CLINICOPATHOLOGICAL CORRELATION

CLINICOPATHOLOGICAL CORRELATION

Asthma?
Chronic relapsing inflammatory disorder characterized by hyperactive airways leading to episodic, reversible bronchoconstriction owing to increased responsiveness of the tracheobronchial tree to various stimuli

CLASSIFICATION OF ASTHMA

Extrinsic(immune mediated) Asthma 70%

Initiated by type 1 hypersensivity reaction induced by exposure to extrinsic antigen.
Pathogenesis: In the airway initial sensitization to antigen (allergen) with stimulation of TH2 type T cells and production of cytokines (IL-4, IL- 5, and IL-13). IgE-mediated reaction to inhaled allergens elicits: 1. acute response (within minutes) 2. a late phase reaction (after 4-8 hours)

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. stress

6. exercise.

Extrinsic(immune mediated) Asthma

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 of histamine) Mast cell tryptase (inactivate normal bronchodilator).

Mediators induce BRONCHOSPASM, vascular permeability &

MUCOUS PRODUCTION.

Late phase reaction:

RECRUITMENT OF LEUKOCYTES mediated by product of mast cells including:

1.

Eosinophil and neutophil chemotactic factors

2 . 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.

Late phase reaction:

The arrival of leukocytes at the site of mast cell degranulation lead to: 1. RELEASE OF MORE MEDIATORS to activate more mast cells 2. Cause EPITHELIAL CELL DAMAGE .

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

These amplify and sustains injury without additional antigen.

Intrinsic (non immune mediated) Asthma

 Triggered by respiratory tract infection including viruses and inhaled air pollutants e.g. sulfur dioxide, ozone. Positive family history is uncommon. Serum IgE normal. No other associated allergies. Skin test negative. HYPERIRRITABILITY of bronchial tree. Subtypes: 1. Drug-induced asthma. 2. Occupational asthma.

PATHOGENESIS
Drug induced: E.g Aspirin
Inhibits cyclooxygenase pathway without affecting lipoxygenase route thus bronchoconstrictor leukotrienes are more elaborated

 The classic acute asthmatic attack lasts up to several hours In its most severe form, status asthmaticus, the severe acute paroxysm persists for days and even weeks, and under these circumstances airflow obstruction might be so extreme as to cause severe cyanosis and even death The clinical diagnosis is aided by the demonstration of an increase in airflow obstruction (from baseline levels), difficulty with exhalation (prolonged expiration, wheeze), With appropriate therapy to relieve the attacks, most individuals with asthma are able to maintain a productive life.

Clinical findings
difficulty in breathing and wheezing. decreased FEV1 Suggests a lung disease. The decreased FEV1 implicates an obstructive lung disease Acute phase reaction(Mediators induce BRONCHOSPASM, vascular permeability & MUCOUS PRODUCTION)

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

 he could barely talk and was breathing 30 times/minute. Physical exam was remarkable for rare wheezing and markedly diminished breath sounds. Arterial blood gases pH = 6.9, pCO2 = 88, pO2 = 35. While awaiting therapy the patient suffered a cardiac arrest and could not be resuscitated. Wheezing, diminished breath sounds, respiratory acidosis further implicate a lung disease, in addittion to which, the autopsy showed gross findings limited to the respiratory tract.

presented to the ER with severe shortness of breath of 8 hours duration.

status asthmaticus, the severe acute paroxysm persists for days and even weeks, and under these circumstances airflow obstruction might be so extreme as to cause severe cyanosis and even death

Lab dx
bronchial lumen contains large amounts of mucus, a moderate number of macrophages and eosinophilic leukocytes. The bronchiole is plugged with mucus and cellular debris. The bronchiolar epithelium is intact, but there is a marked inflammatory infiltrate in the bronchiolar wall. The basement membrane is thickened and hyalinized. The submucous glands are increased in size. The smooth muscle of the bronchial wall appears hypertrophic. Eosinophils, some PMNs, lymphocytes and plasma cells are seen in the bronchial wall. These changes of the bronchial wall are typical for asthma.

Beta agonists METHYLXANTHINE DRUGS ANTIMUSCARINIC AGENTS CORTICOSTEROIDS CROMOLYN & NEDOCROMIL LEUKOTRIENE PATHWAY INHIBITORS

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 cyclic adenosine monophosphate (cAMP). In the lung, cAMP causes a decrease in the intracellular calcium concentration and, via activation of protein kinase A, both inactivates myosin light chain kinase and activates myosin light chain phosphorylase. In addition, beta-2 agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle 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

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 vascular permeability by vasoconstriction, and inhibiting the release of LTC4 and LTD4. Corticosteroids inhibit the late phase reaction by inhibiting the inflammatory response and interfering with chemotaxis. This action may be due to the inhibition of LTB4 release. The eosinopenic effect of corticosteroids may help to prevent the cytotoxic effect of the major basic protein and other inflammatory mediators released from eosinophils. By blocking the late reaction, they prevent the increased airway reactivity observed with late bronchial reactions.
LATE PHASE REACTION(RELEASE OF MORE MEDIATORS to activate more mast cells 2. Cause EPITHELIAL CELL
DAMAGE )