1. Lower respiratory tract infections Mark Jorge
2. Respiratory tract
3. Anatomy of lower respiratory tract- Trachea Trachea – 11-12cm tube, thickened by cartilage, which extends from the larynx into the thoracic cage. It is lined with pseudostratified epithelium, containing ciliated and mucous-secreting cells, and branches to form the left and right primary bronchi. It represents the change from upper to lower respiratory tract.
4. Bronchi One primary bronchus supplies each lung. They are lined with pseudostratified, ciliated epithelium and, on entering the lungs, divide to form the secondary lobar bronchi, one for each lobe of the lungs. Each secondary bronchus divides to produce tertiary bronchi, which in turn produce the bronchioles
5. Bronchial tree This successive branching produces a ‘bronchial tree’ of ever decreasing diameter which is characterised by a gradual loss of cartilage, increase in smooth muscle within the wall and change from columnar to cuboidal epithelium.
6. Lungs Each lung is divided by fissures into lobes: 2 in the left (superior and inferior), 3 in the right (superior, middle and inferior). The lobes are further subdivided into lobules.
The lungs are housed in a pleural membrane.
Within the lobules, the bronchial tree is now at the level of the bronchioles and subsequently the alveoli. It is estimated that the adult human lung contains 300 million alveoli, which collectively offer a total surface area of 70m2 for gaseous exchange.
The lungs therefore, are primarily composed of alveoli, the capillaries of the pulmonary circulation and connective tissue. Adequately perfused lungs may consist of 40% by weight of blood in the circulation.
7. Normal Host Defence Mechanisms Mucocilliary escalator
8. Mucocilliary escalator The normal airway epithelium provides an effective barrier against penetration of inhaled bacteria into deeper lung tissues. The mucocilliary escalator helps remove bacteria that deposit along the airways. Viral infection often compromises the integrity of the epithelial barrier and the effective function of the mucociliary escalator.
10. Bronchitis Inflammation of the bronchial tubes
Tissues become irritated
More mucous then usual produced
Results in cough
11. Acute bronchitis Only lasts for a few weeks
Generally viral in origin
Can get secondary bacterial overgrowth
12. Chronic respiratory diseases Bronchiectasis
Localised, irreversible dilation of part of the bronchial tree
This is a term used for a number of conditions including-
Alveoli lose their elasticity resulting in shortness of breath
13. COPD Acute exacerbations generally caused by viruses (rhinoviruses, parainfluenza)
Secondary bacterial invasion is extremely common (H.influenzae, Moraxella)
14. Prevention of COPD Stop smoking
Avoid cold damp weather
15. Microbial causes of infective exacerbations of chronic bronchitis
16. Pneumonia Inflammation of the alveoli of the parenchyma of the lung with consolidation and exudation
Production of purulent sputum
17. Pneumonia Risk factors
Cardiac / Renal failure
Reduced levels consciousness
Anything that inhibits the gag / cough reflex
18. Causes of pneumonia acquired outside or inside hospital in patients other than those with AIDS
19. Causes of pneumonia acquired outside or inside hospital in patients other than those with AIDS (continued)
20. Community acquired pneumonia S. pneumoniae
K. pneumoniae (Friedlander’s bacillus)
21. Hospital acquired pneumonia Risk factors include mechanical ventilation
22. Atypical pneumonia Mycoplasma pneumoniae (Eaton agent)
Obligate human pathogen
Epidemics occur at 4-6 year intervals
Spread requires close contact
Common in children <5 years – mild illness
Most common in 5-20 year age group – walking pneumonia
23. Atypical pneumonias Chlamydia pneumoniae
Q fever (Coxiella burnetti)
24. Investigations for pneumonia Blood culture
Resp specimens/blood for viruses, chlamydia & mycoplasma
Urine for legionella & pneumococcal antigen testing
25. Pleurisy Inflammation of the pleura, the lining of the pleural cavity
Shortness of breath, cough, fever, chills, Unexplained weight loss, Sore throat followed by pain in and swelling in joints, rapid shallow breathing
26. Pleurisy - Causes Viral infection
Fungal infections or parasites
Non-infective causes such as chest injuries, cancer, pneumothorax or autoimmune diseases
27. Pleural effusion Transudative – left ventricular failure, cirrhosis
28. Empyma Collection of pus in the pleura
Usually starts off as a pneumonia
29. Cystic fibrosis Most common autosomal-recessive disease in caucasians, affecting approximately 1 in 3,000 individuals.
First described in 1938 by Andersen.
30. Genetics The CFTR (cystic fibrosis transmembrane conductance regulator)[ATP-binding cassette sub-family C, member 7]. Gene is located on the long (q) arm of chromosome 7 at position 31.2. It is located from base pair 116,907,252 to base pair 117,095,950. More than 1,000 mutations in the CFTR gene have been identified in people with cystic fibrosis.
Mutations in the CFTR gene disrupt the function of the chloride channel, preventing the usual flow of chloride ions and water into and out of cells.
As a result, cells that line the passageways of the lungs, pancreas, and other organs produce mucus that is abnormally thick and sticky. The abnormal mucus obstructs the airways and glands, leading to the characteristic signs and symptoms of cystic fibrosis. More than 1,000 mutations in the CFTR gene have been identified in people with cystic fibrosis.
Mutations in the CFTR gene disrupt the function of the chloride channel, preventing the usual flow of chloride ions and water into and out of cells.
As a result, cells that line the passageways of the lungs, pancreas, and other organs produce mucus that is abnormally thick and sticky. The abnormal mucus obstructs the airways and glands, leading to the characteristic signs and symptoms of cystic fibrosis.
31. Diagnosis of CF Sweat test – abnormal amounts of sodium & chloride
Newborn Screening – raised immunoreactive trypsinogen
32. Diseases associated with CF The abnormal sodium and chloride transport leads to obstruction and disease in the lungs, pancreas, paranasal sinuses, and sweat glands.
Common pulmonary findings include bronchitis, recurrent pneumonia, and parenchymal scarring. In the paranasal sinuses, nasal polyposis and bacterial colonization of retained mucus results in chronic sinusitis.
Most people with cystic fibrosis also have digestive problems because thick, sticky mucus interferes with the function of the pancreas.
33. Diseases in adulthood Cystic fibrosis used to be considered a fatal disease of childhood. With improved treatments and better ways to manage the disease, many people with cystic fibrosis now live well into adulthood.
Most men with cystic fibrosis are infertile because the vas deferens are blocked by mucus and do not develop properly. This condition is known as congenital bilateral absence of the vas deferens (CBAVD). Infertility is also possible, though less common, in women with cystic fibrosis.
34. Acquisition Clinical deterioration due to infection with
35. Progression of disease Streptococcus pneumoniae
Mucoid Pseudomonas aeruginosa
36. Other infections Aspergillus fumigatus
37. Pneumocystis jiroveci Unicellular Fungus
Found only in humans (although other species occur in other animals)
Carried by healthy people
AIDS defining disease
38. History of PJP Organism first described in 1906 by Chagas
Jirovec first isolated it from humans
Interstitial pneumonia in central & eastern Europe in World War 2 in severely malnourished and premature infants
In the first decade of the HIV epidemic 100,000 cases were reported in the US
39. Morphological stages The trophozoite (trophic form), in which it often exists in clusters
The sporozoite (precystic form)
The cyst, which contains several intracystic bodies (spores)
40. Pneumocystis jiroveci – life cycle
41. Pneumocystis jiroveci- stains Panel A shows typical pneumocystis cyst forms in a bronchoalveolar-lavage specimen stained with Gomori methenamine (x100). Thick cyst walls and some intracystic bodies are evident. Wright–Giemsa staining can be used for rapid identification of trophic forms of the organisms within foamy exudates, as shown in Panel B (arrows), in bronchoalveolar-lavage fluid or induced sputum but usually requires a high organism burden and expertise in interpretation (x100). Calcofluor white is a fungal cyst-wall stain that can be used for rapid confirmation of the presence of cyst forms, as shown in Panel C (x400). Immunofluorescence staining, shown in Panel D, can sensitively and specifically identify both pneumocystis trophic forms (arrowheads) and cysts (arrows) (x400).
42. Aspergillus fumigatus
43. Aspergillus fumigatus
44. Aspergillus fumigatus bronchopulmonary diseases Asthma – type I, immediate hypersensitivity response. IgE mediated in bronchii
Allergic bronchopulmonary aspergillus. Spores reaching the lung stimulates extrinsic allergic bronchoalveolitis due to type I and III hypersensitivity. Bronchial plugs found in sputum.
Aspergilloma. Chronic infection damages areas of lung (eg. Healed TB cavity). Production of a fungus ball. Massive haemoptysis and secondary bacterial infections common.
Desseminated Aspergillosis. Invasive lung infection. Can spread to brain and liver. Rare implications include endocarditis. Very high mortality.
45. Bronchial plugs
46. Invasive Aspergillosis (silver stain)
48. Bronchiolitis RSV
Parainfluenzae type 1 & 3
50. Mycobacteria M. tuberculosis complex:
Mycobacteria other than tuberculosis (MOTT)
52. Mycobacteria Obligate aerobe
60% cell wall composed of lipids
53. Tuberculosis Physicians in ancient Greece called this illness “phthisis" to reflect its wasting character.
During the 17th and 18th centuries, TB caused up to 25% of all deaths in Europe. In more recent times, tuberculosis has been called "consumption.“
Robert Koch isolated the tubercle bacillus in 1882 and established TB as an infectious disease.
54. TB Virulence factors Cell entry - TB can bind directly to mannose receptors of macrophage cell wall-associated mannosylated glycolipid, Lipoarabinomannan (LAM), or indirectly via certain complement receptors or Fc receptors.
Intracellular survival - TB can survive in macrophages by preventing phagosome - lysosome fusion. The organism may remain in the phagosome or may escape from there to another intra-cellular site.
Interference with toxic effects of reactive oxygen intermediates glycolipids and cell wall-associated mannosylated glycolipid down regulate the oxidative cytotoxic mechanism
Macrophage uptake via complement receptors may bypass the activation of a respiratory burst.
55. TB Virulence factors Antigen 85 complex - These proteins bind fibronectin and may aid in walling off the bacteria from the immune system and may facilitate tubercule formation
Slow generation time
High lipid concentration in cell wall
Cord factor – surface glycolipid. Toxic to mammalian cells & prevent polymorphonucleur cell migration
56. Infective droplet size 5µ.
5-200 inhaled bacilli required for infection.
Bacteria deposited into alveoli.
Alveolar macrophages phagocytose but do not kill them. Bacteria continue to multiply.
Carried to regional lymph nodes.
Lymphohaematogenous dissemination to other lymph nodes eg in kidneys, bones, meninges.
57. Cell mediated immunity (CMI) After 2-3 weeks the CMI halts the unimpeded growth of TB.
CD4 helper T cells activate the macrophages to kill intracellular bacteria.
CD8 T cells lyse the macrophages infected with mycobacteria. This results in caseating granulomas. The extracellular environment is too acidic for mycobacterial growth.
Most people infected with M. tuberculosis do not develop active disease.
58. Risk factors for acquisition of TB Nodular lesions have 100-10,000 organisms, cavitary lesions have 10 million to 1 billion bacilli.
Ventilation & exposure to UV light – poor housing, overcrowding.
59. Treatment of TB
Streptomycin, the first antibiotic to fight TB, was introduced in 1946.
60. Treatment of TB The standard treatment for TB is a combination of three or four antibiotics for a period of two months, and then two antibiotics for a further four months. The four main antibiotics for treating TB are ISONIAZID, RIFAMPICIN, PYRAZINAMIDE and ETHAMBUTOL. RIFATER (rifampicin, isoniazid, pyrazinamide) AND RIFINAH (rifampicin, isoniazid) are single tablets which contain a combination of drugs to make it easier for the patient.
62. Treatment of MOTT Treatment of atypical mycobacterial infections depends upon the infecting organism and the severity of the infection. In most cases a course of antibiotics is necessary. These include rifampicin, ethambutol, isoniazid, minocycline, ciprofloxacin, clarithromycin, azithromycin and cotrimoxazole. Usually treatment consists of a combination of drugs. Some points to consider when treating atypical mycobacterial infections:
Mycobacterium kansasii should be treated for at least 18 months.
Mycobacterium chelonae is best treated by clarithromycin in combination with another agent, Sometimes surgical excision is the best approach.
AIDS patients on HIV protease inhibitor drugs cannot be treated with rifampicin because it significantly increases the breakdown of these drugs.
64. Mycobacterial culture methods
65. Mycobacterial culture media
66. BACTEC MGIT & BACT/ALERT 3D Both use modified 7H9 Middlebrook broth base
BACTEC MGIT – Add PANTA contains Polymyxin B, Amphotericin B, Nalidixic acid, Trimethoprim and Azlocillin
BACT/ALERT 3D - Add amphotericin B, azlocillin, nalidixic acid, trimethoprim, polymyxin B, and vancomycin
67. Decontamination Petroff’s method – 4% NaOH
Sodium dodecyl (lauryl) sulfate (SDS)-NaOH
Cetylpyridinium chloride-sodium chloride
Benzalkonium chloride-trisodium phosphate
12 % H2SO4 and 1.5% HPC
68. Genitourinary tuberculosis Common cause of extrapulmonary TB
Insidious onset – nonspecific presentation
69. Genitourinary tuberculosis Frequency
Patient often presents with a history of sterile pyuria and chronic cystitis unresponsive to treatment
70. Tuberculous arthritis
71. Tuberculous arthritis Hips
Most cases involve just one joint.
About 50% have no evidence of pulmonary tuberculosis
72. Tuberculosis meningitis Haematogenous spread
Small caseating lesions (tubercules) in meninges & brain tissue
These rupture discharging AAFB into the CSF
73. Tuberculoma Tumour like mass – Tuberculoma
Consists of caseous necrotic material
Rupture releases AAFB into the sub arachnoid space leading to meningitis
74. Tuberculosis meningitis In some cases, tuberculous meningitis has a fulminant presentation
Sometimes it acts insidiously and progresses slowly over weeks or months, causing headache, confusion and cranial nerve deficits.
75. Diagnosis of Tuberculosis meningitis CSF
Slightly raised protein & depressed glucose
76. Miliary TB Widespread dissemination - haematogenous
Millet-like seeding of organs including lungs, liver, spleen & brain
77. Miliary TB Primary site in lung
Non-specific presentation – low grade fever, enlarged lymph nodes
Can also have enlarged spleen, liver, inflammation of pancreas
78. Miliary TB - Diagnosis Sputum culture
CT MRI of brain
79. Miliary TB 100 % mortality in untreated cases
With early and appropriate treatment, the mortality rate is reduced to less than 10%
Most deaths occur within the first 2 weeks of admission to the hospital. This may be related to delayed onset of treatment
Up to 50% of all cases of disseminated TB detected at autopsy were missed antemortem in reported case series.
80. Other extra-pulmonary sites of infection Lymph glands
81. Multi drug resistant TB
82. Multi drug resistance Due to:
Failure to complete treatment
83. Multi drug resistant TB A 1997 survey of 35 countries found rates above 2% in about a third of the countries surveyed.
Highest rates in the former USSR, the Baltic states, Argentina, India and China
Associated with poor or failing national tuberculosis control programmes
MDR strains of TB do not dominate naturally as they appear to be less robust and less transmissible
Outbreaks tend to occur in people with weakened immune systems (e.g., patients with HIV)
84. Multi drug resistance Risk factors for MDR-TB include HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment.
Usually can be cured with second line anti-tuberculous drugs
85. Treatment MDR-TB Aminoglycoside (amikacin) or polypeptide antibiotic (capreomycin)
high-dose INH(if low-level resistance)
86. Treatment MDR-TB Response to treatment must be obtained by repeated sputum cultures (monthly if possible).
Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture-negative for a minimum of nine months
It is not unusual for patients with MDR-TB to be on treatment for two years or more
87. Poverty and MDR-TB Problems occur mainly in impoverished areas
Community-based treatment programs such as DOTS-Plus based on short course treatment
These have been successful in Lima, Peru, where the program has seen cure rates of over 80%