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Bronchiectasis
Key points
Chris Johnson
Charles Haworth
C
Abstract
C
Denition
Bronchiectasis is a pathological term used to describe irreversible
airways dilatation often accompanied by the formation of a
chronic inflammatory exudate. It was first described by Laennec
in the 19th century and is the structural endpoint of a number of
diseases. Clinically, it leads to a chronic productive cough,
obstructive airways disease and recurrent chest infections.
Epidemiology
It has proven challenging to accurately estimate the incidence
and prevalence of bronchiectasis. As the common structural
endpoint of a number of disease processes, it is often not reported separately from the more severe or primary pathology.
For example, one study found that as many as 50% of patients
with a diagnosis of chronic obstructive pulmonary disease had
Chris Johnson MA MRCP is a Consultant Physician at the Cambridge
Centre for Lung Infection, Papworth Hospital, UK. Competing
interests: none declared.
Charles Haworth MD FRCP is a Consultant Physician at the Cambridge
Centre for Lung Infection, Papworth Hospital, UK. Competing
interests: I have received speaker fees and/or consultancy fees from
Actavis, Chiesi, Gilead, Novartis, Vertex and Zambon.
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Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017
BRONCHIECTASIS
Pathology
The histopathological appearances of bronchiectasis are of
dilated airways larger than the accompanying pulmonary artery
and filled with an inflammatory exudate dominated by macrophages and neutrophils. The underlying respiratory epithelium is
altered to a squamous metaplasia, sometimes with ulceration,
and lacks ciliated cells, which impedes mucus clearance. The
bronchial wall is weakened as a consequence of a loss of elastin
and smooth muscle. There is often bronchial wall thickening
caused by peribronchial fibrosis and a chronic inflammatory cell
infiltrate accompanied by the formation of germinal centres.
Eosinophils or granulomas may be present, either as a reflection
of chronic inflammation or in association with fungal or mycobacterial infection. There is often obliteration of small airways,
which contributes to the airflow obstruction. As a consequence
of the cycle of inflammatory destruction followed by healing,
there is formation of bronchopulmonary anastomoses and
enlargement of bronchial arteries, which can lead to airway
haemorrhage and haemoptysis.2
There has been significant progress in recent years in our
understanding of the molecular and cellular pathogenesis of
bronchiectasis. There appear to be defects in lung defence
mechanisms (mechanical, humoral, cellular), and there is now
good evidence to support a pathological role for chronically
infecting bacteria.
Chronic infection
There is evidence to support a role for chronic infection in the
progression of bronchiectasis. Studies using conventional
sputum culture techniques have shown that bacteria can be
cultured from 65 to 79% of chronically productive patients even
when they are clinically stable. The most common pathogens
are Haemophilus influenzae and Pseudomonas aeruginosa.2
More recent studies using sequencing of bacterial 16S ribosomal DNA have shown that pathogenic bacteria can be
detected in all sputum samples from bronchiectatic patients.
Bacterial colonization has been associated with clinically
important outcomes such as frequency of pulmonary exacerbation and hospitalization. Finally, P. aeruginosa is associated
with a particularly difficult clinical course characterized by a
more rapid loss of lung function, frequent exacerbations and
increased mortality.
A vicious cycle of infection and inammation
Clinically, the most helpful unifying concept of the pathogenesis
of bronchiectasis remains Coles vicious cycle of inflammation
and infection. This describes a primary insult causing bronchial
wall inflammation followed by disordered mucociliary clearance,
chronic or recurrent infection, bronchial wall damage, airflow
obstruction and further inflammation that perpetuates the cycle
(Figure 1).
Mechanical
Reductions in the cough reflex are associated with recurrent
chest infections, and recurrent aspiration is certainly a wellrecognized cause of bronchiectasis.
The mucociliary escalator functions to move inhaled organic
and inorganic particles caught in mucus to the throat. This
viscous layer is propelled by cilia that beat in a coordinated
fashion within a more fluid and tightly regulated airways surface
liquid (ASL). Changes in the electrolyte composition of the ASL,
as seen in cystic fibrosis (CF), lead to an altered volume and
height of this more fluid layer and so impair ciliary movement.
Genetic defects in the structure of the proteins making up the
cilia also lead to abnormal movement and are the cause of primary ciliary dyskinesia. Finally, airway infection itself, whether
viral or bacterial, can directly impair cilial function.
Inflammatory
insult
Bronchial
wall damage
Immunity
Both the adaptive and innate immune systems contribute to
humoral and cellular mechanisms of defence in the lung.2 It is
beyond the scope of this article to describe these in detail, but
there is a complex and multilayered response to infection
involving multiple receptors and cell types. Defects in many of
these pathways have been described in patients with bronchiectasis. For example, abnormal antibody production, seen in
patients with common variable immunodeficiency (CVID), is
central to pathogenesis and is treatable with immunoglobulin
(Ig) replacement.
Our understanding is evolving, and new molecular defects
to explain clinical syndromes continue to be described. A
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Chronic or
recurrent
infection
Disordered
mucociliary
clearance
Airflow
obstruction
Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017
BRONCHIECTASIS
Causes of bronchiectasis
Bronchiectasis is the common structural endpoint of a number of
diseases (Table 1). Nevertheless, even with the rigorous application of an extensive set of recommended investigations, it is
not possible to identify a primary cause in 35% of patients.
Causes of bronchiectasis
Post-infection
C
Whooping cough (Bordetella pertussis)
C
Viral, e.g. measles
C
Pneumonia, especially in childhood
C
Tuberculosis (Mycobacterium tuberculosis)
C
Non-tuberculous mycobacterial pulmonary disease,
e.g. M. avium, M. intracellulare, M. abscessus
Fungal infection
C
Allergic bronchopulmonary aspergillosis
C
Allergic bronchopulmonary mycoses
Defects of mucociliary clearance
C
Primary ciliary dyskinesia
C
CF e CFTR protein dysfunction
C
Other channelopathies
Toxic inhalation
C
Inhalation injury
C
Chronic aspiration secondary to neuromuscular disease
C
Gastro-oesophageal reflux disorder
C
Tracheo-oesophageal fistula
Obstruction of a single bronchus
C
Tumour
C
Foreign body
Obstructive airways disease
C
Asthma
C
Chronic obstructive pulmonary disease
C
a1-Antitrypsin deficiency
Interstitial lung disease (traction bronchiectasis)
Structural lung conditions
C
WilliamseCampbell syndrome
C
Mounier-Kuhn syndrome
C
EhlerseDanlos syndrome
Bronchiectasis in systemic disease
C
Inflammatory bowel disease
C
Yellow nail syndrome
C
Autoimmunity including:
Rheumatoid arthritis
grens syndrome
Sjo
Sarcoidosis
Relapsing polychondritis
Primary immunodeficiency
C
CVID
C
X-linked agammaglobulinaemia
C
Chronic granulomatous disease
C
Specific antibody deficiency
C
Hyper-IgE syndrome
C
Many others, including APDS
Secondary immunodeficiency
C
HIV infection
C
Haematological malignancy
C
Drug-induced bone marrow suppression
C
Immunosuppressant drugs
C
Graft-versus-host disease
Diagnosis
The most common presentation is with a chronic productive
cough, often accompanied by a history of recurrent chest infections. It is essential to carefully document symptoms during
exacerbations to help guide treatment in a setting where there is
no single reliable biomarker for all patients.4 Patients rarely
present with signs and symptoms of acute sepsis. Instead, the
features of exacerbation are often an increase in sputum volume,
viscosity or colour, breathlessness, wheeze and chest pain. These
symptoms can be accompanied by a low-grade systemic response
that can include night sweats and fever. A careful systems
enquiry is necessary and should include direct questions relating
to allergen exposure, sinus disease, dysphagia and gastrooesophageal reflux.
Clinical signs are not always present but can include wheeze
and crackles on auscultation. Finger clubbing is sometimes a
feature of severe disease. Careful examination to exclude respiratory failure and cor pulmonale should be undertaken.
Investigations
A diagnosis of bronchiectasis is now made on the basis of
consistent symptoms and confirmed on high-resolution CT
(HRCT) of the chest. It is recommended that patients are referred
to a specialist unit for investigation. Many of the primary diagnoses significantly alter management. The British Thoracic
Society guidelines recommend that a series of investigations are
undertaken for all patients with bronchiectasis regardless of
severity. These tests are summarized in Table 2 alongside suggestions for second-line testing in specific circumstances.
Immunological assessment
A number of immunological conditions are associated with
bronchiectasis, only some of which are summarized in Table 1.
Humoral immunity can be impaired by low concentrations of
IgG, IgA and IgM, and in certain instances by low concentrations
of IgG subclasses. Further information can be obtained by
checking specific antibody levels to pneumococcal serotypes, H.
influenzae type B and tetanus. If these are low, vaccination is
recommended, with repeat measurement of the serotype responses 4e6 weeks later.
Abnormal results must be interpreted in consultation with an
Immunologist with suitable expertise. Consensus definitions of
CVID and specific antibody deficiency continue to be revised, not
least in light of variability in laboratory testing and the vaccinations used. The decision to treat these patients with Ig
replacement is a complex one, but this intervention can
dramatically change the prognosis.
Bronchiectasis Severity Index
The Bronchiectasis Severity Index is summarized in Table 3. It is
the first clinical prediction tool for the likelihood of hospital
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Table 1
Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017
BRONCHIECTASIS
Domain
Radiology
C
Thoracic HRCT e interpreted in clinical context
Microbiology
C
Sputum microscopy, culture and sensitivities
C
Sputum fungal culture
C
Three sputum samples for acid-fast bacillus microscopy and
mycobacterial cultures
C
Bronchoscopy with bronchial lavage where indicated
Respiratory physiology
C
Spirometry and flowevolume loop post bronchodilator
C
Body plethysmography
C
Diffusion capacity
C
Exercise testing and echocardiography
C
Arterial blood gas
C
Exhaled nitric oxide
CF and channelopathy screening
C
Sweat test with laboratory analysis of sweat chloride
C
CFTR genetic analysis
C
CFTR sequencing
C
Nasal potential difference
Primary ciliary dyskinesia screening
C
Nasal nitric oxide
C
Cilial biopsy, culture and electron microscopy
a1-Antitrypsin screen
C
a1-Antitrypsin concentration
C
a1-Antitrypsin phenotype
Allergy screening
C
Skin prick testing based on history of exposure
C
RAST profile to common aeroallergens
C
Total IgE, Aspergillus RAST, Aspergillus IgG
Immunology
C
Autoimmune profile e ANA, ANCA, ENA, RF, anti-CCP
C
Protein electrophoresis e IgG, IgG subclasses, IgA, IgM, paraprotein strip
C
Specific antibody levels to Pneumococcus, Haemophilus influenzae type B, tetanus
C
HIV testing
C
Vaccination and repeat serological tests 4e6 weeks
C
Lymphocyte profile
C
Neutrophil function testing
C
Interferon-gamma studies
C
Ultrasound to exclude splenomegaly
Other tests
C
Full blood count, differential white cell count, renal and liver
function
C
Sleep study
C
Barium swallow, oesophageal manometry and pH studies
C
Videofluoroscopy or flexible endoscopic evaluation of swallow
Points
Age (Years)
<50
50e69
70e79
80
Body mass index (kg/m2)
<18.5
18.5
FEV1 % predicted
>80
50e80
30e49
<30
Hospital admissions in the past 2 years
Yes
No
Exacerbation frequency in the past 12 months
0e2
3
MRC dyspnoea score
1e3
4
5
Bacterial colonization
Pseudomonas aeruginosa
Other organisms
None
Radiological severity
3 lobes involved or cystic
<3 lobes involved
0
2
4
6
2
0
0
1
2
3
5
0
0
2
0
2
3
3
1
0
1
0
Table 3
Table 2
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Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017
BRONCHIECTASIS
Anti-inammatory agents
Oral corticosteroids are used in the treatment of bronchiectasis
during exacerbations or when the patient has a dual diagnosis of
ABPA, asthma or chronic obstructive pulmonary disease. Combination inhaled long-acting b-adrenoreceptor agonists and corticosteroids are also prescribed to patients with bronchiectasis
alone who demonstrate bronchial hyperresponsiveness. In
addition, a trial of treatment is warranted in patients with
radiological and lung function evidence of small airways disease.
The available limited clinical trial data indicate an improvement
in sputum parameters, but these studies did not demonstrate an
improvement in exacerbation frequency.
Macrolide antibiotics, in particular azithromycin, are
frequently prescribed, especially in patients chronically infected
with P. aeruginosa. As well as an antimicrobial action against a
broad range of Gram-positive and Gram-negative pathogens,
they have also been shown to have anti-inflammatory properties.
Three double-blind, randomized controlled trials have demonstrated a significant improvement in exacerbation frequency and
quality of life even in patients from whom P. aeruginosa could
not be cultured, and who had only one or more exacerbations per
year. The duration of effect is less certain, and patients prescribed this treatment need careful monitoring for potential
hepatotoxicity and auditory, vestibular and cardiac adverse effects. In addition, it is recommended that infection with nontuberculous mycobacteria is excluded with three negative
sputum mycobacterial cultures before starting treatment, to
avoid promoting mycobacterial resistance.
Physiotherapy
The promotion of chest clearance is central to the treatment of a
condition in which mucociliary dysfunction plays such an
important role. There is little clinical trial evidence to suggest
that any individual technique or adjunctive device provides
particular benefit over others. Instead, it is a matter of developing
an individualized chest clearance programme based on severity
of disease, chronic symptoms and patient competence with a
step-up plan to use during exacerbations. The plan should
include advice on exercise, and referral to a pulmonary rehabilitation programme should be considered.
The development of this plan requires a comprehensive
assessment by a specialist respiratory physiotherapist as a
number of techniques and devices are available. Independent
techniques including the Active Cycle of Breathing and autogenic drainage can be further augmented with positive expiratory pressure valves, oscillators such as flutter valves and
Acapella devices. Inhaled or nebulized bronchodilators are
often used to augment clearance further. In more severe cases
or in acute settings, it may be necessary to step up to the use of
manual techniques (percussion, chest wall vibrations), postural
drainage and intermittent positive-pressure breathing support
using a Bird ventilator device, cough-assist device or noninvasive ventilator.
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Eradication of P. aeruginosa
As discussed above, there is good evidence for a poorer clinical
course in patients chronically infected with P. aeruginosa. A first
isolate from sputum should prompt a further sample as this organism can be cleared spontaneously. Although there are few data
to support eradication outside CF, consensus guidelines suggest
that an attempt should be made. This can take the form of 2e6
weeks of oral ciprofloxacin or intravenous anti-pseudomonal antibiotics with or without 3 months of nebulized colistin.
Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017
BRONCHIECTASIS
Oral antibiotic
Intravenous antibiotic
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Coliforms
Stenotrophomonas maltophilia
Vancomycin
Teicoplanin, linezolid, tigecycline, fosfomycin
Tobramycin plus one of: ceftazidime 2 g t.d.s.
Piperacillin with tazobactam, meropenem,
aztreonam
Cefuroxime 1.5 g t.d.s.
Piperacillin with tazobactam, meropenem,
aztreonam
Co-trimoxazole 1.44 g b.d.
Tigecycline, colistin
Table 4
Antibiotic prophylaxis
Consensus guidelines advise that antibiotic prophylaxis should
be prescribed to patients with three or more exacerbations per
year, severe exacerbations or those chronically infected with P.
aeruginosa. This treatment could be in oral or nebulized form,
although there are few recently published data on the former.
There have been a number of trials of nebulized antibiotics in
Oral antibiotic
Nebulized antibiotic
(Off licence use in UK)
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Colomycin 2 MU b.d.
Table 5
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Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017
BRONCHIECTASIS
FURTHER READING
Ameratunga R, Woon S-T, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common variable immune deciency (CVID), which
may assist with decisions to treat with intravenous or subcutaneous
immunoglobulin. Clin Exp Immunol 2013 Nov; 174: 203e11.
Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT.
Short- and long-term antibiotic treatment reduces airway and
systemic inammation in non-cystic brosis bronchiectasis. Am J
Respir Crit Care Med 2012 Oct 1; 186: 657e65.
Davis SD, Ferkol TW, Rosenfeld M, et al. Clinical features of childhood
primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med 2015 Feb 1; 191: 316e24.
Goeminne PC, Nawrot TS, Ruttens D, Seys S, Dupont LJ. Mortality in
non-cystic brosis bronchiectasis: a prospective cohort analysis.
Respir Med 2014 Feb; 108: 287e96.
Haworth CS, Bilton D, Elborn JS. Long-term macrolide maintenance
therapy in non-CF bronchiectasis: evidence and questions. Respir
Med 2014 Oct; 108: 1397e408.
Masekela R, Anderson R, Moodley T, et al. HIV-related bronchiectasis
in children: an emerging spectre in high tuberculosis burden areas.
Int J Tuberc Lung Dis 2012 Jan; 16: 114e9.
KEY REFERENCES
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2 Floto R, Haworth CS. ERS monograph: bronchiectasis. Shefeld:
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3 Angulo I, Vadas O, Garcon F, et al. Phosphoinositide 3-kinase
d gene mutation predisposes to respiratory infection and airway
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4 Murray MP, Turnbull K, Macquarrie S, Hill AT. Assessing response
to treatment of exacerbations of bronchiectasis in adults. Eur
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5 Johnson C, Haworth CS. Inhaled antibiotics for bronchiectasis: are
we there yet? Curr Pulmonol Rep 2015 Sep 9; 4: 198e204.
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Please cite this article in press as: Johnson C, Haworth C, Bronchiectasis, Medicine (2016), http://dx.doi.org/10.1016/j.mpmed.2016.02.017