Principles of Disease and Epidemiology

Pathology, Infection, and Disease

• Pathology: The scientific study of disease, including its causes (etiology), development (pathogenesis), and the structural and functional changes it produces in the body.

• Etiology: The cause of a disease.

• Pathogenesis: The manner in which a disease develops.

• Infection: The invasion and multiplication of microorganisms in body tissues, which may or may not cause disease.

• Disease: An abnormal state in which the body is not functioning normally.

The Human Microbiome

• The microbiome is established during the first 10 years of life.

• Normal microbiota: Microorganisms that establish permanent residence but do not cause disease under normal conditions.

• Transient microbiota: Present for days, weeks, or months and then disappear.

• Factors affecting microbial growth: temperature, pH, oxygen, CO2, salinity, sunlight.

• Microbial antagonism: Normal microbiota inhibit the growth of harmful microbes (e.g., E. coli maintains pH balance, prevents Candida overgrowth).

• Most gut bacteria are commensal (benefit from the host without affecting it), but relationships can also be mutualistic or parasitic.

• Opportunistic pathogens: Normally harmless but can cause disease in a different environment or in immunocompromised hosts (e.g., E. coli in the urinary tract).

Etiology of Infectious Diseases

• Not all disease etiologies are known.

• Koch's postulates: Experimental criteria to prove a specific microbe causes a specific disease:

  1. The microorganism must be found in all cases of the disease.

  2. It must be isolated and grown in pure culture.

  3. The cultured microbe must cause the disease when introduced into a healthy host.

  4. The microbe must be reisolated from the newly diseased host.

• Exceptions: Some pathogens cannot be cultured, cause multiple diseases, or only infect humans (e.g., HIV).

Classifying Infectious Diseases

• Symptoms: Subjective changes felt by the patient (e.g., pain, malaise).

• Signs: Objective changes observable or measurable (e.g., lesions, swelling, fever, paralysis).

• Syndrome: A specific group of symptoms or signs that always accompany a disease.

• Diseases are classified by their behavior in hosts and populations:

  • Communicable disease: Can be transmitted from one person to another (e.g., COVID-19, measles).

  • Contagious disease: Easily spread from person to person (e.g., chickenpox, influenza).

  • Non-communicable disease: Not spread from host to host (e.g., tetanus).

• Incidence: Number of new cases in a population during a specific time period.

• Prevalence: Total number of cases (old and new) in a population at a given time.

• Frequency of occurrence:

  • Sporadic: Occasional cases.

  • Endemic: Constantly present in a population.

  • Epidemic: Sudden increase in cases in a region.

  • Pandemic: Worldwide epidemic.

• Severity assessment:

  • Infection Fatality Ratio (IFR):

  • Case Fatality Ratio (CFR):

• Herd immunity: Resistance of a population to infection due to immunity of a high proportion of individuals.

• Types of infection: local, systemic, focal, sepsis.

Patterns of Disease

• Predisposing factors: Variables increasing susceptibility (e.g., nutrition, sex, genetics, age, environment, behavior, vaccination status, compromised host).

• Stages of disease development:

  1. Incubation period: Interval between initial infection and first symptoms.

  2. Prodromal period: Early, mild symptoms.

  3. Period of illness: Disease is most severe.

  4. Period of decline: Signs and symptoms subside.

  5. Period of convalescence: Recovery and return to normal.

Spread of Infection

• Reservoir of infection: Source providing a pathogen with conditions for survival and multiplication (human, animal, nonliving).

• Carriers: People who harbor pathogens without symptoms (asymptomatic, incubating, convalescent, chronic, passive).

• Transmission of disease:

  • Contact transmission: Direct or indirect (fomites), droplet transmission.

  • Vehicle transmission: By air, water, or food.

  • Vector transmission: Animals (e.g., insects) transmit pathogens mechanically (on body parts) or biologically (bite, feces).

Healthcare-Associated Infections (HAIs)

• HAIs: Infections acquired during treatment for other conditions in healthcare settings (also called nosocomial infections).

• Common pathogens: Staphylococcus aureus, Clostridioides difficile, Enterococcus, E. coli.

• Compromised host: Weakened resistance due to broken skin/mucosa or suppressed immune system.

• Transmission routes: Direct contact (staff to patient, patient to patient), indirect contact (fomites), airborne (ventilation).

• Control: Universal, standard, and transmission-based precautions (contact, airborne, droplet).

Emerging Infectious Diseases (EIDs)

• Diseases that are new, changing, or increasing in incidence.

• Contributing factors: New strains/serovars, antibiotic/pesticide use, genetic instability, global warming, modern transportation, vector spread, vaccination failures, bioterrorism.

Microbial Mechanisms of Pathogenicity

How Microorganisms Enter a Host

• Pathogenicity: Ability to cause disease by overcoming host defenses.

• Virulence: Degree of pathogenicity.

• Portals of entry:

  • Mucous membranes (respiratory, digestive, genitourinary tracts, conjunctiva)

  • Skin (through hair follicles, sweat glands)

  • Parenteral route (direct deposition beneath skin or mucous membranes)

• Preferred portal of entry is often required for disease (e.g., Salmonella must be ingested).

• ID50: Infectious dose for 50% of the population.

• LD50: Lethal dose for 50% of the population (for toxins).

• Adherence: Pathogens attach to host tissues via adhesins/ligands binding to host cell receptors (e.g., viral capsid proteins, bacterial fimbriae).

How Bacterial Pathogens Penetrate Host Defenses

• Capsules: Prevent phagocytosis (e.g., Streptococcus pneumoniae).

• Cell wall components: Facilitate adherence or resist phagocytosis (e.g., M protein, Opa protein, mycolic acid).

• Enzymes:

  • Coagulase: Clots blood plasma.

  • Kinase: Digests clots (e.g., fibrinolysin).

  • Hyaluronidase: Hydrolyzes hyaluronic acid (spreading factor).

  • Collagenase: Breaks down collagen.

  • IgA protease: Destroys IgA antibodies.

• Invasins: Surface proteins that rearrange host cytoskeleton, allowing entry (membrane ruffling, macropinocytosis).

• Biofilms: Communities of microbes resistant to phagocytosis and antimicrobials.

How Bacterial Pathogens Damage Host Cells

• Mechanisms:

  1. Using host nutrients (e.g., siderophores for iron acquisition).

  2. Direct damage (cell rupture, macropinocytosis).

  3. Producing toxins (exotoxins, endotoxins).

  4. Inducing hypersensitivity reactions.

• Exotoxins: Proteins produced inside mostly Gram-positive bacteria, secreted or released after lysis. Types include:

  • A-B toxins (A = active, B = binding component)

  • Membrane-disrupting toxins (cause hemolysis, leukocyte lysis)

  • Superantigens (cause excessive cytokine release, e.g., toxic shock syndrome)

  • Genotoxins (damage eukaryotic DNA, may lead to cancer)

• Endotoxins: Lipid A component of lipopolysaccharide (LPS) in Gram-negative bacteria outer membrane; cause fever, inflammation, and shock.

• Antitoxins: Antibodies against toxins.

• Toxoids: Inactivated toxins used in vaccines.

• Detection: Limulus amebocyte lysate (LAL) assay for endotoxins.

• Lysogenic conversion: Bacteriophage genes can confer pathogenic properties to bacteria.

Pathogenic Properties of Fungi, Algae, and Helminths

• Fungi: May cause disease via toxins (e.g., ergotism).

• Algae: Some produce neurotoxins.

• Helminths: Cause disease by mechanical damage or metabolic waste.

Antimicrobial Drugs

History and Principles

• Chemotherapy: Use of chemicals to treat disease (Paul Ehrlich).

• Antibiotics: Discovered by Alexander Fleming; many produced by Streptomyces.

• Selective toxicity: Drugs are toxic to pathogens but not to the host.

Spectrum of Antimicrobial Activity

• More difficult to treat eukaryotic pathogens (fungi, protozoa, helminths) due to similarity to host cells.

• Viruses are hard to treat because they replicate inside host cells and use host machinery.

• Gram-negative bacteria: Outer membrane (LPS) restricts drug entry; only small, hydrophilic drugs pass through porins.

Action of Antimicrobials

• Bactericidal: Kill microbes directly.

• Bacteriostatic: Inhibit growth, allowing host defenses to eliminate microbes.

• Five major modes of action:

  1. Inhibit cell wall synthesis (e.g., penicillins, vancomycin)

  2. Inhibit protein synthesis (target 70S ribosomes; e.g., tetracyclines, erythromycin)

  3. Injure plasma membrane (e.g., polymyxin B, ethambutol)

  4. Inhibit nucleic acid synthesis (e.g., ciprofloxacin, rifampin)

  5. Inhibit synthesis of essential metabolites (e.g., sulfonamides)

Common Antimicrobial Drugs

• Penicillins: Beta-lactam antibiotics; inhibit peptidoglycan synthesis in Gram-positive bacteria.

• Types: Natural, penicillinase-resistant, extended-spectrum, semisynthetic, combinations with beta-lactamase inhibitors.

• Carbapenems: Broad-spectrum beta-lactams (e.g., imipenem, doripenem).

• Monobactams: Single-ring beta-lactams (e.g., aztreonam).

• Cephalosporins: Similar to penicillins; inhibit cell wall synthesis.

• Polypeptide antibiotics: Bacitracin, vancomycin, teixobactin.

• Antimycobacterial antibiotics: Isoniazid, ethambutol, rifampin (target mycobacteria).

• Protein synthesis inhibitors: Chloramphenicol, aminoglycosides, tetracyclines, macrolides, streptogramins, oxazolidinones.

• Antifungals: Target ergosterol synthesis (e.g., fluconazole, clotrimazole, amphotericin B).

• Antivirals: Oseltamivir (influenza), acyclovir (herpesviruses).

• Antihelminthics: Ivermectin, quinacrine, chloroquine.

Tests to Guide Chemotherapy

• Disk-diffusion method: Antibiotic-impregnated disks on agar; zone of inhibition indicates effectiveness.

• E test: Determines minimal inhibitory concentration (MIC).

• Broth dilution test: Determines MIC and minimal bactericidal concentration (MBC).

Resistance to Antimicrobials

• Persister cells: Survive initial antibiotic treatment.

• Mechanisms of resistance:

  1. Block entry of drug.

  2. Inactivation by enzymes (e.g., beta-lactamases).

  3. Alteration of drug target.

  4. Efflux of antibiotic.

• Resistance genes can be transferred vertically (mutation) or horizontally (conjugation, transduction, plasmids).

Microbial Diseases of the Skin and Eyes

Structure and Function of the Skin

• Epidermis: Thin, outer layer of epithelial cells; contains keratin (waterproof protein).

• Dermis: Inner, thick portion of connective tissue; contains hair follicles, sweat and oil glands.

• Perspiration: Moisture, contains salt and lysozyme (antimicrobial).

• Sebum: Oily secretion; nutrients for microbes.

• Mucous membranes: Line body cavities; acidic, contain mucus and lysozyme.

Normal Microbiota of the Skin

• Resistant to drying and high salt.

• Common genera: Staphylococcus, Micrococcus, Corynebacterium, Cutibacterium (formerly Propionibacterium), Malassezia (yeast).

• Produce acids to maintain low pH; some cause dandruff (Malassezia furfur).

Microbial Diseases of the Skin

• Lesion types:

  • Vesicle: Small, fluid-filled lesion.

  • Bullae: Larger fluid-filled lesion.

  • Macule: Flat, reddened lesion.

  • Papule: Raised lesion.

  • Pustule: Raised lesion with pus.

  • Exanthem: Skin rash from disease.

  • Enanthem: Rash on mucous membranes.

• Bacterial diseases:

  • Staphylococcal: S. aureus (coagulase-positive, pathogenic; causes impetigo, scalded skin syndrome, toxic shock syndrome), S. epidermidis (coagulase-negative).

  • Streptococcal: S. pyogenes (Group A; causes impetigo, erysipelas, necrotizing fasciitis).

  • Pseudomonads: P. aeruginosa (opportunistic in burns, produces blue-green pus).

  • Buruli ulcer: Mycobacterium ulcerans (produces mycolactone toxin).

  • Acne: Cutibacterium acnes (comedonal, inflammatory, cystic types).

• Viral diseases:

  • Warts: Caused by papillomaviruses.

  • Smallpox: Variola virus.

  • Monkeypox: Similar to smallpox, less severe.

  • Chickenpox/Shingles: Varicella-zoster virus (HHV-3).

  • Herpes simplex: HSV-1 (oral), HSV-2 (genital).

  • Measles (Rubeola): Morbillivirus; Rubella: Rubivirus.

  • Fifth disease: Parvovirus B19.

  • Roseola: Human herpesvirus 6/7.

  • Hand-Foot-Mouth Disease: Enterovirus.

• Fungal diseases:

  • Cutaneous mycoses: Dermatophytes (e.g., Trichophyton, Microsporum, Epidermophyton); cause ringworm, athlete's foot.

  • Subcutaneous mycoses: Sporothrix schenckii (sporotrichosis).

  • Candidiasis: Candida albicans; more common in immunosuppressed.

• Parasitic infections:

  • Scabies: Sarcoptes scabiei.

  • Pediculosis (Lice): Pediculus humanus capitis (head), P. humanus corporis (body).

Microbial Diseases of the Eye

• Conjunctivitis: Inflammation of the conjunctiva; caused by bacteria (e.g., Pseudomonas, Haemophilus) or viruses.

• Ophthalmia neonatorum: Neisseria gonorrhoeae; risk of blindness in newborns.

• Inclusion conjunctivitis: Chlamydia trachomatis.

• Trachoma: Chronic infection by C. trachomatis; leading cause of blindness.

• Acanthamoeba keratitis: Protozoan infection, associated with contact lens use.

• Herpetic keratitis: HSV-1 infection of the cornea.

Neglected Tropical Diseases

• Protozoan: African trypanosomiasis, Chagas disease, leishmaniasis.

• Helminthic: Taeniasis, cysticercosis, dracunculiasis.

• Bacterial: Trachoma, leprosy, Buruli ulcer, yaws.

• Viral: Dengue, rabies, chikungunya.

Microbial Diseases of the Nervous System

Structure and Protection of the Nervous System

• Protected by bones, meninges, and the blood-brain barrier.

• Microbes can enter via trauma, bloodstream, lymphatic system, or peripheral nerves.

• Lipid-soluble drugs can cross the blood-brain barrier.

Bacterial Diseases of the Nervous System

• Bacterial meningitis:

  • Haemophilus influenzae type B: Gram-negative, capsule, grows in blood/spinal fluid.

  • Neisseria meningitidis: Gram-negative, polysaccharide capsule, endotoxin causes symptoms.

  • Streptococcus pneumoniae: Gram-positive, capsule, common in nasopharynx.

• Treatment: Spinal tap for diagnosis; cephalosporins or vancomycin.

• Listeriosis: Listeria monocytogenes; Gram-positive rod, grows at refrigerator temps, foodborne, can cross placenta.

• Tetanus: Clostridium tetani; endospore-forming Gram-positive rod, produces neurotoxin (tetanospasmin), causes muscle spasms (lockjaw), vaccine targets toxin.

• Botulism: Clostridium botulinum; Gram-positive rod, produces exotoxin blocking acetylcholine release, causes flaccid paralysis.

Fungal, Viral, Protozoan, and Prion Diseases

• Fungal: Cryptococcus neoformans; starts as lung infection, spreads to brain, associated with bird droppings.

• Viral:

  • Polio: Invades lymph nodes, can cause paralysis.

  • Rabies: Transmitted by animal bites, affects CNS, fatal if untreated.

  • Arboviral encephalitis: Transmitted by mosquitoes (e.g., West Nile virus).

  • Zika virus: Mosquito-borne, can cause birth defects.

• Protozoan: African sleeping sickness (Trypanosoma brucei gambiense), Chagas disease.

• Prion diseases: Infectious proteins causing spongiform encephalopathies (e.g., Creutzfeldt-Jakob disease, Kuru, bovine spongiform encephalopathy).

Table: Comparison of Exotoxins and Endotoxins

Table: Major Antibacterial Drug Classes and Their Targets

Additional info: Some explanations and examples were expanded for clarity and completeness, including the tables and the summary of drug classes and mechanisms.