proteins
(PBPs)  decreased crosslinking of
peptidoglycan layer  bactericidal
 Glycopeptides:
o Vancomycin, bacitracin, telavancin,
dalbavacin, oritavancin
o MOA: bind to D-alanyl-D-alanine section
of peptidoglycan precursor  inhibited
peptidoglycan synthesis  bactericidal
 Epoxides:
o Fosfomycin
o MOA: inactivate enolpyruvate transferase
(MurA)  inhibition of N-acetylmuramic
acid formation  disruption of
peptidoglycan synthesis  bactericidal
 Disruption of cell membrane integrity
 Lipopeptides:
o Daptomycin
o MOA: lipid portion binds bacterial
cytoplasmic membrane  formation of
ion-conducting channels  intracellular K+
efflux  bacterial cell membrane
depolarization  bactericidal
 Polymyxins:
o Polymyxin E (colistin), polymyxin B
o Cationic detergents (polypeptides) bind to
outer cell membrane (phospholipids on
gram- bacteria)  increased permeability
 bacterial lysis
 Inhibition of protein synthesis – 30S ribosomal
 Aminoglycosides:
o Gentamicin, amikacin, tobramycin,
streptomycin, neomycin
 o MOA: inhibit initiation complex  protein
mistranslation  bactericidal
 Tetracyclines:
o Tetracycline, doxycycline, minocycline,
eravacycline, sarecycline, omadecycline
o Glycylcyclines (tetracyclin derivative)
tigecycline
o MOA: block incoming aminoacyl-tRNA
with amino acids  decreased protein
synthesis  bacteriostatic
 Inhibition of protein synthesis – 50S ribosomal
subunit
 Macrolides and ketolides:
o Erythromycin, clarithromycin,
azithromycin
o MOA: bind to 23S rRNA  inhibition of
transpeptidation, translocation, and chain
elongation  bacteriostatic
 Lincosamides:
o Clindamycin
o MOA: impair transpeptidation  inhibition
of chain elongation bacteriostatic
 Streptogramins:
o Quinupristin-dalfopristin
o MOA: dalfopristin to 23S portion of 50S 
conformation change  facilitation of
binding of quinupristin, which blocks 50S
subunit  inhibition of polypeptide
elongation  bacteriostatic when used
separately, bactericidal when together
 Oxazolidinones:
o Linezolid
o MOA: prevent association of 50S with 30S
subunit  impairment of initiation
complex formation  interruption of
protein synthesis  bacteriostatic but
bactericidal in streptococci
 Amphenicols:
o Chloramphenicol
o MOA: prevent binding of aa-containing
aminoactyl-tRNA  inhibition of
peptidyltransferase  bacteriostatic and
bactericidal in high concentrations
 DNA gyrase inhibition
 Fluoroquinolones:
o Norflaxin, moxifloxacin, Gemifloxacin,
ciprofloxacin, ofloxacin, levofloxacin,
enoxacin
o MOA: inhibit prokaryotic topoisomerase II
(DNA gyrase) and topoisomerase IV 
inhibited DNA synthesis  both
bacteriostatic and bactericidal
 Disruption of DNA integrity
 Nitroimidazoles:
o Metronidazole, tinidazole
o MOA: free radical formation  single-
strand breaks in DNA molecules 
bactericidal
 Inhibition of folic acid synthesis and reduction
 Sulfonamides and diaminopyramidines:
o Trimethoprime-sulfamethoxazole,
sulfadiazine and pyrimethamine,
sulfisozaxole
o MOA: prevent bacterial tetrahydrofolate
formation (THF)  decreased methylation.
Sulfamethoxazole inhibits THF,
trimethoprim inhibits dihydrofolate
reductase (DHFR)  sulfa is bactericidal,
trimethoprim is bacteriostatic
 Antimycobacterial drugs
 Rifamycins
o Rifampin, rifabutin, rifaximin
o MOA: block mRNA synthesis via
inhibition of bacterial DNA-dependent
RNA-polymerase  decreased protein
synthesis  both bacteriostatic and
bactericidal
 Hydrazide:
o Isoniazid
o MOA: inhibits mycolic acid synthesis 
decreased cell wall synthesis 
bactericidal
 Nicotinamides:
o Pyrazinamide
o MOA not understood  bacteriostatic
 Ethylenediamine derivatives:
o Ethambutol
o MOA: inhibits arabinosyltransferase 
decreased cell wall synthesis 
bacteriostatic
 Sulfones
o Dapsone
o MOA: competitive antagonism of para-
aminobenzoic acid  inhibited
dihydrofolic acid synthesis  both
bacteriostatic and bactericidal
 Other
 Nitrofurans
o Nitrofurantoin
o MOA: bind to bacterial ribosomes 
inhibition of DNA, RNA, and protein
synthesis  bacteriostatic and bactericidal
in higher concentrations
CLINICAL USE
 Natural penicillins: ADEs include
hypersensitivity, hemolytic anemia with positive
direct Coombs test, interstitial nephritis
 Penicillinase-resistant penicillins: narrow
spectrum gram-positive aerobes, esp. S aureus.
ADEs include hypersensitivity and interstitial
nephritis
 Aminopenicillins, also penicillinase-resistant:
broad spectrum to gram-positive aerobes, gram-
negative rods. Most effective against H. pylori, H.
influenzae, E. coli, Listeria monocytogenes, proteus
mirabilis, salmonella, shigella, enterococci. ADEs
include diarrhea, pseudomembranous colitis,
hypersensitivity
 Antipseudomonal penicillins: broad spectrum but
penicillinase-sensitive. Gram-positive aerobes and
gram-negative rods, esp. pseudomonas. ADEs
include hypersensitivity reactions
 Carbapenems: last-resort because of significant
ADEs. Broad-spectrum with intrinsic beta-
lactamase resistance: gram+ cocci, gram- rods,
anaerobes. ADEs include CNS toxicity (lower
 seizure threshold at high serum concentrations), GI
upset, rash
 Monobactams: effective against gram- only,
alternative for penicillin-allergic and patients with
renal insufficiency. ADEs include GI upset
 Cephalosporins: cephalexin (oral) or cefazolin
(IV,IM) for perioperative wound infection
prophylaxis. Cefixime (oral) or ceftriaxone or
cefotaxime or ceftazidime (IV) for perioperative
wound infection prophylaxis. Ceftriaxone good
CNS penetrance used to treat meningitis and good
for gonorrhea and disseminated Lyme disease.
Cefepime (IV) for severe life-threatening infections.
ADEs include potential cross-reactivity in penicillin
allergy, autoimmune hemolytic anemia, vitamin K
deficiency (bleeding), disulfiram-like reaction,
nephrotoxic effect of aminoglycosides
 Glycopeptides: effective against multidrug-
resistant wide range of gram+ bacteria, MRSA, S.
epidermis, enterocci, C. difficile. ADEs include
nephrotoxicity, oto/vestibular toxicity,
thrombophlebitis, red man syndrome
(anaphylactoid reaction by rapid infusion of
vancomycin), DRESS syndrome (IV),
predominantly dysgeusia and GI upset (oral)
 Epoxides: women with uncomplicated UTIs. ADEs
include mild electrolyte imbalances, diarrhea
 Lipopeptides: gram+ bacteria, S. aureus esp.
MRSA, mainly used in skin and skin structure
infections, bacteremia, endocarditis, vancomycin-
resistant enterococci. ADEs include reversible
myopathy and rhabdomyolysis
 Polymyxins: severe infections caused by
multidrug-resistant gram- bacteria. ADEs include
nephrotoxicity, neurotoxicity, respiratory failure
 Aminoglycosides: severe gram- rod infections, not
affective against anaerobes. ADEs include
nephrotoxicity, oto/vestibulotoxicity resulting in
tinnitus, ataxia, vertigo, neuromuscular blockade,
teratogenicity
 Tetracyclines: bacteria that lack cell wall and
intracellular bacteria, community-acquired MRSA.
Avoid substances with divalent cations because
inhibit intestinal absorption. ADEs include
hepatotoxicity, deposition in bones and teeth
(inhibition of bone growth and discoloration teeth),
damage to mucous membranes, photosensitivity
 Glycylcyclines: gram+ aerobes, MRSA, VRE,
braod spectrum anaerobes. ADEs include GI upset,
hepatotoxicity, deposition in bones and teeth,
photosensitivity
 Macrolides: atypical pneumonia, bordetlla
pertussis, STIs caused by chlamydia, gram+ cocci,
mycobacterium avium, H. pylori, ureaplasma
urealyticum, babesia spp. ADEs include GI upset,
QT-interval prolongation, arrhythmia, acute
cholestatic hepatitis, eosinophilia, rash, increased
risk of hypertrophic pyloric stenosis in infants <6
weeks
 Lincosamides: anaerobes, group A streptococcus.
ADEs include GI upset, pseudomembranous colitis,
fever, teratogenicity
 Streptogramin: skin and skin structure infection
with S. aureus or pyogenes, vancomycin-resistant
E. faecium. ADEs include GI upset, nausea,
headache, arthralgia/myalgia, thrombophlebitis
 Oxazolidinones: multidrug-resistant gram+
bacteria (VRE, MRSA). ADEs include GI upset,
pancytopenia due to bone marrow suppression,
peripheral neuropathy, serotonin syndrome
 Amphenicols: meningitis (H. influenzae, N.
meningitidis, S. pneumoniae), rickettsia infections.
ADEs include bone marrow suppression, gray baby
syndrome (premature infants)
 Fluoroquinolones: norfloxacin, ciprofloxacin, and
ofloxacin for gram- rods causing UTI or GI
infections, genitourinary infections; levofloxacin,
moxifloxacin, Gemifloxacin for atypical bacteria.
ADEs include GI upset, neurological symptoms
such as headache, dizziness,
hyperglycemia/hypoglycemia, QT prolongation,
skin rash, superinfection, in children damage to
growing cartilage
 Nitroimidazoles: anaerobes, certain protozoa.
ADEs include headache, disulfiram-like reaction
when consumed with alcohol, metallic taste
 Sulfonamides and diaminopyrmidine: common
indications include UTIs and acute otitis media.
Sulfisoxazole for gram+ and gram- bacteria.
TMP/SMX for shigella, salmonella, prophylaxis of
P. jirovecii and toxoplasmosis. ADEs include fever,
photosensitivity, Stevens-Johnson syndrome,
hemolytic animea in G6PD-deficient patients, BM
suppression, nephrotoxicity, kernicterus infancy,
displacement of other drugs from albumin
(sulfonamides); megaloblastic anemia, leukopenia,
granulocytopenia, artificially decrease creatinine
(diaminopyramide derivatives)
 Nitrofurans: treatment and prophylaxis of UTI
gram+ and -; asymptomatic bacteriuria in pregnant
women. ADEs include pulmonary fibrosis,
hemolytic anemia in patients with G6PD
deficiency, GI upset

SEPSIS
 Dysregulated immune response to infection
resulting in organ dysfunction
DEFINITION
THIRD INTERNATIONAL CONSENSUS
 Sepsis: severe, life-threatening condition from
dysregulation of patient’s response to infection,
causing tissue and organ damage and subsequent
organ dysfunction
 Septic shock: sepsis syndrome accompanied by
circulatory and metabolic abnormalities that can
significantly increase mortality
o Persistent hypotension: vasopressors
required to maintain mean arterial pressure
(MAP) >= 65 mmHg
o Persistent lactic acidosis: lactate >
2mmol/L (18mg/dL) despite adequate fluid
resuscitation
OTHER
 Systemic inflammatory response syndromes
(SIRS) criteria: infectious or noninfectious insult
o At least 2/4
o Temp >38C or <36C
o HR >90 bmp
o RR >20/min or PaCO2 < 32 mmHg
o WBC count >12,000/mm3 or <4,000mm3 or
>10% immature bands
 Sepsis: SIRS plus suspected or confirmed
underlying infection
 Severe sepsis: sepsis plus dysfunction of at least
one organ or system
 Multiple organ dysfunction syndrome (MODS):
progressive and potentially reversible failure in
function of several organs and/or systems
 SOFA (sequential organ failure assessment)
score: identify organ failure and predict mortality.
After 24 hours of ICU admission and then every 48
hours
ETIOLOGY
 Common sources
o Pneumonia most common cause
o Abdominal infections (e.g. abscess)
o Genitourinary, pyelonephritis
o Skin and soft tissue infections
o Implanted devices (central venous catheter,
urinary catheter, endotracheal tube)
 Pathogens
o Gram+ most common in US, gram- bacteria
o Fungal, viral, parasitic rare
 Common risk factors
o <1 year or >75 years
o Primary comorbidities (DM, cirrhosis,
community acquired pneumonia,
bacteremia, alcoholism)
o Immunosuppression
o Intensive care or prolonged admission
o Recent antibiotic or corticosteroid treatment
PATHOPHYSIOLOGY
 1. Local activation of inflammatory mediators (e.g.
complement, mast cells, macrophages) results in
vessel dilation and further release of
proinflammatory cytokines (esp TNFa, IL-1)
 2. Generalized endothelial disruption  capillary
leak  generalized edema due to shift of
intravascular fluid and albumin into surrounding
tissue
 3. Vasculitis  excessive triggering of extrinsic
coagulation cascade  DIC and microvascular
thrombosis
 4. Decreased oxygen utilization and tissue ischemia
 cellular injury  organ dysfunction
 **Pulmonary edema accompanied by plasma
proteins so decreased PaO2
CLINICAL FEATURES
 Fever, chills, diaphoresis
 Tachycardia and tachypnea
 Generalized edema
 Organ dysfunction based on SOFA score
o CNS impairment: altered mental status
o CV failure: hypotension
o Coagulopathy: DIC, petechiae, purpura
o Liver failure: jaundice
o Kidney failure: oliguria
o Respiratory failure: ARDS
 In septic shock
o Hypotension (MAP <65 mmHg)
o Initially warm skin and normal capillary
refill time (warm shock)  cold cyanotic,
pale, or mottled skin with prolonged
capillary refill time (cold shock)
MANAGEMENT
 1. Sepsis surveillance with quick SOFA
o Alteration in mental status; systolic BP
<=100 mmHg, RR >=22/min
 2. Initial clinical evaluation (ABCDE, disability,
exposure)
o Vital signs
o Bloodwork: CBC with WBC differential,
BMP, electrolytes, creatinine, glucose, liver
chemistry, coagulation panel, D dimer
o Microbiology: 2 sets of blood cultures
(aerobic and anaerobic) before antibiotics
 Consider urinalysis, urine culture,
sputum culture, lumbar puncture,
thoracentesis
o Imaging: CXR is pneumonia/ARDS,
abdominal XR if perforation or obstruction,
U/S for cellulitis and soft tissue abscess, CT
for thoracic and abdominal/pelvic
pathology; echocardiogram for valve
vegetations
 3. Initial resuscitation and ongoing assessment
o 30mL/kg of crystalloid fluid resuscitation
  Complete within 3 hours
o If persistent hypotension, start vasopressors
and titrate to maintain MAP > 65 mmHg
 First-line NE
 Second-line: add vasopressin OR
add continuous IV EN infusion
 Third-line: dopamine, dobutamine
o Consider corticosteroids (hydrocortisone)
for shock refractory to first vasopressor
o May need secure airway, oxygen therapy,
mechanical ventilation
 4. Antibiotic therapy
o Start as soon as blood cultures drawn
o Choice of empiric guided by
 Source of infection
 Local prevalence of common and
resistant pathogens
 Prior infections
 Immune status and patient
comorbidities
 Presence of implanted devices
o Evident sources: pneumonia,
pyelonephritis, intraabdominal infection
o Unclear:
 Unknown risk factors: vancomycin
+ one of following: broad-
spectrum carbapenem
(meropenem, doripenem);
extended-range penicillin/B
lactamase inhibitor
(piperacillin/tazobactam,
ticarcillin/clavulanate); third-gen
or higher cephalosporin
(cefotaxime, ceftriaxone, cefepime)
 MRSA: vancomycin
 Resistant gram- organisms: at least
one of a carbapenem,
piperacillin/taxobactam, cefepime
 Consider adding polymyxin B,
colistin, aminoglycoside
 Anaerobes: metronidazole
o Fungal: echinocandins, azoles, liposomal
formulations
o Source control (6-12 hours): abscess
drainage, debridement of infected necrotic
tissue, removal of infected devices, surgical
pathologies
 4. Supportive care
o Fluids, nutrition, electrolytes
o VTE prophylaxis, renal replacement
therapy for AKI, stress ulcer prophylaxis
SURGICAL SITE INFECTION
 Infection within 30 days of surgical procedure at
site of intervention
 Etiology
o During first 4 days: group A streptococci, C
perfringens
o After 4 days: bacteria in skin, genital tract,
or GI tract
o >30 days: indolent organisms (e.g.
coagulase-negative staphylococci)
 Risk factors
o Corticosteroid therapy, malnutrition,
obesity, DM, advanced age
o Large incision, degree of wound
contamination
 Classification
o Clean: noninflamed, respiratory,
alimentary, genital, and urinary tracts have
not been entered
o Clean-contaminated: noninflamed but tracts
have been entered
o Contaminated: fresh, open, inflamed, clean
or clean-contaminated wounds with break
in sterile technique during surgery
o Dirty or infected wounds: old traumatic
wounds, inflamed operative wound with
purulent drainage
o Chance of SSI increases with each stage
PNEUMONIA CAUSES
 Community-acquired
o Typical: strep pneumoniae, Staph aureus,
haemophilus influenzae
o Atypical: mycoplasma pneumoniae,
chlamydophila pneumoniae, legionella
pneumophila
 Viruses: RSV, influenza viruses,
CMV, adenovirus, coronaviridae
 Hospital-acquired
o Gram-negative pathogens: pseudomonas
aeruginosa, Enterobacteriaceae,
Acinetobacter spp
o Staph aureus, strept pnemoniae
PRIMARY IMMUNE DEFICIENCY
 Congenital deficiency, absence, or defect in one or
more components of immune system, most are X-
linked or autosomal recessive
 Genetically determined and typically show during
infancy/childhood as frequent, chronic, or
opportunistic infections
EPIDEMIOLOGY
 Primary immunodeficiency diseases are rare
 Approx. 1-2/1,000 general population are immune
deficient
CLINICAL PRESENTATION
 Mainly pathological susceptibility to infection
 B-cell deficiencies typically recurrent bacterial
o Antibodies fight extracellular organisms
 T-cell deficiencies typically recurrent viral and
fungal
o T cells fight intracellular microorganisms

 Diagnosis: tests such as differential WBC count,
absolute lymphocyte count, quantitative Ig
measurements, antibody titres
 Treatment: prophylactic antibodies to manage and
prevent infections
B-CELL IMMUNODEFICIENCIES
 Selective IgA deficiency: most common primary
immunodeficiency with unknown mechanism 
low serum IgA, normal IgG and IgM
o Often asymptomatic
o Respiratory infections and/or chronic
diarrhea
 Bruton agammaglobulinemia: X-linked recessive
BTK gene defect  defective Burton tyrosine
kinase expressed in B cells  absent or low B cells,
low Ig of all classes, normal T cell count
o 3-6 months of age when maternal IgG
levels in fetal serum start to decrease
o Recurrent and severe pyrogenic infections
esp. by encapsulated bacteria and
enteroviruses
 Common variable immunodeficiency: unknown
but phenotypically normal B cells unable to
differentiate into plasma cells  low plasma cells,
low Igs of all classes, normal B and T cell counts
o 20-40 years of age usually
o Recurrent sinopulmonary infections
 Hyper-IgM syndrome: X-linked mutation in
CD40LG gene encoding CD40 ligand  defect in
class switch recombination (CSR)  normal or
high IgM levels, low IgG and IgA levels
T-CELL IMMUNODEFICIENCIES
 DiGeorge syndrome: autosomal dominant
microdeletion at 22q11.2  defective development
of 3rd and 4th pharyngeal pouches  hypoplastic or
absent thymus and parathyroids  low PTH and
Ca2+, low T cells
o CATCH-22 (cardiac anomalies, anomalous
face, thymus aplasia/hypoplasia, cleft
palate, hypocalcemia)
 Autosomal dominant hyper-IgE syndrome (Job
syndrome): STAT3 gene mutation  decreased
Th17 cells  defective neutrophil/macrophage
chemotaxis  increased IgE, low IFN-y, increased
eosinophils
o FATED: fractures and facies, abscesses
mainly staph, retained primary teeth, hyper-
IgE and eosinophilia, dermatologic features
(e.g. severe eczema)
 IL-12 receptor deficiency: autosomal recessive 
decreased IL-12  impaired Th1 response  no
release of IFN-y  low IFN-y
o Disseminated disease, esp. tuberculosis
o Fungal infections
 Chronic mucocutaneous candidiasis: several
congenital defects (e.g. STAT1 gain of function
mutation, AIRE protein deficiency)  impaired T
cell function  impaired or absent immune
response to Candida  no cutaneous reaction to
Candida antigen
o Noninvasive Cnadida infections of skin,
nails, and mucous membranes
CONGENITAL COMBINED IMMUNODEFICIENCIES
 Severe combined immunodeficiency: various
mutations resulting in impaired function of B and T
cells. X-linked recessive defective IL-2R gamma
chain most common; autosomal recessive adenosine
deaminase deficiency; human RAG mutations
defects in VDJ recombination  absent T cells (X-
linked); absent T, B, and NK cells (AR variant), no
thymic shadow, absent germinal centers
o Asymptomatic at birth
o Recurrent bacterial, viral, fungal, protozoal
infections
o Failure to thrive
 Wiskott-Aldrich syndrome: X-linked recessive
WASp gene mutation  decreased WASp protein
synthesis  impaired remodelling of T cells actin
cytoskeleton  defective antigen presentation 
normal or low IgG/IgM, increased IgE/IgA,
thrombocytopenia with small platelets
o Present at birth
o Wis-PER: Wiskott-Aldirch syndrome,
purpura due to thrombocytopenia, eczema,
recurrent pyogenic infections with
encapsulated organisms
 Hyper-IgM syndrome: X-linked recessive class
switching defect of Th cells (most commonly CD40
ligand deficiency)  low IgG, IgA, IgE, normal or
increased IgM, absent germinal centres
o Recurrent sinopulmonary infections,
commonly pneumocystis jirovecii,
histoplasma, cryptosporidium, CMV
o Failure to thrive
 Ataxia telangectasia: autosomal recessive ATM
gene defect  failure to recognize and repair
dsDNA breaks  no cell cycle arrest  continuous
replication of damaged DNA  increased AFP,
lymphopenia, low IgA, IgG, IgE, MRI vermis
atrophy
o Early childhood
o Triad of 3 As: progressive ataxia due to
cerebellar atrophy, spider angiomas, IgA
deficiency
NEUTROPHIL AND PHAGOCYTE DISORDERS
 Chronic granulomatous disease: X-linked
defective NADPH (generation of peroxidase and
superoxides)  decreased intracellular ability of
neutrophils to kill engulfed bacteria  formation of
granuloma  can become large enough to obstruct
esophagus, bladder
 o Opportunistic infections by certain bacteria
and fungi, esp. Serratia and Burkholderia
o Nitroblue tetrazolium dye reduction
confirms diagnosis
 Leukocyte adhesion deficiency syndrome:
autosomal recessive gene for integrin  impaired
adhesion and defective phagocytosis of bacteria
o Pyogenic infections including pneumonia
and otitis
 Chediak-Higashi syndrome, myeloperoxidase
deficiency
COMPLEMENT DISORDERS
 CH50 assay screening test
 C1 esterase inhibitor deficiency: autosomal
dominant unregulated activation of kallikrein 
increased bradykinin  angioedema  elevated
bradykinin levels, low C4 levels
o Recurrent angioedemas provoked by
triggers (e.g. trauma, surgery, infections)
 Early complement deficiencies (C1-C4):
autosomal co-dominant inheritance  lowered
levels, most common C2
o Risk of severe infections of respiratory tract
and sinus
 Terminal complement deficiency: autosomal
recessive  inability to form membrane attack
complex  most common C5, C6, C8
o Recurrent Neisseria or gonococcal
pyogenic infections
 C3 deficiency: deficiency of C3 and cleaved
fragments  impaired opsonization of pathogens
 reduced clearance of C3b-bound immune
complexes  susceptibility to type iII HSR
o Recurrent, severe infections with
encapsulated bacteria
o <6 months: T-cell defect because maternal
antibodies protective for 6-9 months
o 6-12 months: combined B- and T-cell
defects or B-cell defect, when maternal
antibodies are disappearing
o >>12 months: B-cell defect or secondary
immunodeficiency
o In general, the earlier the onset the more
severe the immunodeficiency
PHYSICAL EXAMINATION
 Macular rashes, vesicles, pyoderma, eczema,
petechiae, alopecia, or telangiectasis may be evident
 Small or absent cervical lymph nodes and
adenoid and tonsillar tissue
o X-linked agammaglobulinemia, X-linked
hyper-IgM syndrome, severe combined
immuodeficiency, and other T-cell
immunodeficiencies
 Enlarged liver and spleen
o Patients with CVID or chronic
granulomatous disease

ACQUIRED IMMUNODEFICIENCY
ETIOLOGY
 Drugs (steroids)
o Direct effects on immune cell traffic and
functions, cytokine synthesis inhibited
o T cells more affected than B cells
 Nutrient deficiencies
o Multiple enzymes with important roles
require zinc, iron, other micronutrients
o Cell-mediated immunity, antibody
production, phagocyte function,
complement system, and cytokine synthesis
 Obesity
o Altered NK function and cytotoxicity and
phagocytosis impaired INITIAL TESTING
 AIDS  If secondary, testing focus on that disorder
o Caused by HIV, retrovirus transmitted o DM, HIV infection, CF, primary ciliary
sexually, perinatally, or blood dyskinesia
o Direct effects of HIV and impairment of  CBC with manual differential, quantitative Ig
CD4 T cells  decreased response to measurements, antibody titers, skin testing for
antigens and mitogens, including less delayed hypersensitivity
cytokines o If normal can be excluded and/or monitored
EVALUATION OF SUSPECTED with more tests over time
IMMUNODEFICIENCY  CBC
HISTORY o Neutropenia: congenital or cyclic or in
 Family history suggests primary immunodeficiency aplastic anemia
 Age of onset:
 o Lymphopenia: T-cell disorder because 70%
of circulating are T cells
o Leukocytosis: between infections,
leukocyte adhesion deficiency
o Thrombocytopenia: Wiskott-Aldrich
syndrome
o Anemia: chronic disease or hemolytic
which may occur in CVID
 Peripheral blood smear
o Howell-Jolly bodies and other unusual
RBC, suggest primary asplenia or impaired
splenic function
 Quantitative serum Ig levels
o Low serum IgG, IgM, or IgA suggest
antibody deficiency
 Skin testing
o Most immunocomptent individuals react to
0.1 mL of Candida albicans extract
intradermally
 CXR
o Absent thymic shadow suggests T-cell
disorder
ADDITIONAL TESTING
 Lymphopenia
o Lymphocyte phenotyping using flow
cytometry and monoclonal antibodies to T,
B, and NK cells
 Cellular immunity deficiency
o Flow cytometry assay followed by in vitro
mitogen stimulation studies to assess T cell
quantity and function
o If MHC antigen deficiency suspected,
serologic HLA typing indicated
 Humoral immunity deficiency
o Specific mutations – e.g. BTK, CD40 and
CD40L, nuclear factor-kappa-B essential
modulator (NEMO)
o Sweat chloride test to rule out CF
 Combined cellular and humoral deficiency
o Mutations, e.g. IL-2 receptor gamma gene
 Phagocytic cell defects
o CD15 and CD18 by flow cytometry
o Test neutrophil chemotaxis
o Flow cytometric oxidative burst assay
(NBT) can detect whether oxygen radicals
produced during phagocytosis
 Complement deficiency
o Serum dilution required to lyse 50% of
antibody-coated RBCs measured
o CH50 assay detects deficiencies in classical
pathway but not which is abnormal
o AH50 detect deficiencies in alternative
pathway
TREATMENT
 Avoid environmental exposures and live-virus
vaccines
 Prophylactic antibiotics (e.g. TMP/SMZ)
 Antivirals may be indicated in acute infection
 Replacement of missing immune components
o IVIG: most forms of antibody deficiency.
o Subcutaneous Ig: can be given at home
o Hematopoietic stem cell transplantation:
using BM, umbilical cord blood, or adult
peripheral blood stem cells (sibling or
parent) effective for lethal
immunodeficiencies. Pretransplantation
chemo required in patients with intact or
partial T-cell function
IVIG
INDICATIONS
 1. Replacement therapy in immunodeficiencies
 2. Immunomodulatory (hematological and organ-
specific autoimmune disorders) and anti-
inflammatory (rheumatic inflammatory, infectious,
neurologic disorders)
 3. Hyperimmune therapy against specific infectious
agents
CONTRAINDICATIONS
 Sugar-stabilized IVIG avoided in renal failure or
DM
 Hyperosmolar IVIG not for post-transplantation due
to risk of renal failure and osmotic nephropathy
 High Na-containing cautiously individuals with
cardiac conditions and hypertension
 Severe anaphylactic reactions rare due to presence
of IgG or IgE anti-IgA antibodies in patients with
IgA deficiency
 Measles, mumps, rubella vaccine not in children
receiving IVIG as IgG may inactivate attenuated
virus
HUMAN IMMUNODEFICIENCY VIRUS
EPIDEMIOLOGY
 Peak incidence 20-30 (~35/100,000)
 AIDS: peak incidence ~45 (~14/100,000)
 Incidence significantly higher in Blacks
ETIOLOGY
 Retroviridae (family) lentivirus (genus)
 HIV-1 most common worldwide
 HIV-2 restricted almost completely to West Africa
 Structure: icosahedral with conical capsid and
spiked envelope. Retrovirus, single-stranded RNA
 Genome: pseudodiploid (2 RNA molecules
yielding 1 DNA molecule)
o 9 genes, total 15 proteins
 Function of proteins
 Pol gene  polyprotein
o Protease: cleavage of gag and gag-pol
proteins during maturation of virion
o Reverse transcriptase: viral RNA to dsDNA
o Integrase: insert viral genes into host
genome
 Gag gene  gag protein
o Matrix protein (p14 protein), nucleocapsids,
capsid proteins (p24 protein)
 Env gene  gp160
o Cleaved into envelope glycoproteins
o Gp120: attaches to host CD4 cells
o Gp41: assists in fusion and entry of virus
into host cell
ROUTES OF TRANSMISSION
  Sexual responsible for 80% infections
o Modifying factors: viral load,
circumcisions (reduced risk), coinfection
increases local virus concentration, genital
mucosal damage
 Parenteral transmission
o In descending order of risk, needle sharing
(0.67%), needlestick injuries, infectious
blood on mucous membranes, blood
transfusion (low risk 0.00005%)
 Vertical transmission
o Childbirth 5-15%
o Breastfeeding 5-20%
 Overall: lowered risk of transmission if viral load
below limit of detection
PATHOPHYSIOLOGY
HIV INFECTION
 1. HIV enters body (e.g. mucosal lesions or
infection of mucosal/cutaneous immune cells)
o Immune cells thinly interspersed in
mucosal and cutaneous areas, spreads
slowly initially and several days before
blood detectable
 2. Attaches to CD4 receptor on target cells with
gp120 glycoprotein binding
o T helper cells, macrophages, monocytes,
dendritic cells
 3. Viral envelope fuses with host cell and capsid
enters
o CD4 receptor and coreceptor (CCR5 in
macrophages, CCR5 early or CXCR4 later
in T cells) must be present
 Individuals without CCR5
receptors seem to be resistant to
HIV, if heterozygous then slower
course
 4. Virion’s RNA transcribed into dsDNA by viral
reverse transcriptase
 5. Integrated into host’s DNA by viral integrase
 6. Viral DNA replicated and virions assembled
 7. Virion repurposes portion of cell’s membrane as
envelope and ‘budding’  cell death
PROGRESSION TO AIDS
 HIV infects CD4 and spreads to others near site of
infection  infection of CD4 in specialized
lymphoid tissue  explosive growth and
dissemination  acute HIV syndrome with high
viral load
o 107-108 copies/mL, usually lasts 2-4 weeks,
~50% patients with primary infection
 After acute stage, decreases to relatively stable
level 103-104/mL for ~8-10 years
 During this clinical latency stage virus mainly
replicates inside lymph nodes  increasing loss of
CD4 lymphocytes esp. T cells  increased risk of
opportunistic infections and malignancies
ROLE OF IMMUNE RESPONSE
 Activation of cellular immunity that helps virus
spread and ensures chronic persistence of infection
o Because HIV infects immune cells
 Evades immune control via
o Genetic mutation and recombination so
different viral epitopes
o Downregulation of MHC I in infected
CLINICAL PRESENTATION
 Patients often asymptomatic early on
 Incubation period usually 2-4 weeks
 Infectiousness two peaks, within first few months
and during AIDS-stage
ACUTE HIV INFECTION
 Acute retroviral syndrome or mononucleosis-like
syndrome
 Fever, fatigue, myalgia and arthralgia
 Generalized nontender lymphadenopathy
 GI (nausea, diarrhea)
 Oropharyngeal (sore throat, ulcerations, painful
swallowing)
NON-AIDS-DEFINING CONDITIONS
 Common when CD4+ count <500cells/mm3
 Chronic subfebrile temperatures
 Generalized lymphadenopathy
 Chronic diarrhea
 Localized opportunistic infections
o Oral candidiasis
o Vaginal infections (yeast, trichomonads)
 Oral hairy leukoplakia
 HPV-related: squamous cell carcinoma of anus or
cervix
 Skin manifestations: molluscum contagiosum,
warts, exacerbations of psoriasis, shingles
HIV-ASSOCIATED CONDITIONS
 CNS: cerebral toxoplasmosis, primary CNS
lymphoma, cerebral abscess, progressive multifocal
leukoencephalopathy, HIV-associated
encephalopathy
 Ocular: HIV retinopathy, herpes simplex keratitis,
varicella zoster retinitis, cytomegalovirus retinitis,
toxoplasma retinitis
 Cancer: Kaposi sarcoma, cervical cancer, bacillary
angiomatosis
 Other: reactivation tuberculosis,
coccidioidomycosis, cryptosporidiosis,
pneumocystis pneumonia, isosporiasis,
histoplasmosis, cryptococcis (extrapulmonary, esp.
meningitis), esophageal candidiasis, mycobacterium
avium complex (MAC) infection
OVERALL MOST COMMON INFECTIONS
 HSV-1 infection (lips and mouth)
 Salmonella infection (intestine)
 Candidiasis (mouth, esophagus, respiratory, vagina)
 Toxoplasmosis (brain)
CLASSIFICATION
CDC
 >=500, 200-499, <200 CD4 cells/mm3
  Clinical categories: A = asymptomatic, acute HIV,
or PGL; C = AIDS-defining conditions; B =
symptomatic not A or C
 AIDS = A3, B3, or C1-3
WHO
 Primary: acute retroviral syndrome or
asymptomatic
 Clinical stage 1: persistent generalized
lymphadenopathy (PGL) or asymptomatic
 Clinical stage 2: unexplained moderate weight loss
(<10%), recurrent fungal/viral/bacterial infections
 Clinical stage 4: AIDS-defining
DIAGNOSIS
 All individuals with possible past exposure and
one-time testing early in every pregnancy
 Screening tests
o Combination antigen/antibody tests: both
HIV antigen (p24 protein) and anti-HIV
antibodies (IgG against HIV1/2). Rules out
because almost 100% sensitivity
 Not for neonatal because false-
positive, viral RNA instead
o Antibody-only tests: ELISA 1-3 hours;
rapid ~20 minutes
 Confirmatory tests
o HIV-1/HIV-2 antibody differentiation
immunoassay: ~20 minutes and distinguish
 Detection of viral RNA
o Detects earlier than antibody/antigen-based
o Indications: neonatal HIV infection,
presenting before seroconversion,
indeterminate results
 HIV drug resistance testing
o Newly diagnosed patients to determine
appropriate therapy
o Genotypic >> phenotypic assays
 Post-treatment monitoring
o Viral RNA load  indicator of treatment
effectiveness and prognostic markers
o CD4 count  correlates with overall
immune function; initiating opportunistic
infection prophylaxis
o CD4/CD8 ratio: expected to increase
TREATMENT
 All persons should begin combined antiretroviral
therapy (ART) ASAP, esp. in patients
o Low CD4 count
o High viral load
o Presence of AIDS-defining illness
 Therapy based on HIV genotype.
Recommendations:
o 3 NRTI
o 2 NRTI and 1 NNRTI, 1 PI, or 1 INI
o Most NRTIs ‘ine’, protease ‘navir’,
integrase ‘gravir’
 Combined to prevent resistance, all can target both
HIV-1 and 2 except enfuviritide and NNRTIs
NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS
 Zidovudine, lamivudine, emtrictabine, abacavir,
stavudine, didanosine, tenofovir
 MOA: nucleoside analogs  competitive blockage
of nucleoside binding to reverse transcriptase 
inhibition of formation of 3’ to 5’ phosphodiester
linkages  termination of DNA chain  inhibition
of RNA to DNA reverse transcription
o Requires intracellular phosphorylation,
dependent on kinase availability and
activity
 Side effects: BM suppression, mitochondrial
toxicity (myopathy, peripheral neuropathy, hepatic
steatosis), pancreatitis, HIV-associated
lipodystrophy (loss of fatty tissue in face and
extremities)
NONNUCLEOSIDE REVERSE-TRANSCRIPTASE
INHIBITORS
 Nevirapine, efavirenz, delavirdine
 MOA: noncompetitive inhibitors of reverse
transcriptase that bind at different locations
o Do not require intracellular phosphorylation
 Side effects: hepatotoxicity, CNS toxicity,
hypersensitivity
ENZYME INHIBITORS
 Protease: idinavir, ritonavir, nelfinavir, lopinavir
o Inability to cleave viral mRNA into
functional units  impaired viral proteins
 immature/noninfectious virions
o GI upset, lipodystrophy, nephrolithiasis,
thrombocytopenia, hyperglycemia
 Integrase: raltegravir, dolutegravir, bictegravir,
elvitegravir
o Increased creatine kinaes
 Entry: inhibit binding or fusion of HIV virions
o Enfuvirtide: competitively binds gp41; skin
irritation at side of drug infection
o Maraviroc: blocks CCR5 coreceptor on T
cells and monocytes; hepatotoxicity
PROGNOSIS
 Untreated, death average 8-10 years after infection
 Average life expectancy with adequate antiviral
treatment approaching that of noninfected
individuals
 Prognostic factors
o Treatment, viral load, CD4 count, exposure
to opportunistic pathogens, genetic
properties
PREVENTION
 Pre-exposure prophylaxis, continued for 1 month
o Emtricitabine + tenofovir disoproxil
fumarate (TDF-FTC)
o Emtricitabine + tenofovir alafenamide
(TAF-FTC)
 Post-exposure prophylaxis,
o Emtricitabine + tenofovir + dolutegravir
o Emtricitabine + tenofovir + raltegravir
 Led to resurgence of STIs because unprotected
HIV REPORTING
 If anonymous testing (no name or personal
information), doctors at testing clinics not required
to report name and contact information to Public
Health, as long as you get counselling
 Pay for own drugs, some plans:
o Private insurance plan
 o ODBP: social assistance; seniors’ coverage;
community care access centre; Trillium
drug program
o Interim federal health
HUMAN HERPES VIRUS
 Members of family of DNA viruses, Herpesviridae
 Three main groups
 Alpha herpes viruses
o HSV1, HSV2, VZV
o Fast replication cycle and broad host range
o Persist in ganglion cells for lifespan of host
 Beta herpes viruses
o Cytomegalovirus (5), HHV6, HHV7
o Slow replication cycle and limited host
range
o Persist in granulocytes and lymphocytes
 Gamma herpes viruses
o Epstein-Barr virus (4), Kaposi’s sarcoma-
associated virus (8)
o Oncogenic potential and very restricted
host range
o Persist in B cells
HHV1/HSV1
 >=50% in adults
 Transmission: saliva, respiratory secretions
 Dormancy: after primary infection, dormant in
ganglia, typically trigeminal ganglia
 Disease: herpes labialis (cold sores seldom HSV2),
herpetic gingivostomatitis, eczema herpeticum,
herpetic whitlow, herpes simplex encephalitis, HSV
keratitis (less common HSV2), HSV conjunctivitis,
HSV esophagitis, erythema multiforme
 Management: antivirals may be indicated
HHV2/HSV2
 10-20% in adults
 Transmission: sexual intercourse, perinatal
 Dormancy: nerve ganglia, typically sacral ganglia
 Disease: genital herpes (seldom HSV1), eczema
herpeticum, herpetic whitlow, viral meningitis (less
common HSV1), congenital herpes simplex,
neonatal herpes simplex
 Management: antivirals may be indicated
MORE ON HERPES SIMPLEX VIRUSES
PATHOPHYSIOLOGY
 Enters through mucosal surfaces or small dermal
lesions  invades and replicates in nerve cells 
remains in ganglion neurons  reactivation
triggered by various factors (e.g.
immunodeficiency, stress, trauma)
 Infection may spread to unusual sites (e.g. lungs,
GI, eyes) in patients with severe immunodeficiency
DIAGNOSIS
 Sometimes asymptomatic; primarily based on
clinical features with confirmation via
 Light microscopy/Tzanck smear
o Detects multinucleated giant cells
o Eosinophilic intranuclear Cowdry A
inclusion bodies
o Unable to differentiate between ½, and also
positive in VZV
 Viral culture
o Skin and/or mucosal HSV infections
o Sample from fresh vesicle, skin or genitals
 PCR
o Detects HSV DNA
o Method of choice for CNS infections (CSF
analysis) and skin and mucosal lesions
 Direct fluorescent antibody test: virus genotype
 Serum antibody testing: genital lesions but negative
culture or PCR; infection status if sex with
documented HSV infection; risk of vertical
transmission
TREATMENT
 Antiviral
o Decrease in duration and severity of
infection, but cannot prevent recurrence
because only affects active virus
o First-line oral acyclovir
 If resistant, foscarnet
o Others: valacyclovir, penciclovir,
famciclovir
o Prophylaxis if frequent or severe relapses
 long term with (val)acyclovir
 Symptomatic
o IV fluids, pain relief, antipyretics,
antibiotics
 Prevention
o Condoms, gloves
o Isolation of hospitalized patients with
shedding lesions
HHV3/VZV
 Up to 90% adults
 Transmission: respiratory secretions, vesicular
fluid
 Dormancy: dorsal root ganglia and trigeminal
ganglia
 Disease: primary = viremia = chickenpox/varicella;
reactivation = shingles/zoster; mostly due to
immunosuppression (advanced age, malignancy,
HIV, iatrogenic, malnutrition, chronic stress) =
replicates in dorsal root ganglia = travels through
peripheral sensory nerves to skin
 Management: vaccinations widely used in children
MORE ON VZV
CLINICAL FEATURES
 Pain: burning, throbbing, or stabbing
 Erythematous maculopapular rash that quickly
evolves into vesicular lesions
o Initially clear
o Pustulation and rupture in 3-4 days
o Crusting and involution day 7-10
 Systemic: fever, headache, fatigue, itching, motor
deficits
 Disseminated herpes zoster
o >20 extradermatomal lesions, involvement
of >=3 dermatomes, and/or visceral organ
involvement
o Pneumonia, hepatitis, meningoencephalitis,
acute retinal necrosis
o Typically in immunocompromised patients
SUBTYPES
 Herpes zoster ophthalmicus: ophthalmic division of
trigeminal nerve
 o Can result in blindness
Herpes zoster oticus: geniculate ganglion, affecting
facial and vestibulocochlear cranial nerves
o Vertigo, sensorineural hearing loss, facial
paralysis
DIAGNOSIS
 PCR of VZV DNA
o Skin lesions (vesicular fluid), CSF, blood
 Serologic assay of VZV (IgM and IgG) can indicate
active or passive immunity
 Evaluate malignancy if disseminated
 Tzanck test of skin vesicles and DFA of skin
scrapings not recommended because low sensitivity
TREATMENT
 Antiviral therapy most effective if administered
within ~72 hours
 Indications
o >50 years
o Moderate or severe rash and pain
o Immunocompromised status
o Signs of disseminated and/or neurologic
o Nontruncal involvement
 Regimen
o Immunocompetent: acyclovir,
valacyclovir, famciclovir
o Immunocompromised or disseminated:
IV acyclovir
 Supportive care
o Anti-inflammatory and analgesic:
acetaminophen, NSAIDs, tramadol,
oxycodone
 If moderate to severe: nortriptyline,
gabapentin, pregabalin
HHV4/EBV
 65% in children and teens, and young adults 6-19yo
 Transmission: saliva, respiratory secretions
 Dormancy: CD21 receptor to infect B cells  can
immortalize and transform (oncogenic potential)
 Disease: infectious mononucleosis; oral hair
leukoplakia; Burkitt lymphoma; nasopharyngeal
carcinoma (esp. Southeast Asian)
 Management: avoid physical activity that may
trigger splenic rupture (e.g. contact sports) for at
least 3 weeks
HHV5/CMV
 ~50% in US
 Transmission: congenital, sexual intercourse,
transfusions, transplants, saliva, urine
 Dormancy: uses integrins to infect; large atypical
lymphocytes with intranuclear inclusion bodies that
have owl-eye appearance
 Disease: cytomegalovirus infection; CMV
mononucleosis (immunocompetent individuals),
congenital CMV infection
 Management: antivirals may be indicated
HHV6/HHV7
 ~90% in US
 Transmission: saliva
 Dormancy: reactivation of latent virus may occur
later in life, esp. if immunocompromised
 Disease: Roseola infantum (high fever, ends
abruptly after 3-5 days, followed by sudden
maculopapular truncal rash that sometimes spreads
to face and extremities, fading within two days)
mainly in infants and toddlers – AKA sixth disease
 Management: self-limiting; symptomatic
HHV8/KSHV
 <10% in US; higher in men who have sex with men
and HIV+ patients
 Transmission: sexual intercourse
 Dormancy: infects endothelial cells causing
malignant, multifocal, highly vascularized tumor.
Oncogenic potential
 Disease: Kaposi sarcoma
 Management: treatment of underlying disease (e.g.
HIV)
IMMUNOSUPPRESSION
CANCER
NORMAL KILLING
 NK cells sense stress-associated molecules on
damaged and cancerous cells
 Dendritic cells activate cytotoxic T cells which can
sense tumor-associated antigens
 NK and cytotoxic T cells release perforin and
granzymes  punch holes  apoptosis
 Helper T cells
o Helper T cells activate cytotoxic
o Produces cytokines such as IFN-y that
recruits and activates more NK cells
IMMUNOEDITING HYPOTHESIS
 Three phases
 1. Elimination phase: immune system recognizes
and destroys potential tumor cells
 2. Equilibrium phase: if elimination is not
completely successful. Tumor cell undergoes
mutations that aid in survival due to selection
pressure
o Cancer immunoediting continuously shapes
properties of tumor cells that survive
 No longer express molecules
sensed by immune cells
 Actively suppress T cells by
expressing PDL1 (PD1)
 Attract immune cells that suppress
others’ activity (e.g. regulatory
cells, macrophages)
 3. Escape phase: tumor cells with ability to evade
immune system grow unimpeded
CLINICAL RELEVANCE
 In immunocompetent, equilibrium phase continually
removes tumor cells and delays tumor growth
 If immunocompromised, equilibrium phase quickly
turns to escape as no tumor cells removed
 Another situation: post-transplant
lymphoproliferative disorder
 Usually B-cell expansion driven by EBV in which
B cells undergo mutations and become malignant
 o Depressed antiviral functions Shape: round/discoid; oval; annular (round with
central clearing); reticular (net-like); linear;
RASH TERMINOLOGY iris/target (purple papule in centre of pink macule);
serpignous (snakelike); polycyclic (interlocking
DEFINITIONS circles); morbilliform (measles-like)
 Atrophy: thinning or epidermis and/or dermis  Border/margin: discrete (psoriasis) or indistinct
causing shiny/fine wrinkling/depression (eczema) or irregular (melanoma)
 Dermatitis: inflammation of skin  Feel: indurated, hard, soft, sclerotic
 Eczema: generic term for acute or chronic  Color: erythema (pink, salmon, brawny),
inflammatory conditions of the skin violaceous, yellow, tan-brown, black, pearly,
o Typically erythematous, edematous, honey-colored
popular, vesicular, crusted LOCATION AND DISTRIBUTION
o Usually itches and burns  Localized, regional, generalized
 Eruption: ‘breaking out’ of skin or rapidly  Dermatomal – herpes zoster
developing dermatosis  Sun-exposed areas – sunburn, SLE, porphyria,
 Exanthem: skin eruption typically due to viral or photosensitivity to drugs
bacterial systemic disease  Clothing covered area – contact dermatitis, miliaria
 Fissure: vertical ‘cut’ extending into dermis  Flexural areas – atopic dermatitis, intertrigo,
 Hyperkeratotic: localized thickening of epidermis candidiasis, tinea cruris
 Keloid: abnormally hypertrophied scar  Extensor areas – psoriasis, atopic dermatitis infants,
 Lichenification: leathery induration and thickening eruptive xanthomas
of skin with hyperkeratosis due to long standing  Truncal – pityriasis rosea, drug eruptions
scratching or irritation, marked prominence of
normal skin lines
 LESIONS:
 Primary skin lesion: basic skin changes (macule,
patch, papule, plaque, nodule, vesicle, bulla, tumor,
pustule, wheal, cyst, telangiectasia)
 Secondary skin lesion: change occurs due to natural
development or external manipulation (scale,
lichenification, keloid, excoriation, fissure, erosion,
ulcer, atrophy, crust, hyperkeratosis)
 Vesicle: well circumscribed fluid-filled lesion up to
5-10mm. >10mm then bulla. Coalescence of
vesicles then blister
 Urticarial: well-defined, localized area of edema
 Crust: dried residue of serum, blood, or pus
 Cyst: circumscribed, usually compressible, round,
walled lesion, below epidermis
 Pustule: circumscribed lesion filled with purulent
material alone
 Macule: flat, nonpalpable lesion with color change
less than 5-10mm. >10 mm then patch
 Papule: raised lesion <5-10mm. >10mm then
plaque
 Maculopapular: 50/50 both APPROACH TO RASH
 Nodule: solid lesion (5-20mm) with appreciable
deep (dermal and/or subcutaneous) component
 Tumor: solid lesion (>2cm) with deeper dermal or
subcutaneous thickness
 Petechiae: <5mm hemorrhagic discoloration, non-
blanchable. If >5mm then purpura
 Scale: flaky appearance due to abnormal
proliferation of outermost epidermal layer, stratum
corneum
 Erosion: loss of portion of epidermis, superficial RED FLAGS
and non-scarring  Fever
 Ulcer: loss of skin extending into dermis  Toxic appearance
 Telangiectasia: dilated superficial capillary/venule  Hypotension
 Wheal/hive: localized edematous plaque-like lesion,  Blistering or skin sloughing
somewhat irregular and transient  Diarrhea and/or abdominal pain
MORPHOLOGICAL CHARACTERISTICS  Petechiae and/or purpura
 Mucosal lesions
  Severe pain
 Photophobia
 Non-blanching
 Arthralgia and muscle pains
 Very old or young age
 Immunosuppressed
 New medication
HISTORY/PHYSICAL
 Distribution and progression of skin lesions
 Recent exposures including medications
 Undress to check trunks and extremities
 Palms, soles, mucous membranes
 Press on lesions to see if blanch
 Rub erythematous to see if it sloughs
TESTING
 CBC: leukocytosis or thrombocytopenia
 Serology: infectious causes
 Mineral oil mounts and KOH scrapings: scabies or
dermatophytes
 Skin biopsy with or without direct/indirect
immunofluorescence: confirm lichen planus,
dermatitis herpetiformis, mycosis fungoides, and
staphylococcal scalded skin syndrome
ALKALINE PHOSPHATASE
 Outer layer of cell membrane catalyze hydrolysis of
organic phosphate esters present in ECM
 Found in liver, bones, placenta or pregnant women,
intestine, kidneys, other parts of body
 Elevated:
o Most commonly hepatobiliary disorders
o Increased osteoblast activity in bone
disorder or physiologically during periods
of growth
o Influx of placental alkaline phosphatase in
late third trimester
 Majority of serum from liver and bone, small
amounts for intestine
 Elevated in many cancers
LUNG CANCER
EPIDEMIOLOGY
 Leading cause of cancer death worldwide
 Second most common cancer
 Peak incidence 65-75 years
 More common in men except for adenocarcinoma
ETIOLOGY
 Tobacco smoking
o ~90% of lung cancers
 Occupational and environmental carcinogen
exposure
o Radon (second leading cause) and uranium
(radioactively decays into radon)
o Abestos
o Environmental air pollution
 Family history
 Others
o Pulmonary scarring or fibrosis
o Previous radiation
o Chronic infections (e.g. tuberculosis)
CLASSIFICATION
Squamous cell carcinoma and small cell lung
cancer are ‘sentrally’ located
NON-SMALL CELL LUNG CANCER
 Adenocarcinoma
o Peripheral location
o Most common type of primary lung cancer
o More common in women and nonsmokers
o Mutations in EGFR, ALK, KRAS gene
o Hypertrophic osteoarthropathy (clubbing,
swelling and pain in joints and long bones)
o Prognosis usually better than other types
o Histology: glandular, positive mucin
staining, lepidic adenocarcinoma  growth
along walls  alveolar thickening,
expression of napsin A, TTF-1
o Subtypes:
 Preinasive: atypical adenomatous
hyperplasia, pulmonary
adenocarcinoma in situ
 Invasive: minimally-invasive,
lepidic-predominant, mucinous-
predominant
 Squamous cell carcinoma
o Central
o Strong association with smoking
o Cavitary lesions arising from hilar bronchus
o PTHrP  hypercalcemia
o Histology: solid epithelial, intracellular
bridges, keratin pearls, expression of p40,
p63, CK5, CK6
 Large cell carcinoma
o Peripheral
o Strong association with smoking
o Early metastases and poor prognosis
o Histology: large polygonal tumor cells,
undifferentiated, prominent nucleoli
LUNG NEUROENDOCRINE TUMORS
 Small cell lung cancer
o Central
o Strong association with smoking and
several paraneoplastic syndromes
o Associated with L-myc oncogene
o Very aggressive with early metastases
o Histology: neuroendocrine Kulchitsky cells
(small, dark blue, hyperchromatic nuclei
salt and pepper), many mitotic figures,
expresses chromogranin A, synaptophysin,
neuron-specific enolase
 Large cell neuroendocrine carcinoma
o Peripheral
o High-grade tumors, poor prognosis
o Histology: large cells with abundant
cytoplasm organized in trabecular or
palisading patterns, many mitotic figures,
expresses chromogranin A and
synaptophysin
 Bronchial carcinoid
o Central or peripheral
o Most common cancer in children and
adolescents
o Good prognosis with indolent course
o Mass effect of tumor e.g. wheezing
 o Histology: polygonal cells in organoid,
trabecular, or insular patterns, fine
chromatin with small nucleoli, expresses
chromogranin A and synaptophysin
 Histology of all neuroendocrine
OTHER VARIANTS
 Pancoast tumor
o Apical lung carcinoma located in superior
sulcus
o Predominantly NSCLC
 Pancoast syndrome
o Due to mass effect
o Cervical sympathetic ganglion: Horner
syndrome (ipsilateral miosis, ptosis,
anhidrosis)
o Brachial plexis: neuralgia of axilla and
shoulder, motor and sensory deficits of
upper limb
o Recurrent laryngeal nerve: hoarseness
o Brachiocephalic vein: unilateral edema of
arm, facial swelling
o Phrenic nerve: paralysis of hemidiaphragm
CLINICAL FEATURES
 Often only becomes symptomatic in late stages 
negative prognosis
 Pulmonary symptoms
o Cough, hemoptysis
o Progressive dyspnea
o Wheezing
o Chest pain
 Extrapulmonary symptoms
o Constitutional
o SVC syndrome: venous congestion in head,
neck, upper extremities
o Recurrent laryngeal nerve: hoarseness
o Phrenic nerve: dyspnea and diaphragmatic
elevation
o Malignant pleural effusion: dullness on
percussion and reduced breath sounds
 Metastatic disease
o Over half present with metastatic
o Brain: headaches, seizures, focal motor
deficits
o Liver: typically none but nausea, jaundice,
ascites
o Adrenal gland: typically none
o Bones: bone pain, elevated ALP and
calcium
NEOPLASTIC SYNDROMES
 Shared: dermatomyositis, acanthosis nigricans,
thrombocytosis and DIC
 NSCLC: hypercalcemia, gynecomastia,
hypertrophic osteoarthropathy
 SCLC: Cushing syndrome, SIADH, Lambert-Eaton
syndrome, cerebellar degeneration
DIAGNOSIS
 Solitary pulmonary nodule: <30 mm, well-defined
 Obtain chest CT and compare to previous scans
 Decision to perform serial imaging, PET/CT,
biopsy, surgical excision depends:
o Probability of cancer, surgical and biopsy
risk, patient’s desires and preferences
o Low risk: <8 mm, <40 age, no smoking,
lower/middle lobe, smooth border
o Intermediate risk: 8-20 mm, 40-60 age,
smoking, upper lobe, scalloped border
o High risk: >20 mm, >60 age, smoking,
upper lobe, spiculated border
IMAGING MODALITIES
 CXR: may show atelectasis, pleural effusion
o Adenocarcinoma in situ: hazy infiltrates
o SCC: cavitating lesion with air-fluid levels
 CT chest: IV contrast preferable
o Irregular margins, large size >2cm, upper
lobe location, absent calcifications
 PET/CT: occult lymph node involvement and
extrathoracic metastases
o False positives in inflammatory, infections,
granulomatous
o False negatives in small size <1cm
 Metastatic: MRI brain, PET/CT elsewhere
 Tissue biopsy: confirmatory test
o Bronchoschopy transbronchial, CT-guided
transthoracic are nonsurgical
o Mediastinoscopy, video-assisted
thoracoscopy, anterior mediastinotomy are
surgical
LAB STUDIES
 CBC – anemia, thrombocytopenia, neutropenia
 Chemistry – hypercalcemia, ALP, LFT
 Molecular testing and PD-L1 testing – metastatic
NSCLC
DIFFERENTIAL DIAGNOSIS
 Lung metastases, infectious granulomas
(tuberculosis, histoplasmosis, coccidioidomycosis),
inflammatory (sarcoidosis, granulomatosis with
polyangiitis)
TREATMENT
 Surgical resection with or without chemotherapy for
early-stage lung cancers (1-2A)
o Lobectomy, sublobar resection,
pneumonectomy
 Radiotherapy for inoperable early-stage disease
(poor pulmonary reserve or comorbidities)
 Stage IIb-IIIC requires multimodal with
chemotherapy, radiotherapy, surgical resection, and
immunotherapy
 Most diagnosed at advanced stage and therefore
palliatively with chemo and immunotherapy
BREAST CANCER
EPIDEMIOLOGY
 Peak incidence postmenopausal
ETIOLOGY
 Hormonal risk factors
o Increased exposure to endogenous estrogen
(high # of total menstrual cycles) 
nulliparity, absence of breastfeeding, early
menarche, obesity in postmenopausal
(lipocytes convert androstenedione to
estrone)
o HRT, hormonal contraception
 Individual
o Lower risk in men
 o Individuals of European descent higher risk
o Smoking, alcohol consumption, low-fibre
and high-fat diet
o Breast conditions with cellular atypia (e.g.
fibroadenoma), endometrial cancer
 Hereditary
o Family history
o Autosomal dominant mutations in BRCA1
and BRCA2 (tumor suppressor genes that
code for DNA repair protein)
o Mutations for receptor overexpression:
estrogen/progesterone, ERBB2
o Genetic conditions: Li-Fraumeni syndrome
(p53 mutation), Peutz-Jeghers syndrome,
Klinefelter syndrome
TYPES
NONINVASIVE
 Ductal carcinoma in situ (DCIS)
o Preceded by ductal atypia
o No penetration of basement membrane
o Grouped microcalcifications on
mammography
o Higher risk of ipsilateral invasive
carcinoma
o Histology: enlarged ducts lined with
atypical epithelium, neoplastic cells in
lumen, microcalcifications
 Comedocarcinoma
o Subtype of DICS characterized by central
necrosis
o Histology: high-grade nuclei, dystrophic
calcifications
INVASIVE
 Invasive ductal carcinoma (IDC)
o Most common type of invasive (~80%)
o Localization unilateral, mostly unifocal
o Aggressive formation of metastases
o Histology: disorganized, small, duct-like
glandular cells with stromal invasion,
surrounding fibrosis, microcalcifications
 Tubular subtype: tubular structures,
stromal invasion radial pattern
 Mucinous subtype: well-
circumscribed, copious
extracellular mucus
 Medullary breast cancer
o Rare subtype of invasive ductal carcinoma
o Well-circumscribed soft tumor with smooth
borders
o Usually triple-negative
o Lymphadenopathy
o Histology: large, poorly differentiated cells
with syncytial growth involving
lymphocytic and plasma cell infiltration
 Invasive lobular carcinoma (ILC)
o ~10% of all invasive
o Bilateral in ~20% of cases and frequently
multifocal
o Less aggressive than ductal
o Histology: monomorphic cells in single file
pattern due to decrease in E-cadherin
expression, absence of new duct formation
 Less common subtypes
o Mucinous carcinoma, mixed carcinoma
(ductal/lobular), tubular carcinoma,
papillary carcinoma, micropapillary
carcinoma
CLINICAL FEATURES
 Most commonly asymptomatic until later
 Early
o Single, nontender, firm
o Poorly defined margins
o Most commonly upper outer quadrant
 Locally advanced
o Changes in size/shape  asymmetric breast
o Retractions or dimpling (fixation of
pectoral muscles, deep fascia, Cooper
ligaments, and/or overlying skin)
o Peau d’orange
o Nipple inversion and blood-tinged
discharge
 Progressive
o Ulcerations
o Edema of arm
o Paget disease of nipple
 Lymphatic spread
o Lymphadenopathy (nontender, firm,
enlarged, fixed)
o Most commonly axillary and later
supraclavicular and/or infraclavicular
 Hematogenous spread
o Bone: pain, pathologic fractures, spinal
compression
o Liver: abdominal pain, nausea, jaundice
o Lung: cough, hemoptysis, dyspnea, chest
pian
o Brain: headaches, seizures, focal
neurological deficits
VARIANTS
 Paget disease of breast
o Lactiferous ducts and skin of nipple/areola
o Erythematous, scaly, or vesicular rash
affecting nipple and areola
o Pruritis
o Nipple retraction
o Ulceration that causes blood-tinged nipple
discharge
o Diagnosis: nipple tissue biopsy has Paget
cells
 Inflammatory breast cancer
o Dermal lymphatic invasion of tumor cells
o Peau d’orange (erythematous, warm,
edematous skin plaques with hair follicles
that resemble orange peel)
o Tenderness, burning sensation
o Usually no palpable mass
o Blood-tinged nipple discharge
o Diagnosis: clinical with core needle biopsy
confirming invasive carcinoma
DIAGNOSIS
 Most patients from routine mammography
screening; alternatively young women with self-
identified
 Low risk: <35 age, no family history, soft and
movable mass
  High-risk: >35 age, positive family history, firm
and rigid mass with irregular borders, skin changes,
fixation to skin or chest wall, adenopathy,
asymmetrical breast
RADIOGRAPHY
 <30 should undergo U/S (higher breast tissue
density makes detection with mammography
difficult)
 >=30 should mammography
 Breast U/S: homogenous vs. heterogenous texture,
fluctuant vs. firm and rigid structure, well-
circumscribed/smooth vs. irregular and poorly
defined, posterior enhancement vs. posterior
shadowing
 Mammography: well-defined, circumscribed vs.
focal mass or density; surrounding radiolucent ring
(halo) vs. poorly defined, spiculated margins;
diffuse microcalcification or coarse calcification vs.
clustered microcalcifications
 Concerns in both  fine needle aspiration or core
needle biopsy
BIOPSY
 Fine-needle aspiration (cytology)
o Preferred if low probability of malignancy
o Simple, fast, non-invasive, lesions close to
skin
o Small sample = high false-positive rate,
cannot distinguish noninvasive and invasive
o If potential, core needle biopsy
 Core needle biopsy
o Larger needle with image guidance
o Preferred if suspicious mass on U/S or
mammography
o Able to distinguish noninvasive and
invasive carcinoma, allows testing for
receptor status
o Invasive, local anesthesia required, higher
risk of complications
 Surgical biopsy/full-thickness skin biopsy if
inflammatory breast cancer or Paget disease
o Incisional (part) or excisional (entire)
o Only if CNB is not feasible or inconclusive
o Larger tissue sample for more accurate
o Highly invasive, general anesthesia
required, highest risk of complications
RECEPTOR TESTING
 Identifying receptor overexpression crucial for
treatment because targeted directly with hormone
therapy or biologics
 80% positive for overexpression at least one:
o Estrogen receptor (75%)
o Progesterone receptor (65%)
o Both (65%)
 20% positive for human epidermal growth factor
receptor 2 (HER2/neu, c-erbB2)
o Epidermal growth factor receptor with
intracellular tyrosine-kinase activity that
promotes cell growth and differentiation
and inhibits apoptosis
 10-15% triple-negative breast cancer
o Most commonly African American women
o Typically more aggressive, high-grade
tumors
METASTASIS
 Lymph node status: U/S and/or CT
 Set: CXR, CT-CAP, MRI of brain
o May show increased ESR, ALP, calcium
 Bone: MRI followed by bone scan if positive to
identify occult lesions
 Pleural effusion: thoracocentesis
DIFFERENTIAL DIAGNOSIS
 Benign: fibrocystic breast changes, gynecomastia
 Inflammatory: mastitis, fat necrosis, breast abscess,
eczema of breast
 Neoplastic: fibroadenoma, phyllodes tumor,
intraductal papilloma
TREATMENT
 Depends on histopathologic classification and
cancer stage
 Breast-conserving surgery
o Removal of cancerous breast tissue only
o Contraindications: large tumor-to-breast
ratio, multifocal tumors, fixation to chest
wall, involvement of skin or nipple,
subareolar location
 Mastectomy: removal of entire breast
o Total, skin-sparing, nipple-sparing, radical,
modified radical, double
 Intraoperative lymph node evaluation
o Sentinel lymph node biopsy if no clinical
signs
o Axillary dissection if signs present
 Radiation following surgery, for patients with high
risk of local recurrence
 Chemotherapy
o Indicated if >2cm, triple-negative breast
cancer and >=0.5, HER-2 positive and
>1cm, positive lymph nodes
o FEC-D: 5-fluorouracil PLUS epirubicin
PLUS cyclophosphamide, followed
docetaxel
 Hormone therapy
o All ER/PR-positive tumors
o Suppression of extraovarian hormone
production and blockade of estrogen
receptors to decrease risk of recurrence
o Premenopausal: tamoxifen, GnRH
agonists
o Postmenopausal: aromatase inhibitors
o Preventive: raloxifene
 Targeted therapy
o Trastuzumab: monoclonal antibody against
HER2 receptor  all HER2-postivie breast
cancer and gastric cancer
PROGNOSTIC FACTORS
 Large tumors, lymphatic spread, higher histological
grade, hormone-negative status, triple-negative,
advanced age, aneuploidy = worse prognosis
COLORECTAL CANCER
EPIDEMIOLOGY
 12% new cancer cases and 12% cancer deaths in
Canada
RISK FACTORS
HEREDITARY SYNDROMES
  Family (~25%) and personal history
 Familial adenomatous polyposis (100%)
 Lynch syndrome
 Rare genetic conditions: Turcot syndrome, MYH-
associated polyposis, juvenile polyposis, Peutz-
Jeghers syndrome, hereditary mixed polyposis
syndrome
 Personal history of breast, ovarian, uterine cancer
ASSOCIATED CONDITIONS
 Polyps or adenomas in colon and rectum
 IBD  hyperplasia  non-polyploid dysplasia 
neoplasia (UC, Crohn)
 DM2
LIFESTYLE
 Ashkenazi Jewish ancestry
 Sedentary lifestyle, obesity
 Alcohol, smoking
 Red meat, processed meat, high fat, low fibre
PROTECTIVE
 Aspirin and other NSAIDs
 Physical activity, rich in fiber and lower in meat
ETIOLOGY
 85% chromosomal instability pathway
o Accumulation in mutations that result in
hyperproliferative epithelium  adenoma
 carcinoma
o APC mutation (decreased intracellular
adhesion and increased proliferation) 
KRAS mutation (unregulated signaling and
cellular proliferation)  TP53 and DCC
mutation
 15% microsatellite instability pathway
o Accumulation in mutations that result in
sessile serrated adenoma  carcinoma
o Methylation or mutations in mismatch
repair genes (e.g. MLH1, MSH2)
 Other
o Hypermethylation phenotype pathway:
CpG island methylator phenotype. Global
hypermethylation of CpG islands 
silencing of MMR gene expression
o COX-2 overexpression: potential
protective effect of long-term aspirin and
NSAIDs
CLINICAL FEATURES
 Constitutional symptoms
 Right-sided colon carcinoma
o Cecum, ascending colon, transverse colon
o Occult bleeding or melena
o Iron deficiency anemia
 Left-sided colon carcinoma
o Splenic flexure, descending colon, sigmoid
colon, rectosigmoid junction
o Blood-streaked stools
o Changes in bowel habits (size, consistency,
frequency)
o Colicky abdominal pain due to obstruction
 Earlier than right-sided as distal has
smaller lumen and solid feces
 Rectal carcinoma
o <=15 cm from anal verge
o Hematochezia, decreased stool calibre
(pencil-shaped stool)
o Tenesmus (persistent but ineffectual urge to
clear rectum or bladder)
 Fecal incontinence
o Rectal pain
 Metastases
o Liver: ascites, abdominal distention,
hepatomegaly, RUQ pain, jaundice
o Lung: dyspnea, cough, hemoptysis
o Peritoneal: ascites, abdominal distension,
diffuse abdominal pain, bowel destruction
DIAGNOSTICS
 DRE
o Distal rectal cancers may be palpable
o Blood may indicate CRC
 Flexible sigmoidoscopy with or without anoscopy
o Consider with scanty intermittent
hematochezia and <40, no other risk factors
or red flags for CRC
 Complete colonoscopy
o Gold standard
o Typical findings: ulceroproliferative friable
mass + biopsy
 Double-contrast barium enema
o Cannot or decline colonoscopy
o Endoluminal filling defect, apple core
lesion due to stenosing CRC
BIOPSY
 Right-sided = mostly exophytic mass
 Left-sided = mostly infiltrating mass
 Adenocarcinoma 95%
 Less common: mucinous adenocarcinoma, signet
ring cell carcinoma, small cell carcinoma,
adenosquamous carcinoma
OTHER DIAGNOSTICS
 CT-CAP for spread
 Carcinoembryonic antigen (CEA) before treatment
and during follow-up to assess treatment response
 CBC, liver chemistries and coagulation
STAGING
 Stage 0: only in mucosa
 Stage 1: grown into submucosa or muscularis
propria
 Stage 2:
o A: into layer between muscularis propria
and serosa, or beyond muscularis propria
o B: through serosa/visceral peritoneum
o C: through wall of colon or rectum and into
other organs or areas, e.g. bladder/prostate
 Stage 3: cancer cells in lymph nodes near colon or
rectum, A-C depending on how many nodes
 Stage 4: metastatic
o A: 1 organ or distant lymph node
o B: more than 1 organ
o C: peritoneum
 Local (same) vs. regional vs. distant recurrence
TREATMENT
 Curative
o Complete resection of primary tumor
 Hemicolectomy, sigmoid
colectomy, subtotal or total
colectomy based on location or
underlying disease
 Transanal excision for early,
localized
 Low anterior resection,
abdominoperineal resection for
more advanced rectal cancer
o Regional lymph node dissection
o Resection of metastases, best for patients
with limited metastatic disease
 Palliative
o Nonresectable metastases to prevent
complications of CRC
o Intestinal bypass or enteral stenting for
obstructing/occlusive CRC
 Systemic
o Chemotherapy:
 Folinic acid (leucovorin), 5-
fluorouracil (5-FU), oxaliplatin =
FOLFOX
 FOLFIRI: same but irinotecan last
 CAPOX: capecitabine, oxaliplatin
o Biologics: may be added for metastatic
 Anti-VEGF antibodies (e.g.
bevacizumab)
 EGFR antibodies (e.g. cetuximab)
o Radiation: standard in rectal, but adverse
effects in colon  enteritis and strictures of
small intestine
FOLLOW-UP
 CEA level every 3-6 months, CT-CAP annually,
colonoscopy, proctoscopy/sigmoidoscopy if rectal,
for 5 years with colonoscopy continuing
 After 5 years, considered to be cured. Breast cancer
is not like this
PROGNOSIS
 Factors: stage (most important), surgical margins,
cells in lymph and blood vessels, CEA levels,
bowel obstruction or perforation, grade, type of
tumor (mucinous, signet ring, and small cell
poorer), microsatellite instability (more = better),
KRAS or BRAF gene mutation
PROSTATE CANCER
EPIDEMIOLOGY
 In men, second most common cancer after skin
cancer and second leading cause of cancer death
RISK FACTORS
 Age >50, family history, African-American
descent, genetic (e.g. BRCA2, Lynch syndrome)
 Sexual activity and benign prostatic hyperplasia are
NOT associated
PATHOPHYSIOLOGY
 Most common type: adenocarcinoma expressing
PSA
 Most common localization: peripheral zone
(posterior lobe) of prostate)
CLINICAL MANIFESTATIONS
 Early-stage typically asymptomatic
o Some found incidentally, e.g. patients that
require transurethral resection due to BPH
 Advanced-stage
o Constitutional symptoms
o Urinary: retention (prostate enlargement),
hematuria (terminal hematuria indicates
damage to vessels of bladder or prostate),
incontinence (tumor infiltrates urinary
sphincter), hydronephrosis (infiltration of
bladder ostium)  flank pain, renal failure
 Metastatic
o Most commonly pelvic lymph nodes,
osteoblastic bone metastases esp. in
lumbosacral spine due to Batson vertebral
venous system
o Bone clinical features
 Local pain and swelling
 Pathologic fractures (osteolytic)
 Spinal cord compression  pain,
motor and sensory deficits, bowel
or bladder incontinence
 Elevated serum calcium
o Lymphedema due to obstructing nodes 
swelling, pain, redness
DIFFERENTIAL
 Benign prostatic hyperplasia
 o Homogenous, rubbery, nontender prostate
Prostatitis
o Extremely painful, swollen, and tender
prostate
DIAGNOSIS
 DRE and PSA levels  if suspicious then multiple
transrectal, U/S-guided biopsies to confirm
 Digital rectal exam
o Normally smooth, nonfarm, symmetric,
heart-shaped, painless
o Early-stage localized indurated nodules
o Advanced-stage asymmetric areas, frank
nodules, still painless
o 30% sensitivity but 90% specificity
 PSA
o Serine protease splits semenogelin-1
protein and therefore liquefies semen
 Only produced by prostate gland
o Total PSA > 4 ng/mL suggests malignancy,
but can be elevated due to BPH, UTI,
prostatitis, trauma
o Screening is controversial but can be used
to monitor recurrence
o Not sensitive or specific
 Biopsy
o Microscopic appearance graded by Gleason
score from 2-10; higher = worse prognosis
STAGING
 Abdominal U/S and CT/MRI
 Spinal X-ray, detection of bone metastases as
hyperdense osteoblastic lesions
 Bone scintigraphy, contrast-enhanced MRI, PET
scan for bones as well
TREATMENT
 Based on age and life expectancy
 Early-stage
o Active surveillance or watchful waiting
(less intensive for elderly with slow-
growing tumors, limited life expectancy
due to other causes)
o Treatment only started if tumor progresses
 Advanced-stage
o Radiation therapy or radical prostatectomy
if localized disease
o Antiandrogen therapy if androgen sensitive
 Medical castration (GnRH agonists
(leuprolide) or antagonist (dagrelix)
+/- antiandrogen (flutamide,
bicalutamide))
 GnRH agonist transient
increase in androgen levels
for weeks then decrease
 Flutamide competitive
inhibition at androgen
receptors
 Surgical castration
o Chemotherapy with docetaxel
o Osteoclast inhibitors in bone metastases
 Castration-resistant prostate cancer
o Continue ADT
o Additional systemic therapy, including
chemo and immunotherapy
o IV zoledronic acid (bisphosphonate inhibits
osteoclast activity) every 3 to 4 weeks or
denosumab if asymptomatic bone
metastases to prevent fracture and
compression
o Palliative external beam radiotherapy for
symptomatic bone metastases
COMPLICATIONS
 From surgery or radiotherapy: erectile dysfunction,
urinary incontinence, infertility
 Radiation-specific: proctitis, enteritis, cystitis,
urethritis
PROGNOSIS
 Stage, grade, PSA level, smoking, high ALK-P and
lactate dehydrogenase; low hemoglobin and
albumin; genetic signatures
 Nearly 100% 5-year survival when 1, 2, 3, and 4
when cancer hasn’t spread to other parts of body
 Stage 4 and has spread to other parts, 28%
ONCOLOGIC EMERGENCIES
 Metabolic, hematologic, structural, or iatrogenic
TUMOR LYSIS SYNDROME
 Associated with hematologic, particularly acute
leukemia, and high-grade lymphomas
 Rapid, acute cell lysis; often associated with
chemotherapy
 Release of intracellular uric acid, phosphates,
calcium, potassium
 Commonly azotemia (elevated BUN and
creatinine), hyperphosphatemia, hyperkalemia,
hyperuricemia  cardiac arrhythmias
 Vigorous rehydration, maintain urine output, lower
uric acid levels
HYPERCALCEMIA OF MALIGNANCY
 Associated with multiple myeloma, breast cancer,
squamous cell carcinoma
 Can occur from humoral (PTH), bone invasion and
local osteolysis, and parathyroid carcinoma
 Progressive decline in mental function, weakness,
anorexia, thirst, constipation, nausea, vomiting,
decreased urine output
 Aggressive rehydration until euvolemia followed by
careful diuresis with furosemide
 IV bisphosphonates and newer monoclonal
antibodies inhibit osteoclastic activity
SIADH
 Associated with SCLC (ectopic source)
 Hyponatremia, concentrated urine, nausea,
vomiting, constipation
 Fluid restriction if slow or hypertonic saline if rapid
FEBRILE NEUTROPENIA
 Associated with current chemotherapy (highest-risk
are anthracyclines, taxanes, topoisomerase
inhibitors, platinums, gemcitabines, vinorelbine,
and alkylating agents)
 Sustained fever for one hour and absolute
neutrophil count <500 cells/mm3
 Get them in frequently to look at neutrophil counts;
if falling rapidly, then stop
 Rapid administration of empiric antibiotics
HYPERVISCOSITY SYNDROME
  Associated with Waldenstrom macroglobulinemia,
leukemia, multiple myeloma
 Elevated levels of circulating serum Igs coat cells
 increased viscosity, sludging of blood 
hypoperfusion
 Spontaneous bleeding, SOB, peripheral
neuropathies, ‘sausage-like’ hemorrhagic retinal
veins
 Plasmapheresis followed by targeted chemotherapy
SVCS
 Associated with lung cancer, lymphoma, metastatic
mediastinal tumors or lymph nodes, indwelling
venous catheters
 Gradual compression of SVCS where enters right
atrium  edema and retrograde flow
 Facial edema hallmark, cough, dyspnea at rest,
hoarseness, chest and shoulder pain
 Intravascular stenting
MALIGNANT EPIDURAL SPINAL CORD
COMPRESSION
 Associated with breast cancer, multiple myeloma,
lymphoma, lung and prostate cancers
 New-onset back pain, paraplegia more common
than sensory deficits, later cauda equina
(incontinence, saddle paresthesia)  Complete medical history, including toxic habits
 Steroids and/or surgery and radiation therapy  Physical exam head and neck, rectal/testes males,
MALIGNANT PERICARDIAL EFFUSION pelvic/breasts in females
 Associated with lung, esophageal, and breast  Labs
cancers; lymphoma; leukemia; melanoma o CBC, liver and kidney function,
 Dyspnea, chest pain, or palpitations; pulsus electrolytes, lactate dehydrogenase
paradoxus; Beck triad (muffled heart sounds, o Serum tumor markers: PSA only in males
hypotension, increased jugular venous pressure) with bone metastases; B-HCG and alfaFP
 Pericardiocentesis to rule out extragonadal germ tumor; alfaFP
TREATMENT-RELATED for hepatocarcinoma
 Chemotherapy  extravasation referring to liquid  Rest only useful for monitoring
leaking into surrounding tissues  Imaging
o Pain, erythema, swelling - - -> blanching, o CT-CAP
blistering, discoloration, necrosis o Mammography in cases of adenocarcinoma
 Radiation  CVD, esophagitis, cystitis, sexual in women
dysfunction, depression o PET recommended in patients with cervical
 Abdominal pain, nausea, vomiting, diarrhea, squamous-cell lymph node involvement
constipation, dehydration  Invasive
o Fluid resuscitation and use of antiemetics o Laryngoscopy (cervical lymph node)
and antidiarrheals followed by further o Bronchoscopy (hilar or mediastinal lymph
investigation node, or pulmonary symptoms)
o Gastroscopy (positive fecal occult blood
CANCER OF UNKNOWN PRIMARY SITE test or abdominal symptoms)
o Colonoscopy (positive fecal occult blood
 Metastatic tumors for which standardized test or abdominal symptoms)
diagnostic work-up fails to identify site of origin o Testicular U/S (retroperitoneal or
 IHC testing info about three aspects: mediastinal mass)
o Tumor lineage (carcinoma, melanoma, o Gynecologic U/S (pelvic or peritoneal
lymphoma, or sarcoma) metastases on biopsy)
o Subtype (adenocarcinoma, germ-cell, o Breast MRI: adenocarcinoma with negative
hepatocellular, renal, thyroid, mammogram and metastasis to axillary
neuroendocrine, squamous cell) lymph nodes
o Primary site of adenocarcinoma
PALLIATIVE MEDICINE

OVERVIEW
 Guiding principles
o Person- and family-centered
 o Death, dying, grief, bereavement are part of
life
o Caregivers are both providers and
recipients of care
o Integrated and holistic
o Access if equitable
o Recognizes and values diversity
o Improves QOL
o Is a shared responsibility
 Approach that aims to reduce suffering and improve
QOL for people with life-limiting illness
o Pain and symptom management
o Psychological, social, emotional, spiritual,
and practical support
o Support for caregivers during illness and
death of person they are caring for
o Needs-based, person- and family-centered
 Members of team
o Physicians, nurses, pharmacists, social
workers, psychologists, chaplains
APPROACH
 Consider patients with cancer or other high-
morbidity illness
 Frequently reassess the patient’s symptoms
 Discuss risk-benefit profile and goals of care prior
to initiating management of new complication
o Adjust or eliminate diagnostic and
therapeutic procedures that are too invasive,
painful, or other side effects not aligned
with patient’s wishes
OVERVIEW OF SYMPTOM MANAGEMENT
TYPES OF PAIN
 Nociceptive: damage to tissue
 Neuropathic: damage to somatosensory nerve
 Nociplastic: altered nociception despite no damage
 Emotional: mental suffering and impact of emotions
on experience of pain
APPROACH TO PAIN
 Maximize nonpharmacological therapy
o Spiritual and social services
o Physical interventions (therapy,
acupuncture, massage)
o Mental health interventions: CBT,
relaxation therapy
 WHO analgesic ladder to structure treatment
o 1. nonopioid analgesics only for mild pain
o 2. nonopioid analgesics and mild opioids in
moderate
o 3. nonopioid analgesics, mild opioids, and
strong opioids in severe pain
 Nonopioids
o First-line acetaminophen and NSAIDs
o Neuropathic: add gabapentinoids and
antidepressants
o Metastatic bone pain: add bisphosphonates
and denosumab (inhibit RANK-L),
consider external beam radiotherapy
 Opioids
o Most combination of regularly slow-
release, fast-acting as needed
o Parenteral followed by oral once controlled
GASTROINTESTINAL
 Nausea and vomiting: antiemetics, fluid therapy
 Constipation: optimize fluid and fiber intake,
consider stimulant laxatives
 Loss of appetite: dexamethasone or prednisolone
 Diarrhea: fluid and electrolyte replacement
PULMONARY
 Dyspnea: if cannot cure underlying, then low-dose
opioids and breathing/relaxation techniques
 Cough: expectorants (productive) or antitussive
(nonproductive)
CNS
 Anxiety and depression: benzodiazepines,
antidepressants, psychotherapy
 Delirium: antipsychotics, benzodiazepines
TERMINAL PHASE
 Discontinue unnecessary investigations, treatment
 Optimize mouth care and patient positioning
 Manage noisy terminal respiratory secretions
o Respiratory physiotherapy, repositioning,
anticholinergic drugs to reduce secretions
 Palliative sedation in select patients for refractory
distress or agitation
HOSPICE CARE
 Principles
o Preserve dignity of patients at final stages
o Provide maximum comfort
o Ensure pain relief (opioids, anxiolytics, or
sedatives)
o Prioritize positive effects over potential
negative effects, according to principle of
double effect
IADLS
 Activities which allow an individual to live
independently in a community
o Domains: cooking, cleaning, transportation,
laundry, and managing finances
o Not necessary for basic functional living
but can improve QOL
 Activities of daily living (ADL) domains
o Feeding, dressing, bathing, walking
o Necessary for basic functional living
 Scales
o Lawton and Brody IADL, Health and
Retirement Study Care Questionnaire,
Pfeffer Functional Activities Questionnaire
EXTRA
 Antimycobacterial drug notes
 Wound healing
 Inflammation
 Look at tutorial 1 objectives
 Types of leukocytes in amboss
 Understand DIC
 Neoadjuvant vs. adjuvant chemotherapy
TUTORIAL
 Macrophage and neutrophils can already exit
vessels
 Complement and antibodies beneficial with
permeability of vessels
 Carbon monoxide in smoke  hypoxic  poor
wound healing
 No longer shaving skin before surgical
 Bacteria use coagulase to activate clotting system to
make cap that hides from body
 Direct access from skin organisms during surgery
can form biofilms
 Bacteria gets into blood all the time. Hematogenous
spread to hips. Can form biofilms and protect
themselves
 Look at guidelines for broad-spectrum
 Culture (specific type) and sensitivity (antibody
profile)
o Give least expensive, least toxic, most
easily dosed antibiotic based on sensitivity
 In medicine, care about those that cause disease and
one that is most lethal
 Gram-positive rods: clostridium botulinum and
difficile, tetani are spore formers
 Unknown: want to cover gram-negative rods (late-
gen cephalosporin, tetracycline, aminoglycosides),
gram-positive cocci (amoxicillin or early
cephalosporin), anaerobes (clindamycin,
metronidazole)
 1st-2nd gen, mostly gram+; 4th-5th gen, mostly gram-
 Good for gram+ coverage after surgery because
most on skin is gram+
 Asymptomatic bacteriuria don’t treat in most pops,
some like pregnant yes
 Spleen, unable to protect against encapsulated
pathogens
 Lactic acidosis due to hypoperfusion (shock) even
when well-oxygenated, not due to hypoxemia in the
context of good perfusion
o In males, most metabolically active
contributor is muscle
 MHC I is flagpole – helps to differentiate self from
abnormal (virus, bacteria, cancer)
 Klebsiella in pneumonia, common in alcoholics
 In males, anemia
o Rule out GI bleed
o Malnutrition, e.g. chronic disease
 Bone marrow biopsy – anemia of chronic disease –
see lots of iron/blue
 Viral infections:
o CD8 mainly, NK if MHC I underexpressed
o Antibodies neutralize virions
 Proportion of HSV1, HSV2, VZV can become
fulminant (hepatitis, encephalitis, etc.) and cause
death – so worried
o Prodromes (from ganglia activate nerves) –
prodromes (itchy, burn, itch) – take
antiviral therapy to prevent outbreak
o Have to be really careful – if infected, be
careful where to touch (auto-inoculate esp.
eyes or spread to other people)
 EBV and CMV give lymphocytosis (can be
confused with leukemia)
 HL = lymphatics; NHL = hematogenic spread
(worse prognosis, more involvement of extranodal
organs)
 DIC in sepsis causes petechiae because low
platelets – used up and being destroyed in
vasculitis?
 Brain and testes = privileged places = affects
treatment for cancer spread
 Pap smear frequency may decrease as HPV
vaccinations increase
 Most evidence on risk factors for disease come
from prospective cohort (Rochester, Framingham)
o Look at magnitude of risk ratio
o Control for other risk factors
o Assess absolute risk
o Prevalence of disease – do we care about it?
 BRCA1 and BRCA2 increased risk of breast,
ovarian, and pancreatic + prostate in males
 Fibrosis could be from occupational exposure or
radiation for malignancy
 Pre-test probability for colorectal cancer same for
postmenopausal women (no reason to be iron-
deficient)
 Stored in distal colon - mix of inflammatory stuff
and carcinogens
 Obesity risk factor: chronic inflammatory state,
insulin and IGFs (growth factors) are permissive,
hyperglycemia
 Radiation to colon: bacteria may enter blood, small
intestine complications
 Liver and lungs are both filters - get metastasis here
 Side effect of morphine-related substances:
constipation
 Spinal cord compression: young most common
trauma, old most common cancer
 Glucocorticoids = anti-inflammatory for both mass
and radiotherapy; catabolic hormone
 Why no PSA?
o Not specific
o Does not change management/outcomes,
including mortality and morbidity
o Costly when diagnosis and treatment
afterwards, also complications
o Decreases QOL because of investigations