PH 370 Exam 2

describe aging

decrease in immune function

• decrease in T cells, takes longer to destroy non self cells, vax less effective

what are the ways in which our immune system can fail us

aging, chronic inflamm diseases, immunodeficiency diseases, allergy/hypersensitivity, autoimmunity, cancers

describe immunodeficiency diseases

HIV/AIDS (HIV kills helper T cells), suseptible immune system

describe allergy/hypersensitivity

response to harmless antigen

describe autoimmunity

indivs develop autoantibodies to their own tissues/self antigens

describe the cost of inflammation

inflamm mechs = response to stimuli that disrupts homeostasis in a severe way

• high benefit and high cost

• cost = interfere with normal function and risk of tissue death, later in life

• benefits = early in life

• chronic inflamm —> many types of diseases

describe pathogens and the immune system

pathogens work hard to trick the immune system

• antigenic variation = multiple variations of an antigen

• latency = period of inactivity of antigen

• use immune system cells as hosts

describe antigenic variation

alters surface proteins to avoid immune response

• multiple variations of an antigen

• used to trick immune system

antigenic shift vs. antigenic drift

1. shift = abrupt, major change in virus resulting in new proteins to be produced

2. drift = small changes in the genes of viruses that happen continually over time

describe immunoglobins

immunoglobins = antibodies (our adaptive immune system wants to remember antigens)

• IgG = 75%, toxins viruses bacteria

• IgA = 15%, mucous membrane structures

• IgM = 10%, activates inflammation

• IgD = 0.2%, bound to B cells

• IgE = 0.004%, histamine present —> inflamm

challenges = immunodeficiency, hypersensitivity, autoimmunity

describe immunodeficiency

most severe type of immune suppression

1. primary = caused by inherited or genetic defects in the cells and tissues of the immune system

2. secondary = immune system is compromised due to an environmental or external factor

describe PIDD

selective IgA-deficiency

• IgA protects mucous membrane lined tissues

• undetectable levels of IgA, but normal levels of other immunoglobins

• common, 1/300

• pheno varies from no symptoms to severe illness

• recurrent ear infections, lung infections, requires antibiotics, high prev in pops with autoimmune diseases and allergies

• treatment of symptoms only

  • IgA replacement is NOT feasible

describe secondary immunodeficiency diseases (???)

• caused by anything that weakens immune system (diet, stress, sleep dep, HIV/AIDS, cancer, environ, viruses, immunosuppressive treatments, age, burns, other diseases)

• examples = immune system cancers, hepatitis, AIDs

how is a diagnosis of immunodeficiency disorders made?

medical history, physical exam, blood work

describe allergy/hypersensitivity

disorders that result from excessive immune responses to harmless antigens

• types = enviorn, proteins in meds, insect stings

• type 1, type 2, type 3, and 4 hypersensitivity

describe type 1 hypersensitivity

most common, immediate symptoms

• triggers IgE response → release histamine → inflammation

• allergens can cause anaphylaxis

  • constriction of blood vessels → low bp, rapid weak pulse, hives, vomiting

  • treat with antihistamines, epinephrine, corticosteroids

diagnosed by skin prick test/intradermal test, skin patch test, blood measurement of IgE, elimination diet

why is there a rise in food allergy prevalence

hygiene hypothesis = less biodiversity in orgs found in gut, system not challenged, need exposure to allergens earlier, overreporting

• eggs, milk, wheat, soy, peanuts, tree nuts

describe type 2 hypersensitivity

cytotoxic: IgM or IgG mediated destruction of cells

• in developing fetus, can result in isoimmunization

• hemolytic disease of the fetus and newborn by maternal IgG alloantibodies which target paternally inherited

• antigensdestroys RBCs

• ex. Rh disease, ABO incompatability

define isoimmunization

also known as Rh sensitization or hemolytic disease of the fetus, is a condition that occurs when a pregnant woman’s immune system attacks the baby’s blood cells

describe type 3 hypersensitivity

soluble mass of immune complexes forms in blood, deposit in tissues and vessels —> inflammation

• ex.) glomerulonephritis (inflamm kidney)

describe type 4 hypersensitivity

delayed hypersensitivity, activation of T cells, skin reaction

• ex.) poison ivy, tuberculin skin tests

describe autoimmunity

when immune system ability to distinguish self vs. non-self fails or is uncontrollable: occurs in 2 ways

1. recognizes self antigens to attack

2. overzealous response to chronic infection

can be focused on specific organ or be systemic (grave’s = thyroid; lupus = body), often has familial tendency

systemic lupus erthematosus (SLE)

autoantibodies targeted against cell membrane, cytoplasm, and cell nucleus

• common in women

• includes periods of exacerbations and quinescence

• diagnosis upon american college of rheumatology criteria

how many autoimmune disorders are there?

a LOT

• celiac disease, RA, sjogrens, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, vasculitis

what is the conundrum with the immune system?

our immune syst protects us from disease, but dysfunction of the immune syst can cause disease

describe the burden of infectious diseases

more common in low and middle income countries

• 90% conc on small subset of diseases: low respiratory diseases, diarrheal, HIV/AIDs, TB, malaria, measles

pathogenic microorganisms

pathogens = disease causing microorgs that grow around body triggering signs/symptoms

• small % of microorgs in nature are virulent in humans (few have the ability to cause disease)

epidemiologic triad

1. host

   • the who (org thats harbouring the patho)

2. environment

   • the where

3. agent

   • the what (microbe causing disease)

center of triangle = vector = the living agent that carries pathogen

communicable diseases

diseases with human vectors

what do we want to know to prevent infectious disease

infectious period, latent period, subclinical infectious period, preclinical phase

infectious period (period of contagion)

time interval when an infected host can transmit to susceptible hosts (highly variable across diff hosts)

latent period

time interval from infection to onset of infectious period

subclinical infectious period

time period from start of infectiousness to onset of symptoms

preclinical phase

incubation period in infectious disease natural history terms: interval from infection to onset of signs/symptoms

horiz vs. vertical transmission

horizontal = transmission from reservoir to sus human

vertical = one gen → next gen

direct vs. indirect transmission

direct = indiv infected thru direct contact with reservoir (including droplet transmission)

indirect = pathogen can live outside host before infecting another indiv

• sometimes on fomites (contaminated inatimate object)

• fecal-oral transmission

describe vector transmission

pathogen moves from one reservoir to indiv through another organism

• insect bite

what is a nosocomial infection?

hospital-acquired (due in part to vulnerability of host)

endemic

normal f of disease w respect to time, pop, geo

sporadic

occasional disease thats unexpected but doesn’t prompt further cases

epidemic & pandemic

epidemic = occurence of disease in excess of normal expectency with respect to TPG

pandemic = an epidemic on a world wide scale

State-Based Notifiable Diseases

Each state might have its own special list of diseases that they need to know about because they might be more common or important in that state. So, doctors in each state tell the state health department about these diseases so they can protect everyone in that state.

• local health department responsible for case investigation and action, LHD forwards it to state health dep, state assists LHD as needed

National Notifiable Diseases

These are diseases that doctors and hospitals in the U.S. have to tell a the CDC about. The CDC collects this information and shares it to make sure everyone across the whole country is healthy and safe.

• reporting is voluntary

• cases must meet national surveillance case definition

• some are non-infectious such as cancer, CO poisoning, lead, pesticide

NNDSS = nationally notifiable disease surveillance system

International Notifiable Diseases

These are diseases that could spread quickly around the world or are very dangerous, so countries have to tell big health organizations, like the World Health Organization (WHO), about them. all WHO members must report PHEIC (internationally concerning events).

• can spread from any major city on any continent in <36 hours

• international health regs = legally binding agreement of 196 countries requiring all to have ability to assess, report, respond to PH events (only ~1/3 countries)

• countries must assess PH risks <48hrs, report to WHO if notifiable in <24hrs

• smallpox, new subtype human influenza, SARS, potential events

classes of pathogens

bacteria, viruses, protozoa, fungi, helminths, prions

bacteria

• single celled orgs (cell walls, no nuc, no organelles)

• shapes = coccus, bacillus, vibrio, spirilla

gram staining

gram (+) = resist decolorization: retain purple = thick walled cells which can hang onto the color

gram (-) = decolorized and accept red counterstain = thin walled cells which couldn’t hang onto the first color

aerobic vs. anaerobic

aerobic = use oxygen to perform aerobic respiration where oxygen acts as the final electron acceptor in the electron transport chain, which produces a high yield of ATP (energy) for cellular processes.

anaerobic = doesnt require oxygen, They rely on anaerobic respiration or fermentation to produce energy, less ATP produced but more sustainable

bacteria biochemical and cultural characteristics

varying levels of bacterium’s ability to grow in environs w/ varied temp and acidity

flagella

hair like processes covering bacterias surface and give motility

endospores

spherical structures produced by bacterial cells that can survive extreme conditions

describe staphylococci

• normal inhabitants of skin and nasal cavity

• type of bacteria, generally not pathogenic, but some are very virulent

  • nonpathogenic ones don’t hemolyze (break down) RBCs

• pathogenic staphlococci: boils, skin infections, post op wound infections, systemic infections

• some strains are antibiotic resistant

describe streptococci

bacterium classified on basis of serologic group and type of hemolysis of RBCs

• serologic = based on antigens on cell walls

• 20 diff groups: important = A,B,D

hemolysis types:

1. Alpha = mouth/throat, no patho

2. Beta = complete hemolysis

Describe antibiotics

substances that destroy bacteria or inhibit their growth

• act on bacteria in many diff ways: inhibit cell wall synthesis, metabolic function, protein synthesis

Describe Viruses

infectious particles with a core of genetic material wrapped in a protein coat (protein spikes, lipid envelope)

• parasitic: require a host cell, don’t independently grow, metabolize, reproduce

• can be latent

• diff viruses target diff tissues

• no cure

• smallpox, rabies, common cold, ebola, flu, HIV/AIDS, SARS, herpes, polio, zika, hepatitis

latent

a virus that is present in the body but is not actively replicating and causing symptoms

treatment for viruses

• no cure, but vax can confer protection

• monoclonal antibodies

• convalescent plasma

• antiviral drugs dont destroy the pathogen

  • inhibit development and slow disease progression, interfere w virus rep, new virus assembly, and attachment of viruses to host cells

protozoa

single celled euk microorgs

• have nuc and organelles

• no viruses!

• most don’t cause disease; many can destroy tissue and induce inflammation

• types = amoeboids, flagellates, ciliates, sporozoans (malaria)

fungi

single or multi celled orgs within a cell wall that contain chitin (polysacc)

• reproductive structures bear spores, known allergens

• mycoses = fungal infections

mycoses

fungal infections

• often opportunistic

• can be endogenous or exogenous

• classified as superficial, cutaneous, subcutaneous, systemic (deep)

History of Tuberculosis

• originally spread animals → humans 100,000 y/a

• many names throughout history: consumption, phyhisis, scrofula, potts disease, white plague

• early disagreement about etiology:

  1. hippocrates ~ hereditary; lungs

  2. aristotle ~ air has smthn in it thats disease producing

Describe the discovery of Tuberculosis etiology

Robert Koch = “father of bacteriology”

• developed new staining method to view pathogens under a microscope

• won nobel prize in physiology in 1905

• confirmed TB not hereditary

TB pathogenesis

pulmonary TB: affects lungs (85% of cases, contagious)

extrapulmonary TB: affects other sites (skin, kidney, skeleton, brain, not contagious)

describe modern day TB (1880s-1940s)

contagious and airborne infectious disease

• sanatoriums = first PH step, not effective in curbing TB

• curable and preventable in 1940’s with first antibiotic

• no longer a significant effect to wealthy nations

TB burden

a top COD worldwide in 2015 (more than HIV/AIDS)

only 5-15% of TB infection will develop active TB

• # deaths fell 1/3 between 2000-2017

• 90% of all TB cases are adults

• male to female = 1.6:1

• 55% of TB patients globally have documented HIV+ test result

• wide variation in case fatality ratio (5-20%)

TB transmission

direct transmission: spread when people sick with pulmonary TB expel bacteria into the air (droplets can hang in air for hours)

• ppl with active, untreated TB infect 10-15 ppl/yr

Immune response to M.tuberculosis

macrophages try to contain pathogen by phaocytosis: if not killed, break out of phagocytic vesicle and multiply inside macrophage

• after several phases, tubercule is formed

• spread through blood stream and lymph that drain to lungs

Tubercule

tumor-like module: lumps of scar tissue where bacteria can remain dormant for decades/lifetime

Latent TB infection and TB Disease

Latent Infection:

• no symptoms, doesnt feel sick

• cannot spread TB bacteria to others

• usually has a skin/blood test result indicating TB infection, normal chest xray and sputum smear

• needs treatment for latent TB to prevent disease

Disease:

• has TB symptoms, usually feels sicks

• may spread TB bacteria to others

• usually has a skin/blood test result indicating TB infection, may have abnormal chest xray or positive sputum smear or culture

• needs treatment to treat TB disease

TB symptoms

bad cough lasting 3+ weeks, pain in chest, coughing up blood/sputum, weakness or fatigue, weight loss, no appetite, chills/fever/night sweats

TB: Latent VS. Disease

• 5% develop TB disease in first 2 years after infection

• after first 2 years of infection, 5% risk of reactivation (developing TB disease)

• risk of reactivation 10-15% per year for HIV+ patients

Broadly describe testing for TB

there are several types of tests:

• testing that doesn’t initiate treatment

• tests that does initiate treatment

describe tests for TB that don’t initiate treatment

1. tuberculin skin test: tells if youve been infected (2 visits, if + → additional testing)

2. blood test: tells if infected, addtnl testing required

3. chest xray: nonspecific, insufficient to begin treatment

describe tests that initiate treatment

1. sputum spear microscopy = look for presence of bacteria

   • koch’s method

2. culture methods

   • current standard but require a lab, many weeks

   • allows testing for drug susceptibility

3. rapid molecular tests - PCR assay

   • can be used on pulmonary TB and certain forms of extrapulmonary TB

   • better accuracy than microscopy

TB prognosis

often treatable: many treatments are old (60’s antibiotic)

without treatment, 1/3 theory

• 1/3 die, 1/3 self cure, 1/3 remain infectious

Treatment of drug-susceptible TB

New cases (never treated before) - category 1 regimen (85% success rate)

• 6 month regimen of 4 first line drugs

  • isoniazid, rifampicill, ethambutol and pyrazinamide

• daily dosing

• supplied by global TB drug facility ($40/person)

failed or interrupted treatment (60-80% success rate)

• old guidlines = cat 2 regimen = 8 months of first line drugs + injectable antibiotic for 2 months (stopped in 2017 due to AMR concerns)

• new guidelines = drug susceptibility testing

  • if not resistant, repeat cat 1 regimen

  • if resistant, move to MDR-TB regimen

Describe antibiotic resistance

resistant bacteria can travel: food, people, animals, international borders

• 3 million abx resist infections/year

• antibiotics kill both good and infectious bacteria in body: nonspecific utility of antibiotics → body may be unable to fight these resistant bacteria

• most susceptible bacteria die first, leaving resistant bacteria → multiply to create a more hearty disease

What are bacterial resistant mechanisms / defense strategies?

1. restrict access of the antibiotic

2. get rid of the antibiotic

3. change or destroy the antibiotic

4. bypass the effects of the antibiotic

5. change the targets of the antibiotic

treatment for drug-resistant TB

requires use of second line drugs ($, more toxic, long), regimen shortened to 9-12 months (decreased cost, $1000)

• every TB antibiotic has 1+ resistant strain

• not all MDR-TB is curable: 52% cure rate, 28% cure rate for extensively resistant TB (XDR-TB)

• only ¼ needing MDR-TB treatment were enrolled in it

describe DOTS

DOTS = directly observable therapy

• clinical intervention + community based PH

• monitor medication intake; monitoring done by nurse or health dep outreach member

• increases liklihood of completing therapy

  • 90% on DOT vs 60% self admin

• patient-centered approach: removing barriers, education, incentives

Vaccines for TB

Bacille Calmette-Guerin (BCG) vaccine

• developed in 1921, can prevent TB in kids, widely used, given to all infants in high burden areas

• no vax effective in preventing TB in adults

• 13 vaxes in phase 1,2,or 3

describe TB prevention

treatment of latent TB prevention, infection control to prevent transmission, vax of children with BCG vaccine in high risk areas/indivis

describe the WHO end TB strategy

goal by 2030, written in 2015:

80% drop in new TB cases, 90% drop in TB deaths, 100% of TB affected families protected by catastrophic costs

• 43m lives saved, 47% decrease mortality rate, 32% decline in HIV related TB deaths, MDR-TB treatment increased

What are the Pillars of ending TB

1. integrated patient centered care and prevention

2. bold policies and supportive systems

3. intensified research and innovation (vaxes tools)

Describe the financing of TB

$8.3 billion dollars spent in 2016, $1.4 billion funding gap

• low income countries rely on international donors for 90% funds

• funding gap for research = $1.3 billion

describe the most common influenza pandemic

H1N1 = recurring through time

• many major influenza subtypes since 1885

• very common because it is unstable and easy to recombinate

The flu vs. influenza (seasonal)

“the flu” = the public description of cold like symptoms; nonspecific symptoms

• “ILI” = influenza-like-illness

• may or may not be caused by influenza virus

influenza = substantial morbidity & mortality, predictable and persistent (yr-to-yr & seasonally), has an infrastructure for prevention

Describe respiratory viruses

RSV, Flu A, Flu B, Corona, Adeno, Paraflu

• PH implications of influenza vs. other = significant because it mutates quickly

Influenza Symptoms

start 2 days (1-4) after infection

• systemic = fever, headache, myalgia, malaise

• respiratory tract symptoms

• possibility for superinfection: secondary bacterial pnemonia

  • large contributer to morbidity/mortality of influenza

  • possible resistance

Influenza transmission

1. direct: inhalation of aerosolized viral particles

2. indirect: contacting a contaminated surface

   • virus can survive for several hours on fomites

   • avian influenza - water and feces

Influenza etiology

Orthomyxoviruses: 3 species classified by core proteins

1. Influenza A: most signif, highly pathogenic in humans, very virulent

   • seasonal outbreaks peaking during winter

   • affects many mammals and birds

2. Influenza B: human illness, less common, less pathogenic

   • seasonal outbreaks

   • humans and seals

3. Influenza C: mild disease, no seasonal variation

   • humans and pigs

Influenza Pathogen

Transmitted through droplet contact from coughing and sneezing; most efficient when virus reaches lower respiratory tract

• enveloped RNA, segemented genome 80-120nm

Influenza type A: enveloped by a protein based core, Neuraminidase (NA) on outside, Hemagglutinin (HA) on outside, M2 ion channel protein

• B has diff channel ion protein

Describe Hemagglutinin and Neuraminidase

viral proteins on surface of influenza virus

• Hemagglutinin binds the virus to the cell being infected

• Neuraminidase is the protein enzyme that helps the virus enter cell walls

How is Influenza named

viral proteins that both identify themselves and are the mechanism by which that pathogen can enter host cells

• H1N1, H2N2, etc.

WHO/CDC naming convention:

antigenic type, host of origin if not human (determined by sampling), geographical origin, strain number, year of isolation, & for influenza A designate H and N antigen description

• 6 H types & 3 N types contribute to disease in humans

A / Perth / 16 / 2009 (H3-N2)

Attachment and Entry of Influenza

wants to get into cell to release its viral RNA so that it can use cells machinery to rep (viruses are not cells, theyre just particles with RNA)

1. binds through hemagglutinin

2. binds to receptors on cells

3. secrete Neuraminidases to break down cell structure

4. create pit allowing virus to go deeper into cytosol

5. adopted in, move enveloped in membrane

6. fuse, burst, use cell for RNA

Describe the age specific morbidity and mortality of influenza

RIR = relative illness ratio (% sick in age group : & pop in age group)

• worst symptoms and RIR in younger individuals

RMR = relative mortality ratio

• ratio >1 indicates an excessive risk

• older adults affected more by superinfections

Influenza Seasonality

A and B peak in winter months in both hemispheres, infections mapped by morbidity week (defined start of influenza surveillance szn)

• 24-25 szn starts oct.1

tied to bird migration patterns

Antigenic variation: influenza shift vs. drift

antigenic shift = abrupt, major changes in virus resulting in new proteins to be produced

• only occurs in A because its the only one that shares recombinant species

• 2 subtypes of virus infect same host, exchange genetic components and new surface molecules

antigenic drift = small changes in the genes of viruses that happen continuously over time

• require targeted annual vaccine

1918 influenza pandemic

young ppl affected, lasted many years, started developing natural immunity

• 1944 = development of inactivated flu vaccine (UM SPH dr. thomas francis jr and jonas salle)

• 1945=military and students; 1946=civilian

1957 influenza pandemic

first flu pandemic with a vaccine

• didnt hear much about this one because able to curb # cases and core outcomes from 1 mil to 70k

• developed vax in 4 months after identifying the new pathogen because they had the right tools

seasonality: knew when its coming —> start production early