Clinicopathological Correlation

7/30/2019 Clinicopathological Correlation

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CLINICOPATHOLOGICAL

CORRELATION


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CLINICOPATHOLOGICAL CORRELATION


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Asthma?

Chronic relapsing inflammatory disordercharacterized by hyperactive airwaysleading to episodic, reversible

bronchoconstriction owing to increasedresponsiveness of the tracheobronchialtree to various stimuli


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Extrinsic(immune mediated) Asthma 70%

Initiated by type 1 hypersensivityreaction induced by exposure toextrinsic antigen.

Pathogenesis:

In the airway initial sensitizationto antigen (allergen) withstimulation of TH2 type T cells andproduction of cytokines (IL-4, IL- 5,and IL-13).

IgE-mediated reaction to inhaledallergens elicits:

1. acute response (within minutes)

2. a late phase reaction (after 4-8hours)

Intrinsic (non immune mediated) Asthma 30%

Initiated by diverse,non-immune mechanisms,including:

1. ingestion of aspirin

2. pulmonary infections,

3. cold

4. inhaled irritant

5. stress6. exercise.

CLASSIFICATION OF ASTHMA


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Extrinsic(immune mediated) Asthma


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Acute-phase response

Begin 30 to 60 minutes after inhalation of antigen.

Mast cells on the mucosal surface are activated.

Mediator produced are : Leukotrienes C4, D4 & E4 (induce BRONCHOSPASM, vascular permeability

&MUCOUS PRODUCTION) Prostaglandins D2, E2, F2 (induce BRONCHOSPASM and vasodilatation)

Histamine ( induce bronchospasm and increased vascular permeability)

Platelet-activating factor (cause aggregation of platelets and release ofhistamine)

Mast cell tryptase (inactivate normal bronchodilator).

Mediators induce BRONCHOSPASM, vascular permeability &MUCOUS PRODUCTION.


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Late phase reaction:

RECRUITMENT OF LEUKOCYTES mediated by product of

mast cells including:

1. Eosinophil and neutophil chemotactic factors2 . IL-4 & IL-5 and induceTH2 subset ofCD4+ T cells

3. Platelet-activating factor

4. Tumor necrosis factor.

Other cell types are involved: activated epithelial cells,macrophages and smooth muscle.


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Late phase reaction:

The arrival of leukocytes at the site of mast cell degranulation leadto:

1. RELEASE OF MORE MEDIATORS to activate more mast cells

2. Cause EPITHELIAL CELL DAMAGE .

Eosinophils produce major basic protein, EOSINOPHILICCATIONIC PROTEIN AND EOSINOPHIL PEROXIDASE( TOXIC TO EPITHELIAL CELLS).

These amplify and sustains injury without additionalantigen.


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Intrinsic (non immune mediated) Asthma


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Triggered by respiratory tract infection includingviruses and inhaled air pollutants e.g. sulfurdioxide, ozone.

Positive family history is uncommon. Serum IgEnormal. Noother associated allergies. Skin test negative. HYPERIRRITABILITYof bronchial tree. Subtypes:

1. Drug-induced asthma.2. Occupational asthma.


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PATHOGENESIS

Drug induced:

E.g Aspirin

Inhibits cyclooxygenase pathway without affecting

lipoxygenase route thus bronchoconstrictor

leukotrienes are more elaborated


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The classic acute asthmatic attack lasts up toseveral hours

In its most severe form, status asthmaticus, the

severe acute paroxysm persists for days and evenweeks, and under these circumstances airflowobstruction might be so extreme as to causesevere cyanosis and even death

The clinical diagnosis is aided by thedemonstration of an increase in airflowobstruction (from baseline levels), difficulty withexhalation (prolonged expiration, wheeze),

With appropriate therapy to relieve the attacks,most individuals with asthma are able to maintaina productive life.


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Clinical findings

difficulty in breathing and wheezing.

decreased FEV1

Suggests a lung disease. The decreased FEV1implicates an obstructive lung disease

Acute phase reaction(Mediators induce

BRONCHOSPASM, vascular permeability &

MUCOUS PRODUCTION)

d ki ll di i f h


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stopped taking all medication for the

past several weeks

With appropriate therapy to relieve the

attacks, most individuals with asthma are

able to maintain a productive life.

Patient could not afford medication


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he could barely talk and was breathing 30times/minute. Physical exam was remarkablefor rare wheezing and markedly diminishedbreath sounds. Arterial blood gases pH = 6.9,

pCO2 = 88, pO2 = 35. While awaiting therapy thepatient suffered a cardiac arrest and could notbe resuscitated.

Wheezing, diminished breath sounds, respiratory

acidosis further implicate a lung disease, inaddittion to which, the autopsy showed grossfindings limited to the respiratory tract.

t d t th ER ith


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presented to the ER with severeshortness of breath of 8 hours

duration. status asthmaticus, the severe acute

paroxysm persists for days and even weeks,

and under these circumstances airflowobstruction might be so extreme as to cause

severe cyanosis and even death


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Lab dx

bronchial lumen contains large amounts of mucus, a moderate numberof macrophages and eosinophilic leukocytes.

The bronchiole is plugged with mucus and cellular debris.

The bronchiolar epithelium is intact, but there is a marked inflammatoryinfiltrate in the bronchiolar wall.

The basement membrane is thickened and hyalinized. The submucousglands are increased in size.

The smooth muscle of the bronchial wall appears hypertrophic.Eosinophils, some PMNs, lymphocytes and plasma cells are seen in thebronchial wall. These changes of the bronchial wall are typical forasthma.


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Beta agonists

METHYLXANTHINE DRUGS

ANTIMUSCARINIC AGENTS

CORTICOSTEROIDS

CROMOLYN & NEDOCROMIL

LEUKOTRIENE PATHWAY INHIBITORS

f ff f b d i i t Th


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few puffs of b-adrenergic agonist. The

patient was prescribed a b-adrenergic

inhaler Beta-adrenergic receptors are coupled to the stimulatory G protein.

activates adenylyl cyclase, which catalyzes the production of cyclicadenosine monophosphate (cAMP).

In the lung, cAMP causes a decrease in the intracellular calcium

concentration and, via activation of protein kinase A, both inactivatesmyosin light chain kinase and activates myosin light chain phosphorylase.

In addition, beta-2 agonists open large conductance calcium-activatedpotassium channels and thereby tend to hyperpolarize airway smoothmuscle cells.

The combination of decreased intracellular calcium, increased membrane

potassium conductance, and decreased myosin light chain kinase activity leads to SMOOTH MUSCLE RELAXATION and BRONCHODILATION.

Early phase reaction


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patient continued to experience

episodes of breathlessness Corticosteroids enhance the beta-adrenergic response to relieve the

muscle spasm.

They also act by reversing the mucosal edema, decreasing vascularpermeability by vasoconstriction, and inhibiting the release of LTC4 andLTD4.

Corticosteroids inhibit the late phase reaction by inhibiting theinflammatory response and interfering with chemotaxis. This action maybe due to the inhibition of LTB4 release. The eosinopenic effect ofcorticosteroids may help to prevent the cytotoxic effect of the majorbasic protein and other inflammatory mediators released fromeosinophils.

By blocking the late reaction, they prevent the increased airwayreactivity observed with late bronchial reactions.

LATE PHASE REACTION(RELEASE OF MORE MEDIATORS to activate more mast cells 2. Cause EPITHELIAL CELLDAMAGE )


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Clinicopathological Correlation