Download Histopathology of bronchiectasis

Chapter 3
Histopathology of
bronchiectasis
M. Goddard
HISTOPATHOLOGY
Summary
The clinical presentation of bronchiectasis occurs after initial
irreversible damage to the airway has occurred. The clinician then
has to control symptoms and limit the progression of the disease.
A clearer understanding of the pathogenesis of this disease will
enable the development of better treatment strategies.
Bronchiectasis is a multi-factorial disease process in which
there are a number of key steps, although they are not always
clinically identifiable. There is often an initiator or damaging
event such as a viral infection which, in an individual with a
predisposing risk such as a degree of immune dysfunction or an
impaired mucociliary clearance system, leads to persistent
and damaging bacterial infections. These infections go on to
provoke an inappropriate and self-damaging inflammatory
response in which neutrophil activity leads to progressive tissue
damage and a relentless cycle of infection, inflammation and
bronchial wall injury. Persistent infection and chronic inflammatory cell infiltration further amplify the local inflammatory
milieu and may lead to systemic complications.
Keywords: Aetiology, bronchiectasis, histopathology,
inflammation, neutrophils, pathogenesis
Correspondence: M. Goddard, Dept
of Pathology, Papworh Hospital NHS
Foundation Trust, Papworth Everard,
Cambridge, CB23 3RE, UK, Email
[email protected]
Eur Respir Mon 2011. 52, 22–31.
Printed in UK – all rights reserved.
Copyright ERS 2011.
European Respiratory Monograph;
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003310
B
ronchiectasis was first described at the beginning of the 19th century by LAENNEC [1]. He
ascribed the term to the pooling of secretions in the airways leading to wall weakening and
dilatation. Whilst the term is often used loosely by radiologists to describe any airway dilatation,
pathologically the term is used to describe an irreversible dilatation of the airway often associated
with chronic suppuration.
Aetiology and classification
Aetiologically, bronchiectasis may be divided into obstructive and nonobstructive types (table 1).
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In the obstructive type of bronchiectasis airway dilation may develop from obstruction due to any
cause. The disease is confined to the airways distal to the obstruction. Causes of obstruction may
be luminal, such as the inhalation of foreign bodies. This is most common in children and shows a
The pathogenesis of obstructive bronchiectasis is
relatively straightforward, as bronchial secretions accumulate distal to the obstruction and become
infected producing inflammation and damage to
the bronchial wall which becomes weakened and
dilated. This was recognised by LAENNEC [1].
Table 1. Causes of bronchiectasis
Bronchial obstruction
Foreign bodies
Tumours
Carcinoid tumours
Endobronchial chondromas and lipomas
Mucous plugs
ABPA
Nonobstructive
Post-infective
Measles
Adenovirus
Pertussis
Tuberculosis
Mucociliary abnormalities
Cystic fibrosis
Ciliary dysmotility syndromes
Primary ciliary dyskinesia
Immunological abnormalities
Hypogammaglobulinaemia IgA and IgG
sub-class deficiencies
Neutrophil function abnormalities
Ataxia telangiectasia
Associated with systemic diseases
Rheumatoid arthritis
Sjögren’s syndrome
Ankylosing spondylitis
a1-antitrypsin deficiency
Pulmonary fibrosis
ABPA: allergic bronchopulmonary aspergillosis;
There have been several attempts to classify nonIg: immunoglobulin.
obstructive bronchiectasis, which are variably based
on a mixture of historic bronchographic and, more
recently, high-resolution computed tomography (HRCT), appearances (saccular or cystic,
fusiform or cylindric) [10] and histological appearances (follicular) with lymphoid follicles in
the wall, as defined by WHITWELL [11]. Nonobstructive bronchiectasis is typically more widespread, affecting more than one lobe and most commonly affecting the basal segments of the lower
lobes [11–13]. The left lung is more frequently affected than the right and the disease process
typically involves the middle-order bronchi (fourth to ninth generations).
M. GODDARD
predilection for the right lower lobe and posterior
segment of the right upper lobe [2–5]. The risk of
developing bronchiectasis following foreign body
inhalation has been assessed as 3–16% [6]. However,
other causes of obstruction include mucus inspissation in allergic bronchopulmonary aspergillosis
(ABPA) [7], with central or upper lobe bronchiectasis, and distal to broncholitis. Tumours may also
cause obstruction and bronchiectasis but this is more
prevalent in the slower growing often polypoid tumours, such as carcinoid tumours, endobronchial
lipomas and chondromas [8]. Extrinsic compression
of the bronchus may also lead to obstruction, and
typically hilar tuberculous lymphadenopathy can
lead to bronchiectasis, particularly of the right
middle and lower lobes. The middle lobe, because
of its relatively narrow lumen, is at particular risk of
compression or obstruction, a condition sometimes
referred to as middle lobe syndrome [9].
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This classification is now probably unsatisfactory and of little pathological significance; although
the distribution of changes may provide a clue to the underlying aetiology. Post-infective
bronchiectasis is traditionally the most common underlying cause, is most often basal and may
be confined to a single lobe. However, nonobstructive bronchiectasis may occur in association
with a number of other conditions. In diseases where mucociliary clearance is impaired,
bronchiectasis frequently, if not inevitably, develops. In cystic fibrosis [14] and ciliary
dysmotility syndromes, such as primary ciliary dyskinesia arising from a defect in the dynein
arms [15], bronchiectais is more widespread, sometimes with upper lobe predominance. The
association of bronchiectasis with disturbances in mucociliary clearance mechanisms highlights
the importance of local defence mechanisms within the airways in aetiological terms and in
terms of the pathogenesis of the disease. There may be primary defects in the immune system
with abnormalities of neutrophil function, hypogammaglobulinaemia [16], immunoglobulin
(Ig)A and IgG sub-class deficiencies [17], and in ataxia telangiectasia. Bronchiectasis may also be
associated with some autoimmune conditions including ulcerative colitis [18], rheumatoid
disease [19], Sjögren’s syndrome [20] and ankylosing spondylitis. Bronchiectasis is also associated with several noninflammatory conditions within the lung, such as a1-antitrypsin
deficiency, and is reported in some cases of pulmonary fibrosis but in these cases may be due to
traction effects of the surrounding fibrosis.
Of the known causes or associations of bronchiectasis, childhood infection is probably the most
common accounting for up to 30% of cases, with immunodeficiencies present in up to 18%.
However, in some studies, no underlying abnormality can be detected in .50% of cases.
Histopathological appearances
Histopathologically, bronchiectatic airways appear dilated and on examination have a crosssectional area that is much larger than the accompanying pulmonary artery (fig. 1). The airway
lumen is often filled with a mucopurulent exudate with neutrophils and macrophages (figs 2 and 3).
The respiratory epithelium lining shows variable changes from a reserve cell hyperplasia to
squamous metaplasia (fig. 4) with active inflammation shown by epithelial and mucosal infiltration
by neutrophils and in severe exacerbations, ulceration (figs 5 and 6). The bronchial wall is often
destroyed due to loss of fibromuscular tissues and the elastic framework, and may show erosion and
loss of cartilage [21]. There is usually a reduction in submucosal glands. The wall may be thin but is
more often greatly thickened with extensive peribronchial fibrosis extending into the adjacent lung
parenchyma (fig. 7) [22]. There is an associated chronic inflammatory cell infiltrate within the wall,
predominantly lymphocytes and plasma cells, and in some cases lymphoid follicles with germinal
centres may be prominent [23]. The presence of B-cell immune activation through the presence of
germinal centres and plasma cells in the walls of bronchiectatic airways, would support the role of
antibodies in the immune response to persistent infection. However, bronchiectasis is associated
with some autoimmune connective tissue diseases, in particular rheumatoid arthritis [19, 24, 25],
and a role for autoimmunity in the destruction of the airway has also been suggested.
HISTOPATHOLOGY
Eosinophils may be seen as part of
the infiltrate as with any chronic
airways inflammation. Whilst nonspecific, they raise the possibility of
an associated fungal infection such
as Aspergillus. Although eosinophils
are commonly seen in the mucus
plugs of ABPA, their presence
within the airway wall inflammation is nonspecific. Granulomas and
multinucleate giant cells may be
seen in the wall and might be a
reaction to the inspissated luminal
material but the possibility of concomitant fungal or mycobacterial
infection should always be considered. In established bronchiectasis,
the histological pattern of chronic
inflammation within the airway wall
with superimposed active inflammation, most likely reacting to
concomitant infection, has a fairly
uniform appearance and provides
little insight into the underlying
aetiology or pathogenesis.
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Figure 1. Low-power view of a bronchiectatic airway; note the
airway lumen is much larger than that of the accompanying
pulmonary artery. Magnification64.
The surrounding lung parenchyma
may show a number of changes.
Where there is distal luminal obliteration of bronchi and bronchioles, the lung parenchyma may
The airways are supplied by the
bronchial arteries and the inflammatory destruction and healing processes
result in the formation of bronchopulmonary anastamoses, probably due
to a mixture of new vessel formation
and the re-opening of pre-existing,
pre-capillary bronchopulmonary connections (fig. 8). Ulceration of the airways can lead to severe haemorrhage
and haemoptysis. The formation of
anastamoses and the loss of some of
the alveolar capillary bed leads to the
development of pulmonary hypertension [27].
Figure 2. Bronchiectatic airway wall with dense chronic
inflammatory cell infiltrate, which includes lymphocytes, plasma
cells and eosinophils. Magnification620.
M. GODDARD
show atelectasis due to absorption
and collapse. Obliterative changes in
small airways are important in contributing to airflow obstruction in
bronchiectasis [10, 11]. Destructive
inflammation may lead to the formation of an abscess cavity, although
this may be difficult to distinguish
from a distended, ulcerated airway.
There may be accompanying interstitial pneumonitis, particularly in
cases of follicular bronchiectasis, and
also changes of an organising pneumonia. Small airway changes, such
as bronchiolectasis, may be seen as
part of the whole disease process or
may be part of an underlying disease
leading to more proximal dilatation, as has been seen with small
airways disease, such as bronchiolitis
[18, 26].
Focal proliferations of neuroendocrine
cells are also seen and may lead to
the formation of multiple tumourlets,
small aggregates of neuroendocrine
cells in the walls of small airways.
These are not specific to bronchiectasis and may be seen in a number of
chronic lung conditions [28].
Figure 3. Bronchiectatic airway wall with luminal pus, neutrophil
infiltration of the airway epithelium and a dense chronic
inflammatory cell infiltrate. Magnification640.
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It has also been recognised that the
persistent chronic activation of the immune system in the wall of the airway may lead to the development of
bronchus-associated lymphoid tissue
(BALT), especially in bronchiectasis
associated with Sjögren’s syndrome
[29]. Increased incidence of BALTomas,
low-grade, B-cell lymphomas, is associated with Sjögren’s syndrome
but not specifically related to bronchiectasis [20].
In chronic disease, further complications may arise. Locally, the lung
may develop abscesses and even empyema, although this is less common
as the pleural space is often obliterated by fibrous adhesions. Bronchiectatic spaces may become colonised
by saprophytic fungi, most commonly
Aspergillus sp.
HISTOPATHOLOGY
Systemic dissemination of infection
may lead to abscesses in other organs,
notably the brain, and chronic suppuration may be complicated by
systemic amyloidosis (type AA). The
incidence in bronchiectasis is unclear
but in one study of patients with
systemic amyloidosis requiring haemodialysis, 40% had underlying bronchiectasis [30].
Figure 4. Squamous metaplasia of the epithelium lining in
bronchiectasis. Magnification640.
Pathogenesis
The pathogenesis of bronchiectasis
is complex and a number of different mechanisms contribute to the development of a similar
morphological appearance and different factors act together to set up a cycle of inflammation and
destruction that leads to damage and destruction of the bronchial wall [31].
The initiator to this sequence is usually damage to the bronchial epithelium. This may be due to an
external insult or to an intrinsic deficiency within the patient. The most common predisposing
factor to the development of bronchiectasis is a severe childhood respiratory infection, which may
be viral, such as measles or adenovirus, or bacterial, such as Bordetella pertussis [32–34]. The
resultant permanent dilatation of
the airways is thought to be due
not only to inflammation and destruction of the bronchial wall but
also, in part, to a traction effect
produced by collapse of the surrounding lung parenchyma. However, the persistence of infection
and inflammation are of paramount
importance in the progression of the
disease.
Figure 5. Severely inflamed ulcerated bronchiectatic airway with
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no epithelium and surface granulation tissue. Magnification620.
Whilst an underlying cause is not
established in all cases, the number
and type of associations for bronchiectasis gives us some indication
of what the important underlying
pathogenetic mechanisms may be.
In post-infectious causes, the initiating viral infection appears to be
transitory and, in the case of adenoviruises, it has not been possible to
demonstrate the persistence of the
virus within bronchiectasis by in situ
hybridisation [35]. However, some
respiratory viruses have been shown
to lead to abnormalities in ciliary
function, which may persist for several
weeks [36].
In the early stages of bronchiectasis, the most common bacterial isolate is Haemophilus influenzae,
which has the capacity to directly damage the airway epithelium and induce the production of
inflammatory mediators [37]. The typical immune response to H. influenzae is a T-helper (Th)1
response. However, some bronchiectasis patients with persistent infection have been found to have
a Th2 response with a cytokine profile of interleukin (IL)-4 and IL-10. The release of cytokines
contributes to the inflammatory response within the airway and at the same time may also result
in a failure of the response to satisfactorily remove the organism [38].
Figure 7. A bronchiectatic airway showing an attenuated inflamed
epithelium with surrounding inflammation and fibrosis extending into
the peribronchial lung parenchyma. Magnification620.
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Over time, a number of other organisms have been found to be
established within the airways, particularly Streptococcus pneumoniae
and Pseudomonas aeruginosa. The
initial damage to the epithelium
lining allows this secondary bacterial colonisation to occur, which further inhibits ciliary clearance and
promotes the persistence of infection and damaging inflammation
[39]. The importance of this persistence in bacterial colonisation may
be related to the production of heatlabile products by the bacteria,
which further damage ciliated cells
and inhibit ciliary activity. P. aeruginosa can be a particular problem
as it is protected from cellular and
humoral attack because it survives
in a biofilm on the mucosal surface
[40]. Pseudomonas has been shown
M. GODDARD
Clinically, it is the recurrence and
persistence of bacterial infections
in the airways with which most
patients present that are of most
importance and are linked to the
progression of the disease. There is a
Figure 6. Ulcerated airway with surrounding fibrosis of the wall.
prevailing view that bacterial infecMagnification610.
tion in the lower respiratory tract
provokes an exaggerated and uncontrolled neutrophilic response and that the complex interplay between bacterial infection and airway
inflammation, along with the release of tissue damaging substances, leads to the progressive damage
which typifies bronchiectasis.
to produce phenazine pigments that
can inhibit ciliary action through a
mechanism which leads to a reduction in cellular cAMP and ATP.
Furthermore, pseudomonal pyocyanin can lead to epithelial disruption
and rhamnolipids have a ciliostatic
effect [41, 42]. Alveolar macrophages are an important mediator of
defence against Pseudomonas and
stimulated macrophages secrete cytokines that both recruit and activate
neutrophils, thus potentially amplifying both the inflammatory response
and the potential for further tissue
damage [43, 44].
The resultant inflammatory reaction
is an important pathogenic mechanwall. Magnification620.
ism in the weakening of the bronchial wall. Much of the damage
appears to relate to the release of proteolytic enzymes and oxygen free radicals from neutrophils.
The severity of an inflammatory response is dependent on the interplay of several cytokines, which
may be both pro- and anti-inflammatory [45]. In a well-regulated system, the inflammatory
cascade is proportionate to the triggering bacterial stimulation and is switched off. There is
evidence that in bronchiectasis the inflammatory response is disproportionate to the infective
burden and that the inflammatory response persists [43, 46]. Indeed, in the early phases of
bronchiectasis, active airway inflammation has even been reported in the absence of identifiable microbial infection, suggesting a dysregulation of the cytokine network independent of
infection [47].
HISTOPATHOLOGY
Figure 8. Thick-walled bronchial artery in a bronchiecatic airway
Neutrophils are potent effectors in inflammatory responses and secrete anti-microbial substances,
as well as reactive oxygen free radicals [48]. Bronchoalveolar lavage (BAL) studies have demonstrated that neutrophils are consistently present in patients with bronchiectasis, even when
sterile and clinically stable, but increase in the presence of potential pathogens [49, 50].
Recruitment and migration of neutrophils in airways is facilitated by the activation of neutrophils
and the upregulation of adhesion molecules on endothelial cells [51–53]. These changes are
regulated by cytokines, particularly IL-1 and tumour necrosis factor (TNF)-a, as well as
lipopolysaccharide (LPS), which have been shown to be increased in the airways of patients with
bronchiectasis [54, 55]. Activated neutrophils secrete potentially tissue damaging enzymes such as
neutrophil elastase, proteinase 3 and metalloproteinases. Levels of these enzymes in BAL samples
have been shown to correlate with neutrophil numbers and markers of disease activity such as 24hour sputum production [56]. These enzymes can directly damage the structural integrity of the
airway via damage to the basement membrane and elastin framework [57–60]. Neutrophils are
also an important source of oxygen free radicals. Release of oxygen free radicals are an important
part of the defence against infection and are regulated by a protective anti-oxidant system.
However, the excessive release of these oxidants can overwhelm the defence mechanisms and cause
tissue damage via lipid peroxidation. Furthermore, reactive oxygen species may amplify the
inflammatory response through the induction of cytokine and chemokine production by the
stimulation of genes regulated by nuclear factor-kB. Studies in bronchiectatic patients have shown
increased levels of exhaled H2O2 correlating with neutrophil counts and disease activity [61, 62].
28
Macrophages also play a role in the disease progression as they secrete TNF-a, which promotes
neutrophil recruitment, as well as other inflammatory mediators including IL-8, monocyte
chemotactic protein-1 and chemokines [23, 63]. Lymphocytes are also typically present in
bronchial biopsies within the lamina propria and may also infiltrate the overlying epithelium.
Studies assessing the relative proportions of CD4+ and CD8+ have produced mixed and, at times,
conflicting results. Nonetheless, their presence indicates a cell-mediated immune response
contributing to the overall inflammatory process [22].
Whilst the epithelial layer may be seen as a protective barrier through mucociliary clearance and
generation of anti-bacterial substances, it also contributes to the inflammatory process through the
direct generation of pro-inflammatory cytokines [64]. Exposure to LPS leads to the generation of
IL-8 and TNF-a which, as stated previously, are important in neutrophil recruitment. Bronchial
epithelial cells are also able to upregulate surface adhesion molecules, such as intracellular
adhesion molecule-1, aiding the migration of neutrophils [65, 66].
Thus, a number of pathways lead to the activation and recruitment of neutrophils into the airways
which, if not adequately regulated and controlled, results in the destruction of local tissue and the
persistence and progression of bronchiectasis. Individual variability in this innate response may
help to explain why not all individuals exposed to predisposing triggers will go on to develop
bronchiectasis and offers potential targets for therapeutic intervention.
Statement of interest
None declared.
29
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