Lower respiratory tract infections

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Lower respiratory tract infections

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1. Lower respiratory tract infections Mark Jorge Colchester [email protected]

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 Phagocytosis Alveolar macrophages Lysozyme s IgA Interferons

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 Rhinovirus, parainfluenzae Can get secondary bacterial overgrowth H. influenzae S. pneumoniae S.aureus

12. Chronic respiratory diseases Bronchiectasis Localised, irreversible dilation of part of the bronchial tree COPD This is a term used for a number of conditions including- Emphysema Alveoli lose their elasticity resulting in shortness of breath Chronic bronchitis

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 Influenza vaccination Chemoprophylaxis (nebulisers) Steroids Bronchodilators Diet

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 Cough Pleuritic pain Production of purulent sputum

17. Pneumonia Risk factors COPD Diabetes Cardiac / Renal failure Immunosuppression 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 H. influenzae Moraxella K. pneumoniae (Friedlander’s bacillus) Pasturella N. meningitidis

21. Hospital acquired pneumonia Risk factors include mechanical ventilation Enterobactericiae Acinetobacter Pseudomonas apecies S.aureus (MRSA)

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 Chlamydia psittaci Legionairre’s disease Q fever (Coxiella burnetti) Hantavirus (ARDS)

24. Investigations for pneumonia Blood culture Resp specimens/blood for viruses, chlamydia & mycoplasma Urine for legionella & pneumococcal antigen testing Sputum BAL Pleural fluid

25. Pleurisy Inflammation of the pleura, the lining of the pleural cavity Pain 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 Bacterial infections Fungal infections or parasites Non-infective causes such as chest injuries, cancer, pneumothorax or autoimmune diseases

27. Pleural effusion Transudative – left ventricular failure, cirrhosis Exudative Bacterial pneumonia TB Autoimmune Trauma

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 Genetic screening

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 EBV Influenza A

35. Progression of disease Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Pseudomonas species Mucoid Pseudomonas aeruginosa Burkholderia cepacia

36. Other infections Aspergillus fumigatus Mycobacterium avium Mycobacterium chelonae

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)

47. Aspergilloma

48. Bronchiolitis RSV Adenovirus Parainfluenzae type 1 & 3 Influenzae Human metapneumovirus

49. Mycobacteria

50. Mycobacteria M. tuberculosis complex: M. tuberculosis M. bovis M. africanum Mycobacteria other than tuberculosis (MOTT)

52. Mycobacteria Obligate aerobe Catalase positive 60% cell wall composed of lipids Wax D Mycolic acids

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. Antibiotic treatment. 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.

63. AAFB

64. Mycobacterial culture methods

65. Mycobacterial culture media Egg based Ogawa Lowenstein Jensen Agar Middlebrook’s media Liquid media Kirchner Dubos

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 N-acetyl-L-cysteine-NaOH method Oxalic acid Sodium dodecyl (lauryl) sulfate (SDS)-NaOH Cetylpyridinium chloride-sodium chloride Benzalkonium chloride-trisodium phosphate 12 % H2SO4 and 1.5% HPC (1-Hexadecylpyridinium Chloride)

68. Genitourinary tuberculosis Common cause of extrapulmonary TB Insidious onset – nonspecific presentation

69. Genitourinary tuberculosis Frequency Dysuria Haematuria Flank pain Patient often presents with a history of sterile pyuria and chronic cystitis unresponsive to treatment

70. Tuberculous arthritis

71. Tuberculous arthritis Hips Knees Wrists Ankles 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 Slight lymphocytosis AAFB Spiderweb clot

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 Blood cultures Chest X-ray Bronchoscopy 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 Pleura Bowel Pericardium Skin

81. Multi drug resistant TB

82. Multi drug resistance Due to: Inappropriate therapy 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) PZA EMB Fluoroquinolone (moxifloxacin) Rifabutin Cycloserine Ethionamide PAS Clarithromycin Linezolid 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%

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