Respiratory Infections including
Tuberculosis
Dr Terry O’Connor
Mercy University Hospital
Cork
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
62-yr male smoker
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
29-yr homeless male
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
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)
b)
c)
d)
Lung Cancer
Pneumonia
COPD
Hermansky-Pudlak syndrome
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Multiple Choice Questions
• The incidence of tuberculosis in Ireland is:
–
–
–
–
a)
b)
c)
d)
Increasing
Remaining constant
Decreasing
Fluctuating
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Multiple Choice Questions
• Tuberculous pleural effusions are characterised by:
–
–
–
–
a)
b)
c)
d)
Negative Mantoux tests in > 70%
Pleural fluid neutrophil predominance
High pleural fluid adenosine deaminase activity
Low pleural fluid protein content
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Pneumonia
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Respiratory Deaths by Cause, 2004
Total Deaths
6007
Pneumonia
Respiratory Cancers
COPD
1973 (33%)
1692 (28%)
1417 (24%)
Brennan N, McCormack S, O’Connor T. INHALE. 2008.
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Bronchopneumonia vs Lobar Pneumonia
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Pneumonia
RUL
RML
RLL
LUL
LLL
Aspiration
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Pathogens in CAP
• Bacteria
–
–
–
–
–
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Gram negative bacilli
Miscellaneous
• Atypical Agents
– Legionella
– Mycoplasma pneumoniae
– Chlamydia pneumoniae
• Viruses
• Aspiration
50-60%
5-10%
2-5%
2%
3-5%
10-20%
2-5%
5-10%
5%
2-15%
5-10%
Streptococcus pneumoniae
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
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
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, nonproductive 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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Pathogens in HAP
• Bacteria
–
–
–
–
–
–
Pseudomonas aeruginosa
Staphylococcus aureus (MRSA)
Gram negative bacilli
Streptococcus pneumoniae
Haemophilus influenzae
Polymicrobial
25-30%
25%
25%
3-5%
3-5%
10-20%
• Atypical Agents
–
Legionella
2-5%
• Fungi (Aspergillus / Candida)
5-10%
• Aspiration
5-10%
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
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
(eg. Bronchiectasis):
Pseudomonas aeruginosa, Burkholderia cepacia,
S. aureus
• Endobronchial obstruction:
Anaerobes, S. pneumoniae, H. influenzae, S.aureus
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Antimicrobial Therapy for Specific
Pathogens
Organism
Preferred antimicrobial(s)
Alternative antimicrobial(s)
Streptococcus pneumoniae
Penicillin nonresistant;
MIC !2 mg/mL
Penicillin G, amoxicillin
Macrolide, cephalosporins,
clindamycin, doxycyline, respiratory
fluoroquinolone
Vancomycin, linezolid, high-dose
amoxicillin
Penicillin resistant;
MIC 2 mg/mL
Agents chosen on the basis of
susceptibility, including cefotaxime,
ceftriaxone, fluoroquinolone
Haemophilus influenzae
Non–β-lactamase
producing
β-Lactamase producing
Amoxicillin
Fluoroquinolone, doxycycline,
azithromycin, clarithromycin
Second- or third-generation
cephalosporin, amoxycillinclavulanate
Fluoroquinolone, doxycycline,
azithromycin, clarithromycin
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.
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Antimicrobial Therapy for Specific
Pathogens
Organism
Preferred antimicrobial(s)
Alternative antimicrobial(s)
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
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.
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Antimicrobial Therapy for Specific
Pathogens
Organism
Preferred antimicrobial(s)
Alternative antimicrobial(s)
Pseudomonas aeruginosa
Antipseudomonal β-lactam plus
(ciprofloxacin or levofloxacin or
aminoglycoside)
Aminoglycoside plus (ciprofloxacin or
levofloxacin)
Methicillin susceptible
Antistaphylococcal penicillin
Cefazolin, clindamycin
Methicillin resistant
Vancomycin or linezolid
TMP-SMX
β-Lactam/ β-lactamase inhibitor,
clindamycin
Oseltamivir or zanamivir
Carbapenem
Staphylococcus aureus
Anaerobe (aspiration)
Influenza virus
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.
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Poor prognostic features
• Age
> 65 years
• Coexisting disease
Diabetes, renal / heart failure, neoplasia, others
• Clinical findings
RR > 30/min, SBP < 90mmHg, T > 38.3oC
Altered mental status
• Lab tests
WCC low or very high, Haematocrit < 30%
Low pO2
Renal failure
Multilobar involvement on CXR, pleural effusion
• Microbial pathogens
Streptococcus pneumoniae
Legionella pneumophilia
Staphylococcus aureus
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
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.
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Aspiration Pneumonia
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Lung Abscess
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
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Tuberculosis
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
The White Plague
Much Ado About Nothing (1600), Macbeth (1606)
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
‘Patricia’
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
TB incidence in Ireland
Tuberculosis in Ireland
Incidence / 100,000 population
250
200
150
Ireland
100
50
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1990
1982
1972
1962
1952
0
Year
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Incidence / 100,000 population
30
TB incidence in Ireland
25
20
Ireland
Irish
15
10
5
0
1991 1993 1995 1997 1999 2001 2003 2005
Year
Health Protection Surveillance Centre Ireland 2008
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Transmission of M. tuberculosis
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-
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Transmission of M. tuberculosis
Musher DM. N Engl J Med 2003;348:1256-66.
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Transmission of M. tuberculosis
•
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
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.
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Asymptomatic
100
Symptomatic
Patients 50
0
Pleural TB
Pulmonary TB
LTBI
Jahangir A, et al. Ir J Med Sci (Suppl) 2008
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Diagnosis of tuberculosis
• 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 1012 weeks before the results are reported. TB
specimens which contain very few TB
organisms are often AFB negative but culture
positive.
Ziehl-Nielsen Staining
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
False TST Reactions
Positive
• Nontuberculous mycobacteria
• BCG vaccination
Negative
•
•
•
•
•
•
•
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
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Species specificity of ESAT-6 and CFP-10
Tuberculosis
complex
Antigens
ESAT
M tuberculosis
+
M africanum
+
M bovis
+
BCG substrain
gothenburg
-
moreau
-
tice
-
tokyo
-
danish
-
glaxo
-
montreal
-
pasteur
-
Respiratory Medicine Session
Environmental
strains
Antigens
ESAT
CFP
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
of the RCPI Masterclass on Treating the Acutely Ill Patient
Treatment of Tuberculosis
Millet Seeds.
The term "miliary tuberculosis" derives from
the resemblance of the granulomatous
nodules to millet seeds
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Current Antituberculous Drugs
First-Line Drugs
Second-Line Drugs
• Isoniazid
• Streptomycin
• Rifampicin
• Cycloserine
• Pyrazinamide
• p-Aminosalicylic acid
• Ethambutol
• Ethionamide
• Rifabutin
• Amikacin
• Rifapentine
• Kanamycin
• Capreomycin
• Levofloxacin
• Moxifloxacin
• Gatifloxacin
• Clarithromycin
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Recommended Treatment Regimens
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
2 months
• Rifinah ‘300’ 2 tabs OD
• Pyridoxine 25 mg OD
4-7 months
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
New Antituberculous Drugs
Diarylquinolones
R207910
Trans-Cinnamic Acid
Quinolones
Ofloxacin
Levofloxacin
Moxifloxacin
Pyrroles
BM212
Oxazolidinones
Linezolid
RBx 7644
RBx 8700
Macrolides
Clarithromycin
Azithromycin
Roxithromycin
Nitroimidazopyrans
PA-824
OPC-67683
Newer Rifamycins
Rifabutin
Rifapentine
Rifalazil
Ethambutol Analogues SQ109
Aerosolized
interferon gamma
Barry PJ, O’Connor TM. Current Medicinal Chemistry 2007;14:2000-8.
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
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Pulmonary Tuberculosis
Sputum ZN positive
Rx
Rifater
Ethambutol
Pyridoxine
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
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Pulmonary Tuberculosis
Miliary Tuberculosis
Sputum ZN positive
Rx
Rifater
Ethambutol
Pyridoxine
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
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)
b)
c)
d)
Lung Cancer
Pneumonia
COPD
Hermansky-Pudlak syndrome
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Multiple Choice Questions
• The incidence of tuberculosis in Ireland is:
–
–
–
–
a)
b)
c)
d)
Increasing
Remaining constant
Decreasing
Fluctuating
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Multiple Choice Questions
• Tuberculous pleural effusions are characterised by:
–
–
–
–
a)
b)
c)
d)
Negative Mantoux tests in > 70%
Pleural fluid neutrophil predominance
High pleural fluid adenosine deaminase activity
Low pleural fluid protein content
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient
Thank you
Questions
Respiratory Medicine Session of the RCPI Masterclass on Treating the Acutely Ill Patient