Asthma

• Asthma is a chronic inflammatory disorder of the airways that causes

recurrent episodes of wheezing, breathlessness, chest tightness, and
cough, particularly at night and/or early in the morning.

• Many cells play a role in the inflammatory response, in particular

eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and
epithelial cells.

• The hallmarks of asthma are intermittent, reversible airway

obstruction; chronic bronchial inflammation with eosinophils;
bronchial smooth muscle cell hypertrophy and hyperreactivity; and
increased mucus secretion.
 Pathogenesis
• Major factors contributing to the development of asthma
include genetic predisposition to type I hypersensitivity
(atopy), acute and chronic airway inflammation, and
bronchial hyperresponsiveness to a variety of stimuli
• Asthma may be subclassified
• atopic (evidence of allergen sensitization)
• nonatopic.
• In both types, episodes of bronchospasm may be triggered
by diverse exposures, such as respiratory infections
(especially viral), airborne irritants (e.g., smoke, fumes),
cold air, stress, and exercise.
• There also are varying patterns of inflammation—
eosinophilic (most common), neutrophilic, mixed
inflammatory, and pauci-granulocytic
 Pathogenesis Classic atopic
• The classic atopic form is associated with excessive type 2
helper T (TH2) cell activation.
• Cytokines produced by TH2 cells account for most of the
features of atopic asthma— IL-4 and IL-13 stimulate IgE
production, IL-5 activates eosinophils, and IL-13 also stimulates
mucus production.
• IgE coats submucosal mast cells, which on exposure to allergen
release their granule contents and secrete cytokines and other
mediators.
• Mast cell–derived mediators produce two waves of reaction: an
early (immediate) phase and a late phase
• Early-phase reaction
– The early-phase reaction is dominated by bronchoconstriction,
increased mucus production, and vasodilation.
– Bronchoconstriction is triggered by mediators released from mast
cells, including histamine, prostaglandin D2, and leukotrienes LTC4,
D4, and E4, and also by reflex neural pathways.
• late-phase reaction
– The late-phase reaction is inflammatory in nature.
– Inflammatory mediators stimulate epithelial cells to produce
chemokines (including eotaxin, a potent chemoattractant and
activator of eosinophils) that promote the recruitment of T 2 cells,
H

eosinophils, and other leukocytes, thus amplifying an inflammatory

reaction that is initiated by resident immune cells.
• Airway remodeling (sub-basement membrane thickening
and hypertrophy of bronchial glands and smooth muscle)
adds an irreversible component to the obstructive disease.
• Atopic Asthma
– This is the most common type of asthma and is a classic example of
type I IgE–mediated hypersensitivity reaction
– It usually begins in childhood
– A positive family history of atopy and/or asthma is common, and the
onset of asthmatic attacks is often preceded by allergic rhinitis,
urticaria, or eczema.
– Attacks may be triggered by allergens in dust, pollen, animal dander, or
food, or by infections.
– A skin test with the offending antigen results in an immediate wheal-
and-flare reaction
– Atopic asthma also can be diagnosed based on serum
radioallergosorbent tests (RASTs) that identify the presence of IgEs
that recognize specific allergens
• Non-Atopic Asthma
– Patients with nonatopic forms of asthma do not have evidence of
allergen sensitization, and skin test results usually are negative.
– A positive family history of asthma is less common.
– Respiratory infections due to viruses (e.g., rhinovirus,
parainfluenza virus) and inhaled air pollutants (e.g., sulfur
dioxide, ozone, nitrogen dioxide) are common triggers.
– the ultimate humoral and cellular mediators of airway
obstruction (e.g., eosinophils) arecommon to both atopic and
nonatopic variants of asthma
Drug-Induced Asthma
– Several pharmacologic agents provoke asthma, aspirin being the
most striking example. Patients with aspirin sensitivitypresent
with recurrent rhinitis, nasal polyps, urticaria,and bronchospasm.
– The precise pathogenesis isunknown but is likely to involve some
abnormality in prostaglandinmetabolism stemming from
inhibition of cyclooxygenaseby aspirin.
• Occupational Asthma
– Occupational asthma may be triggered by fumes (epoxy resins,
plastics), organic and chemical dusts (wood, cotton,platinum),
gases (toluene), and other chemicals.
– Asthma attacks usually develop after repeated exposure to the
inciting antigen(s).
• Clinical Features
– An attack of asthma is characterized by severe dyspneaand wheezing
due to bronchoconstriction and mucus plugging, which leads to
trapping of air in distal airspacesand progressive hyperinflation of the
lungs.
– can be detected by pulmonary function tests
– The associated hypercapnia, acidosis, and severe hypoxiamay be fatal,
although in most cases the condition is more disabling than lethal
– Standard therapies include anti-inflammatory drugs, particularly
glucocorticoids and bronchodilators such as beta-adrenergic drugs
andleukotriene inhibitors (recall that leukotrienes are
potentbronchoconstrictors).
– Agents that block specific immune mediators, such as IL-4 and IL-5,
are of modest benefit in some patients
– Another approach called bronchial thermoplasty, which involves
controlled deliveryof thermal energy during bronchoscopy to
reduce themass of smooth muscle and airway responsiveness,
isbeing evaluated in patients with severe, poorly
controlledasthma.
 OBSTRUCTIVE LUNG (AIRWAY) DISEASES
• Four disorders in this group—emphysema, chronic bronchitis,
asthma, and bronchiectasis—have distinct clinical and anatomic
characteristics , but overlaps between emphysema,chronic
bronchitis, and asthma are common
• It should be noted that emphysema is defined on the basis of
morphologic and radiologic features, whereaschronic bronchitis
is defined on the basis of clinical features
• emphysema and chronic bronchitis often are grouped together
under the rubric of chronic obstructive pulmonary disease
(COPD).
 Emphysema
• Emphysema is characterized by permanent enlargementof the
air spaces distal to the terminal bronchioles, accompanied by
destruction of their walls without significant fibrosis.
• It is classified according to its anatomic distribution.
• There are four major types of emphysema:
(1) centriacinar,
(2) panacinar,
(3) distal acinar,
(4) irregular.
• Only the first two types cause significant airway obstruction,
with centriacinar emphysema being about 20 times more
common than panacinar disease
• Centriacinar (centrilobular) emphysema
– The distinctive feature of centriacinar emphysema is that the
central or proximal parts of the acini, formed by respiratory
bronchioles, are affected, while distal alveoli are spared.
– Both emphysematous and normal air spaces exist within the
same acinus and lobule
– The lesions are more common and severe in the upper lobes,
particularly in the apical segments
– In severe centriacinar emphysema, the distal acinus also
becomes involved
– This type of emphysema is most common in cigarette smokers,
often in association with chronic bronchitis
• Panacinar (panlobular) emphysema.
– In panacinar (panlobular) emphysema, the acini are uniformly
enlarged, from the level of the respiratory bronchiole to the
terminal blind alveoli
– In contrast to centriacinar emphysema, panacinar emphysema
occurs more commonly in the lower lung zones and is associated
with α1-anti-trypsin deficiency.
• Distal acinar (paraseptal) emphysema.
– In this form of emphysema, the proximal portion of the acinus
is normal but the distal part is primarily involved.
– The emphysema is more striking adjacent to the pleura, along
the lobular connective tissue septa, and at the margins of the
lobules
– The characteristic finding is the presence of multiple, contiguous,
enlarged air spaces ranging in diameter from less than 0.5 mm to
more than 2.0 cm
– The cause of this type of emphysema is unknown
• Irregular emphysema.
– Irregular emphysema, so named because the acinus is
irregularly involved, is almost invariably associated with
scarring, such as that resulting from healed inflammatory
diseases.
– Although clinically asymptomatic, this may be the most common
form of emphysema.
 Pathogenesis
– Inhaled cigarette smoke and other noxious particles cause lung
damage and inflammation,
– In patients with a genetic predisposition, result in parenchymal
destruction (emphysema) and airway disease (bronchiolitis and
chronic bronchitis).
• Factors that influence the development of emphysema
– Inflammatory cells and mediators
– Protease–anti-protease imbalance
– Oxidative stress
– Airway infection
 Inflammatory cells and mediators
• A wide variety of inflammatory mediators have been shown to
be increased (including leukotriene B4, IL-8, TNF, and others)
that attract more inflammatory cells from the circulation
(chemotactic factors), amplify the inflammatory process
(proinflammatory cytokines), and induce structural changes
(growth factors).
• The inflammatory cells present in lesions include neutrophils,
macrophages, and CD4+ and CD8+ T cells.
• It is not known if the T cells are specific for a particular antigen
or are recruited as part of inflammation.
• Protease–anti-protease imbalance:
– Several proteases are released from the inflammatory cells and
epithelial cells that break down connective tissues. In patients
who develop emphysema, there is a relative deficiency of
protective anti-proteases.
• Oxidative stress:
– Reactive oxygen species are generated by cigarette smoke and
other inhaled particles and released from activated inflammatory
cells such as macrophages and neutrophils.
– These cause additional tissue damage and inflammation
• Airway infection:
– Although infection is not thought to play a role in the initiation of
tissue destruction, bacterial and/or viral infections cause acute
exacerbations
– The idea that proteases are important is based in part on the
observation that patients with a genetic deficiency of the anti-
protease α1-anti-trypsin have a predisposition to develop
pulmonary emphysema, which is compounded by smoking.

– α1-anti-trypsin, normally present in serum, tissue fluids, and

macrophages, is a major inhibitor of proteases (particularly
elastase) secreted by neutrophils during inflammation.

– α1-anti-trypsin is encoded by a gene in the proteinase inhibitor

(Pi) locus on chromosome 14.
– Protease-mediated damage of extracellular matrix has a central
role in the airway obstruction seen in emphysema.

– Small airways are normally held open by the elastic recoil of the
lung parenchyma, and the loss of elastic tissue in the walls of
alveoli that surround respiratory bronchioles reduces radial
traction and thus causes the respiratory bronchioles to collapse
during expiration.

– This leads to functional airflow obstruction despite the absence of

mechanical obstruction.
• Clinical Features
– Dyspnea usually is the first symptom; it begins insidiouslybut is
steadily progressive.
– In patients with underlying chronic bronchitis or chronic asthmatic
bronchitis, cough and wheezing may be the initial complaints.
– Pulmonary function tests reveal reduced FEV with normal or near-
1

normal FVC
– Prominent dyspnea and adequate oxygenation of hemoglobin, these
patients sometimes are sometimes called “pink puffers”
– Most patients with emphysema also have signs and symptoms of
concurrent chronic bronchitis, since cigarette smoking is a risk factor
for both.
 Chronic Bronchitis
– Chronic bronchitis is diagnosed on clinical grounds: it isdefined by
the presence of a persistent productive coughfor at least 3
consecutive months in at least 2 consecutive years.
– It is common among cigarette smokers and urban dwellers in smog-
ridden cities;
– the cough raises mucoid sputum, but airflow is not obstructed
– chronic bronchitis have evidence of hyperresponsive airways, with
intermittent bronchospasm and wheezing (asthmatic bronchitis),
while other bronchitic patients, especially heavy smokers, develop
chronic outflow obstruction, usually with associated emphysema
(COPD).
 Pathogenesis
• The distinctive feature of chronic bronchitis is
hypersecretion of mucus, beginning in the large airways
• the most important cause is cigarette smoking, other air
pollutants, such as sulfur dioxide and nitrogendioxide, may
contribute
• These environmental irritants induce hypertrophy of
mucous glands in the trachea andbronchi as well as an
increase in mucin-secreting gobletcells in the epithelial
surfaces of smaller bronchi and bronchioles.
• These irritants also cause inflammation marked by the
infiltration of macrophages, neutrophils, and lymphocytes.
• Mucus hypersecretion is primarily a reflection of
involvement of largebronchi, the airflow obstruction in
chronic bronchitisresults from
• (1) small airway disease, induced by mucousplugging of the
bronchiolar lumen, inflammation, andbronchiolar wall
fibrosis
• (2) coexistent emphysema
• Environmental irritants on respiratory epithelium are
mediated by localrelease of cytokines such as IL-13 from T
cells and innate lymphoid cells.
• The transcription of the mucin gene in bronchial epithelium
and the production of neutrophilelastase are increased as a
consequence of exposure to tobacco smoke.
• Microbial infection often is present but has a secondary
role, chiefly by maintaining inflammation and exacerbating
symptoms.
• Clinical Features
• The course of chronic bronchitis is quite variable.
• In some patients, cough and sputum production persist
indefinitely without ventilatory dysfunction, while others
develop COPD with significant outflow obstruction marked by
hypercapnia, hypoxemia, and cyanosis.
• Patients with chronic bronchitis and COPD have frequent
exacerbations, more rapid disease progression, and poorer
outcomes than those with emphysema alone.
• Progressive disease is marked by the development of pulmonary
hypertension, sometimes leading to cardiac failure recurrent
infections; and ultimately respiratory failure.