Respiratory diseases

Upper respiratory tract
1. Infections of the URT are most common
2. Pathogens that enter the repiratory tract can infect any other parts of the body
  1. Gateway for infection
3. Structures of the URT
  1. Nose - external part of the respiratory system
  2. Nasal cavity - internal part of the nose, lined with ciliated mucous membranes and hairs (acts as a filter/trap for particles)
  3. Pharynx - lined with ciliated mucous membranes that pushes contaminents into the digestive tract
  4. Tonsils - aggregations of lymphoid tissue
  5. Mucous - contains antimicrobial agents
4. Functions
  1. Exchange of gases between the atmosophere and blood
  2. URT - collects and filters air before delivering it to the lower respiratory tract (LRT)
    1. LRT - Gas exchange
5. Infections of the URT (sinuses and ears)
  1. Diptheria
    1. Caused by: Cornybacterium diptheriae
      1. Pathogen and virulence factors: virulent C. diptheriae produces diptheria toxin which inhibits polypeptide synthesis - causing cell death
        Diptheria toxin inhibits protein synthesis (at the ribosome) and can cause heart, renal or nerve damage
    2. Signs and symptoms: sore throat, oozing fluid that hardens into a pseudomembrane that can obstruct the airways
    3. Pathogenesis + epidemiology: Spread via droplet infection or skin contact, causes symptomatic infection in both immuno- / non-immunocomprimised people
      1. Still common in developing countries - 40-50% of untreated patients die
    4. Diagnosis: based on clinical picture and presence of pseudomembrane
      1. Rarely by microscopy: Gram positive rods (with clubbed ends) seen in two formations: V-sahpes (two bacteria) or palisade arrangement (multiple)
      2. Pseudomembrane is diagnostic (= fibrin, dead cells and bacterial cells)
    5. Treatment and prevention: antitoxin and antibiotics, immunization (vaccine = DTaP) is an effective prevention
      1. Abx = Penicillin G, erythromycin or metronidazole
    6. Cutaneous form (especially in people >30yrs) - infected skin wound results in a slow healing ulcer
  2. Otitis media (infection of the middle ear) and sinusitis
    1. Causes: various bacteria including; Strep pneumoniae (35%), Staph aureus (1-2%), Haemophilus influenzae (20-30%), Moraxella catarrhalis (10-15%)
    2. Can occur as a complication of nose/throat infection
    3. Signs and symptoms: (sinusitis) pain of the affected sinus with malaise; (otitis media) ear pain +/- fever
Lower respiratory tract
1. The LRT is usually sterile due to the action of the ciliary escalator
  1. Microorganisms hoping to infect the respiratory tract are trapped in the sticky mucous membrane of the tract and moved towards the oesophagus
2. When bacterial infection of the LRT occurs, life-threatening illness can result
3. Bacterial pneumonia
  1. Inflammation of the lungs accompanied by fluid filled alveoli and bronchioles
  2. Can bedescribed by either the location of the infection or the causitive organism (e.g. lobar pneumonia, involving the entire lobe)
  3. Most serious and frequent in adults
  4. Primary atypical (mycoplasma) pneumonia
    1. Cause: Mycoplasma pneumoniae
      1. Virulence factors: adhesion protein
    2. Signs and symptoms: fever, maaise, sore throat, excessive sweating
    3. Epidemiology: droplet infection (nasal secretions)
    4. Diagnosis: microscopy (mycoplasma bacteria - with capsule), PCR, cold agglutination test, clinical picture
      1. Advaced techniques: PCR and serological testing (capsule)
    5. Treatment: Abx = tetracyclin and erythromycin
    6. Prevention: difficult as individuals can be infective without symptoms
  5. Common causes of classical pneumonia: G+; Strep pneumoniae and Staph aerues; less common = G-; Haemophilus influenzae, Klebsiella pneumoniae etc.
    1. Strep pneumonia = G+ diplococci (with capsule)
  6. Klebsiella pneumonia
    1. Cause: K. pneumoniae
      1. Virulence factors: a capsule
    2. Signs and symptoms: typical pneumoniae symptoms with thick bloody sputum and reccurent chills
    3. Epidemiology: Immunocomprimised indicviduals at greatest risk
    4. Diagnosis: microspcopy (G-, bacilli), culture (facultative anaerobe, lactose fermenting)
    5. Treatment: Abx = aminoglycosides (kanamycin, amikacin, streptomysin) and cephalosporins
    6. Prevention: good aseptic technique by healthcare workers
  7. Other bacterial pneumonias
    1. Causes: Strep pneumonia, Haemophilus influenza, Staph aureus, Yersinia pestis (plague) and Chlamydial spp.
    2. Portal of entry: inhalation (Y. pestis can infect via blood as well)
    3. Signs and symptoms: typical pneumonia symptoms, with frothy, bloody sputum in the case of Y. pestis
    4. Incubation period: variable depending on the causitive organism (although Y. pestis can cause symptoms within hours)
    5. Epidemiology: typically young children more susceptibile
    6. Treatment: amoxicillin (Strep pneumoniae), flucloxacillin (S. aureus), doxycycline (H. influenzae and Chlamydial spp) and Streptomycin/gentamycin (Y.)
    7. Prevention: good hygiene; vaccine available for H. influenzae
  8. H. influenzae pneumonia
    1. Gram negative coccobacillus
    2. Predisposing factors: alcoholism, poor nutrition, cancer or diabetes
    3. Signs and symptoms: similar to pneumococcal pneumonia (Strep pneumonia)
    4. Diagnosis: isolation; special media for culture requirements (Chocolate agar with added factors; X ( haem) and V (NAD))
    5. Treatment: cephalosporins
  9. Legionellosis
    1. Cause: Legionella pneumophila
      1. G- rod
      2. Found in water
      3. Transmitted by aerosols (not human to human)
    2. Signs and symptoms: potentially fatal; mutli system involvement (including; lungs, kidneys, liver, CNS and GIT)
    3. Diagnosis: culture on selective media (CYE media with added iron and cysteine), poor Gram stainer (stains with silver)
      1. Advaced: Sera agglutination test, fluorescent Ab's, ELISA or DNA probe (fluorescent probe for L. pneumoniae genes)
    4. Epidemiology: The elderly, smokers and immunocomprimised individuals are highest risk
    5. Treatment: Quinolones or macrolides
    6. Prevention: reduction o bacterial presence in water sources
    7. Pathogenesis: L. pneomoniae kills human cells causing tissue damage and inflammation
      1. Require macrophage uptake -> reside within endosome and divide (inhibit lysosome fusal by injecting effector proteins into macrophage)
        Effector proteins injected via a Type IV secretion system called Dot/ICM)
        This causes the endocytotic vesicle to recruit ER membrane and form a protective vacuole in which it divides
        Stimulates a massvie immune response in tissues - tissue death
4. Other LRT infections
  1. Pertussis (whooping cough)
    1. Cause: Bordetella pertussis
      1. Virulence factors: various toxins
        Pertussis toxin - inhibits Gi proteins (remain GDP-bound and therefore inacitve) meaning adenylate cyclase cannot be turned off - excessive cAMP
        Can cause hypoglycaemia via constant release of insulin
        Adenylate cycalse toxin
        Dermonecrotic toxin
        Tracheal cytotoxin
        Causes ciliated cell damage
    2. Signs and symptoms: Initially cold-like, followed by characteristic cough
    3. Epidemiology: Highly contagious; droplet infection
    4. Pathogenesis: 4 phases - incubation (7-10 days), catarrhal (mild respiratory symptoms), paroxysmal (chronic, uncontrollable coughing with whoops)...
      1. ... and convalescent (reduction and eventual ceasation of coughs)
    5. Diagnosis: symptoms alone are diagnostic
    6. Treatment: primarily supportive (self limiting)
    7. Prevention: with DTaP vaccine
  2. Inhalation anthrax
    1. Cause: Bacillus anthracic
      1. G+, rod-shaped and endospore forming
      2. Virulence factors: capsule and anthrax toxin
    2. Signs and symptoms: Resemble cold/flu, progress to severe coughing, shortness of breath, shock then death
    3. Epidemiology: not person-person transmissible, but acquired through contact and inhalation
    4. Diagnosis: based on identification of bacteria in sputum
    5. Treatment: early, agressive treatment with Abx (doxycycline, erythromycin, vancomycin and penicillin)
    6. Prevention: Anthrax vaccine available to military personnel, researchers and health care workers dealing with anthrax patients
  3. Tuberculosis
    1. Cause: Mycoplasma tuberculosis
    2. Epidemiology: immunocomprimised people at greatest risk (leading killer of HIV patients)
      1. Its global occurence and monitoring of MDR and XDR strains can be achieved by molecular identification
        PCR of variable number tandem repeats (VNTR), RFLP etc.
    3. Pathogenesis: M. tuberculosis remain viable for long periods of time in aerosol drops, there are three types
      1. Primary - initial case of TB
      2. Secondary - reestablished TB
      3. Disseminated - systemic infeciton
      4. 1) Bacteria reaches the alveoli and is ingested by a macrophage, some survive and cause infection but no symptoms
        2) Bacteria replicate in macrophages cause a chemotactic repsonse which recruits further macrophages - fomring a protective layer (tubercle)
        Most macrphages can't kill the bacteria so release enzymes and cytokines that cause a chronic inflammtion (lung damage)
        3) After a few weeks symptoms appear as many macrophages die, releasing more bacteria and creating a caseous centre (necrosis) to the tubercle
        4) In the mature tubercle the caseous centre enlarges (liquefaction) and forms an airfilled centre in whic bacteria can divide outside of macrophages
        5) Liquefaction continues, the tubercle ruptures - bacteria can access; bronchioles for local spread and the blood/lymphatics for systemic spread
    4. Treatment; prolonged Abx treatment - "RIPE" (rifampicin, isoniazid, pyrazinamide and ethambutol)
      1. Problem now: MDR and XDR TB
    5. Prevention: BCG vaccine (live, attenuated M. bovis) - not widely used in the USA
      1. Screening: tuberculin skin test - six needle test thing (can indicate a current or previous TB infection
    6. Diagnosis from specimen (after referal to doctor with persistent cough, >7weeks)
      1. Culture
        Solid media (Jensen-lowenstein) - takes >8 weeks
        If growth positive
        Subculture (for biochemical typing and Abx sensitivity)
        Microscopy
        Molecular biological identification/typing
        PCR (for drug resistence genes, and 16S ribosome)
        Relatively high sensitivity (if smear and culture positive)
        RFLP (restriction fragment length polymorphism) - using restriciton enzymes to cleave homologous DNA
        Differences will be apparent by loss of cleavage sites (and therfore loss different specieis subtype DNA fragment lengths)
        Viewed by agarose gel electrophoresis, transferring to membrane and hybridising with DNA probe (IS6110) - that binds to the conserved IS6100 sequence
        DNA probes (Gen Probe) that hybridise with drug resistence/subspecies specific sequences
        Liquid media (faster)
      2. Smear sputum and stain with Zhiel Neelsen (acid fast) technique
        Microscopy
      3. PCR (fast) - using commercial kits (COBAS or AMPLICORE MTB)
    7. About 1/3 of the world's population infected, with around 10,000,000 new cases each year and 3,000,000 deaths yearly
      1. TB comprise 25% of all avoidable deaths in developing countries
        Highest incidences in India and China
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