1. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Respiratory Infections including Tuberculosis Dr Terry O’Connor Mercy University Hospital Cork

2. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient 62-yr male smoker

3. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient 29-yr homeless male

4. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient 34-yr HIV+ South African male Pulmonary Tuberculosis Sputum cultures –Resistant Rifampicin Isoniazid Pyrazinamide Ethambutol Streptomycin –Sensitive Amikacin Capreomycin Ciprofloxacin Clarithromycin Cycloserine Ethionamide

5. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Multiple Choice Questions The commonest cause of respiratory death in Ireland is: –a)Lung Cancer –b)Pneumonia –c)COPD –d)Hermansky-Pudlak syndrome

6. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Multiple Choice Questions The incidence of tuberculosis in Ireland is: –a)Increasing –b)Remaining constant –c)Decreasing –d)Fluctuating

7. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Multiple Choice Questions Tuberculous pleural effusions are characterised by: –a)Negative Mantoux tests in > 70% –b)Pleural fluid neutrophil predominance –c)High pleural fluid adenosine deaminase activity –d)Low pleural fluid protein content

8. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pneumonia

9. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Respiratory Deaths by Cause, 2004 Total Deaths 6007 Pneumonia 1973 (33%) Respiratory Cancers 1692 (28%) COPD 1417 (24%) Brennan N, McCormack S, O’Connor T. INHALE. 2008.

10. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pneumonia Definition by Microbes –Bacterial – Pneumococcal, Streptococcal –Atypical pathogens –Fungal –Viral Definition by Location –Lobar pneumonia –Bronchopneumonia Definition by Acquisition –Community acquired pneumonia –Hospital acquired pneumonia –Ventilator-associated pneumonia

11. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Bronchopneumonia vs Lobar Pneumonia

12. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pneumonia RULRML RLL LUL Aspiration LLL

13. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pathogens in CAP Bacteria –Streptococcus pneumoniae50-60% –Haemophilus influenzae5-10% –Staphylococcus aureus2-5% –Gram negative bacilli2% –Miscellaneous3-5% Atypical Agents10-20% –Legionella2-5% –Mycoplasma pneumoniae5-10% –Chlamydia pneumoniae5% Viruses2-15% Aspiration5-10% Streptococcus pneumoniae

14. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Typical Atypical Sudden onset Toxic patient appearance Productive cough High fever (>39 C) Elevated WBC with left shift Sputum - bugs Defined consolidation Slow onset Patient appears relatively well Non-productive or dry cough No left shift in WBC Sputum - no bugs Interstitial or patchy infiltrate

15. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Streptococcus pneumonia Most common cause of CAP Gram positive diplococci “Typical” symptoms (e.g. malaise, shaking chills, fever, rusty sputum, pleuritic hest pain, cough) Lobar infiltrate on CXR 25% bacteremic

16. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Atypical Pneumonia Second commonest cause (especially in younger population) Commonly associated with milder symptoms: subacute onset, non- productive cough, absence of focal infiltrate on CXR Mycoplasma: younger patients, extra-pulmonary symptoms (anemia, rashes), headache, sore throat Chlamydia: year round, upper respiratory symptoms, sore throat Legionella: higher mortality rate, water-borne outbreaks, hyponatremia, diarrhoea

17. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pathogens in HAP Bacteria –Pseudomonas aeruginosa25-30% –Staphylococcus aureus (MRSA)25% –Gram negative bacilli25% –Streptococcus pneumoniae3-5% –Haemophilus influenzae3-5% –Polymicrobial10-20% Atypical Agents –Legionella2-5% Fungi (Aspergillus / Candida)5-10% Aspiration5-10%

18. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pneumonia patient characteristics Alcoholism:S. pneumoniae, oral anaerobes, Klebsiella, Acinetobacter species, MTB Smoker/COPD: S. pneumoniae, H. influenzae, Moraxella catarrhalis, Pseudomonas, Legionella Aspiration:Gram-negative enteric pathogens, oral anaerobes Lung Abscess:MRSA, oral anaerobes, endemic fungal pneumonia, MTB, atypical mycobacteria Exposure to birds:Chlamydophilia psittaci (if poultry, avian influenza) Exposure to farm animals or parturient cats:Coxiella burnetti (Q fever) Hotel or cruise ship in previous 2 weeks:Legionella species

19. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pneumonia patient characteristics HIV infection:Early - S. pneumoniae, H. influenzae, MTB Late – Pneumocystis, Cryptococcus, Histoplasma, Aspergillus, Atypical mycobacteria Post viral bronchitis: S. pneumoniae, Staphylococcus aureus, H. influenzae IV drug user: S. aureus, anaerobes, M. tuberculosis, S. pneumoniae Structural lung disease Pseudomonas aeruginosa, Burkholderia cepacia, (eg. Bronchiectasis): S. aureus Endobronchial obstruction:Anaerobes, S. pneumoniae, H. influenzae, S.aureus

20. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Antimicrobial Therapy for Specific Pathogens Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clinical Infectious Diseases 2007; 44:S27–72. OrganismPreferred antimicrobial(s)Alternative antimicrobial(s) Streptococcus pneumoniae Penicillin nonresistant; MIC !2 mg/mL Penicillin G, amoxicillinMacrolide, cephalosporins, clindamycin, doxycyline, respiratory fluoroquinolone Penicillin resistant; MIC 2 mg/mL Agents chosen on the basis of susceptibility, including cefotaxime, ceftriaxone, fluoroquinolone Vancomycin, linezolid, high-dose amoxicillin Haemophilus influenzae Non– β -lactamase producing AmoxicillinFluoroquinolone, doxycycline, azithromycin, clarithromycin β -Lactamase producingSecond- or third-generation cephalosporin, amoxycillin- clavulanate Fluoroquinolone, doxycycline, azithromycin, clarithromycin

21. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Antimicrobial Therapy for Specific Pathogens OrganismPreferred antimicrobial(s)Alternative antimicrobial(s) Mycoplasma pneumoniaeMacrolide, a tetracyclineFluoroquinolone Legionella speciesFluoroquinolone, azithromycinDoxycyline Chlamydophila psittaciA tetracyclineMacrolide Coxiella burnetiiA tetracyclineMacrolide Yersinisa pestisStreptomycin, gentamicinDoxycyline, fluoroquinolone Bacillus anthracis (inhalation)Ciprofloxacin, levofloxacin, doxycycline Other fluoroquinolones; β-lactam, if susceptible; rifampin; clindamycin; chloramphenicol Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clinical Infectious Diseases 2007; 44:S27–72.

22. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Antimicrobial Therapy for Specific Pathogens OrganismPreferred antimicrobial(s)Alternative antimicrobial(s) Pseudomonas aeruginosaAntipseudomonal β -lactam plus (ciprofloxacin or levofloxacin or aminoglycoside) Aminoglycoside plus (ciprofloxacin or levofloxacin) Staphylococcus aureus Methicillin susceptibleAntistaphylococcal penicillinCefazolin, clindamycin Methicillin resistantVancomycin or linezolidTMP-SMX Anaerobe (aspiration) β -Lactam/ β -lactamase inhibitor, clindamycin Carbapenem Influenza virusOseltamivir or zanamivir Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clinical Infectious Diseases 2007; 44:S27–72.

23. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Tests for Pneumonia Chest Radiograph Arterial Blood Gas Complete Blood Count Chemistry – Electrolytes, Renal function, Liver function Serologic Testing (Atypical pneumonia screen) Blood Culture Sputum Gram stain and culture, AFB Pneumococcal Urinary Antigen Legionella Urinary Antigen Pleural fluid analysis

24. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Poor prognostic features Age> 65 years Coexisting diseaseDiabetes, renal / heart failure, neoplasia, others Clinical findingsRR > 30/min, SBP 38.3 o C Altered mental status Lab testsWCC low or very high, Haematocrit < 30% Low pO 2 Renal failure Multilobar involvement on CXR, pleural effusion Microbial pathogensStreptococcus pneumoniae Legionella pneumophilia Staphylococcus aureus

25. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient CURB-65 C = Confusion U = Urea > 7mmol/L R = Respiratory rate >/= 30/min B = BP systolic < 90mmHg or diastolic </=60mmHg 65 = Age >/= 65 years Score one point for each feature present 0 or 1- low risk of death, non-severe pneumonia, home treatment 2 – increased risk of death, consider short inpatient stay or hospital supervised outpatient treatment 3 or more – high risk of death and should be managed as having severe pneumonia

26. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Non-invasive ventilation CPAP may be of value in selected patients with hypoxic respiratory failure but good evidence lacking BiPAP of more established benefit in patients with hypercapnic respiratory failure, particularly those with COPD Delclaux et al. JAMA 2000;284:2352-2360. Cochrane Database Syst Rev. 2004;CD004104.

27. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Aspiration Pneumonia

28. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Lung Abscess

29. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Lung Abscess Pathophysiology Localized necrotic lesion of the lung parenchyma containing purulent material Lesion collapses and forms a cavity

30. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Lung Abscess Aetiology –Aspiration –Staphylococcal aureus –Klebsiella –Anaerobic organisms Antimicrobial Therapy –4-6 weeks

31. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Tuberculosis

32. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient The White Plague Much Ado About Nothing (1600), Macbeth (1606)

33. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient ‘Patricia’

34. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient TB incidence in Ireland

35. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient 0 5 10 15 20 25 30 19911993199519971999200120032005 Year Incidence / 100,000 population Ireland Irish TB incidence in Ireland Health Protection Surveillance Centre Ireland 2008

36. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Risk factors for progression –HIV infection –Diabetes mellitus –Acquisition of LTBI in infancy or early childhood –Apical fibronodular changes on chest radiograph –Use of agents that antagonize the effect of tumor necrosis factor-  Transmission of M. tuberculosis

37. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Musher DM. N Engl J Med 2003;348:1256-66. Transmission of M. tuberculosis

38. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Characteristics of the source-case –Concentration of organisms in sputum –Presence of cavitary disease on chest radiograph –Frequency and strength of cough Characteristics of the exposed person –Previous M. tuberculosis infection –Innate / genetic susceptibility to M. tuberculosis infection Characteristics of the exposure –Frequency and duration of exposure –Dilution effect (i.e., the volume of air containing infectious droplet nuclei) –Ventilation (i.e., the turnover of air in a space) –Exposure to ultraviolet light, including sunlight Virulence of the infecting strain of M. tuberculosis Controlling tuberculosis in the United States. Am J Respir Crit Care Med. 2005 Nov 1;172:1169-227 Transmission of M. tuberculosis

39. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Susceptibility to tuberculosis Polymorphism within the interferon gamma/receptor complex is associated with pulmonary tuberculosis. Recurrent tuberculosis in the United States and Canada is rarely due to reinfection with a new strain of M. tuberculosis. Incidence rate of tuberculosis attributable to reinfection after successful treatment could be four times that of new tuberculosis in an area with high prevalence of disease, such as South Africa. Cooke GS, et al. Am J Respir Crit Care Med. 2006 EPub May 11. Jasmer RM et al. Am J Respir Crit Care Med. 2004;170:1360-6. Verver S, et al. Am J Respir Crit Care Med 2005;171:1430–1435.

40. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Symptoms of TB infection –Cough –Sputum –Haemoptysis –Weight loss –Night sweats Key issues in the diagnosis and management of tuberculosis Milburn J R Soc Med.2007; 100: 134-141

41. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient 50 100 0 Pleural TB Pulmonary TBLTBI Patients Symptomatic Asymptomatic Jahangir A, et al. Ir J Med Sci (Suppl) 2008

42. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Diagnosis of tuberculosis Ziehl-Nielsen Staining Mycobacterium tuberculosis is discovered in the laboratory by one of two methods: –Acid and alcohol fast bacilli stain (also called AFB or smear). TB specimens which contain a lot of TB organisms are often AFB positive. –Tuberculosis culture – TB is very slow growing so, unlike bacterial infections, it may be 10- 12 weeks before the results are reported. TB specimens which contain very few TB organisms are often AFB negative but culture positive.

43. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient False TST Reactions Nontuberculous mycobacteria BCG vaccination Anergy Poor nutrition Immunosuppressive drugs Recent TB infection (2-10 wks) Very young / old age Malignancy Live virus vaccination (measles, smallpox) Overwhelming TB disease Poor TST administration PositiveNegative

44. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Interferon Gamma Release Assays Rapidly replacing the Mantoux test in developed economies More specific than Mantoux for diagnosis of TB infection Preventing thousands of treatments for latent TB infection

45. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Environmental strains Antigens ESATCFP M abcessus-- M avium-- M branderi-- M celatum-- M chelonae-- M fortuitum-- M gordonii-- M intracellulare-- M kansasii++ M malmoense-- M marinum++ M oenavense-- M scrofulaceum-- M smegmatis-- M szulgai++ M terrae-- M vaccae-- M xenopi-- Tuberculosis complex Antigens ESATCFP M tuberculosis++ M africanum++ M bovis++ BCG substrain gothenburg-- moreau-- tice-- tokyo-- danish-- glaxo-- montreal-- pasteur-- Species specificity of ESAT-6 and CFP-10

46. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Millet Seeds. The term "miliary tuberculosis" derives from the resemblance of the granulomatous nodules to millet seeds Treatment of Tuberculosis

47. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Isoniazid Rifampicin Pyrazinamide Ethambutol Rifabutin Rifapentine First-Line Drugs Second-Line Drugs Current Antituberculous Drugs Streptomycin Cycloserine p-Aminosalicylic acid Ethionamide Amikacin Kanamycin Capreomycin Levofloxacin Moxifloxacin Gatifloxacin Clarithromycin

48. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Recommended Treatment Regimens

49. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Combination Agents Rifampicin Isoniazid Pyrazinamide Ethambutol Pyridoxine Rifampicin Isoniazid Pyridoxine Rifater 5 tabs OD Ethambutol 1.2g OD Pyridoxine 25 mg OD Rifinah ‘300’ 2 tabs OD Pyridoxine 25 mg OD 2 months 4-7 months

50. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient New Antituberculous Drugs Barry PJ, O’Connor TM. Current Medicinal Chemistry 2007;14:2000-8. DiarylquinolonesR207910Trans-Cinnamic Acid QuinolonesOfloxacin Levofloxacin Moxifloxacin PyrrolesBM212 OxazolidinonesLinezolid RBx 7644 RBx 8700 MacrolidesClarithromycin Azithromycin Roxithromycin NitroimidazopyransPA-824 OPC-67683 Newer RifamycinsRifabutin Rifapentine Rifalazil Ethambutol AnaloguesSQ109Aerosolized interferon gamma

51. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Determining when during therapy a patient is noninfectious Patient has negligible likelihood of multidrug-resistant TB Patient has received standard multidrug anti-TB therapy for 2– 3 weeks Patient has demonstrated complete adherence to treatment and evidence of clinical improvement All close contacts of patient have been identified, evaluated, advised, and, if indicated, started on treatment for latent TB infection Controlling tuberculosis in the United States. Am J Respir Crit Care Med. 2005 Nov 1;172:1169-227

52. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient In the Emergency Department Active infectious TB should not be managed in the ED Isolate if active infectious TB suspected, negative pressure room ideally Staff wear FFP2 masks (N95 equivalent) Do not start empiric therapy Sputum x 3, consider bronchoscopy, Mantoux, Quantiferon If sputum AFB +, initiate therapy, HIV test, visual acuity and baseline LFTs, contact public health to initiate contact tracing

53. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pulmonary Tuberculosis Sputum ZN positive Rx Rifater Ethambutol Pyridoxine

54. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pulmonary Tuberculosis Sputum ZN negative Bronchoscopy / Washings RUL Rx Rifater Ethambutol Pyridoxine

55. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Pulmonary Tuberculosis Miliary Tuberculosis Sputum ZN positive Rx Rifater Ethambutol Pyridoxine

56. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Tuberculous Pleurisy Mantoux positive Pleural fluid analysis – 90% lymphocytes High adenosine deaminase (ADA) activity

57. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Multiple Choice Questions The commonest cause of respiratory death in Ireland is: –a)Lung Cancer –b)Pneumonia –c)COPD –d)Hermansky-Pudlak syndrome

58. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Multiple Choice Questions The incidence of tuberculosis in Ireland is: –a)Increasing –b)Remaining constant –c)Decreasing –d)Fluctuating

59. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Multiple Choice Questions Tuberculous pleural effusions are characterised by: –a)Negative Mantoux tests in > 70% –b)Pleural fluid neutrophil predominance –c)High pleural fluid adenosine deaminase activity –d)Low pleural fluid protein content

60. Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Thank you Questions