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

Reta

ined

cili

a is

an e

vide

nce

of

beni

gn n

atur

e of

the

bron

chia

l ce

lls

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

WWW.

DO NOT FORGET TO SEARCH FOR MORE PICS AND VIRTUAL SLIDES

THANK YOUH a z e m A l i