PHRM2005 Respiratory Infections Part 1 Notes

Respiratory Infections Part 1

Overview of Respiratory Tract

  • The respiratory tract includes:
    • palate
    • tongue
    • sinuses
    • larynx
    • trachea
    • bronchi
    • bronchioles
    • alveoli
  • Defensive structures:
    • Defensive ring of lymphoid tissue
    • Tonsils
    • Cervical lymph nodes
    • Tracheobronchial lymph nodes
    • Alveolar macrophages

Lecture Outline

  • Review of respiratory tract first-line defenses.
  • Overview of common respiratory tract residents and disease-causing pathogens.
  • Specific infections:
    • Common cold (Rhinitis)
    • Throat infections (Streptococcus pyogenes)
    • Infectious mononucleosis (Epstein-Barr Virus)
    • Diphtheria (Corynebacterium diphtheriae)
    • Whooping Cough (Bordetella pertussis)

Anatomy and Affected Areas

  • Rhinitis: Rhinovirus, Coronavirus.
  • Sinusitis: Haemophilus influenzae
  • Pharyngitis: Streptococcus pyogenes
  • Laryngitis: Parainfluenza virus
  • Tracheitis: Viruses
  • Bronchitis: viruses
  • Bronchiolitis: Respiratory Syncytial Virus (RSV)
  • Pneumonia: influenza virus

Normal Flora of the Respiratory Tract

  • Common Residents (>50% of normal people):
    • Oral streptococci
    • Neisseria spp.
    • Branhamella
    • Corynebacteria
    • Bacteroides
    • Anaerobic cocci (Veillonella)
    • Fusiform bacteria
    • Candida albicans
    • Streptococcus mutans
    • Haemophilus influenzae
  • Occasional Residents (<10% of normal people):
    • Streptococcus pyogenes
    • Streptococcus pneumoniae
    • Neisseria meningitidis
  • Uncommon Residents (<1% of normal people):
    • Corynebacterium diphtheriae
    • Klebsiella pneumoniae
    • Pseudomonas
    • E. coli
    • C. albicans (especially after antibiotic treatment)
  • Residents in Latent State in Tissues:
    • Lung: Epstein-Barr virus, Pneumocystis jirovecii
    • Lymph nodes: Mycobacterium tuberculosis
    • Sensory neurone/glands connected to mucosae: Cytomegalovirus (CMV), Herpes simplex virus

Types of Respiratory Infections

  • Restricted to Surface:
    • Examples: Common cold viruses, Influenza, Streptococci in throat, Chlamydia (conjunctivitis), Diphtheria, Pertussis, Candida albicans (thrush).
    • Consequences: Local (mucosal) defenses important; adaptive (immune) response sometimes too late; short incubation period (days).
  • Spread through Body:
    • Examples: Measles, mumps, rubella, EBV, CMV, Chlamydophila psittacia, Q fever, Cryptococcosis.
    • Consequences: Little/no lesion at entry site; microbe spreads, returns to surface for multiplication/shedding; adaptive immune response important; longer incubation period (weeks).

Respiratory Pathogens: Obligate or Opportunistic

  • Professional Invaders (infect healthy respiratory tract):
    • Requirement: Adhesion to normal mucosa, ability to interfere with cilia, resist destruction in alveolar macrophage, damage local tissues.
    • Examples:
      • Respiratory viruses (influenza, rhinoviruses)
      • Streptococcus pyogenes (throat)
      • Strep. pneumoniae
      • Chlamydia
      • Bordetella pertussis, M. pneumoniae, Strep. pneumoniae (pneumolysin)
      • Legionella, Mycobacterium tuberculosis
      • Corynebacterium diphtheriae (toxin), Strep. pneumoniae (pneumolysin)
  • Secondary Invaders (infect when host defenses impaired):
    • Initial infection and damage by respiratory virus:
      • Staphylococcus aureus; Strep. pneumoniae
    • Local defenses impaired (e.g., cystic fibrosis):
      • Staph. aureus, Pseudomonas
    • Chronic bronchitis:
      • Haemophilus influenzae, Strep. pneumoniae
    • Depressed immune responses (e.g., AIDS):
      • Pneumocystis jirovecii, cytomegalovirus, M. tuberculosis
    • Depressed resistance (e.g., elderly, alcoholism):
      • Strep. pneumoniae, Staph. aureus, H. influenzae

Rhinitis - Common Cold

  • Most common infections of the nasopharynx are viral.
  • Many types: Rhinoviruses and coronaviruses (>50%).
  • Viral surface molecules bind to host cells, cilia, or microvilli .resist removal by mucus flow.
  • Spread locally on mucosal surface.
  • Symptoms due to damage to epithelial surface and release of inflammatory molecules.
  • Damage caused by viruses on the epithelium may result in secondary infections by resident, opportunistic bacteria.
  • Transmission by sneezing (aerosols) and contaminated hands.

Streptococcus pyogenes

  • Gram-positive cocci, group A β-haemolytic (appearance on blood agar plates).
  • Most common bacterial cause of sore throat (strep throat).
  • Virulence factors:
    • Encapsulated (avoids phagocytosis).
    • Factors that allow attachment to mucosal epithelium.
    • Toxins and enzymes (e.g., hyaluronidase, DNase) cause damage and invade locally.
  • Treatment: Readily treated with penicillin.
  • Occasional complications:
    • Scarlet fever: Toxin spreads, producing a characteristic rash.
    • Rheumatic fever: Cross-reactivity between antibodies and self-antigens; can lead to heart damage.
    • Mimicry: meromysin in cardiac muscle

Streptococcus pyogenes - Haemolysis

  • Haemolysis is the destruction of red blood cells.
  • Three types of haemolysis determined on blood agar plates:
    • Gamma haemolysis: No destruction of RBCs.
    • Alpha-haemolysis: Incomplete destruction of RBCs, greenish halo.
    • Beta-haemolysis: Complete destruction of RBCs, clear area.
  • Beta-haemolysis is characteristic of S. pyogenes; classified as Group A.

Diphtheria – Corynebacterium diptheriae

  • Gram-positive rod with characteristic club-shaped cells.
  • Non-sporing, no capsule, no flagella; characteristic cytoplasmic granules.
  • Not all strains cause disease; some are normal flora.
  • Respiratory diphtheria is caused by strains carrying the toxic (tox) gene.
  • Non-toxin-carrying strains can cause milder symptoms, no pseudomembrane.
  • Diphtheria name derived from Greek, meaning ‘hide, leather’, for the pseudomembrane in pharynx.

Diphtheria - Transmission and Epidemiology

  • Transmission: Between humans through respiratory droplets, secretions, or direct contact.
  • Epidemiology:
    • Uncommon in developed countries due to vaccination programs.
    • Still endemic in S. America, E. Europe, SE Asia, Africa.
    • Prior to vaccination, was the major infectious cause of death in Australia.
  • Mortality: 5-10%

Diphtheria - Treatment and Vaccines

  • Treatment:
    • Treated with antitoxin and antibiotics.
    • Prior to antibiotics, treated with heterologous sera from horses.
  • Prophylaxis:Toxoid vaccine, combined with tetanus and pertussis (DTPa).

Diphtheria - Clinical Features

  • Toxin acts on mucous membranes of respiratory tract, destroys epithelium, triggers inflammation.
  • Inflammatory exudate forms a greyish/green pseudomembrane in the upper respiratory tract.
  • Pseudomembrane can cause acute severe respiratory obstruction, asphyxiation.
  • Physical removal damages underlying tissue.
  • Swollen neck due to enlarged lymph nodes and oedema (“bull neck”).
  • Life-threatening complications from toxin absorption: myocarditis and neuritis (peripheral nerve inflammation).

Diphtheria Pathogenesis

  • Toxin gene is carried by a bacteriophage.
  • Only strains infected by the bacteriophage carrying the toxin gene can cause disease.
  • Example of specialised transduction.
  • Lysogenic conversion following bacteriophage infection results in prophage formation including toxin gene.

Diphtheria Toxin Mechanism

  • Inhibits protein synthesis, resulting in cell death.
  • Consists of two sub-units: A and B.
  • Subunit B binds to receptors on the host cell surface.
  • Subunit A is the toxic segment and inhibits protein synthesis by inactivating elongation factor EF2.
  • Inactivates EF2 by covalently adding an ADP-ribose molecule onto the EF2 protein.
  • A single subunit A molecule is lethal to a cell within hours.

Epstein-Barr Virus (EBV)

  • Also called Human Herpes Virus 4.
  • Widespread, infects nearly everyone.
  • Transmitted through saliva.
  • Causes different diseases in different populations due to genetic predisposition or environmental co-factors.
    • Equatorial Africa: Burkitt’s Lymphoma (genetic rearrangement in B cells).
    • South China, Alaska, Tunisia, East Africa: Nasopharyngeal cancer.
    • Elsewhere: Infectious mononucleosis.
  • Also associated with neurological and hematological diseases.

Infectious Mononucleosis – EBV

  • Glandular fever/mono/“Kissing disease”.
  • Most EBV infections are asymptomatic.
  • EBV is a well-adapted parasite.
  • Some develop infectious mononucleosis after 1-2 months.
  • Symptoms:
    • Fever (~14 days).
    • Sore throat (severe for 3-5 days).
    • Swollen glands.
    • Tiredness.
  • Sometimes associated with “chronic fatigue” like syndrome that lasts for months.

Epstein-Barr Virus (EBV) Infection Cycle

  • Transmitted via saliva.
  • Target cell is naïve B cell.
  • Can also infect epithelial cells.
  • Virus replicates in oro-pharynx before infecting B cells.
  • Naïve B cells become infected in mucosal lymphoid tissues (tonsils) and establish pools of latently infected memory B cells.
  • Reactivation of latently infected memory B cells facilitates infection of epithelial cells in the oro-pharynx.
  • Persistence of EBV in the body is lifelong.

Whooping Cough: Pertussis

  • Causative organism: Bordetella pertussis.
  • Small Gram-negative, aerobic bacillus.
  • Obligate aerobe.
  • Pleomorphic.
  • Transmission: Spread by airborne droplets.
  • Highly infectious respiratory infection.
  • Clinical features: Life threatening in infants.
  • Characterised by violent coughing fits.
  • Clinical disease has three stages: catarrhal, paroxysmal, and convalescent.

Whooping Cough - Clinical Features

  • Catarrhal:
    • Symptoms develop within 5–10 days.
    • Symptoms similar to minor upper respiratory tract infections.
  • Paroxysmal:
    • Numerous, rapid coughs due to difficulty expelling thick mucus.
    • Characteristic "whoop" at the end of the paroxysms.
    • Cyanosis, vomiting, exhaustion, dehydration.
    • Less severe in older children, adults or immunised.
  • Convalescent:
    • Less persistent, paroxysmal coughs that disappear in 2-3 weeks.

Whooping Cough - Pathogenic Mechanisms

  • Bacteria attach to cilia of respiratory epithelial cells (trachea, bronchi and bronchioles).
  • Virulence factors:
    • Filamentous hemagglutinin (FHA) – adhesion
    • Pertussis toxin: Mediates most of the disease
      • Toxin paralyses the cilia
      • Antibodies against pertussis toxin are protective
    • Tracheal cytotoxin – cell wall component that kills epithelial cells
    • Adenylate cyclase toxin – inhibits phagocytic cell functions
    • Endotoxin – LPS

Whooping Cough - Epidemiology

  • Worldwide:
    • WHO estimate 195,000 deaths in 2008
  • Despite vaccination pertussis is prevalent in Australia
    • Epidemics occur every 3-4 years
    • Waning immunity in adults and adolescents contributes
    • Maternal antibodies do not give adequate protection
  • Vaccine schedule has been modified to improve protection
    • Additional boosters and new vaccines
  • Current strategy – minimise exposure if vulnerable infants
    • Booster immunisation of pregnant women - Improves maternal antibodies
    • Booster immunisation for adult family members
    • Improved surveillance

Whooping Cough - Treatment and Vaccine

  • Early antibiotic therapy is recommended - Prophylaxis is used for exposed individuals
  • Current pertussis vaccines are acellular (since 1999) - They contain purified antigens from B. pertussis - Previous whole cell vaccine had adverse reactions
  • Usually combined with diphtheria/tetanus vaccines - Improves immunity to tetanus and diphtheria toxoids - Children given Intanrix Hexa vaccine - Contains 3 antigens: toxoid, haemagglutinin, pertactin - Administration: 6-8 wks, 4, 6 and 18 months, 4 yrs
  • Protective against severe disease but may not prevent mild illness

Summary

  • The upper respiratory tract (URT) contains many resident microbes.
  • Infections may be restricted to surface epithelium, like viruses that cause rhinitis, that can lead to secondary bacterial infections.
  • Streptococcus pyogenes is an occasional resident of the UTR, infects the epithelium and is an obligate pathogen, possessing a number of virulence factors that avoid/damage tissues and immune mechanisms.
  • Corynebacterium diphtheria is an uncommon resident of the URT but only strains containing toxin gene can causes severe respiratory disease, diphtheria. The toxin inhibits protein synthesis resulting in cell death.
  • EVB spread through the epithelium and has a systemic lifecycle.
  • EBV cause infectious mononucleosis in most countries but can cause lymphomas in Equatorial Africa and other cancers in South China and East Africa.
  • Bordetella pertussis causes Whooping cough and carries a number of virulence factors. It affects further down, causing inflammation and congestion of the bronchioles, that is particularly severe in the very young due to their narrowness.