FLASHPATHH a z e m A l i
ASTHMAH a z e m A l i
CLINICAL
Asthma is one of the “obstructive lung diseases” that include:• Chronic bronchitis
• Emphysema
• Bronchiectasis
• Small-airway disease “bronchiolitis”
CLINICALObstructive airway
diseaseRestrictive airway
diseaseGeneral features Increase in resistance to
airflow due to obstruction at any level
Reduced expansion of lung parenchyma
Total lung capacity (TLC)
Increased Reduced
Forced Expiratory Volume in one second (FEV1)
Reduced Normal
CLINICAL• Asthma is:
– Very common disease– Chronic inflammatory disorder of the airways– Bronchial hyper-responsiveness to a variety of stimuli– Widespread but reversible airflow obstruction
• Either spontaneously or with treatment– Attacks of wheezing, breathlessness, chest tightness
and coughing• Particularly at night or early morning
CLINICALAtopic “Extrinsic” Nonatopic “Intrinsic”
Mechanism Type I hypersensitivity Non-immnune Stimulants Environmental allergens:
• Dander• Dust• Pollen• Food
• Aspirin ingestion• Viral infections• Cold• Chemicals and fumes• Stress• Exercise
Age of presentation Childhood AdulthoodFamily history Positive NegativeHistory of other allergic diseases(e.g. eczema, allergic rhinitis)
Positive Negative
Skin test(wheal-and-flare reaction)
Positive Negative
Serum IgE level High Normal
CLINICALTreatment:• Avoidance of trigger agents• Desensitization to specific allergens• Bronchodilator drugs and corticosteroids• Leukotriene and leukotriene receptor antagonists• Antibodies directed against IgE
Status asthmaticus:• Unremitting acute severe asthmatic attacks, may be fatal• Usually in patients with a long history of asthma
PATHOGENESISAtopic = Type I hypersensitivity1) Exposure to allergen
– Through mucosal epithelium2) Activation of TH2 cells / Class switching of B cells
– Dendritic cells present allergen to naïve CD4 T cells– CD4 T cells will differentiate into TH2 cells– TH2 cells will produce cytokines and chemokines
• IL-4: Activate more TH2 cells, Class switching of B cells (IgE – secreting B cells)
• IL-5: Activate eosinophils• IL-13: Increase IgE production, Increase mucus secretion from epithelial
cells• Chemotactic factors: attract more inflammatory cells
The fundamental abnormality in asthma is an exaggerated TH2 response to harmless environmental antigens
PATHOGENESISAtopic = Type I hypersensitivity3) Sensitization of mast cells
– Ig E binds to Fc receptors on mast cells sensitization4) Activation of mast cells
– Repeat exposure to allergen– Bind to IgE on sensitized mast cells activation and release of
mediators Mast cells may also be triggered by several other stimuli:• Complement components (e.g. c5a and c3a = also called
anaphylatoxins)• Chemokines (e.g., Il-8)• Drugs (e.g. codeine and morphine)• Adenosine• Melittin (present in bee venom)• Physical stimuli (e.g., heat, cold, sunlight)
PATHOGENESISAtopic = Type I hypersensitivity5) Tissue reaction:According to the type of released mediators• Immediate reaction:
– Starts within minutes of exposure to allergen– Subsides within few hours– Causes vasodilatation, congestion, edema, muscle spasm, increased glandular
secretions
• Late reaction:– Starts 2 – 24 hours after exposure to original allergen– Subside within few days– Causes leukocytes recruitment (including eosinophils), as well as mucosal
epithelial cell damage
PATHOGENESISAtopic = Type I hypersensitivity6) Mediators of immediate reaction:A) Mast cells granules:Binding of allergen degranulation• Vasoactive amines “e.g. Histamine”• Proteases “e.g. Tryptase, Chymase”• Proteoglycans “e.g. Heparin”
PATHOGENESISAtopic = Type I hypersensitivity6) Mediators of immediate reaction:B) Membrane phospholipids mediatorsBinding of allergen activation of phospholipase A2
Converts membrane phospholipids into Arachidonic acidWhich produce:
– Leukotrienes C4 and D4 (by action of 5-lipoxygenase)– Prostaglandins D2 (by action of cyclooxygenase)
Platelet-activating factor (PAF) is another lipid mediatorNot produced by arachidonic acid pathway
Leukotrienes C4 and D4 are more potent vasoactive and spasmogenic agents than histamine
PATHOGENESISAtopic = Type I hypersensitivity7) Mediators of late reaction:
A) CytokinesBinding of allergen activate cytokine gene• Cytokines “e.g. TNF and IL-1”• Chemokines leukocytes recruitment (including eosinophils)
B) Leukotriene B4 (lipid mediator)Synthesis: As before• Leukotriene B4 is chemotactic factor for leukocytes recruitment (including
eosinophils)
PATHOGENESIS
E o s i n o p h i l s• Main cellular component of Late – phase reaction• Recruited in the inflammatory site by Chemokines produced from
TH2 cells, mast cells and damaged epithelial cells– Eotaxin is a famous eosinophils – chemotactic factor (released by
tissue)– IL-5 is a famous eosinophils – activating factor (released by TH2)
• Release Proteolytic enzymes as well as two unique proteins called Major basic protein and Eosinophil cationic protein
– Causing more epithelial damage
PATHOGENESIS
M a s t c e l l s v s B a s o p h i l sMast cells Basophils
Location Normally present in “Tissue”• Sub-epithelial connective
tissue• Perivascular connective tissue
• Normally present (in small amount) in “blood”
• In inflammation recruited in tissue
Surface Fc receptors(for IgE binding) Present in both
Cytoplasmic granules Present in both
PATHOGENESISNon-Atopic• Aspirin-induced
– Aspirin inhibits cyclooxygenase pathway• So the prostaglandins level is rapidly decreased
– Prostaglandin E2 inhibits the generation of leukotrienes B4, C4, D4, E4• So if aspirin decreases the level of prostaglandin E2
– It results in high level of leukotrienes asthma
GROSSBronchi:• Thick mucus plugs• May be saccular bronchiectasis
Lung parenchyma:• Hyperinflation (but no emphysema)• May be focal, small areas of atelectasis
MICROSCOPYBronchi:• Mucus hypersecretion (Plugs)• Thickened basement membrane• Smooth muscle hypertrophy• Moderate increase of submucosal glands• Goblet cell hyperplasia• Peribronchial chronic inflammation
– Rich in eosinophils
MICROSCOPYComplications / associations:• Churg-Strauss Syndrome
– Small vessels vasculitis– Mainly affect skin, GIT, kidneys, heart and lungs– Vasculitis / Necrotizing granulomas near blood vessels
(angio-centric)– Also eosinophilic infiltration and peripheral eosinophilia– P-ANCAs are seen in 50% of cases
MICROSCOPYComplications / associations:• Allergic Bronchopulmonary Aspergillosis
– Hypersensitivity reaction to Aspergillus fumigatus– Necrotizing granulomas around airways (broncho-centric)
• Necrotic material contain aspergillus hyphae– Also mucus impaction and eosinophilic pneumonia– Later on, bronchial dilatation and bronchiectasis– Elevated IgE directed against aspergillus antigens
CYTOLOGYEosinophils
Charcot-Leyden crystals• Rhomboid-shaped crystalloids• Composed of galectin-10
– Lysophospholipase– Derived from degenerating eosinophils
Curschmann spirals• Excess Mucus • Also seen in Chronic bronchitis
– No Charcot-leyden crystals– No Eosinophils
CYTOLOGYBenign bronchial cell changes1. Reactive changes
– Columnar, ciliated bronchial cells– Nuclear enlargement– Coarse chromatin– Prominent nucleoli
2. Creola bodies– Spherical 3D Clusters– Columnar, ciliated bronchial cells– Also seen in Chronic bronchitis
• No Charcot-leyden crystals• No Eosinophils
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CYTOLOGY3. Goblet cell hyperplasia
– Large sheets or round clusters– Composed almost exclusively of goblet cells
• Abundant mucin-filled cytoplasm– Benign columnar, ciliated bronchial cells are also seen
• The bronchi are lined with ciliated or columnar epithelium with scattered gobletcells. Goblet cell hyperplasia is an indication of irritation, such as in bronchitis or asthma
Benign bronchial cells changes can mimic Adenocarcinoma:– LOSS OF CILIA– LESS COHESIVE– MARKED MITOSIS / NECROSIS– CLINICAL HISTORY
• Do not rush for calling adenocarcinoma on just few small group of atypical cells- especially with inflammatory background OR history of COPD, Asthma
• Reactive changes resolve within 1 month treat, wait and repeat cytology
CYTOLOGYOther injury-associated findings1. Bronchial reserve cell hyperplasia
– Tightly packed small cells – Scant cytoplasm– Smudged dark chromatin– Nuclear molding may be seen– No mitoses or necrosis
Bronchial reserve cell hyperplasia can mimic Small cell carcinoma:– LESS COHESIVE– MARKED MITOSIS / NECROSIS– CLINICAL HISTORY
CYTOLOGYOther injury-associated findings2. Reparative “re-epithelialization” of respiratory tract
– Flat, cohesive sheets– Abundant cytoplasm– Enlarged nuclei– prominent nucleoli– Mitoses
Reparative epithelium can mimic Non-Small cell carcinoma:– LESS COHESIVE– MARKED MITOSIS / NECROSIS– CLINICAL HISTORY
DIFFERENTIAL DIAGNOSIS
Chronic bronchitis
Bronchiectasis Asthma
Small-airway disease
“bronchiolitis”
Emphysema
Site L a r g e a i r w a y s ( B r o n c h i ) Bronchioles AlveoliMajor
pathology
• Mucous gland hyperplasia
• Excess mucus
• Inflammation
• Airway dilation & scarring
• Thickened basement membrane
• Smooth muscle hyperplasia
• Excess mucus
• Inflammation(eosinophils)
• Inflammatory scarring & obliteration
• Airspace enlargement
• Wall destruction
• No fibrosis
Other obstructive lung diseases:
DIFFERENTIAL DIAGNOSISChronic Bronchitis Bronchial Asthma
Age Usually adults Any ageSmoking history Almost invariable PossibleCough Persistent
ProductiveIntermittentNon-productive
Breathlessness Persistent IntermittentNocturnal symptoms Uncommon CommonFamily history Uncommon
“unless family members smoke”
Common
Other allergic diseases Uncommon Common“eczema or allergic rhinitis”
Airflow obstruction Irreversible ReversibleSputum Macrophages
NeutrophilsCreola bodies
EosinophilsCharcot–Leyden crystalsCurschmann’s spiralsCreola bodies
DIFFERENTIAL DIAGNOSISChronic Bronchitis Bronchial Asthma
Gross Excess mucusBronchial dilatationAssociated emphysema
Mucous plugsHyperinflation but no emphysema
Airway inflammation CD8+ T cellsNeutrophils periodically
CD4+ T cellsEosinophilsMast cells
Airway epithelium IntactGoblet cell hyperplasiaSquamous metaplasia
Fragile with strippingGoblet cell hyperplasiaSquamous metaplasia
Basement membrane thickening
Mild to moderate Marked
Bronchial glands enlargement
Marked Moderate
Airway muscle hypertrophy
May be seen Marked
Major complications Cor pulmonale Allergic bronchopulmonary aspergillosis
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