Unit 3b Flashcards
3 clinical features of infantile hemangiomas:
- When does it occur?
- rate of growth
- male or female?
- Appear by 2 months of age, or at birth
- Grow rapidly over first few months up to a year, then involute slowly (10% per yr)
- Occurs more in girls
Complications of infantile hemangiomas: Location-> Size-> Ulcerations-> Multiple hemangiomas->
Location → interrupt visual field or have other ocular problems, lip, nasal tip, ear, breast, and anogenital area may cause issues
Size → distort normal tissue and interfere with function
Ulcerations → infection and pain
Multiple hemangiomas → possible visceral hemangiomas (on liver, GI, lungs, CNS)
Systemic complications possible
EX of congenital syndrome associated with infantile hemangiomas
PHACES
Histology of infantile hemangiomas
Dermal proliferation of capillary-sized endothelial cell-lined vessels
Stain with Glut-1 (placental antigen)
Clinical features of cherry hemangiomas (5)
a. Most common vascular feature in adults
b. Benign
c. Primarily on trunk
d. Typically multiple (maybe hundreds)
e. Bright red, smooth-topped papules, small (1-4 mm in size)
Complications of cherry hemangiomas
NONE except for trauma
Clinical features of port wine stain (4)
a. DO NOT resolve spontaneously, may worsen
b. Present at birth and grow in proportion to growth of patient
c. May follow distribution of trigeminal nerve in face
d. Do NOT stain with Glut-1
Complications of port wine
a. Associated with varicose veins, venous stasis, edema, ulceration
b. Associated with systemic abnormalities
2 Systemic abnormalities associated with port wine stains
- Sturge Weber syndrome- V1 port wine distribution
2. Klippel-Trenaunal syndrome- large port wine on limb, overgrowth of extremity
Sebaceous hyperplasia clinical features: (6)
- tumor of?
- age
- induced by
- distribution
- description
- TX
a. Common benign tumor of oil gland
b. Higher frequency after middle age
c. Sunlight induced?
d. Distribution = face > trunk > extremities
e. Yellowish-white papule (globules) with central dell (1-6 mm)
f. No treatment needed
Nevus sebaceous clinical features
- Papillomatous, yellow-orange linear plaque on the face or scalp
i. Scalp → associated with alopecia
ii. Hairless
- Rapid growth during puberty with enlargement of sebaceous glands and epidermal hyperplasia
Complications of nevus sebaceous (2)
a. Epidermal nevus syndrome (neurologic abnormalities)
b. Epithelial neoplasms in 10-30%
Nevi
Moles
Intradermal nevus
nests exclusively within dermis
Clinical features of intradermal nevus (4)
- area affected
- description
- color
- size
i. Head and neck most common
ii. Papule or nodule
iii. Skin colored to tan to light brown
iv. Less than 6 mm
Junctional nevus
nevus cells at dermal-epidermal junction just above basement membrane zone of epidermis
Clinical features of junctional nevis (3)
- description
- size
- location
i. Darkly pigmented (tan, brown, black) , flat, smooth
ii. 1-5 mm macule
iii. Located anywhere - esp on plantar and palmar surfaces
Compound nevus
melanocytes assimilate into dermis
Clinical features of compound nevus (6):
- nests located where in skin
- areas affected
- size
- color
- age
- TX
i. Nests present at dermal-epidermal junction AND within the dermis
ii. Located on trunk and proximal extremities
iii. Less than 6 mm
iv. Tan, brown, black
v. any age and on any skin surface
vi. Only treat if malignant
Blue nevus (3)
- Dermal proliferation of melanocytes that produce abundant melanin
- Blue color due to optical effect
- Blue to gray/white papule or nodule
Congenital nevi (3)
- Dermal proliferation of melanocytes that produce abundant melanin
- Blue color due to optical effect
- Blue to gray/white papule or nodule
Café-au-lait macules (3)
- Subtle increase in # of melanocytes and melanin production
- Congenital or early childhood
- Can be associated with NF
Clinical features of neurofibroma (4)
- description
- “___” sign
- path
- Multiple->
a. Soft, flesh colored papules
b. “Button hole sign”
c. Focal proliferation of neural tissue within the dermis
d. Multiple → neurofibromatosis
Neurofibromatosis
defect in neurofibromin tumor suppressor gene (NF-1), AD/sporadic
Acrochordon (4)
- aka Skin Tags (most common fibrohistiocytic tumor of skin)
- Occur in areas of rubbing: neck, axilla, inframammary area in women
- Benign, no malignant potential
- Soft, flesh colored
Dermatofibroma:
a. common?
b. description
c. age
d. area affected
e. “__” sign
f. Could represent larger/enlarging lesion that is malignant ->?
a. Second most common fibrohistiocytic tumor of the skin
b. Brown, firm, papules (3-10 mm)
c. Occur in adults (acquired)
d. Common on legs
e. “dimple sign” with pinching of lesion
f. Could represent larger/enlarging lesion that is malignant = Dermatofibrosarcoma protuberans (DFSP)
Complications of dermatofibroma
pain, pruritus
Seborrheic keratosis:
- tumor of?
- shape
- description
- areas affected
- age
Benign tumor of the hair follicle
b. Oval, slightly raised
c. Light brown-black papules or plaques (less than 3 cm)
d. Common on chest and back (also, scalp, face, neck, extremities - but NOT palms and soles)
e. Begins in 40s or 50s
Dermatosis papulose nigra
subtype of seborrheic keratosis
small, pigmented seborrheic keratoses usually occurring
on the face of people with Fitzpatrick skin type V or VI.
MORGAN FREEMAN
Lipoma (4)
i. Benign tumor of adipose tissue
ii. Most common form of soft tissue tumor
iii. Soft, movable, painless
iv. No treatment or surgical excision
Keloid scar (4)
i. Type III or Type I collagen
ii. Overgrowth of granulation tissue at site of healed skin injury
iii. Firm, rubbery lesions
iv. Grow beyond boundaries of original wound
3 endothelial cell skin growths
i. Hemangioma
ii. Cherry Angioma
iii. Port Wine Stain
5 melanocyte derived skin growths
i. Nevi
ii. Melanoma
iii. Ephelides = freckles
iv. Lentigo = sun spots
v. Cafe au lait macule
Indications for treatment of nevi (5)
- Atypical-appearing nevus
- Atypical evolution (growth, color, symptoms)
- Irritated nevus (e.g. by rubbed clothing)
- Indistinct margins (fuzzy)
- ABCDE, ugly duckling
Impetigo Clinical Features (3)
Most common SUPERFICIAL bacterial infection of children
Acquired by person-to-person contact
Predisposing factors - high humidity, cutaneous carriage, poor hygiene
What bacterial can cause impetigo? (2)
Streptococcus pyogenes
Staphylococcus aureus
Streptococcus pyogenes is a gram _______ bacteria
Where does it appear?
In whom?
What does it look like?
positive, in chains
Most commonly on face
In children
Honey-colored yellow crust
Staphylococcus aureus is a _________ bacteria.
Where does it appear?
In whom?
What does it look like?
gram +, in clusters
Most commonly on face
Any age
Yellow to amber-colored crust with erythema
Cellulitis Clinical Features (5)
Most common in very young, elderly, immunocompromised, or patients with chronic ulcers
Deeper soft tissue involved
Post-surgical complication
More during the summer
Infection occurs through skin breaks (can be microscopic)
What bacteria can cause cellulitis? (2)
β-hemolytic streptococci
Staphylococcus aureus
β-hemolytic streptococci typically causes the facial variant of cellulitis called __________. It manifests with _________ and ____________
Erysipelas
Cliff-drop border
regional lymphadenopathy
Staphylococcus aureus typically causes cellulitis that is … (5)
- Tender
- ill-defined
- erythema
- lymphatic streaking common
- lymphadenopathy may be present
Dermatophyte Infections
Infections acquired from humans, animals, fomites, and soil
Eat keratin - hair, nails, skin
aka “ring worm” -manifest in ring patterns
e.g. tinea capitus, corporus, pedis, cruris (genital)
Diagnosis of Dermatophyte infections
Diagnose with KOH exam of skin scrapings, hair or nails → look at hyphae in stratum corneum
What are dermatophytes and what do they eat?
fungi that require keratin for growth
Trichophyton mentagrophytes = common cause of __________
tinea pedis
Trichophyton tonsurans = common cause of ___________
tinea capitis
hairless, circular grey patch, possible associated lymphadenopathy
Microsporum canis = common cause of _______________
fluorescent tinea capitis
Epidermophyton floccosum = common cause of ___________
tinea cruris (infection of genital region)
“Socks and Jocks”
Candidiasis is caused by __________ ( fungi) which eats _________ causing ____________
Candida albicans
glucose or serum
deeper infections
Candidiasis clinical features
1) common where?
2) common in who?
3) Is Candida normal?
4) Appearance of candida infections?
1) Commonly affects mucous membranes and skin
2) Common in patients with diabetes, occlusion, corticosteroid or abx use
3) Candida is a normal microflora of the GI tract that can overgrow in certain diseases or treatments
4) Mucoid, white, non-scaly lesions or can be bright red diaper rash beyond boundaries of diaper with satellite pustules
How to diagnose candidiasis
KOH study → organisms appear as pseudohyphae or yeast
Tinea (pityriasis) versicolor (4)
where in the world?
in what kind of patients?
where on the body?
Appearance?
1) More common in humid/warm climates (but is distributed worldwide)
2) Only in post-pubertal patients
3) Primarily truncal
4) Asymptomatic, variably colored, scaly macules (can develop into patches)
Tinea versicolor is caused by ___________ which eats ________
Malassezia furfur (yeast on the skin)
Eats oil! → distributed in oily parts of our body, very superficial
Scabies
who is effected? how does it spread? what does it feel like? where is it located? when is it worse?
1) Affects all ages and races
2) Mites spread ONLY by person-to-person contact
3) VERY itchy
4) Symmetric with characteristic appearance in interdigital WEBSPACES (hands, flexural portion of wrist, waist, axillary areas, genitalia, buttocks)
5) Worse at night and with hot baths/showers
What infectious agent causes scabies?
specific to whom?
lifecycle?
Sarcoptes scabiei var hominis
Highly host specific mite confined to humans
30 day lifecycle in epidermis → lay 60-90 eggs → mature in 10 days
Head lice
- Scalp, behind ears, nape of neck
- Intense pruritis
- Nits = tan-brown, oval eggs attached to hair shafts
Body lice
Lice only found ON CLOTHES, except during feeding
Intense pruritis
Erythematous papules and macules
Usually on trunk
Crab lice
Limited to hair of genital area
Intense pruritus of genital area
Attached to base of hairs
Pediculus humanus (capitis)
bloodsucking, wingless insect (lice), prefers scalp
Pediculus humans (corporis)
lice that prefers the body
Phthirus pubis
crab lice that prefers short corse hairs of the genital area
Tzanck smear
Scrape ulcer, look for giant multinucleated (Tzanck) cells
Shows presence of Herpes simplex/zoster, pemphigus vulgaris
Gram Stain in derm diagnosis if infections
Used for bacterial infections - cellulitis (rarely), impetigo (Gram + strep/staph)
KOH prep in diagnosis
Dermatophyte infections?
Candidas?
Tinea Versicolor?
1) potassium hydroxide examination of skin scrapings, hair, or nails
2) Take sample from leading edge → put KOH drop on it → reveals fungus
Dermatophyte Infections →
Long branching, septate hyphae in stratum corneum
Candidas → organisms appear as pseudohyphae or yeast
Tinea Versicolor → spaghetti and meatballs (short hyphae and yeast)
Mineral oil (wet prep)
Scabies → small drop of mineral oil placed on skin, gently scraped and examined under a microscope for evidence of infestation (mites, eggs, or feces)
Fungi
Eukaryotes
Lack chlorophyll (nonphotosynthetic)
Saprophytes (eat dead stuff) or parasites
Life cycle: spores → spore germination → mycelium → mushroom primordia → mature mushroom
Ointments
benefits? (3)
negatives? (1)
best for what part of the body?
Benefits:
1) hydrating, emollient, protective
2) Low risk for sensitization or irritation
3) delivers active ingredient with strong potency
Negatives:
1) Greasy can stain clothing
Best for NON-intertriginous sites
Ointment composition
water (20%) in oil (80%) emulsion
Cream composition
oil (50%) in water (50%) emulsion
Cream: +/- (4)
- Hydrating (not as much as ointments)
- High sensitization risk, low irritation risk
- Amenable for most body areas
- Delivers ingredient with moderate potency
Gel composition
semisolid emulsion in alcohol base
Gel:
Benefits? (1)
Negatives? (2)
Best for use in which areas? Which areas should you avoid?
Benefits:
1) Delivers active ingredient with strong potency
Negatives:
1) High sensitization risk, high irritation risk
2) Drying
Oral mucosal surfaces and scalp
Avoid gels on fissures, erosions, or macerated areas (alcohol in gel will burn)
Lotions/Solutions composition
powder in water (some oil in water)
Lotions/Solutions:
+/- (3)
best for use in which areas? Which areas should you avoid
1) Variably drying
2) Delivers active ingredients in low potency
3) High sensitization risk, moderate irritation risk
- Scalp and intertriginous areas amenable
- Do not use on fissures or erosions
Foams composition
pressurized collections of gaseous bubbles in a matrix liquid form
Foams are good for which areas?
Hair-bearing areas
Foams
- Stable at room temp, melts at body temp
- After application, volatile components quickly evaporate, while lipid and polar components containing supersaturated active ingredients remain
→ Deliver active ingredients with very strong potency
Quick-drying, stain-free, no residue
Water-based vehicles may be contraindicated because…
water-based vehicles (creams, lotions, solutions): contain preservatives that may increase risk of contact allergy and sensitization
Alcohol based gels or acidic vehicles may be contraindicated because…
notable irritancy
FTU = ?
Finger Tip Unit
=0.5 g
1 gram of cream covers…
10 cm x 10 cm of body area; ointment is more efficient
How many FTUs/grams needed?
One hand both sides = ? One arm = ? One foot = ? One leg = ? Trunk, front or back = ? Face and neck = ?
One hand both sides = 0.5 g (1 FTU)
One arm = 1.5 g (3 FTU)
One foot = 1 g (2 FTU)
One leg = 3 g (6 FTU)
Trunk, front or back = 3.5 g (7 FTU)
Face and neck = 1.25 g (2.5 FTU)
Topical Corticosteroids Classified into _____ classes, with ___ being the most potent, _____ being medium potency, and _____ being low potency
7 classes
1-3 = high potency
4-5 = medium potency
6-7 = low potency
Hydrocortisone 2.5% = “?”
class _____
efficacious for ______
what areas of the body?
“The Gently Touch”
Class 7 (low potency)
mild eczema (inflammatory dermatoses) in children and adults
face, intertriginous areas, groin
Triamcinolone Acetonide 0.1% = “?”
Class ____
Effective against _____
Use on _______ but NOT __________
“The Almost All-Purpose Weapon”
Class 4
Effective against moderate spongiotic dermatoses (eczematous dermatitis, atopic dermatitis, allergic contact dermatitis, arthropod bite)
-trunk and extremities
Long term use NOT recommended on face, intertriginous, and groin regions
Clobetasol Propionate 0.05% = “?”
Class _____
Effective against ______
NOT for _______
“Hercules”
Class 1 (high-potency)
Treatment for acute eruptions that need rapid amelioration (contact dermatitis, acute drug eruptions)
- NOT for face, intertriginous areas, or groin
- Long-term use requires monitoring
General Considerations for Selecting a Topical Steroid (3)
1) Severity of condition, location of lesion, need for hydration/drying effect
2) Potential for sensitization or irritation of certain types of vehicles
3) The same active GC steroid ingredient in an ointment may be more potent that the same ingredient in a cream, lotion, or solution vehicle
Adverse effects of GC steroids
More potent = greater adverse effects - consider vehicle as well (ointment>cream)
Skin atrophy: associated with long term use of potent/super-potent topical steroids
Systemic side-effects with potent/super-potent topical steroids
-Adrenal suppression, Cushing’s syndrome, growth retardation in children
UV-B
(280-320 nm) is responsible for most effects of sunlight on the body (sunburn, tan, VD3 synthesis, immune system effects)
UV-B absorbed in superficial tissue layers of 0.1 mm depth
Shorter, higher energy UVB wavelengths → act on keratinocytes, melanocytes, and Langerhans cells
Longer UVA wavelength
penetrate deeper dermis, damage fibroblasts and connective tissue
Which UV associated with skin cancer?
UVA and UVB both associated with skin cancer formation, UVA operates via different mechanisms
UV radiation effects on skin (6)
- damage DNA, RNA, lipids, and proteins
- Pro-inflammatory effects
- Immunosuppressive effects
- Induction of innate defense
- Induction of apoptosis
- Vitamin D synthesis
3 types of UV induced DNA damage
a. Thymine dimer (UVB) → problems with replication
b. Pyrimidine-6-4 pyrimidone (UVB)
c. Hydroxyguanosine (UVA)
UV induced proinflammatory effects
- UVR induces leukocyte migration into the skin
- Cytokines + lipid mediators
a. IL-1, TNF, IL-6, IL-8, IL-10, GM-CSF, histamine
b. PAF, PGE2, LTB4
c. GFs and Progression factors: MSG, ET-1, VEGf, MIA
UVR and immunosuppressive effects (4)
a. Decreased # of Langerhans Cells
b. Induce inhibitory cytokines (IL-10, Th2)
c. Tolerance induced by suppressor cells (Treg, CD4+, CD25+) and Natural Killer Cells (NKT)
d. Induces keratinocyte release of Plasminogen activating factor and cis-urocanic acid
PAF and cis-uronic acid cascade
Cis-UCA → mast or B cell production of IL-10
PAF → prostaglandin E2 → B cell IL-10 production
IL-10 → inhibit IL-12 production
→ T cells not activated to CTLs
Vitamin D metabolism in skin
i. UVR induces non-enzymatic synthesis of cholecalciferol (VitD3) and ergocalciferol (VitD2) from pre-D3/D2
- Dietary supplements contain VitD2 and D3
ii. D2 / D3 converted to active form in liver and kidney → Di-hydroxy Vitamin D3 = important systemic active form
SPF
Sun Protective Factor (refers to UVB rating)
i. Best sun block = UVB and UVA
ii. FDA says sunscreen > SPF15 not necessary ……NOT CORRECT!
1. Photosensitive patients, skiers, patients with cancer risk need more
Composition and effects of solar radiation
UVA (400-320 nm), UVB (320-280 nm), and UVC (280-100 nm)
i. UVR only 1% of the sun’s total radiative output
ii. UVC and shorter wavelengths absorbed in the upper and middle atmosphere
iii. Longer wavelength = lower energy
UVA AND UVB associated with
melanoma
UVA associated with
Causes premature aging, loose skin, wrinkles, dark patches, and DNA damage
ii.Deeper penetration (longer wavelength) → fibroblasts, vessels, connective tissue damage
UVB associated with
- Sunburns
- Eye damage
Shallower penetration (shorter wavelength) → keratinocytes, melanocytes, Langerhans cells damage
4 skin defenses against UVR
- DNA repair
- Apoptosis of cells with DNA damage
- Defense against ROS in epidermis
- Melanin
DNA repair of UV DNA damage
excision of mutated strand of DNA by UVR ABC nuclease
Defenses against ROS in epidermis (4)
- Peroxidases and catalases
- Superoxide dismutase
- Glutathione reductase
- Thioredoxin reductase
UVR immunosuppression NOT inhibited by
high melanin content and will still potentiate induction of NMSC
Melanogenesis
i. Melanin produced by melanocytes
- In basal layer of skin
- Deposit melanin into keratinocytes via dendritic processes
- Functional “slaves” to keratinocytes
ii. Synthesized in melanosomes (intracellular organelles)
iii. Synthesis of melanin results in generation of free radicals → must limit melanin biosynthesis to melanosomes
iv. Increased UVR detected by keratinocytes → increased melanogenesis and melanocyte proliferation
Skin cancer
- Melanoma
- Non-Melanoma
a. Basal Cell Carcinoma
b. Squamous Cell Carcinoma
Photodermatoses caused by UVR
- Idiopathic (immunologic?) solar urticaria
- Diseases associated with photosensitivity to photodermatoses:
a. DNA repair defects (XP) → UVR induced skin cancers
b. Chemical photosensitivity (drug induced, porphyria)
c. Photoaggravated dermatoses (psoriasis, atopic dermatitis)
d. Connective tissue disease (Lupus Erythematosus, Dermatomyositis, Mixed connective tissue disease)
UV phototherapy
i. Treatment of extensive psoriasis, atopic dermatitis
ii. Cutaneous T cell lymphoma
iii. Mastocytosis
iv. Repigmentation of vitiligo
Basal Cell Carcinoma (BCC)
- Rarely fatal, can be highly disfiguring if allowed to grow
- Pink/red, pearly/shiny
- Most BCCs have hedgehog pathway mutation
Squamous Cell Carcinoma (SCC)
- Precursor for SCC is Actinic Keratosis
- Hyperkeratotic papule, variable size and thickness
- Typically found on sun damaged skin
-Metastasis in 0.3-5% (metastasis more common in SCC of lip)
[Something by lip, think SCC!]
Types of SCC (3)
SCC in situ
Keratoacanthoma
Invasive SCC
SCC in situ is an abnormal ________ located ONLY in the ________
keratinocyte
epidermis
Keratoacanthoma
appearance, growth, location?
- Primarily on sun-exposed skin
- Rapid growth over 6-8 weeks (but not that aggressive)
- Crateriform endophytic and exophytic nodule with central keratin plug
How to identify melanoma
ABCDE: Asymmetry, Border irregularity, Color variation, Diameter (> 6 mm), Evolution (or change)
The Ugly Duckling
Can appear black/dark
Melanoma Locations:
Blacks
Men
Women
Blacks - acral and mucosa
Men- back
Women - legs and then torso
Incidence of BCC
Most common malignancy in the US
2.3 million diagnosed in US annually
Incidence of SCC
Second most common cutaneous malignancy
More common in transplant patients/immunosuppressed
Incidence of Melanoma
- 76,100 new melanomas diagnosed, 9,710 expected to die of melanoma
- One person dies of melanoma every hour
- Most common form of cancer in young adults (25-29)
- Melanoma cancer incidence is increasing!
Risk factors for non-melanoma skin cancer
Fair skinned individuals in geographic areas with higher UV exposure
Also occur after ionizing radiation, arsenic, or polycyclic hydrocarbon exposure
BCC risk factors
UV radiation most common cause
10x risk of BCC in transplant pts
SCC risk factors
UV damage, thermal injury, radiation, HPV, burn scars, and chronic injury
Occurs more in immunosuppressed patients (65x risk of SCC)
Melanoma risk factors
Fair skin Excessive sun exposure Immunosuppression: 3.4x risk (e.g. transplant pts) MM in first degree relative Whites Large congenital nevus (>20cm) Sporadic dysplastic nevus syndrome **FAMMM (148x risk) - lots of moles genetic predisposition
Actinic Keratoses (AKs)
precursors to squamous cell carcinoma (SCC)
Intraepidermal neoplasia
Most common precancer (Affects 58 million Americans)
65% of SCC and 36% of BCC begin as AKs
Patch1 mutation is common in ________ and can be treated with _________
BCC
Vismodegib
PTCH1
tumor suppressor protein
PTCH1 normally acts to block smoothened (SMO) → SMO goes unchecked and signals cell growth
Vismodegib
inhibitor of SMO for treatment of PTCH1 mutation in BCC
Approved for metastatic or inoperable BCCs
Not a permanent cure - excision is best
Expensive
BRAF Mutation is common in ________ and can be treated with __________
melanoma
Vemurafinib
BRAF
mutation in BRAF activates cell growth and proliferation
mutation present in majority of normal moles
–> mutation persists when they turn into melanoma (in 50%)
Vemurafinib
inhibits melanomas with BRAF mutation
Can combine with MEK inhibitors (in BRAF pathway) and C-KIT inhibitors
Melanoma is a neoplastic proliferation of _______
melanocytes
Breslow Depth
Tumor invasion in millimeters
Best prognostic factor
Clark’s Level
I - Epidermis II - Papillary Dermis III - Mid Dermis IV - Reticular Dermis V - Subcutaneous fat
Treatment for premalignant skin tumors (actinic keratosis)
Cryosurgery (liquid nitrogen) Topical 5-fluorouracil Topical Imiquimod Topical Diclofenac (non-steroidal) Photodynamic therapy Sun protection
Treatment for non-melanoma skin cancer
Cryosurgery (liquid nitrogen) Topical 5-fluorouracil Topical Imiquimod Electrodessication and Curettage Excision Mohs micrographic surgery Radiation
Treatment for melanoma skin cancer
Surgical excision with margins increasing with size of melanoma
Can include sentinel node biopsy
Infection
microbe entering into a relationship with the host
May or may not cause disease
Infectious disease
disease caused by an infection with a microbe
i.Can be communicable (transferred person-to-person) or noncommunicable (not transmitted patient-patient)
Etiologic agent
organism responsible for disease manifestations
Can be direct (direct damage to tissue) or indirect (host immune response)
Pathogenicity and two types
ability to cause disease/damage a host
i. Frank pathogens = cause disease readily in normal hosts
ii. Opportunistic pathogens = cause disease primarily in compromised hosts
Virulence
degree of pathogenicity, capacity to cause damage in a susceptible host
ii.High virulence → cause disease when introduced into a host in small numbers
Measuring Pathogenicity/Virulence of Microbes and/or Susceptibility of Host:
Number of organisms it takes to causes disease
- Dose-Response Curves - compares virulence of bacterial isolates
ii. Route of infection can cause virulence/pathogenicity to vary (minimally infectious dose)
iii. Genetic differences in host can vary virulence
Koch’s postulates (4)
1) Specific microbes present regularly in characteristic lesions of the disease
2) The specific microbes can be isolated and grown in vitro
3) Injection of cultured microbes into animals reproduces disease seen in humans
4) Specific microbes can be re-isolated from lesions of disease in animals
Limitations to Koch’s postulates (3)
- Some infections diseases do not have a characteristic lesion
ii. Some microbes cause specific infectious diseases but cannot be grown in vitro
iii. Traditional concepts of pathogenicity focus on properties of microbes vs. hosts Indirect tissue damage) - Can also reflect complex interactions between microbes and their host
6 stages of pathogenesis
- encounter
- entry
- spread
- multiplication
- damage
- outcome
Encounter stage of pathogenesis
agent meets host
- Source: endogenous, exogenous
- Route of infection
- What is infectious dose
Entry stage of pathogenesis
agent enters host
- Active (invasion) or passive injection
- Colonization of body surface: 1st step in pathogenesis of many microbial infections
- Adherence: specific binding of microbial surface components (pili or non-pilus adhesions) to host receptors on tissues
Spread stage of pathogenesis
agent spreads from site of entry
- Inhibited or promoted by microbial products
- Spreading Factors: hyaluronidase, elastase, collagenase → facilitate spread of microbes through tissues
- Anti-Spreading Factors: coagulase → promotes deposition of fibrin → helps wall off and localize infection
Multiplication stage of pathogenesis
agent multiplies in host
1.Replication must exceed clearance by defense mechanisms
Damage stage of pathogenesis
tissue damage caused by agent or host response
- Virulence Factor
- Direct damage to host - microbial toxins, bacterial enzymes
- Block or interfere with host defense - antiphagocytic capsules, leukotoxins
Outcome stage of pathogenesis
agent or host wins, or they coexist
Acquired host defense to antigens
antibody production, lymphokine-mediated functions, complement-mediated lysis, opsonophagocytosis
Defense: multiplies inside tissue cells (most viruses
prevent entry of microbes into cells with antibodies
Defense: multiplies inside phagocyte cells (certain viruses)
T cells generate lymphokines that activate phagocytes and render them resistant to infection
Defense: multiplies outside cells (most bacteria)
kill microbe extracellularly (complement-mediated lysis) or kill microbe intracellularly (opsonized phagocytosis)
Defense: attach to body surface
Prevent attachment with IgA
Microbiome can vary with (4)
- Diet
- Suppression of microbial flora with abx
- Anatomic abnormalities
- Genetic differences between individuals
Important functions of Microbiome (4)
- Effect tissue/organ differentiation
- Produce vitamins (gut flora)
- Biochemical conversions (drug metabolism, bilirubin degradation, formation of potential carcinogens)
- Competition with pathogens for colonization of body surfaces (conversely, also source of endogenously acquired infections)
Cholera
toxin mediated disease pneumonia
i.Alters secretory function of SI, but does NOT cause histological damage
Pneumococcal
acute inflammation caused by bacterial pathogen that grows extracellularly
Tuberculosis
chronic disease caused by a facultative intracellular bacterium and controlled by cell-mediated immunity
Rheumatic fever
Disease resulting from immunopathology triggered by response to a prior group A strep infection
1.Protective Ab made in response to strep infection → cross reactive antibodies that bind heart valve antigens and initiate complement
Basic properties of viruses (5)
i. Submicroscopic, obligate intracellular parasites
ii. Virus particles themselves are not alive and do not grow/undergo division
iii. In appropriate host cell, viral genome is replicated and directs synthesis of viral components that will be assembled to form progeny viruses
iv. Particles produced from self-assembly of newly-synthesized components within host cell
v. New virions produced transport viral infection to another host cell or organism
Three strategies for viral survival
1) House their DNA or RNA genomes in small proteinaceous particles (capsids)
2) Genome contains all info to initiate and complete an infectious cycle
3) Establish a relationship in a population of hosts, ranges benign to lethal
Classical system of viral classification
based on shared physical properties
- Genetic material in virion (DNA or RNA)
- Symmetry of capsid (helical or icosahedral)
- Naked or enveloped
- Dimensions of virion and capsid
Baltimore system of viral classification
based on central dogma DNA → RNA → Proteins, how viruses produce mRNA
- strand = “ribosome read” translatable mRNA (positive sense)
a. + strand mRNA made from - strand DNA
- strand = “ribosome read” translatable mRNA (positive sense)
- strand = complementary sequence to mRNA (negative sense)
Methods for studying viruses (6)
i. Electron microscopy (can’t use light microscopy, viruses too small)
ii. Cell culture (study virus replication)
- Can use primary cells - limited growth potential, limited life span
- May give rise to a different cell strain
- Can use cells derived from tumor
- Plaque Assay: quantification of viruses in sample: Count number of plaques made by virus when applied to cell culture
iii.ELISA:
- Direct detection - virus antigen on plate + virus specific ab with indicator
- Indirect detection - virus antigen + virus specific ab + label ab
iv. Animal Models: infect susceptible animals
1. Used for viruses that can’t be grown well in culture
v. Serology
vi. Sequence Analysis
Viral capsids and two types
- protein shell surrounding nucleic acid genome
- Protect genome, specific genome delivery device
- Assembled from components made during infection
Helical Capsids:
a.Can be rigid or flexible
Icosahedral Capsids: make bigger sphere by adding subunits
EX) Canine Parvovirus - 60 subunits make up capsid
- True icosahedral symmetry
EX) Adenovirus - complex capsid
Viral envelope
host cell derived lipid bilayer
Spikes and three functions
virally encoded glycoproteins, decorate outside of capsids
Function:
i. Entry and host range determinants
ii. Assembly and egress
iii. Evasion from immune system
7 basic virus genomes
- dsDNA
- Gapped circular DNA
- ssDNA
- dsDNA
- ss (+) RNA
- ss (-) RNA
- Retroviruses: ss(+) RNA with DNA intermediate
Replication strategies of dsDNA
- Replication exclusively nuclear - dependent on host cell
- May involve viral polymerases and accessory factors - Replication in cytoplasm (Poxviruses) - virus has all necessary factors for replication → independent of cellular machinery
Replication strategies of gapped circular dsDNA
portion that is naked ssRNA
1.Use virally encoded reverse transcriptase to copy viral genomes from mRNAs transcribed from template genome
Replication strategies of ssDNA
Replication occurs in nucleus
Form dsDNA intermediate → template for synthesis of ssDNA
Replication strategies for dsRNA
- sense RNA transcribed from genome to have gene expression
- NOT “ribosome ready”
- Package RdRp in virus particle to convert - to + mRNA
Replication strategy for ss (+) RNA
Genome of virus translated directly by host ribosomes
a. Must be translated before any RNA replication of mRNA synthesis can occur
b. NOT dependent on RdRp
Replication strategy for ss (-) RNA
- sense RNA transcribed from genome to have gene expression
- NOT “ribosome ready”
- Package RdRp MUST be in virus particle to convert - to + mRNA
Replication strategy for retroviruses
Viruses copy (+) ssRNA genome into dsDNA with reverse transcriptase
a. Reverse transcriptase NOT present in animal cells
2. dsDNA copy of viral genome integrates into host cell DNA → mRNA transcribed from virus genome using host cell-encoded RNA pol II
Eclipse period
No infectious material ready
Latent period
new virus components being assembled but not outside of cells
Viral attachment to cell
1) Non-specific, electrostatic binding places virus in close proximity to cell surface
2) Specific virus-attachment protein interacts with cellular receptor molecule to initiate entry process
3. Target receptor = protein (glycoproteins) or carbohydrates (on glycolipids or glycoproteins)
a.Influenza = carb receptor
b.Viruses can use more than one receptor and type
E.g. HIV
Entry of virus into cell
- Penetration of target cell by virus
- Energy dependent process
a. Endocytosis into intracellular vesicles (endosomes)
i. Enveloped or nonenveloped viruses
ii. Clathrin and caveolin-dependent and independent mechanisms
b.Fusion of virus envelope with cellular membrane (only envelope viruses)
Susceptible cell
has functional receptor for given virus
Resistant cell
no receptor
permissive cell
capacity to replicate virus (may not be susceptible)
Susceptible and permissive cell
ONLY cell that can take up a virus and replicate it
Uncoating of viral genome
after entry into cell, virus capsid completely or partially removed exposing virus genome
DNA viral genome expression
a. Transcribe mRNA using - strand of DNA genome as template
b. Host RNA polymerase II must fill in gaps BEFORE genes can be transcribed
c.Occurs in nucleus
Exception = poxviruses (replicate in cytoplasm of infected cells, and encode their own RNA polymerase)
d.Produces mRNA that is capped and polyadenylated by cellular machinery for translation by host ribosomes
RNA viral genome expression
Use viral RNA-dependent RNA polymerase (RdRp) to produce mRNA and replicates RNA genomes
i. Host cell has no RdRp → virus must encode it in its genome
b. mRNA produced is readable by host ribosomes
Viral genome replication
copy of viral genome must be made to package into progeny virions
1.Virus replication is done in BURSTS
Viral assembly
package genome into capsid
- Icosahedral Capsids:
a. Capsid assembles around virus genome
b. Genome “fed” into preformed capsids - Helical Nucleocapsids:
a. Viral genome coated with nucleocapsid protein during synthesis
Viral egress (naked capsids vs. enveloped viruses)
exit from infected cell
- Naked capsids: released by lysis
a. So much virus produced, cells breaks open - Envelope virus: acquire cell membrane via budding
a. Bud into plasma membrane → released extracellularly
b. Bud into Golgi, ER membrane → secreted from infected cell
Tissue tropism
given virus likely to infect certain tissues and not others
i. Enterotropic viruses → replicate in gut
ii. Neurotropic viruses → replicate in nervous system tissue
Tissue tropism determined by (4)
- Access to tissue in which it can replicate
- Receptors required for virus binding and entry
- Expression of host genes required for virus infection/production of new progeny virus
- Relative failure of host defenses
Virulence
capacity of infection to cause disease
i.Can range from avirulent to attenuated to virulent
Four types of virulent genes
1) Affect ability of virus to replicate
2) Modify host defense mechanism
3) Facilitate virus spread in and among hosts
4) Are directly toxic to host cells
Virus shedding
release of infectious particles from an infected host
Transmission
affected by site of virus replication and release, and relative stability of virus particle in the environment
- Enveloped = fragile, sensitive → transmitted by close contact
- Non-enveloped = hardier → transmitted via virus-associated objects and respiratory or fecal/oral routes
Host factors in susceptibility to viral disease (6)
i. Expression of appropriate receptors for virus entry
ii. Permissivity of infected cells (ability of cells to support virus replication)
iii. Age of host
iv. Genetic background
v. Exposure history
vi. Immune status
Host immune response
Virus-induced immunopathology
i. Can mediate viral disease
ii. Ab-mediated (immune complex diseases) and cell mediated responses (rash, fever, malaise), autoimmunity (cross-reactivity with virus), and transient immune modulation (immune suppression)
Acute disease
high viral replication rate, large number of progeny
i. Limited by death of host or host immune response
ii. Threshold of virus required to activate adaptive immune response
Acute local disease incubation period
1-3 days
- Typically begin as infections of EPITHELIAL cells at body surface (gut, respiratory tract, eyes)
- Time between virus infection to start of symptoms
Acute local disease: virus shedding
shedding occurs from site of initial infection
1.“Closed loop”
Host response to acute local disease
IgA responsible for resistance to reinfection
- Results in short duration of immunity
- Often viruses with many serotypes
- Symptoms are localized to entry epithelium
Likelihood of reinfection: acute local
Common (viruses change rapidly)
Incubation period acute systemic
10-21 days
1.Primary infection in EPITHELIUM
Virus shedding: acute systemic
shedding can take place from multiple or distant sites
- Viremia (virus in blood) - yes, twice
- Systemic infection result in secondary replication in spleen, lung or liver
Host response to acute systemic
Serum IgG and secretory IgA
- Results in lifelong duration of immunity
- Symptoms are systemic
Likelihood of reinfection: acute systemic
unlikely
Persistent infection
refers to virus infections that continue to produce new virus over a long period of time
1.EX) Hep B
Latent infection
virus infection in which virus genome is relatively silent
- Little gene transcription in most infected cells
- Little to no disease in healthy host for a long time
- Retain ability to reinitiate transcription and replication to produce new virus (Reactivation)
- EX) EBV (B lymphocytes), Herpes Simplex Virus (dorsal root ganglia), HPV (basal epithelial cells)
Outcome of acute infection
short-lived, short incubation time, get symptoms, get better, won’t get infected again
i.EX) Rhinovirus, Rotavirus, Influenza virus
Outcome of Persistent infection
long and ongoing infection, can cause death
i.EX) Lymphocytic choriomeningitis virus, Hepatitis B and C
Outcome of latent infection
can be infectious without having symptoms
EX) Herpes simplex virus
Cytopathic effect (CPE)
any detectable morphologic changes in the host cells
- Indirect cell damage can result from
a. Integration of viral genome
b. Induction of mutations in host genome
c. Inflammation
d. Host immune response - Direct cell damage
Syncitia
cell fusion
Transformation
caused by some viruses, conferring cell growth without restraint → oncogenic viruses
Interferon response
interfere with viral infection of neighboring cells
Type I IFNs
IFNa and b: antiviral cytokines
- Transiently produced
- Secreted by most infected cells within hours of infection
- Control genes through ISREs (interferon-stimulated response elements)
Type II IFNs
IFN gamma: produced by T cells and NK cells
- More restricted than Type I production
- Control genes through GAS (gamma activated site) elements
Type I IFNs control genes through ___
ISREs
Type II IFNs control genes through ____
GAS elements
Type I and II IFNs are ____
DISTINCT- produced by different cells and at different stages of infection
Cells respond to IFNs through receptor activation of ____ signalling
JAK/STAT
IFN response triggered/activated by
dsRNA or intracellular signalling proteins (TLRs, RLHs)
Antiviral state
Induced/mediated by IFN
i. Characteristic of a cell that has bound and responded to IFN
- IFN binds specific cell receptors → induce transcription of genes = antiviral state
ii. Responding cell does not need to be infected
iii. IFN alters transcription of more than 100 cellular genes
iv. Optimal state to block viral replication: DOES NOT initiate cell death immediately, but prepares cell to react if infection occurs, “readiness state”
- Block cell proliferation, reduced cell metabolism, increased NK cell activity and IFNy production, increased expression of MHC
- Can lead to apoptosis
2 mediators of IFN-induced antiviral state
Made in inactive form
- PKR
- OAS
** Dampen ability of virus to move through cells
PKR
protein kinase that phosphorylates/inactivates cellular translation initiation factor → decreased protein synthesis
OAS
degrades mRNA
Innate respone
primary defenses, immediate, nonspecific
i. Natural barriers: skin, mucus, ciliated epithelium gastric acid, tears, bile
ii. Cells: macrophages, neutrophils, dendritic cells, NK cells
iii. Soluble factors: interferons, cytokines, complement, chemokines
iv. Critical precursor to adaptive immune response to virus
Adaptive response
acquired over time, specific to particular molecules
i. Acquired during infection
ii. Results in immunologic memory (enhanced response to second exposure)
iii. Cell mediated → induce antiviral state, destroy virus infected cells
iv. Humoral → inhibit virion attachment and fusion, enhance phagocytosis, agglutinate virions, lyse enveloped viruses
v. Possible that viral infection is cleared prior to adaptive response
Intracellular restriction factors
block/inhibit virus infection AFTER virus entry into cells
i. Can determine whether a cell is permissive or nonpermissive
ii. EX) APOBEC3G - in HIV interferes with HIV genome
iii. NOT part of adaptive immune response even though specific to certain antigens
Antibodies in primary responses
i. Sterilizing ab response: prevent infection by binding virion protein attachment molecules on surface of infected cells
ii. Neutralizing antibody: interfere with binding and fusion to host cells, blocks viral infection
1. Used in immunization
2. Critical for preventing re-infection
iii. Antibody levels and effector T cell activity gradually decline after an infection is cleared
Antibodies in secondary responses
- Early reinfection is rapidly cleared by preformed immune reactants
ii. Later reinfection leads to rapid increase in ab and effector T cells (immunological memory) → infection mild/inapparent
Cells involved in innate defenses (4)
- Mononuclear phagocytes: phagocytosis, release inflammatory mediators, antigen presentation
- Dendritic Cells: present antigens to T cells, stimulate B cell differentiation/proliferation, modulate adaptive immune responses, secrete antiviral/immunoregulatory cytokines
- NK Cells: contain virus infections before adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection
- Granulocytes: release inflammatory mediators
Cells involved in adaptive defense (2)
- T cells (Th1, Th2, CTL, Tfh, Treg)
2. B cells
Virus evasion/manipulation (9)
- antigenic variation
- inhibition of IFN pathway
- inhibition of apoptosis and cell cycle control
- immune tolerance
- infection of immunoprivileged sites
- direct infection of immune system
- restricted infection of viral genes
- Production of viral molecules that act as inhibitors or decoys
- Down regulation of host proteins
Antigenic variation
spontaneous point mutations in antigenic drift (HIV, influenza A) and genome shuffling in antigenic shift (influenza A)
Inhibition of IFN pathways
(influenza NS1)
- Block IFN synthesis
- IFN R decoys
- Block IFN signaling
- Block IFN induced transcription
- Block IFN induced protein functions
Immune tolerance
molecular mimicry or infection prior to competent immune system
Restricted expression of viral genes
go invisible to host defenses as in latent infections
e.g. HIV
Production of viral molecules that act as inhibitors or decoys
of host defense molecules such as TLRs, cytokines, receptors, and Abs
e.g Pox and Herpesviruses
Down regulation of host proteins
such as class I MHC or adhesion molecules
e.g. Pox and Herpesviruses
