Pathophysiology & Therapeutics: Infectious Diseases

Introduction: Infectious diseases are diseases in which tissue damage or dysfunction is produced by microorganisms.

Despite the availability and use of effective vaccines and antibiotics, and improvement in sanitation, infectious diseases remain an important health problem worldwide.

In high-income countries, infectious diseases are important causes of death among older adults and in immunosuppressed or who suffer from chronic diseases.

In lower-income nations inadequate access to medical care and malnutrition contribute to a heavy burden of infectious diseases. In these regions of the world, five of the ten leading causes of death are infectious diseases, most of these deaths occur in children, with respiratory infections, infectious diarrhea, in addition to them malaria and TB continue to affect millions of peoples. Also diseases as Ebola and Covid 19 affect thousands of people daily.

Key Concepts & Definitions

Contiguous: mean person to person transmission.

Non-contiguous: acquired from sources such as animals, insects, soil, air or originating from normal microbial flora of the body.

Infectious Agents

1. Prions

Modified host proteins lacking genetic molecules (RNA or DNA), it is not virus, e.g. prion that cause mad cow disease.

2. Viruses

Obligate intracellular agent which depend on host in their replication, composed of nucleic acid core (DNA or RNA) surrounded by a protein coat.

3. Bacteriophage & Plasmid

Mobile genetic elements that infect bacteria & indirectly causing human diseases by encoding bacterial virulence factors including adhesion, toxins and enzymes so this will convert nonpathogenic bacteria into virulent ones it make the bacteria resistance to antibiotics.

4. Bacteria

Prokaryotes lacking nucleic acid and endoplasmic reticulum. They have cell wall made of 2 phospholipid bilayer. Two types of bacteria identified by their Gram stain properties: Gram-positive and Gram-negative bacteria.

5. Mycoplasma, Rickettsiae, Chlamydia

These infectious agents are grouped together because they are similar to bacteria (they divided by binary fusion and susceptible to antibiotics) but lack certain structures.

6. Fungi

A primitive microorganism having a rigid cell wall, they are larger and more complex than bacteria and are eukaryotes. Thus, they possess nuclear membranes and cytoplasmic organelles, such as mitochondria and endoplasmic reticulum. There are two basic morphologic types of fungi: yeasts and hyphae.

7. Parasites

Include:

  • Protozoa (one celled parasites)
  • Metazoa (Helminths) multi-celled parasites or worms.
  • Ecto-parasites, i.e., Anthrapodes

Host Barriers to Infection

1. Skin

Normal defenses include:

  • Normal cutaneous flora like Staphylococcus epidermidis.
  • Dense keratinized outer skin layer is constantly shed & renewed.
  • Low PH of skin (5.5) & presence of fatty acids within the layer of skin also inhibit microbial growth.

Failure of local defense occurs with:

  • Mechanical defects (puncture, burn, ulcer)
  • Needle sticks (e.g. may transmit hepatitis B or C).
  • Arthropods and animal bites.
  • Direct penetration.

2. Respiratory System

Respiratory barriers to infections are:

  • Mucociliary blanket that lines the nose & upper respiratory tract, this secreted by goblet cells (trapped the larger microorganisms).
  • Alveolar macrophages & neutrophils recruited to the lung by cytokines, these cells phagocytosed smaller microorganisms (less than 5 micron).
  • Mucosal immunoglobulin (IgA).

Note: The distance that infectious agents travel into the respiratory system is inversely proportional to their size, large particles are trapped in the mucociliary blanket that lines the upper respiratory tract, particles smaller than 5 microns are carried into the alveoli.

Failure of local defense occurs with:

  • Smoking (damage the mucociliary action).
  • Ciliary paralysis by infectious agents producing toxins (including Mycoplasma pneumonia and Bordetella pertussis) that enhance infection by impairing ciliary activity.
  • Damage to epithelial cells of respiratory tract (like in viral infections which result in secondary bacterial infection).
  • Damage to alveolar macrophages (tuberculosis).
  • Lowering of cellular immunity (fungal infection this is called opportunistic infection).

3. Gastrointestinal Tract (GIT)

Normal defenses include:

  • Acidic gastric PH.
  • Viscous mucous secretion.
  • Pancreatic enzymes & bile detergents.
  • Immunoglobulin A (IgA) antibodies, secreted by B cells located in the mucosa associated lymphoid tissues.
  • The normal gut flora.

Break down of these barriers by:

  • Low gastric acidity (by drugs).
  • Killing the bacterial flora (by antibiotics).
  • Damage of intestinal lining epithelium (Rotavirus, salmonella, shigella causing bloody diarrhea).
  • Secretion of enterotoxins (like food poisoning by staph. bacteria) or secretion of exotoxins which result in severe diarrhea (vibrio cholera).
  • Resist gastric acidity (cysts of intestinal amoeba).

4. Urogenital Tract

Normal defenses include:

  • Urination.
  • Normal vaginal flora.
  • Intact epidermal / epithelial barrier.

Failure of local defense occurs with:

  • Obstruction, microbial attachment and local proliferation.
  • Antibiotic use.
  • Direct infection/local invasion.
  • Local trauma (e.g. sexually transmitted diseases).

Notes:

  • Urinary tract is protected from infection by regular emptying during micturition.
  • Urinary tract pathogens (e.g., E. coli) almost always gain access via the urethra (ascending infection) and must be able to adhere to urothelium to avoid being washed away.
  • Women have more than 10 times as many urinary tract infections as men because the length of the urethra is 5 cm in women versus 20 cm in men, making women more susceptible to entry of bacteria from the rectum.

Immune Evasion by Microbes

After bypassing host tissue barriers, infectious microorganisms must also invade host innate & adaptive immunity to successfully proliferate & be transmitted to the host by followings strategies:

  1. Remaining inaccessible to host defenses, either in areas not reachable by antibodies or mononuclear cells (e.g GIT lumen or epidermis), inside cells or enshrouded within host proteins.
  2. Constantly changing antigenic properties.
  3. Inactivating antibodies or complements, resisting phagocytosis, or growing within phagocytes after ingestion.
  4. Suppressing the host adaptive immune response e.g. by inhibiting antigen presentation.

Transmission of Microorganisms

In general, the source of infection is another human, or an animal, or the environment.

  1. Direct from person to person as by aerosols, direct contact as in chicken pox, measles, (contagious).
  2. It may need prolonged intimate or mucosal contact e.g sexually transmitted diseases (Chlamydia, syphilis).
  3. Some respiratory bacteria and fungi are transmitted only when the lesion is opened to the airways e.g in T.B.
  4. Other may take the feco-oral route for transmission (ingestion of stool contaminated food or water) as in cholera, rotavirus.
  5. Other microbes need a reservoir host and transmitted from animal to human.
  6. Others may be transmitted by human blood and its products through vertical transmission (mother-to-child), sexual transmission, unsafe injections, and blood transfusions or dialysis as in HBV, HCV and HIV.

Pathogenesis: How Microorganisms Cause Disease

Infectious diseases involve interplay between microbial virulence factors and host responses. The infectious agents damage the tissue in 3 ways:

  1. Enter the cell and cause death or dysfunction directly.
  2. Injury may be due to local or systemic release of microbial products including endotoxin, exotoxins or super antigens.
  3. Induce host cellular responses which may cause additional damage to the surrounding tissues e.g suppuration, scarring, hypersensitivity reactions.

Spectrum of Inflammatory Responses to Infection

Microbes produce 5 types of tissue reaction:

1. Suppurative (Purulent) Inflammation:

  • This pattern is characterized by increased vascular permeability and leukocytic infiltration, predominantly of neutrophils.
  • The causative organisms are pyogenic bacteria (staphylococci, klebsiella and gonorrhea).
  • Masses of dying and dead neutrophils and liquefactive necrosis of the tissue form pus.
  • Abscesses (local collection of pus) differ in size from tiny to large according to the site and sequelae e.g pyogenic pharyngitis will heal completely while acute bacterial infection of the joint can destroy it within few days.

2. Mononuclear & Granulomatous Inflammation:

  • Diffuse, predominantly mononuclear infiltrates are a common feature of all chronic inflammatory processes, but can be seen in acute inflammation like viral diseases, intracellular bacteria e.g. mycobacterium, intracellular parasites e.g. leishmania & helminthes. For example: plasma cells are abundant in syphilis, lymphocytes predominate in HBV infection or viral infections of the brain.
  • Granulomatous inflammation which is characterized by aggregates of activated macrophages which are called epithelioid cells that may accumulate around an area of necrosis, some of which may fuse together forming a giant cells.

3. Cytopathic-Cytoproliferative Response:

This reaction is characteristic of viral mediated damage to the host cell & these include:

  • Virus may replicate inside the cell → formation of viral aggregate which may be visible as inclusion bodies e.g Cytomegalovirus.
  • Virus may induce cells to fuse and form multinucleated cells (e.g., measles virus or herpes-viruses).
  • May cause focal cell damage → discohesion of the epithelial cells → blister formation.
  • May cause proliferation of the epithelial cells, e.g warts that are caused by HPV.
  • May cause dysplastic changes and cancer formation.

4. Tissue Necrosis

Microbes who secrete powerful toxins cause rapid and severe necrosis that tissue damage is the dominant feature with few inflammatory cells, e.g:

  • Entamoeba histolytica which may cause liver abscess (necrosis)
  • Clostridium perfringens that cause severe cell death just like coagulative necrosis.

5. Chronic Inflammation and Scarring:

Many infections elicit chronic inflammation, which can lead either to complete healing or to extensive scarring. This response represent a major cause of dysfunction for example:

  • Chronic HBV infection may cause cirrhosis of the liver.
  • Fibrosis of the bladder wall caused by schistosomal eggs.

Selected Important Infectious Diseases

Covered in subsequent chapters: Staphylococcal infection, Streptococcal infection, Typhoid fever, Cholera, Mycobacterium Tuberculosis, Syphilis, Leishmaniasis, Hydatid disease, Amoebiasis, Candidiasis, Aspergillosis, HIV, Viral Hemorrhagic Fever, Coronavirus (COVID-19).

Detailed Focus: Staphylococcal Infections

Staphylococcus aureus are gram-positive cocci that cause acute diseases due to direct infection or due to the production of toxins. It is a pyogenic infection (suppurative infections = pus forming).

Types of Staph Infections:

1) Skin and soft tissue infections:

  • Furuncle and Carbuncles: Furuncle (boil): start at the hair follicles → small localized, painful abscess which may rupture → extrude pus to the outside and later on will healing. Carbuncle: it is a more extensive lesion & it is dangerous if it occur on the upper half of the face.
  • Impetigo – a highly contagious skin infection that mainly affects children caused by staphylococcal or streptococcal infection.
  • Skin abscess – a collection of pus that appears as a painful lump under the surface of the skin.
  • Staphylococcal scalded skin syndrome (SSSS) – a more serious condition that mainly affects infants and young children, where staph bacteria release a toxin that damages the skin, leading to extensive blistering.

2) Invasive infections: In a small number of people, a staph skin infection can lead to a more serious, invasive infection deeper within the body. Examples include:

  • Staphylococcal food poisoning is caused by preformed S. aureus toxin present in contaminated food.
  • Septic arthritis, Osteomyelitis, Pneumonia, Endocarditis.
  • Sepsis.
  • Toxic shock syndrome – life threatening condition where bacteria release toxins into the blood, which can cause a sudden fever, vomiting, diarrhea, fainting, dizziness, confusion and a rash.

Detailed Focus: Streptococcal Infections

Streptococci are gram-positive cocci that cause acute suppurative infections of the skin, oropharynx, lungs, and heart valves. It classify into α hemolytic and β-hemolytic. β-hemolytic are typed according to their surface carbohydrate antigens.

  • (Group A) Streptococcus pyogenes: one of the most frequent bacterial pathogens of humans. Diseases are in two categories: 1. Suppurative diseases, including pneumonia. 2. Non-Suppurative diseases occur at sites remote from the site of bacterial invasion.
  • (Group B): colonizes the female genital tract and causes sepsis and meningitis in neonates.

Scarlet Fever:

  • Bacterial infection caused by group A β-hemolytic streptococcus.
  • Most clinical features are caused by its erythrogenic toxin.
  • Most common in children between the ages of 3 and 15 years.
  • Manifested by pharyngitis, sore throat, fever, erythematous rash that make the skin rough like sand paper, most prominent over the trunk and inner aspects of the arms and legs.
  • The face is also involved by rash, usually a small area about the mouth remains relatively unaffected to produce circumoral pallor.
  • The tongue is strawberry tongue with white coating.
  • Importance: should be treated well with antibiotic to avoid late complication like rheumatic fever and glomerulonephritis.