Module 5: Chapter 16 Flashcards
1
Q
16.1 The Skin and its Defenses
A
2
Q
the skin, together with the nails, hair, sweat and oil glands, forms the ___________ system.
A
integument
3
Q
total surface area of skin
A
1.5-2 square meters
4
Q
layers of skin from outer to inner
A
epidermis (stratum corneum) -> dermis -> subcutaneous layer
5
Q
composition of the epidermis (four or five distinct layers)
outer to inner
A
stratum corneum (dead cells that have migrated from the deeper layers - packed with keratin, layer replaced every 25-45 days)
below the stratum corneum are three or four more layers of epithelial cells
the lowest layer, stratum basale or basal layer: attached to the underlying dermis and is source for all of the cells that make up the dermis
6
Q
importance of keratin
A
gives epithelial cells ability to withstand abrasion, damage, and water penetration
7
Q
thickest skin is found on the _____________ and the thinnest is on the __________
A
- plantar of the foot
2. eyelids
8
Q
dermis layer (middle layer)
A
composed of connective tissue (instead of epithelium)
- means it is rich in fibroblast cells and fibers such as collagen
- contains macrophages and mast cells
- harbors a dense network of nerves, blood vessels, and lymphatic vessels
—> damage to the epidermis generally does not result in bleeding, whereas damage deep enough to the dermis results in broken blood vessels.
*blister formation, the result of friction trauma, or burns, represents a separation between the dermis and epidermis
—> roots of hair are housed in follicles in the dermis, sebaceous oil glands and sweat glands are also in the dermis
9
Q
____________ of cells from the stratum corneum slough off every day, and attached microorganisms are also sloughed off
A
millions
10
Q
one of the most effective defenses of the skin is a class of molecule called \_\_\_\_\_\_\_\_\_\_ \_\_\_\_\_\_\_\_\_\_. ---> they are positively charged chemical that act by disrupting the negatively charged membranes of bacteria; chiefly responsible for keeping the antimicrobial count on skin relatively low
A
antimicrobial peptides
11
Q
sebum
A
low pH, oil-based secretion of the sebaceous glands (due to high concentration antibodies); makes the skin inhospitable to many microorganisms
12
Q
lipids in sebum can serve as nutrients for normal microbiota, but breakdown of the fatty acids contained in lipids leads to toxic by-products that do what?
A
inhibit the growth of microorganisms not adapted to the skin environment
13
Q
why is sweat inhibitory to microorganisms?
A
because of its low pH and its high salt concentration
—> lysozyme is an enzyme found in sweat (and tears and saliva) that specifically breaks down peptidoglycan
14
Q
- 1 outcomes
- describe the important anatomical features of the skin
- list the natural defenses present in the skin
A
- keratin in the epidermis - protects the skin from damage, abrasion, and water penetration
- collagen in the dermis for withstanding stretching - -antimicrobial peptides
-low pH (sweat)
-sebum
-high salt and lysozyme in sweat
sloughing off of microbes from stratum corneum
15
Q
16.2 Normal Biota of the Skin
A
16
Q
microbes that live on the surface of the skin must be capable of living in what conditions that are on the skin?
A
salty and dry conditions
17
Q
microbes can grow into dense populations in what places
A
moist areas and skin folds such as the underarm and groin areas
18
Q
normal microbiota also live in the protected environment of the ________ follicles and ______ ducts
A
hair
glandular
19
Q
fascinating info about skin normal biota
A
hundreds of species of microbes including well known pathogens inhabit out epidermis, dermis, and subcutaneous skin layers
also common for different species to favor different areas of our bodies, and for different people to have different species
—> seems common for an individual’s microbiota to remain relatively constant over time
20
Q
common fungal colonizers of skin
A
dermatophytes
21
Q
skin defenses
A
keratinized surface, sloughing, low pH, high salt, lysozyme, antimicrobial peptides
22
Q
normal biota of skin
A
Streptococcus, Staphylococcus, Corynebacterium, Propionibacterium, Pseudomonas, Lactobacillus; yeasts such as Candida
23
Q
- 2 outcomes
1. list characteristics of the skin’s normal microbiota
A
- hundreds of species of microbes including some pathogens inhabit the epidermis, dermis, and subcutaneous skin layers
- different species favor different areas of the body
- different people have different species
- common for individuals’ microbiota to remain relatively constant over time
24
Q
16.3 Skin Diseases Caused by Microorganisms
A
25
Methicillin-resistant Staphylococcus Aureus (MRSA)
common cause of skin lesions in non-hospitalized people, and hospitalized patients are more likely to acquire systemic infections, bloodstream infections from MRSA)
-even though the name mentions methicillin, the stain is resistant to multiple antibiotics
26
Staphylococcus aureus r/t MRSA
S. aureus- gram-pos coccus, nonmotile
- much of its destructiveness is due to its array of superantigens
- can be highly virulent BUT also appears as normal biota on the skin of one third of the population
-strains that are methicillin-resistant also found on healthy people
- considered the sturdiest of all non-endospore-forming pathogens
- --> well-developed capacities to withstand high salt (7.5%-10%), extremes in pH, and high temps (60degrees C for 60 minutes)
- --> also remains viable after months of drying and resists the effect of many disinfectants and antibiotics
27
signs + symptoms of MRSA
infections of the skin tend to be raised, red, tender, localized lesions, often featuring pus, and feeling hot to the touch
---> may localize around a hair follicle
*fever is a common feature
28
transmission and epidemiology of MRSA
common contaminant of all kinds of surfaces you touch daily; on gym equipment, shavers, airplane tray tables, electronic devices
29
Pathogenesis and Virulence Factors of MRSA (S. aureus)
all pathogenic S. aureus strains typically produce coagulase, an enzyme that coagulates plasma (highly diagnostic species characteristic)
other enzymes expressed by S. aureus include hyaluronidase (digests intracellular "glue"), staphylokinase (digests blood clots), nuclease (digests DNA), and lipases that help bacteria colonize oily skin surfaces
30
Culture and dx of MRSA
PCR is routinely used to diagnose
- alternatively cultivation on blood agar is useful for dx
- for heavily contaminated specimens, selective media such as mannitol salt agar are used
- the production of catalase, an enzyme that breaks down hydrogen peroxide accumulated during oxidative metabolism, can be used to differentiate the staphylococci, which produce it, from the streptococci which do NOT
- key technique for separating S. aureus from other species of Staphylococcus is the coagulase test: by definition any staph isolate that coagulates plasma is S. aureus, all others are coagulase-negative
31
Prevention and Tx of MRSA
prevention is only possible with good hygiene
- tx of infection often starts with incision of the lesion and drainage of pus
- antimicrobial tx should include more than one antibiotic (current rec'd in US: vancomycin, linezolid, or daptomycin)
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summary of MRSA (gram +)
- most common modes of transmission: direct contact, indirect contact
- virulence factors: coagulase, other enzymes (staphylokinase etc.), superantigens
- culture/diagnosis: PCR, culture and gram stain, coagulase and catalase tests, multitest systems
- prevention: hygiene practices
- tx: vancomycin, linezolid, or daptomycin; serious threat in CDC Ant. Resistant Report
- epidemiology: community associated MRSA infections most common in children and young to middle aged adults; incidence increasing in community/decreasing in hospitals
33
Maculopapular Rash Diseases:
| Measles (Rubeola)
-hundreds of thousands of children die every year, despite there being a vax
- signs & sx: sore throat, dry cough, headache, lymphadenitis, and fever; Koplik's spots = oral lesions that appear as prelude to characteristic red maculopapular exanthem (an eruption of rash) that erupts on the head then progresses to the trunk and extremities + whole body covered
* Subacute Sclerosing Panencephalitis (SSPE), a progressive neurological degeneration of the cerebral cortex, white matter, and brain stem (incidence: 1 in less than a thousand in children who get measles before getting vaccinated)
- pathogenesis & virulence factors: virus implants in the resp mucosa and and infects the tracheal and bronchial cells -> travels to the lymphatic system where it multiplies and and then enters the bloodstream, a condition known as viremia
- -> the virus induces cell membranes of adjacent host cells to fuse into large syncytia (cells will no longer perform reg fx)
- -> virus disables cell-mediated immunity and delayed-type hypersensitivity
- -> tends to erase or diminish the immune system's memory for the microbes
- transmission & epidemiology: measles is one of the most contagious infectious diseases, transmitted principally by resp droplets; human is only reservoir
- -> person is infectious during the periods of incubation, prodrome phase, and the skin rash but usually not during the convalescence phase
- culture & dx: disease can be diagnosed on clinical presentation alone, but if further identification is required an ELISA test is available that tests for pt IgM to measles antigen BUT PCR is also available
- prevention: MMR vaccine = contains live attenuated measles virus, ProQuad vax
- treatment: relies on reducing fever, suppressing cough, and replacing lost fluid
- -> complications require additional remedies to relieve neurological and resp sx and to sustain nutrient, electrolyte, and fluid levels
- -> vit A supplements recommended by some MDs
34
Maculopapular Rash Diseases:
| Rubella (latin for "little red")
- relatively minor rash disease with few complications "3 day measles"
- -> exception is when in utero and can cause damage to fetus (women of childbearing years must be vaccinated before they plan to concieve)
- s&s: two clinical forms: postnatal infection (children or adults) and congenital infection (infection of fetus, expressed in the newborn as various types of birth defects)
- -->postnatal: rash of pink macules and papules first appears on face and progresses down trunk+extremities, resolving in about 3 days; adult rubella s often characterized by joint inflammation and pain rather than rash
- -->congenital: teratogenic virus; in first trimester = miscarriage/multiple permanent defects in newborn; cardiac abnormalities, ocular lesions, deafness, and mental/physical retardation in varying combinations
-causative agent: virus is Rubivirus in family Togaviridae; stops MITOSIS, induces APOPTOSIS, damages vascular endothelium (poor development of organs)
- transmission & epidemiology: contact with resp secretions and sometimes urine; virus spread through prodromal phase and up to a week after rash appears
* congenitally infected infants are contagious for a much longer period of time
- culture & dx: it mimics other diseases, so should not be diagnosed on clinical grounds alone; IgM antibody to rubella virus can be detected early using an ELISA technique or a latex-agglutination card
- prevention & treatment: attenuated rubella virus vaccine is usually given to children in the combined form of MMR or MMRV vax. at 12-15 months and a booster at 4-6 years years of age.
35
```
Maculopapular Rash Diseases:
Fifth Disease (erythema infectiosum)
```
Causative Organism(s): Parvovirus B19
Most Common Modes of Trans: droplet contact; direct contact
Virulence Factors: ---
Culture/Dx: usually diagnosed clinically
Prevention: ---
Treatment: ---
Distinguishing Features of Rash: "slapped face"; rash first, within two days spreads to limbs and trunk, tends to confluent rather than distinct bumps
Epidemiological Features: 60% of population seropositive by age 20; very contagious
Appearance of lesions: see picture in text (table 16.2)
36
Maculopapular Rash Diseases:
Roseola ("sixth disease")
Causative Organism(s): Human herpesvirus 6
Most Common Modes of Trans: unknown
Virulence Factors: ability to remain latent
Culture/Dx: usually diagnosed clinically
Prevention: ---
Treatment: ---
Distinguishing Features of Rash: high fever (105F) precedes rash stage; rash not always present (up to 70% of cases proceed without rash)
Epidemiological Features: nearly 100% seropositive; 90% of disease cases occur before age 2; common in young children/babies
Appearance of lesions: see picture in text (table 16.2)
37
Maculopapular Rash Diseases:
| Other conditions to consider (covered in later chapters)
Zika virus disease
Scarlet fever
Secondary syphilis
Rocky Mountain spotted fever
38
Impetigo
| "I-pet-and-skin-go"
superficial bacterial infection that causes the skin to flake and peel off
- not serious, but highly contagious (especially in children)
- can be caused S. aureus or Streptococcus pyogenes, or a mixture, or S. aureus takes over after a while
Trans: direct contact; fomites; mechanical vector transmission
Prevention: good hygiene
S & S: the lesion looks variously like peeling, crusty, and flaky scabs, or honey-colored crusts; found around face, mouth, extremities, anywhere on skin; very SUPERFICIAL and itches
* what complication is associated with untreated impetigo?
- glomerulonephritis
39
Impetigo caused by Staphylococcus aureus (gram +)
virulence factors: exotoxins called exfoliative toxins A and B, which are encoded by a phage that infects some S. aureus strains
Transmission: direct and indirect contact
Virulence Factors:
- at least one of the toxins attacks a protein that is very important for epithelial cell-to-cell binding in the outermost layer of the skin; breaking up the protein=blistering of the skin and the breakdown of skin = spread of bacterium
- coagulase; other enzymes
Culture/Diagnosis: routinely based on clinical signs; when necessary, culture and Gram Stain, coagulase and catalase tests, multitest systems PCR
Prevention: hygiene
Tx: no tx in uncomplicated cases; topical ointments
Distinguishing Features: seen more often in older children, adults
Epidemiological Features: incidence approx. 2-5% in children in temperate climates; higher in tropical areas
40
Impetigo caused by Streptococcus pyogenes (gram +)
Most Common Trans: direct and indirect contact
Virulence Factors: Streptokinase, plasminogen-binding ability; hyaluronidase, M protein
Culture/Dx: routinely based on clinical signs; when necessary, culture and Gram stain, coagulase and catalase tests, mutlitest systems, PCR
Prevention: hygiene
Tx: uncomplicated cases= no treatment; topical mupirocin or retapamulin; concerning threat
Distinguishing Features: Seen more often in newborns
Epidemiological Features: incidence approx. 2-5% of children in temperate climates; higher in tropical areas
* beta-hemolytic on blood agar
* S. pyogenes also caused Streptococcal pharyngitis (strep throat), scarlet fever, serious bloodstream infections, and poststreptococcal conditions such as rheumatic fever, and poststreptococcal glomerulonephritis
41
Cellulitis
Causative Organism(s): 1. Streptococcus pyogenes (G+), 2. MRSA (G+), 3. other fungi or bacteria
Most Common Trans: Parenteral implantation
Virulence Factors:
1. Streptokinase, plasminogen-binding ability, hyaluronidase, M protein
2. Exfoliative toxin - A, coagulase, other enzymes
3. ---
Culture/Dx: Based on clinical signs
Prevention: ---
Tx:
1. Oral or IV antibiotic (penicillin); surgery sometimes necessary; erythromycin-resistant Streptococcus pyogenes = concerning threat
2. Oral or IV antibiotic (cefazolin, ceftriaxone, vancomycin, linezolid); surgery sometimes necessary; MRSA = serious threat
3. Aggressive treatment with oral or IV antibiotic; surgery sometimes necessary
Distinguishing Features: 1. --- 2. --- 3. More common in immunocompromised
Epidemiological Features: Incidence highest among males 45-64
S & S: pain, tenderness, swelling, and warmth; fever and swelling of the lymph nodes may also occur, lymphangitis (red lines leading away from the area affected)
42
Staphylococcal Scalded Skin Syndrome (SSSS)
Causative Organism(s): Staphylococcus aureus B (G+)
Most Common Trans: direct contact, droplet contact
Virulence Factors: Exfoliative toxins A and B
Culture/Dx: histological sections; cultures performed but false negatives common because toxins alone are sufficient for disease
Prevention: eliminate carriers in contact with neonates
Tx: immediate systemic antibiotics (current rec: cloxacillin)
Distinguishing Features: split in skin occurs WITHIN epidermis; exfoliative toxins cause bullous lesions (fluid-filled blisters)
Epidemiological Features: mortality 1-5% in children; 50-60% in adults
* carriers can harbor bacteria in the nasopharynx, axilla, perineum, and vagina
* most common in newborns and babies
43
Scrum Pox: Herpes Gladiatorum
often spread at the gym or by athletes such as wrestlers or rugby players
once infected = infected for life
direct contact spread, and indirect (fomites)
44
Vestibular or Pustular Rash Diseases:
Chicken Pox
Causative Organism(s): Human herpesvirus 3 (varicella-zoster virus)
Most Common Trans: droplet contact, inhalation of aerosolized lesion fluid
Virulence Factors: Ability to fuse cells, ability to remain latent in genitalia
Culture/Dx: based largely on clinical appearance; PCR available
Prevention: live attenuated vaccine; there is also vaccine to prevent latent virus (shingles)
Tx: uncomplicated cases= no treatment; acyclovir for high risk
Distinguishing Features: no fever prodrome; lesions are superficial and in CENTRIPETAL distribution (more in center of body)
Epidemiological Features: Chickenpox: vaccine decreased hospital visits by 88%, ambulatory visits by 59%
* incubation period of 10-20 days, first symptoms are fever and an abundant rash that begins on the scalp, face, and trunk and radiates to the extremities
- --> skin lesions progress quickly from macules and papules to itchy vesicles filled with clear fluid, in days they will encrust and drop off
45
Vesicular or Pustular Rash Diseases:
Smallpox
Causative Organism(s): Variola virus (enveloped DNA virus)
Most Common Trans: primarily droplet contact, indirect contact (fomites)
Virulence Factors: ability to dampen and/or avoid immune response
Culture/Dx: based largely on clinical appearance; if suspected refer to CDC
Prevention: live virus vaccine (vaccinia virus)
Tx: Tecovirimat, cidofovir (drugs)
Distinguishing Features: fever precedes rash, lesions are deep and in CENTRIFUGAL distribution (more on extremities)
Epidemiological Features: last natural case worldwide was in 1977; Category A Bioterrorism Agent
* S & S: infection begins with fever and malaise and later a rash begins in the pharynx, spreads to the face, and progresses to extremities
- --> initially rash is macular-> papular-> vesicular-> and pustular before eventually crusting -> SCARRING
*two principal forms of smallpox: variola minor and variola major (major is highly virulent form that causes toxemia, shock, and intravascular coagulation
---> those who survived smallpox nearly always develop LIFELONG IMMUNITY
46
Shingles (latent chickenpox)
enveloped DNA virus
---> humans are only natural hosts for HHV-3
after recuperation from chickenpox, the virus enters into the sensory nerve endings of cutaneous spinal nerve branches, especially those that serve the skin of the chest and head
---> becomes latent in the ganglia and may reemerge as shingles (herpes zoster); characteristics asymmetrical distribution on the skin of the trunk or head
How does shingles develop: psychological stress, x-ray tx, immunosuppressive and other drug therapy, surgery, or a developing malignancy.
Virulence Factors: ---> HHV-3 enters resp tract, attaches to resp mucosa, and then invades the bloodstream
- --> viremia disseminates the virus to the skin where the virus causes adjacent cells to fuse and eventually lyse, resulting in characteristic lesions
- --> the virus enters the sensory nerves at this site, traveling to the dorsal root ganglia
Prevention: live attenuated vaccine: Zostavax and Shingrix
47
Variola Major (small pox) early signs
prodrome: high fever, malaise, rash emerges (first in the mouth); sometimes severe back and abdominal pain accompany this phase
- within 24 hours a rash appears and spreads throughout the body
by day 3 or 4 of the rash, the bumps become bigger and fill with thick opaque fluid
DISTINGUISHING FEAT: pustules are indented in the middle, and patients report feeling like there is a BB pellet in the middle
after two weeks most lesions will crust over ---> patient remains contagious until last scab falls off b/c crusts contain the virus
--->lesions occur at the dermal level
---> patient ill during entire rash phase
48
Variola minor (small pox)
has a rash that is less dense (than variola major) and is generally less ill then someone with variola major
49
Large Pustular Skin Lesions
| Leishmaniasis
Causative Organism(s): Leishmania spp. (protozoan)
Most Common Trans: biological vector (sand fly)
Virulence Factors: Multiplication within macrophages
Culture/Dx: usually microscopic visualization
Tx: sodium stibogluconate, pentamidine
Prevention: avoiding sand fly
---> no vaccine, avoidance of female sand flies is only prevention
Distinguishing Features: mucocutaneous and systemic forms
Epidemiological Features: untreated visceral leishmaniasis mortality rate is 100%; 10% for cutaneous leishmaniasis
---> no vaccine, avoidance of female sand flies is only prevention
Cutaneous leishmaniasis: localized infection of the capillaries of the skin caused by L. tropica
50
Large Pustular Skin Lesions
| Cutaneous Anthrax
* most common form and least dangerous version of infection with Bacillus anthracis
- -->caused by endospores entering the skin through small cuts or abrasions
- --> marked by production of a papule that becomes increasingly necrotic and later ruptures to form a painless black ESCHAR (dark, sloughing scab)
Causative Organism(s): Bacillus anthracis bacteria (G+)
Most Common Form of Trans: direct contact with endospores
Virulence Factors: endospore formation; capsule, lethal factor, edema factor
Culture/Dx: culture on blood agar; serology, PCR performed by CDC
Prevention: avoid contact; vaccine available but not widely used (rec'd only for high risk person and the military)
Tx: Ciprofloxacin, plus two additional antibiotics
Distinguishing Features: can be fatal
Epidemiological Features: untreated cutaneous mortality rate: 20%; treated mortality rate less than 1%; CATEGORY A BIOTERRORISM AGENT
51
Cutaneous and Superficial Mycoses (fungal infection)
Ringworm
52
group of fungi that cause infections of the skin and other integument components; they survive by metabolizing keratin
dermatophytes
53
dermatophytes also _______ the immune system and its ability to respond to them
suppress
54
transmission of ringworm
direct or indirect contact with humans or animals, some fungi can be acquired from the soil
55
treatment for ringworm
ointments containing tolnaftate, miconazole, itraconazole, terbinafine, or thiabendazole are applied regularly for several weeks
56
superficial mycoses
fungal infection involving the outer epidermal surface
endogenous (normal biota)
caused by Malassezia species
culture/dx: usually clinical; KOH can be used (potassium hydroxide)
no prevention
highest incidence among adolecscents
topical antifungals are tx
57
16.4 the surface of the eye and its defenses
58
conjunctiva
thin fluid-secreting tissue that covers the eye (except for the cornea) and lines the eyelid
--->secretes and oil and mucus containing fluid that lubricates and protects the eye surface
59
cornea "windshield of the eye"
dome shaped central portion of the eye lying over the iris (colored portion of the eye)
---> has five to six layers of epithelial cells that can regenerate quickly of they are superficially damaged
60
eye's best defense
tears, which consist of an aqueous fluid, oil, and mucus (formed in the lacrimal gland)
61
make up of tears
sugars, lysozyme, and lactoferrin
| *last two have antimicrobial properties
62
why does inflammation not occur in the eye
b/c it hinders vision, flooding the eye with lymphocytes and macrophages would cause blurred vision
63
eyes are not covered by __________ epithelium
keratinized
64
eye and immune privilege
the restriction or deduction of immune response in certain areas of the body that reduces the potential damage to tissues that a normal inflammatory response could cause
---> evolution of vertebrate eye has been toward reduced innate immunity and a corresponding inflammatory response as it harms the function of the eye
65
16.5 normal biota of eye
66
in many cases, ____________ is the most dominant genus of the eye
Corynebacterium
67
16S rRNA analysis of the healthy eye microbiome has revealed a more _______ population, showing high _______ in the bacteria found
robust
| diversity
68
the microbiome of the eye can be compared to that of the ____.
skin
69
defenses of the eye
mucus in conjunctiva and in tears
| lysozyme and lactoferrin in tears (antimicrobial properties + flushing)
70
16.6 Eye diseases caused by microorganisms
71
injection of the conjunctiva
conjunctivitis - relatively common
caused by specific microorganisms that have a predilection for eye tissues, by contaminants that proliferate due to the presence of a contact lens or an eye injury, or by accidental inoculation of the eye by a traumatic event
72
signs and sx of conjunctivitis
many different clinical presentations
- most bacterial infections produce a milky discharge
- viral infections tend to produce a clear watery exudate
--->typical for patient to wake up in the morning with eye "glued" shut by secretions
--->sometimes caused by allergic response and often produce clear fluid as well
73
pink eye or
conjunctivitis
74
viral conjunctivitis is commonly caused by ____________, and is more common in _________ whereas bacterial conjunctivitis is more common in ________.
1. adenoviruses
2. adults
3. children
75
keratitis (more serious than conjunctivitis)
when damage of deeper eye tissues occurs and can lead to complete corneal destruction
---> any microorganism can cause this condition, especially after trauma to the eye
76
cause of herpetic keratitis
a misdirected reactivation of oral herpes simplex virus type 1; upon reactivation it travels into the ophthalmic region instead of mandibular branch of the trigeminal nerve
77
amoeba called _______________ has been causing serious cases of keratitis, especially in those who where contact lenses
Acanthamoeba
78
treatment for HSV keratitis
topical trifluridine and/or oral acyclovir
79
S. aureus and MRSA produce enzymes that breakdown ______ ______
hydrogen peroxide
80
out of measles, rubella, leishmaniasis, and impetigo, which is most likely to be a polymicrobial infection
impetigo
81
steps of diagnostic process in order
anatomic diagnosis, differential diagnosis, etiologic diagnosis
ADE
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steps of diagnostic process in order
anatomic diagnosis, differential diagnosis, etiologic diagnosis
ADE
