Lung Infections: Influenza A and Tuberculosis With Professor Jeremy S. Brown Uclh / Ucl

Lung infections
Influenza A and tuberculosis
With Professor Jeremy S. Brown

UCLH / UCL
FitTest , fittest19@gmail.com
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Influenza A importance
Winter epidemics
• Common cause of bronchitis with marked systemic symptoms
• Also cause exacerbations of chronic lung and cardiac disease
Occasional pandemics that affect younger / healthy people
(e.g. 1918-1920, killed 20,000,000)
Influenza virus subtypes
Very common viral infection of man, pigs and birds
• An RNA virus
Influenza A virion: 120 nm
• Sub-types due to two surface proteins:
• Hamagglutinin (H) haemagglutinin

(glycoprotein)
• Neuraminidase (N) 1000 per virion
neuraminidase
(glycoprotein)
200 per virion
Nucleoprotein +
Single-stranded RNA
(8 segments)
Influenza virus subtypes
Very common viral infection of man, pigs and birds
• Human sub-types: H1N1 H1N2 H3N2

Influenza A virion: 120 nm
• Human types cause:
lipid bilayer
• Winter epidemics each year membrane
derived from
• Occasional pandemics of novel host cell
subtypes
• Bird subtypes occasionally infect man:

called avian flu e.g. H5N1; sporadic
infection only
Nucleoprotein +
Single-stranded RNA
(8 segments)
Influenza virus clinical manifestations
• Infect and kill respiratory epithelial cells

• Weaken the airway immune response to
bacteria
Influenza virus clinical manifestations
• Causes range of clinical problems:

• URTI / bronchitis with marked
systemic symptom
• Occasionally gastroenteritis symptoms /
encephalitis
• Secondary bacterial pneumonias
• Primary viral pneumonias often severe Cause
deaths
• Exacerbations of chronic heart / lung /
renal disease
Influenza virus management
• Confirm diagnosis
• Nasopharyngeal swab for
immunofluorescence or PCR
• Only necessary in high risk patients /
hospitalized
Influenza virus management
• Treatment with neuraminidase inhibitors -

oseltamivir / zanamavir (5 days)
• May also need antibiotics for superadded
bacterial infection
• Isolation highly contagious so must be
separated from other patients
• Vaccination - annual for > 65 years /
patients with chronic disease
Subacute lung infections
• Infections of the alveoli and interstitium

• Slower onset than pneumonia, different
microbial causes, different radiology
Pneumonia
• Short history
• Big inflammatory response
• Rapid response to antibiotics
Lobar consolidation, Interstitial pneumonia
Subacute lung infections
• Infections of the alveoli and interstitium

• Slower onset than pneumonia, different
microbial causes, different radiology
Subacute infections
• Longer history
• Weaker inflammatory response
• Slower response to antibiotics
Most common cause is tuberculosis (TB)

Patchy (non-lobar) consolidation, nodules, cavitation
Pneumonia versus sub-acute lung infection the differences
Community-acquired
Sub-acute pneumonias
Pneumonia (CAP)
Streptococcus pneumoniae Tuberculosis

Haemophilus influenzae Non-tuberculous mycobacteria
Staphylococcus aureus Gram negative bacteria
Influenza Nocardia
Mycoplasma pneumoniae Actinomycosis
Chlamydophila pneumoniae Aspergillus
‘ hydatid, amoebiasis,
endemic fungi, meliodosis etc.)
Epidemiology of tuberculosis
30% world population have latent infection 10 million people with active infection
10% will reactivate over a lifetime 1 million deaths per year
Mycobacterium tuberculosis the cause of TB
• Slow growing bacteria
• Characteristic lipid-rich cell wall
• No environmental source:
specific human pathogen
• Sub-species M. tuberculosis:
• M. bovis
• M. africanus
• BCG (laboratory modified)
Janice Haney Carr, http://www.microbiologyinpictures.com/bacteria%20photos/mycobacterium%20tuberculosis%20photos/MYTU20.html

Mycobacterium tuberculosis the cause of TB
• -
(NTM)
• Environmental species; can cause similar

disease to Tb but rare
Janice Haney Carr, http://www.microbiologyinpictures.com/bacteria%20photos/mycobacterium%20tuberculosis%20photos/MYTU20.html

Mycobacterium tuberculosis pathogenesis
• Inhaled in droplets coughed out by patients

with active TB
• Intracellular pathogen
• Invades macrophages and diverts normal

phagosome pathways
• Helps spread within body and immune

evasion
• Allows longterm persistence: latent

disease
• Stimulates histological immunological

hallmark of granulomas
Mycobacterium tuberculosis pathogenesis
• Lifelong survival inside macrophages: latent

disease
• Active disease mainly lungs (pulmonary

TB) but can spread to affect almost
anywhere (extra-pulmonary TB)
Tuberculosis pathogenesis
A contact with open pulmonary TB

(sputum AFB +ve)
Inhaled M. tuberculosis reach the lungs
Cleared with no Latent infection only / Active primary disease:

infection (50%) healed primary disease (45%) Ghon focus
Tuberculosis pathogenesis
Reactivated disease (10%) Progressive primary

disease (5%):
Increased if:
• Increasing age malnutrition
• Emigration
Clinical syndromes:
• Steroids / HIV
• Pulmonary TB
• Anti-TNF treatment
• Lymph node TB
• Pleural TB
• Pericaridal TB
• Miliary TB
• TB meningitis
• Bone and joint TB
• GI tract TB
• Genito-urinary TB
Tuberculosis who is at risk of disease?
36 years
• Median age 36 • 55% male (United Kingdom)
Chance of initial infection and hence latent disease dictated by local prevalence of open TB:
High Risk Mid Risk
• Sub-saharan Africa • Other Asian
• Indian sub-continent • North Africa / Middle East
• Former USSR • South and Central America
+ margins of society (homeless, alcoholics, prison, drug addicts)
Tuberculosis UK data on ethnic breakdown
Ethnic origin UK data
Black
African South Asian
South Asia
18% 35%
Caucasian
Black African
Afro-Caribbean
Chinese
Caucasian
26%
Reactivation more likely if immune system surveillance reduced
Recent emigration Vitamin D deficiency
HIV co-infection:
Smoking: responsible for
8% cases of TB and increasing
(pre-onset of AIDS) estimated 50% of cases
Reactivation more likely if immune system surveillance reduced
Diabetes: responsible for Elderly

estimated 11% of cases
Homelessness, drug abuse, Immunosuppression

alcoholism, prison (e.g. steroids, post-transplant,
anti-tumor necrosis factor
treatment)
Clinical manifestations of active tuberculosis
Can affect almost anywhere; lungs, pleura, nodes most common sites
Infective if sputum smear positive Not infective
Pulmonary alone: 47% Extrapulmonary alone: 43%:

Pulmonary+extrapulmonary: 9% Extrathoracic nodes 20%
Intrathoracic nodes 7.3%
Pleural 8.0%
Bone and spine 5.3%
Miliary 2.2%
Meningitis 2.0%
Abdominal 3.9%
GU 1.7%
Clinical manifestations of active intrapulmonary tuberculosis
Classic symptoms Systemic symptoms

Lungs • Weight loss / anorexia
• Cough • Malaise
• Hamoptysis • Fevers / night sweats
Mediastinal nodes
• Visible on X-ray
Pleural
• Exudative pleural effusion
Clinical manifestations of other sites of extra-pulmonary tuberculosis
• Cervical / other sites of nodes: smooth,

firm palpable nodes / seen on X-ray
• GI disease: pain, bloating, ascites
• Pericardial: constrictive pericarditis
• Meningitis: chronic headache, focal

neurology, coma
• Miliary: weight loss, but few localizing

symptoms (characteristic chest X-ray)
• Bone / joint: painful mass / swelling
• Can form discharging sinuses
TB case histories
Examples of classic presentations
• 54-year-old Bengali male
• 3/12 of:
• Cough
• Malaise
• Weight loss
• Night sweats
• Long history, patchy upper lobe shadowing
• Cavitation: should be sputum positive
• High risk group
TB case histories
Examples of classic presentations
• 38-year-old Somalian
• 2 months of:
• Back pain
• Systemic symptoms
• High risk for TB exposure as a child
• Recent emigration
• Systemic symptoms
• Characteristic radiology for one type

of extrapulmonary disease
With permission from JP Medical Ltd 2015*
Recognising tuberculosis
Systemic symptoms
(weight loss, fatigue, fever, sweats)
+
Risk group
(ethnic: born in Africa or Asia)
(white: homeless, drug abuse, alcoholism, prison)
(all ethnicity: HIV positive)
+/-
Localizing symptom
(cough, pain, palpable mass)
+/-
History of exposure
(recent close contact)
(known disease or close contact as a child)
Diagnosis of tuberculosis
• Not infrequently clinical diagnosis only
• Confirmed diagnosis requires identification

of M. tuberculosis:
• Lungs: x3 morning sputums for

microscopy and culture
• Biopsies / aspirations of extrapulmonary

sites for microscopy and culture
• Microscopy: look for acid fast bacilli

(AFBs) = mycobacterial infection
• Culture slow: 3 to 4 weeks with liquid

culture
• 60 70% pulmonary sputum are positive

for Microbacterium
• Extrapulmonary tuberculosis
• Positive cultures are not so high for

nodal disease, lymphnode disease,
pleural tuberculosis and Meningitis
• Yield from culture are much lower
• Polymerase Chain Reaction (PCR)
• Identifying tuberculosis
• Rapidly than culture
• Rapidly recognize patients
Histology
• Biopsy of shows caseating granulomas
• Nodes, pleura, abdominal disease
• Main differential is sarcoid
Identify latent disease by immunological

response to TB antigens:
• Heaf test / Mantoux: confounded

by BCG
• Interferon Gamma Release Assays

(IGRA)
Treatment of tuberculosis
Needs prolonged combination therapy to eradicate infection and prevent resistance
• Most sites of disease 6 months treatment
• 12 months for nervous system / bone disease

6 months
• Standard is quadruple therapy
• Dose dictated by patient weight
Isoniazid kills mycobacteria

relatively rapidly
Rifampicin kills slowly replicating

mycobacteria 1 year
Pyrazinamide first two months only
Ethambutol first two months only, test eyes
Additional considerations
• Adjuvant steroids for CNS / pericardial
disease
• All cases need to be notified
Contact tracing
• To identify source of infection for index case

/ people infected by index case
• Test close contacts (e.g. family members)
• Use Heaf testing or IGRA testing,

and / or chest X-ray
Problems
1. Diagnosis: culture is slow (4 weeks+)
2. Compliance: no one likes taking tablets for

several months
3. Toxicity: especially the liver; raised LFTs

common, may need to change treatment
4. Drug resistance:
• Occurs if patient given single agent

therapy
• Needs extended treatment (12 months+)
• Extensively resistant disease is often fatal
Outcome of TB
Non-resistant M. tuberculosis is readily curable
100 Cases
Cured Not Cured
82 cases
3.3 cases Rx continues 8 cases
Rx stopped
6.6 died, 50% related to TB Lost to F/U
Relapse rare
Outcome of TB
Non-resistant M. tuberculosis is readily curable
Extensive lung disease leaves complications
• Poor lung function due to:
• Shrunken lung / pleural thickening
• Airways obstruction
• Cavities colonised by mycetoma:
• Hamoptysis
• Bronchiectasis:
• Recurrent infections
Outcome of TB
Examples of chronic damage
Respiratory failure due to:

1.
• Shrunken lungs
• Pleural thickening 2.
• Airways disease 3.
• Bronchiectasis
1. Apical cavities, bronchiectasis and scarring
2. Pleural calcification
3. Shrunken left lung

Outcome of TB
Examples of chronic damage
Respiratory failure due to:

1.
• Shrunken lungs
• Pleural thickening 2.
• Airways disease 3.
• Bronchiectasis
1. Apical cavities, bronchiectasis and scarring
2. Pleural calcification
3. Shrunken left lung

Summary of main learning points
• Tuberculosis is caused by the slow growing

intracellular pathogen Mycobacterium
tuberculosis
• The risk of tuberculosis is dictated by the

country you grew up in
• Most infection is latent disease: reactivates

to cause active infection
• TB can affect many organs: about 50% is

lung disease
Summary of main learning points
• A confirmed diagnosis of TB requires

identification of M. tuberculosis by
microscopy (AFB) or culture
• Treatment requires four drugs for two

months then two drugs for four months
• Compliance / drug-induced hepatitis / drug

resistance are major problems
• 90-95% of TB should be cured
References
* With permission from Smith LJ, Quint J, Brown J;

Eureka Respiratory Medicine; JP Medical Ltd 2015
** With permission from Darby M, Edey A, Chandratreya L, Maskell N;

Pocket Tutor Chest X-Ray Interpretation; JP Medical Ltd 2012
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Lung infections

Influenza A and tuberculosis

With Professor Jeremy S. Brown

• Common cause of bronchitis with marked systemic symptoms

• Also cause exacerbations of chronic lung and cardiac disease

Occasional pandemics that affect younger / healthy people

(e.g. 1918-1920, killed 20,000,000)

• Hamagglutinin (H) haemagglutinin

• Human sub-types: H1N1 H1N2 H3N2

• Bird subtypes occasionally infect man:

• Infect and kill respiratory epithelial cells

• Causes range of clinical problems:

• Treatment with neuraminidase inhibitors -

• Infections of the alveoli and interstitium

• Big inflammatory response

• Rapid response to antibiotics

Lobar consolidation, Interstitial pneumonia

• Infections of the alveoli and interstitium

• Weaker inflammatory response

• Slower response to antibiotics

Most common cause is tuberculosis (TB)

Streptococcus pneumoniae Tuberculosis

10% will reactivate over a lifetime 1 million deaths per year

• Slow growing bacteria

• Characteristic lipid-rich cell wall

• BCG (laboratory modified)

Janice Haney Carr, http://www.microbiologyinpictures.com/bacteria%20photos/mycobacterium%20tuberculosis%20photos/MYTU20.html

• Environmental species; can cause similar

Janice Haney Carr, http://www.microbiologyinpictures.com/bacteria%20photos/mycobacterium%20tuberculosis%20photos/MYTU20.html

• Inhaled in droplets coughed out by patients

• Invades macrophages and diverts normal

• Helps spread within body and immune

• Allows longterm persistence: latent

• Stimulates histological immunological

• Lifelong survival inside macrophages: latent

• Active disease mainly lungs (pulmonary

A contact with open pulmonary TB

Inhaled M. tuberculosis reach the lungs

Cleared with no Latent infection only / Active primary disease:

Reactivated disease (10%) Progressive primary

• Median age 36 • 55% male (United Kingdom)

High Risk Mid Risk

• Sub-saharan Africa • Other Asian

• Indian sub-continent • North Africa / Middle East

• Former USSR • South and Central America

+ margins of society (homeless, alcoholics, prison, drug addicts)

Ethnic origin UK data

Reactivation more likely if immune system surveillance reduced

Recent emigration Vitamin D deficiency

Reactivation more likely if immune system surveillance reduced

Diabetes: responsible for Elderly

Homelessness, drug abuse, Immunosuppression

Infective if sputum smear positive Not infective

Pulmonary alone: 47% Extrapulmonary alone: 43%:

Classic symptoms Systemic symptoms

• Hamoptysis • Fevers / night sweats

• Exudative pleural effusion

• Cervical / other sites of nodes: smooth,

• GI disease: pain, bloating, ascites

• Pericardial: constrictive pericarditis

• Meningitis: chronic headache, focal

• Miliary: weight loss, but few localizing

• Bone / joint: painful mass / swelling