Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Respiratory Infections including Tuberculosis Dr Terry O’Connor

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

Respiratory Infections including Tuberculosis

Dr Terry O’ConnorMercy University Hospital

Cork


62-yr male smoker


29-yr homeless male


34-yr HIV+ South African male

• Pulmonary Tuberculosis

• Sputum cultures

– Resistant• Rifampicin• Isoniazid• Pyrazinamide• Ethambutol• Streptomycin

– Sensitive• Amikacin• Capreomycin• Ciprofloxacin

• Clarithromycin• Cycloserine• Ethionamide


Multiple Choice Questions

• The commonest cause of respiratory death in Ireland is:

– a) Lung Cancer– b) Pneumonia– c) COPD– d) Hermansky-Pudlak syndrome



• The incidence of tuberculosis in Ireland is:

– a) Increasing– b) Remaining constant– c) Decreasing– d) Fluctuating



• 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


Pneumonia


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.


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


Bronchopneumonia vs Lobar Pneumonia


PneumoniaRUL RML RLL

LUL AspirationLLL


Pathogens in CAP• Bacteria

– Streptococcus pneumoniae 50-60%– Haemophilus influenzae 5-10%– Staphylococcus aureus 2-5%– Gram negative bacilli 2%– Miscellaneous 3-5%

• Atypical Agents 10-20%– Legionella 2-5%– Mycoplasma pneumoniae 5-10%– Chlamydia pneumoniae 5%

• Viruses 2-15%• Aspiration 5-10%

Streptococcus pneumoniae


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


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


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


Pathogens in HAP• Bacteria

– Pseudomonas aeruginosa 25-30%– Staphylococcus aureus (MRSA) 25%– Gram negative bacilli 25%– Streptococcus pneumoniae 3-5%– Haemophilus influenzae 3-5%– Polymicrobial 10-20%

• Atypical Agents– Legionella 2-5%

• Fungi (Aspergillus / Candida) 5-10%

• Aspiration 5-10%


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


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


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.

Organism Preferred antimicrobial(s) Alternative antimicrobial(s)

Streptococcus pneumoniae Penicillin nonresistant; MIC !2 mg/mL

Penicillin G, amoxicillin Macrolide, 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

Amoxicillin Fluoroquinolone, doxycycline, azithromycin, clarithromycin

β-Lactamase producing Second- or third-generation cephalosporin, amoxycillin-clavulanate

Fluoroquinolone, doxycycline, azithromycin, clarithromycin




Mycoplasma pneumoniae Macrolide, a tetracycline Fluoroquinolone

Legionella species Fluoroquinolone, azithromycin Doxycyline

Chlamydophila psittaci A tetracycline Macrolide

Coxiella burnetii A tetracycline Macrolide

Yersinisa pestis Streptomycin, gentamicin Doxycyline, fluoroquinolone

Bacillus anthracis (inhalation)

Ciprofloxacin, levofloxacin, doxycycline

Other fluoroquinolones; β-lactam, if susceptible; rifampin; clindamycin;chloramphenicol





Pseudomonas aeruginosa Antipseudomonal β-lactam plus (ciprofloxacin or levofloxacin or aminoglycoside)

Aminoglycoside plus (ciprofloxacin or levofloxacin)

Staphylococcus aureus

Methicillin susceptible Antistaphylococcal penicillin Cefazolin, clindamycin

Methicillin resistant Vancomycin or linezolid TMP-SMX

Anaerobe (aspiration) β-Lactam/ β-lactamase inhibitor,clindamycin

Carbapenem

Influenza virus Oseltamivir or zanamivir



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


Poor prognostic features• Age > 65 years

• Coexisting disease Diabetes, renal / heart failure, neoplasia, others

• Clinical findingsRR > 30/min, SBP < 90mmHg, T > 38.3oCAltered mental status

• Lab tests WCC low or very high, Haematocrit < 30%Low pO2

Renal failureMultilobar involvement on CXR, pleural

effusion

• Microbial pathogens Streptococcus pneumoniaeLegionella pneumophiliaStaphylococcus aureus


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


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.


Aspiration Pneumonia


Lung Abscess


Lung Abscess

Pathophysiology• Localized necrotic lesion of the lung parenchyma

containing purulent material

• Lesion collapses and forms a cavity


Lung Abscess

• Aetiology– Aspiration– Staphylococcal aureus– Klebsiella– Anaerobic organisms

• Antimicrobial Therapy– 4-6 weeks


Tuberculosis


The White Plague

Much Ado About Nothing (1600), Macbeth (1606)


‘Patricia’


TB incidence in Ireland


0

5

10

15

20

25

30

1991 1993 1995 1997 1999 2001 2003 2005

Year

Inc

ide

nce

/ 1

00,0

00 p

op

ula

tio

n

IrelandIrish

TB incidence in Ireland

Health Protection Surveillance Centre Ireland 2008


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


Musher DM. N Engl J Med 2003;348:1256-66.



• 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. tuberculosisControlling tuberculosis in the United

States. Am J Respir Crit Care Med. 2005 Nov 1;172:1169-227



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.


Symptoms of TB infection

– Cough

– Sputum

– Haemoptysis– Weight loss

– Night sweats

Key issues in the diagnosis and management of tuberculosisMilburn J R Soc Med.2007; 100: 134-141


50

100

0Pleural TB Pulmonary TB LTBI

Patients

Symptomatic

Asymptomatic

Jahangir A, et al. Ir J Med Sci (Suppl) 2008


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.


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

Positive Negative


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


Environmental strains

Antigens

ESAT CFP

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

ESAT CFP

M tuberculosis + +

M africanum + +

M bovis + +

BCG substrain

gothenburg - -

moreau - -

tice - -

tokyo - -

danish - -

glaxo - -

montreal - -

pasteur - -

Species specificity of ESAT-6 and CFP-10


Millet Seeds. The term "miliary tuberculosis" derives from

the resemblance of the granulomatous nodules to millet seeds

Treatment of Tuberculosis


• 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


Recommended Treatment Regimens


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


New Antituberculous Drugs

Barry PJ, O’Connor TM. Current Medicinal Chemistry 2007;14:2000-8.

Diarylquinolones R207910 Trans-Cinnamic Acid

Quinolones OfloxacinLevofloxacinMoxifloxacin

Pyrroles BM212

Oxazolidinones LinezolidRBx 7644 RBx 8700

Macrolides ClarithromycinAzithromycinRoxithromycin

Nitroimidazopyrans

PA-824 OPC-67683

Newer Rifamycins

RifabutinRifapentineRifalazil

Ethambutol Analogues

SQ109 Aerosolized interferon gamma


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 infectionControlling tuberculosis in the United States. Am J

Respir Crit Care Med. 2005 Nov 1;172:1169-227


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


Pulmonary Tuberculosis

Sputum ZN positive

RxRifaterEthambutolPyridoxine



Sputum ZN negative

Bronchoscopy / Washings RUL




Miliary Tuberculosis

Sputum ZN positive



Tuberculous Pleurisy

Mantoux positive

Pleural fluid analysis – 90% lymphocytes

High adenosine deaminase (ADA) activity



• The commonest cause of respiratory death in Ireland is:

– a) Lung Cancer– b) Pneumonia– c) COPD– d) Hermansky-Pudlak syndrome



• The incidence of tuberculosis in Ireland is:

– a) Increasing– b) Remaining constant– c) Decreasing– d) Fluctuating



• 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


Thank you

Questions

Documents

Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient Respiratory Infections including Tuberculosis Dr Terry O’Connor