Asthma

2. 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.

3. The hallmarks of the disease are intermittent and
reversible airway obstruction, chronic bronchial
inflammation with eosinophils, bronchial smooth muscle
cell hypertrophy/hyperreactivity, and increased mucus
secretion.

4. Asthma may be categorized into atopic (evidence of
allergen sensitization, often in a patient with a history of
allergic rhinitis, eczema) and nonatopic.

5. Types and clinical presentations
 Atopic or Extrinsic: Type I hypersensitivity, allergens;
begins in childhood, triggered by environmental allergens
(dander, dust, pollen, food), positive family history;
common in African American children; evidence of
allergen sensitization; skin test causes wheel and flare
reaction .
 Noneosinophilic ("neutrophilic") asthma: atopic
asthma not associated with eosinophilia; IL8 recruiting
neutrophils are an important mechanism;
 patients tend to be less responsive to corticosteroids.

6.  Nonatopic or Intrinsic: nonimmune; due to
pneumonia, cold, stress, exercise; follows respiratory
infection (rhinovirus, parainfluenza virus); normal
serum IgE, negative skin tests; viral induced
inflammation may lower threshold of subepithelial vagal
receptors to irritants.
 Occupational asthma: repeated exposure to fumes,
dusts, gases, chemicals, often in minute quantities;
varying mechanisms of disease depending upon the
stimulus

7.  Drug induced asthma: associated with several drugs,
aspirin related cases are associated with recurrent
rhinitis, nasal polyps and urticaria;
 direct effects of aspirin on cyclooxygenase pathway.
 Status asthmaticus: unremitting attacks due to
exposure to previously sensitized antigen; may be fatal,
usually in patients with a long history of asthma

8. PATHOGENESIS
The major etiologic factors of asthma are genetic
predisposition to type I hypersensitivity (atopy), acute
and chronic airway inflammation, and bronchial
hyperresponsiveness to a variety of stimuli.
The inflammation involves many cell types and
numerous inflammatory mediators, but the role of
type 2 helper T (TH2) cells may be critical to the
pathogenesis of asthma.

9. PATHOGENESIS
• Excessive TH2 reaction against environmental antigens.
Cytokines produced by TH2 cells account for most of the
features of asthma—IL-4 stimulates IgE production, IL-5
activates eosinophils, and IL-13 stimulates mucus
production and also promotes IgE production by B cells.
• IgE coats submucosal mast cells, which, on exposure to
allergen, release granule contents. This induces two waves
of reaction: an early (immediate) phase and a late phase.

10.  The early reaction is dominated by bronchoconstriction,
increased mucus production and variable vasodilation.
 Bronchoconstriction is triggered by direct stimulation of
subepithelial vagal receptors.

11.  Reexposure - immediate reaction is triggered by
antigen-induced cross-linking of IgE antibodies. These
cells release preformed mediators. Collectively, either
directly or through neuronal reflexes, the mediators
induce bronchospasm, increase vascular permeability
and mucus production, and recruit additional
mediator-releasing cells from the blood.

12. • The late-phase reaction consists of inflammation, with
activation of eosinophils, neutrophils, and T cells.
• epithelial cells are activated to produce chemokines
that promote recruitment of more TH2 cells and
eosinophils - eotaxin, a potent chemoattractant and
activator of eosinophils as well as other leukocytes,
thus amplifying the inflammatory reaction.

13.  A fresh round of mediator release from leukocytes,
endothelium, and epithelial cells. Factors, particularly
from eosinophils (e.g., major basic protein, eosinophil
cationic protein), also cause damage to the epithelium

15. Asthma is a complex genetic disorder in which multiple
susceptibility genes interact with environmental factors
to initiate the pathologic reaction. There is significant
variation in the expression of these genes and in the
combinations of polymorphisms that effect the immune
response or tissue remodeling.

16. One of the susceptibility loci is on the long arm of
chromosome 5 (5q), where several genes involved in
regulation of IgE synthesis and mast cell and eosinophil
growth and differentiation map.

17.  The genes at chromosome 5 (5q), locus include IL13
(genetic polymorphisms linked with susceptibility to
the development of atopic asthma), CD14 (single-
nucleotide polymorphisms associated with
occupational asthma), class II HLA alleles (tendency
to produce IgE antibodies), β2- adrenergic receptor
gene, and IL-4 receptor gene (atopy, total serum IgE
level, and asthma).

18. Another important locus is on 20q where ADAM-33 that
regulates proliferation of bronchial smooth muscle and
fibroblasts is located; this controls airway remodeling.
Upregulation of various chitinase enzymes has been
shown to be important in TH2 inflammation and
severity of asthma; high serum YKL-40 levels (a
chitinase family member with no enzymatic activity)
correlate with the severity of asthma.

19. Morphology
 Curschmann spirals, mucous plugs contain whorls of
shed epithelium.
 Charcot-Leyden crystals (crystalloids composed of
galectin-10, an eosinophil lysophospholipase).

23. Characteristic morphologic changes in asthma,
collectively called “airway remodeling,” include
1. Thickening of airway wall
2. Sub-basement membrane fibrosis
3. Increased vascularity in submucosa
4. An increase in size of the submucosal glands and
goblet cell metaplasia of the airway epithelium
5. Hypertrophy and/or hyperplasia of the bronchial
muscle

36. References
1. Baughman RP, Lower EE, du Bois RM: Sarcoidosis. Lancet 361:1111, 2003. [A good review
of this subject, including evidence on the role of genetic polymorphisms that determine
susceptibility to sarcoidosis, and treatment options.] Beasley MB: Smoking-related
small airway disease—a review and update. Adv Anat Pathol 17:270, 2010.
2. [Review of histologic findings and pathogenesis of small airway disease in smoking-
related diseases.] Collard HR, King TE Jr: Demystifying idiopathic interstitial
pneumonia. Arch Intern Med 163:17, 2003.
3. [A review on the histopathologic and clinical features distinguishing interstitial
pneumonias from other causes of pulmonary fibrosis, with particular emphasis on
idiopathic pulmonary fibrosis and the importance of recognizing this pattern.] Cosio
MG, Saetta M, Agusti A: Immunologic aspects of chronic obstructive pulmonary
disease. N Engl J Med 360:2445, 2009. [An excellent review of mechanisms leading to
COPD.]
4. Davies D, Wicks J, Powell RM, et al: Airway remodeling in asthma: new insights. J
Allergy Clin Immunol 111:215, 2003. [A review on the structural changes involved in
asthma pathogenesis, and the role of candidate gene polymorphisms that may confer
potential susceptibility to airway remodeling and asthma.]