Lung infections

Influenza A and tuberculosis

With Professor Jeremy S. Brown

UCLH / UCL
Influenza A importance

Winter epidemics

• Common cause of bronchitis with marked systemic symptomss

• 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:

• Hemagglutinin (H) Hemagglutinin

(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 symptoms
• 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 /
hospitalised
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 vaccination
recommended for all individuals
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

© by Daniela Kildal
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

Commonest cause is tuberculosis (TB)

© by Daniela Kildal
Pneumonia versus subacute lung infection
Community-acquired
Pneumonia (CAP)
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Influenza
Mycoplasma pneumoniae
Chlamydia pneumoniae
the differences
Subacute pneumonias
Tuberculosis
Non-tuberculous mycobacteria
Gram negative bacteria
Nocardia
Actinomycosis
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- M. tuberculosis:

• M. bovis

• M. africanus

• BCG (laboratory modified)

NIAID, Mycobacterium tuberculosis Bacteria, the Cause of TB, https://www.flickr.com/photos/niaid/5149398656, no changes, CC BY 2.0
Mycobacterium tuberculosis the cause of TB

• -
(NTM)

• Environmental species; can cause similar

disease to TB but rare

NIAID, Mycobacterium tuberculosis Bacteria, the Cause of TB, https://www.flickr.com/photos/niaid/5149398656, no changes, CC BY 2.0
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 (extrapulmonary 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
Clinical syndromes:
• Emigration
• Pulmonary TB
• Steroids
• Lymph node TB
• HIV
• Pleural TB
• Anti-TNF treatment
• 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)

Tuberculosis who is at risk of disease?

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%
Tuberculosis who is at risk of disease?

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
Tuberculosis who is at risk of disease?

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%
Bone and spine 5.3%
Miliary 2.2%
Meningitis 2%
Abdominal 3.9%
GU 1.7%
Clinical manifestations of active intrapulmonary tuberculosis

Classic symptoms systemic symptomss

Lungs • Weight loss / anorexia

• Cough • Malaise

• Hemoptysis • Fevers / night sweats

Mediastinal nodes

• Visible on x-ray

Pleural

• Exudative pleural effusion

Clinical manifestations of other sites of extrapulmonary 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

neurologic deficits, 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 months of:

• Cough

• Malaise

• Weight loss

• Night sweats

• Long history, patchy upper lobe shadowing

• Cavitation: should be sputum positive

• High risk group

© by Daniela Kildal
TB case histories
Examples of classic presentations
• 38 year old Somalian

• 2 months of:

• Back pain

• systemic symptomss

• High risk for TB exposure as a child

• Recent emigration

• systemic symptomss

• Characteristic radiology for one type

of extrapulmonary disease
© by Daniela Kildal
Recognizing tuberculosis

systemic symptomss
(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
Diagnosis of tuberculosis

• 60 70% pulmonary sputum are positive

for Mycobacterium

• Extrapulmonary tuberculosis

• Positive cultures are not so high for

nodal disease, lymph node disease,
pleural tuberculosis and meningitis

• Yield from culture are much lower

Diagnosis of tuberculosis

• Polymerase Chain Reaction (PCR)

• Identifying tuberculosis

• Rapidly than culture

• Rapidly recognize patients

Diagnosis of tuberculosis

Histology

• Biopsy shows 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

Treatment of tuberculosis
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
Treatment of tuberculosis
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 colonized by mycetoma:

• Hemoptysis

• Bronchiectasis:

• Recurrent infections
Outcome of TB
Examples of chronic damage

Respiratory failure due to:

• Shrunken lungs

• Pleural thickening

• Airways disease

• Bronchiectasis

1. Apical cavities, bronchiectasis and scarring

2. Pleural calcification

3. Shrunken right lung

© by Daniela Kildal
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