Infection and Disease

Pathology, Infection and Disease

• Pathology: scientific study of a disease• Etiology: cause/ origin of a disease• Pathogenesis: mechanism by which a disease

develops

Pathologists are concerned with etiology and pathogenesis of disease and effect of disease on human body.

Pathology, Infection and Disease

• Infection: invasion or colonization of body by pathogenic bacteria– Also presence of bacteria where they do not belong

• E. coli in urinary tract

• Disease: change of state of health resulting from an infection– Abnormal state– Part of whole body is incapable of performing

normal function

Normal Microbiota

• Normal Microbiota– Normal flora– Permanent residents – Don’t normally cause disease

• Transient Microbiota– Present for days/months/years then disappear

Only certain body areas are colonized:

Nasal epithelium Stomach lining Large intestine

Normal Microbiota

• Skin– Staphylococcus, Micrococcus,

Candida (fungus)– Salt and low pH inhibitory for

others• Eyes– Similar to those on skin– Tears and blinking• Prevent others from colonization

Staph epidermis SEM

Normal Microbiota• Nose & Throat

– S. aureus, S. epidermidis, Haemophilus– Mucus & cilia remove/inhibit most microbes

• Mouth– Streptococcus, Staphylococcus, Lactobacillus– Warm moist environment, food particles as nutrients

SEM of bacteria on the human tongue, most of which are harmless or even beneficial

Normal Microbiota

• Large intestine– E. coli, Lactobaccillus, Enterobacter, Candida (fungus),

Enterococcus– Largest numbers

• Moisture and nutrients

• Urogenital system– Lactobacillus, Staphylococcus, Micrococcus,

Enterococcus, Pseudomonas– Urine flushes out microbes– Low pH inhibits microbes

Factors Affecting Distribution and Composition of Microbiome

• Nutrients• Temperature• pH• Oxygen• Salinity• Sunlight• Host Defenses• Individual Criteria– Age, Diet, Geography, Health, Stress

Normal Microbiota: Host Relationship

• Microbial Antagonism/Competitive Exclusion– Prevent growth of other (pathogenic) microbes• E. coli bacteriocins kill others (Salmonella/ Shigella)

– Alter environment• Lactobacillus lower vaginal/ intestinal pH

– Less desirable for other microbes like Candida

– Compete for nutrients• Growth of C. difficile is kept in check by intestinal

microbiome

Normal Microbiota: Host Relationship

• Symbiosis: relationship between two organisms with at least one dependent on the other– Commensalism: one benefitted, other unaffected• Corynebacteria: NF of eye, no damage/benefit to host

– Mutualism: both benefit• E. coli in gut: nutrients used; synthesizes Vit. K/ B

vitamins

– Parasitism: one benefits at expense of other• Pathogenic microbes

Normal Microbiota: Host Relationship

• Opportunistic Pathogens– Normal Flora: don’t cause disease in their specific

niche– Infection when they access a different environment– Immune suppression– E. coli: mutualistic in large intestine– Pathogen

• UTI• Wound abscess• meningitis

Koch’s Postulates: Etiology of a Disease

• Robert Koch: 1877– Experimental Requirements to determine the microbial

cause of a disease1. The same pathogen must be present in every case of

the disease2. Pathogen must be isolated from diseased host and

grown in pure culture3. Pathogen from pure culture must cause disease when

inoculated into a healthy host4. Pathogen must be isolated from the new host and

shown to be the same as the original organism

Koch’s Postulates

Koch’s Postulates: Exceptions

• Cannot satisfy Postulate 2– Some pathogens cannot be cultured on artificial media

• Viruses (and other oligate intracellular parasites)• Fastidious organisms (mycoplasma)

• Some pathogens cause several different diseases– M. tuberculosis: lungs, bones, skin, internal organs– S. pyogenes

• Some diseases caused by different pathogens– Nephritis (kidney inflammation)– Pneumonia, meningitis, peritonitis

• Viruses that cause Cancer

Disease Classification• Communicable Disease: spreads from host to host (directly/

indirectly)• Contagious Disease: easily spread from host to host

– Influenza• Non-communicable disease: not spread from one host to

another– tetanus

Rusty nails are a prime habitat for Clostridium tetani endospores

Disease Occurence

• Incidence: number of people that develop a disease in a given time period– Indicates the rate of disease spread

• Prevalence: TOTAL number of cases in a given population at a given time– Indicates how long disease affects population

2007: Incidence of AIDS in US: 56,300Prevalence: 1, 185,000

Disease Occurence

• Sporadic: occurs only occasionally in given population– Typhoid fever

• Endemic: constantly present in population– Common cold

• Epidemic: acquired by many people in a given area in a short time period– Influenza

• Pandemic: worldwide epidemic– Some influenza epidemics (H1N1)– SARS– AIDS

Disease Severity/ Duration

• Acute: rapid but short time– Influenza

• Chronic: slow progression, long duration– Mononucleosis– Tuberculosis– Hepatitis B

• Subacute: intermediate between acute and chronic– Subacute sclerosing panencephalitis

• Latent: causative agent remains inactive, can reactivate to produce symptoms– Herpesvirus

Extent of host involvement

• Classify infections based on the affect on host– Local infection: relatively small area• Abscess, boils

– Systemic (generalized): spread through the body by blood/ lymph• Local infection can also get systemic• measles

– Focal infection: start in one area but spread to another confined area via blood/ lumph• Dental plaque linked to heart disease

Extent of host involvement

• Sepsis: whole body inflammation by microbial spread

• Septicemia: blood poisoning – Systemic infection from pathogens multiplying in blood– Toxemia, Bacteremia, Viremia

• Primary infection: acute infection causing initial illness

• Secondary infection: opportunistic pathogen infection because of weakened immune system

Steps in disease development• Incubation Period

– Before signs and symptoms appear• Prodromal period

– Early, mild, non-specific symptoms appear• Period of illness

– Disease specific symptoms– Symptoms most severe– Immune system overcomes pathogen OR patient dies

• Period of decline– Symptoms subside– Vulnerable to secondary infections

• Period of convalescence– Body returns to pre-diseased state

Patient can be infectious at EVERY stage of disease

Patterns of disease

For disease to occur, the following conditions need to be met: Reservoir of infection

Source of pathogens Transmission

Route from reservoir to host Invasion

Pathogen enters host and multiplies Pathogenesis

Causes damage to host

Reservoirs of infection

• Human– Lacking disease symptoms

• Carriers

• Animal reservoirs– Zoonoses

• Animal diseases transmitted to humans• Rabies, Lyme disease

• Non-living reservoir– Contaminated water

• Vibrio, Salmonella

– Soil• Clostridium• Fungi (ringworm)

Reservoirs of infection: Carriers

Typhoid fever = infection of Salmonella typhi characterized by high fever, headache and diarrhea

• Spread only through human feces

Chronic carriers: recovered patients that harbor S. typhi in gall bladder – may shed bacteria indefinitely

“Typhoid Mary” Mallon• Early 1900s – worked as a cook in NY• Linked to several typhoid outbreaks and deaths• Numerous attempts to restrain her from food industry

Transmission of infection: Contact

• Direct• Indirect (fomites: inanimate objects)• Droplet (mucus; travel < 1m)

Transmission of infection: Vehicles

• Waterborne– Contaminated with feces

• Foodborne– Improperly cooked/ stored/ prepared

• Airborne– Travels > 1m to host– Fungal spores, TB, measles

Transmission of infection: Vectors

• Mechanical– Flies sit on feces, sit on food– Pathogens ingested

• Biological– Insect bites infected host– Pathogen replicates in insect– Insect bites uninfected host and transmits

pathogen– Lyme disease, Dengue, plague, malaria

Nosocomial Infections

• Direct Contact– Staff to patient– Patient to patient

• Indirect Contact– Fomites (Catheters, needles)– Airborne (ventilation system)

Prevention of transmission• Aseptic Technique/ Sterilization of equipment• Hand washing• Proper handling/ disposal of contaminated material

Transmission in hospitalsNosocomial infections in the United States• Eighth leading cause of death• Occur because of three factors:

Presence of pathogens Chain of transmission Immune compromised host

Nosocomial infections: most common sites

Invasion and Pathogenesis

• Host v/s pathogen– Host defenses prevent invasion by pathogen• No disease

– Pathogen outwits host defenses• disease

Predisposing Factors

• Alter disease susceptibility• Alter disease course• Genetics– Sickle cell disease

• Heterozygous: sickle cell trait• Homozygous: sickle cell disease

– Deliver less oxygen– Stuck in capillaries– Anemia, organ failure

– Highest prevalence in West Africa– Confers resistance to MALARIA

Predisposing FactorsGenetic predisposing factors continuedMalaria = infectious disease caused by the proliferation of the eukaryotic parasite plasmodium in RBCs• Vector = mosquito

• plasmodium can’t multiply in sickled cells

So… While sickle cell disease is very unfavorable, sickle cell trait provides heightened survival in malaria

prone areas • ensures retention of sickle cell gene

Predisposing FactorsOther predisposing factors:• Environment (nutrition, occupation, lifestyle, climate)• Age • Immunity• Gender

Above: Bear Grylls is environmentally predisposed to all sorts of diseases

Predisposing Factors

Ex) Climate & weather• Increased respiratory diseases in winter• Proximity to others while confined indoors & poor

ventilation• Breathing cold air cough, sneeze, runny nose

transmits pathogens

Invasion

• Portals of Entry: mucous membrane– Conjunctiva: mucous membrane of eyelid and eyeball– Respiratory tract

• Most frequently used portal• Moisture and dust inhaled through nose and mouth• Pneumonia, tuberculosis, influenza

– GI tract• Contaminated food and water• Must survive stomach acid, bile in small intestine• Eliminated in feces: can further contaminate

Invasion

• Portal of Entry: Skin– Impenetrable by microbes

• Unless broken

– Penetrate through hair follicles, sweat ducts– Some fungi and eukaryotic parasites

• Infect unbroken skin • Penetrate intact skin (ex. Hookworm)

Invasion

• Portal of Entry: Parenteral– Deposited under skin or mucous membrane if

barrier broken/penetrated– Cuts, burns, bites, wounds, injections– Tetanus from puncture wound– Malaria from mosquito bite– HepB/ HepC from injection

Invasion

• Size Matters!– Larger the “inoculum” more likely the chance to cause disease– Harder to overcome host defenses

• ID50

– Infectious dose where 50% population is infected– Compare relative virulence under experimental condition

• ID50 of Bacillus anthracis through skin is 10-50 endospores, ID50 through inhalation is 10,000-20,000

• LD50

– lethal dose where 50% of population is killed– Measure of potency of microbial toxin

• botulism toxin LD50 = 0.03 ng/kg; Shiga toxin LD50 = 250 ng/kg

Invasion

• Adherence– Adhesins on microbe to bind to cell receptors– Primarily glycoproteins and lipoproteins

• Bind host receptors: sugars (mannose)

– Adhesins can bind other bacteria• Actinomyces bind glycocalyx of S. mutans on teeth

– Biofilms• Microbes bind to living/non-living • Dental plaque, algae on swimming pool walls, scum on shower stalls• First microbes in biofilm usually bacteria• Can colonize heart valves, catheters, contact lens

– Difficult to treat with antibiotics

Need to avoid host defenses to survive• Antiphagocytic factors– Capsules, cell wall proteins (M-proteins)– coagulase (walls off)– survival in WBC - intracellular parasites

(mycobacteria, Listeria)• Opportunistic pathogens need compromised host• Antigenic Variation

N. meningitidis crosses blood-brain barrier

How do bacteria damage the host?

• Endotoxin• Exotoxins– Toxins acting on cell membranes– Toxins active inside cells– Superantigens–Non-specific proliferation

of T-cells cytokines

Exotoxins

– Proteins expressed by bacteria during replication– Secreted into media or released on lysis– Made by some gram (+) and gram (-) bacteria– Water soluble, easily diffuse into lymph/ blood– Extremely lethal• Cholera Toxin

– Causes cells to secrete fluids & electrolytes diarrhea

• Tetanus neurotoxin– Binds nerve cells, prevents muscle relaxation, causes

convulsive muscle contractions

Endotoxins

• Part of bacterial cell wall– Outer membrane of gram (-)– Lipid A of LPS– Released on cell death– Symptoms for all endotoxins same• Chills, fever, aches• Shock (decrease in BP)

– S. typhi – typhoid fever– Neisseria meningitidis: meningococcal meningitis

Exotoxins & Endotoxins Compared

Signs and Symptoms

Signs: Objective findings observed by healthcare worker

Symptoms: patient complains in own words

Epidemiological TriadThe traditional model of infectious disease causation. Includes three components: an external agent, a susceptible host, and an environment that brings the host and agent together, so that disease occurs.

Science that evaluates the occurrence, determinants, distribution, and control of health and disease in a defined human population

Epidemiology-

Definitions

• Epidemiology– is the study of the behavior of disease in a

community rather than individual patients. Its incidence and spread.

– It includes the study of the reservoirs and sources of human diseases.

• Epidemiologists – looks at the factors involved in the occurrence and

spread of disease within populations of humans or animals.

• AIM: – To understand the mode of transmission and what

predispose a population to a particular agent

Types of studies: Descriptive1. Retrospective• Determine the source/ cause of infection

after the fact• Cholera outbreak in Britain 1848-1849• SARS

2. Prospective• Follow a group of healthy people • Study the effect of subsequent disease• Salk polio vaccine• UF Flu study

Types of Study: Analytical Epidemiology

Analyze particular disease to determine cause1. Cohort– Two populations

• One who had contact with disease• Those that had blood transfusions v/s not

– Hep B association

2. Case-control– Identify factors that preceded disease

• Compare diseased v/s disease-free individuals• Matched by sex, age, socioeconomic status, location

Experimental Epidemiology

• Hypothesis• Experiments to test hypothesis• Drug Effectiveness– Select infected people– Randomly select those that get drug v/s placebo– Compare results