Pathogenesis – Steps of Allergy Development:

1. Typically, an allergen comes into contact with the respiratory tract, digestive tract, or skin.
2. Macrophages engulf the allergen and become Antigen Presenting Cells (APCs) displaying allergen on MHC-IIs.
3. APCs present the allergen to Helper T cells, which have TCRs (T cell receptors that bind to the allergen)
4. The T_H cells are inappropriately activated and stimulate B cell activation, which proliferate to produce Plasma cells that secrete IgE antibodies.
5. IgE antibodies bind to the surface of Mast cells and Basophils, which are located throughout the body.
6. Subsequent exposure to allergen causes Mast cells and Basophils that release a lot of the pro-inflammatory histamine, bradykinin, and prostaglandins, which induces vasodilation and increased capillary permeability.
7. Vasodilation results in an influx of RBCs and WBCs, and the area develops Redness and Warmth
8. Increased capillary permeability leads to exudate and swelling.
9. Histamine also triggers itchiness (via sensory neurons).
   1. Inhaled Allergens: If the allergen is in the respiratory tract, histamine will also induce bronchoconstriction, mucus production, and bronchiole swelling, making it difficult to breathe (dyspnea) and leading to mucus plug formation, air trapping, atelectasis (non-aeration of portions of the lungs), and coughing.
   2. Ingested Allergens: If the allergen is in the digestive tract, the allergen will be absorbed into the bloodstream, meaning that Mast Cells and basophils throughout the body (including the GI tract) will release histamine, which will potentially lead to:
      1. GI irritation (leading to vomiting, nausea, possibly diarrhea)
      2. Skin rashes (areas of inflammation)
      3. Bronchoconstriction, mucus production, and bronchiole swelling, making it difficult to breathe (dyspnea) and leading to mucus plug formation, air trapping, atelectasis (non-aeration of portions of the lungs), hyperinflation of lungs, and coughing.  Watery and red eyes and nose can occur.
      4. Systemic vasodilation – causing a rapid drop in blood pressure (Anaphylactic Shock), which could lead to poor oxygenation of all organs, resulting in signs of shock, which include: anxiety, diaphoresis, weakness, loss of consciousness, and organ failure.

1. • Severe allergic reactions can be prolonged due to the recruitment and proliferation of WBCs (including basophils, neutrophils and eosinophils) which continue to release pro-inflammatory cytokines (e.g., leukotrienes).
   • With inhaled allergens, perpetual damage by many attacks to lungs, can lead to permanent damage and scarring (fibrosis) to occur in lungs.

Anaphylactic Attack Signs & Symptoms (and why each occurs):

1. Respiratory S&S= dyspnea, wheezing, cough, hypoxemia = due to bronchoconstriction and bronchiole swelling (both of which narrow airways), mucus production and mucus plugs, which can lead to air trapping which also reduced ability of gas exchange to occur, leading to hypoxemia, which can lead to anxiety, reflex tachycardia, syncope (fainting), loss of consciousness, incontinence, organ failure. All signs & symptoms are due to inflammatory cytokines (histamine, bradykinin, prostaglandin and leukotriene) release by Mast Cells and Basophils
2. Skin and Mucosal membrane S&S = rash, pruritus, erythema, hives, swelling of face, lips, tongue
3. Digestive S&S = nausea, vomiting, abdominal cramps, diarrhea, due to irritating inflammatory cytokines (histamine, bradykinin, prostaglandin and leukotriene) release by Mast Cells and Basophils
4. Vasculature S&S = systemic vasodilation due to huge release of pro-inflammatory cytokines (histamine, bradykinin, prostaglandins, leukotrienes) = hypotension = anaphylactic shock =which causes poor blood flow and oxygenation of organs and tissues

Treatment of Allergies & Anaphylactic Shock:

1. Airway = ensuring airway is open
2. Epi–Pen = epinephrine intramuscular injection. E is a SNS (sympathetic nervous system) neurotransmitter/hormone which induces vasoconstriction and bronchodilation
3. Fluids = increases blood volume to assist in increasing blood pressure and blood flow
4. Corticosteroids = anti-inflammatory which helps in reducing swelling in airways
5. Anti–histamines = reduce inflammation
6. Bronchodilators = beta-agonists induce bronchodilation
7. Possibly supplemental O₂

Extrinsic Asthma Attack Signs & Symptoms (and why each occurs):

1. Respiratory S&S= dyspnea, wheezing, cough, hypoxemia = due to bronchoconstriction and bronchiole swelling (both of which narrow airways), mucus production and mucus plugs,
   • which can lead to air trapping
   • which also reduced ability of gas exchange to occur, leading to hypoxemia,
   • which can lead to anxiety, reflex tachycardia, syncope (fainting), loss of consciousness, incontinence, organ failure.

• All signs & symptoms are due to inflammatory cytokines (histamine, bradykinin, prostaglandin and leukotriene) released by Mast Cells and Basophils

Treatment of Asthma:

1. Bronchodilators = beta 2 adrenergic agonists which block Epinephrine/Norepinephrine from causing bronchoconstriction.
2. Glucocorticoid = anti-inflammatory and WBC suppressant (blocks migration & activation of WBCs)
3. Anti–cholinergic agents = which block smooth muscle of bronchioles from contracting (which causes bronchoconstriction).
4. Possibly supplemental O2

COPD – Compare lung changes and signs and symptoms of Emphysema and Chronic Bronchitis:

Emphysema:

1. 1. Destruction of alveolar walls and septae,
      • meaning loss of gas exchange surface area,
      • as well as overinflation of lungs
      • possible formation blebs or bullae and even
      • pneumothorax if there is a tear in the visceral pleura.
   2. Leads to damage of surrounding pulmonary blood vessels
      • (which narrow and lead to pulmonary hypertension Destruction of elastic fibers that normally surround alveoli, which increase air trapping, and poorer ventilation of alveoli (which causes reflexive vasoconstriction, leading to less
   3. Risk Factors include:
      • genetic deficiency in alpha 1-antitrypsin, leading to excessive elastase (and loss of elastic fibers),
      • bacteria infections, pollutants, dust (due to damage), and
      • smoking
   4. Signs & Symptoms = Pink Puffer,
      • dyspnea, hyperventilation, over-inflammation,
      • Fatigue,
      • Clubbed fingers,
      • Reduced spirometry lung volumes,
      • Hypercapnia, hypoxemia,
      • Frequent infections,
      • Pulmonary hypertension and cor pulmonale, leading to right-sided congestive heart failure.

 Chronic Bronchitis

1. 1. Damage to bronchioles due to frequent infections which causes:
      • Bronchiectasis (irreversible, abnormal dilation of med-sized bronchi) may occur, in which floppiness causes airway constriction.
      • Arises from recurrent inflammation and infection (e.g. Tuberculosis, COPD, Cystic Fibrosis, AIDS)
      • Risk factors: smoking, frequent respiratory infections
      • Leads to obstruction of airways, weakening of muscle & elastic fibers in bronchial walls, or both
   2. Signs & Symptoms:
      • Cough & rhonchi more severe in the morning, thick and purulent secretions
      • Plus “Blue Bloater” signs and symptoms:
        • Hypoxia, cyanosis, hypercapnia – Due to airway obstruction causes reflexive tachycardia and tachypnea
      • Hypoxemia (pO2 <55) → reflex pulmonary vasoconstriction, making things worse! Creates pulmonary hypertension which can cause cor pulmonale and right-sided congestive heart failure (CHF)
      • Polycythemia,
      • Weight loss, &
      • Cor pulmonale possible as vascular damage & pulmonary hypertension progress
   3. Signs & Symptoms of cor pulmonale and right-sided CHF include:
      • Edema in feet, legs, buttocks, and/or abdomen (e.g., ascites causing weight gain)
      • Increased blood pressure in jugular veins (distention of veins)
      • Fatigue (due to poorer blood flow)
      • Anorexia (loss of appetite), GI distress, and hepatomegaly and splenomegaly due to distended/engorged blood vessels creating portal hypertension.
      • Flushed face, headache, visual disturbances (not enough blood flow to brain).

Pathogenesis of ARDS – Steps of Acute Respiratory Distress Syndrome Development

1. Injury to alveoli due to:
   • smoke, chemical, infection (e.g. SARS or sepsis or severe pneumonia) – affecting all 5 lung lobes OR
   • HEAD TRAUMA damaging breathing centers in the brain OR
   • other disease that affects neuromuscular control of breathing, e.g., ALS, muscular dystrophy) OR
   • aspiration (choking)
2. Or Injury to pulmonary capillaries (atheroma to intestine & cytokines)
3. Inflammation (neutrophils, mast, basophils) are stimulated to release pro-inflammatory cytokines (e.g., histamine, prostaglandin, bradykinin, leukotrienes) which causes
   • Pulmonary vasodilation, and increased capillary permeability which causes pulmonary edema (alveoli fill and become flooded with exudate, WBCs, platelets, and fibrin) which decreases ability for gas diffusion and exchange.
4. Person starts “drowning” in their own fluids. Activated neutrophils release a variety of products that damage the alveolar cells and lead to edema, surfactant inactivation, and formation of a hyaline membrane.
   • Type 1 pneumocytes (lung cells) of the alveoli are damaged/killed = creating loss of gas exchange surface area as well as contributing to cellular debris filling alveoli
   • Type 2 pneumocytes of the alveoli also die contributing to debris accumulating in alveoli and no longer produce surfactant necessary to reduce surface tension required for alveoli to stay inflated, and also reduced compliance (elasticity) which assists with exhalation.
5. The interstitial edema = decreased diffusion = hypoxia
6. ‘Hyaline (fibrous) membranes’ form from protein-rich fluid in the alveoli & platelet aggregation and
   • block gas diffusion, cause stiffness & decreased compliance

Further complication of ARDS:

1. Microthrombi develop in the pulmonary circulation, potentially causing areas of hypoxia if emboli travel and lodge downstream
2.  V/Q mismatch
   • ventilation/perfusion mismatch in lung (where zones within the lungs become poorly ventilated or poorly perfused.
   • Normally alveoli should receive adequate amounts of ventilation that is matched by the amount of blood flow (perfusion) to allow for efficient gas exchange.
   • In ARDS, regions become poorly ventilated (no aeration = atelectasis = no sounds) and
   • areas become poorly perfused.
   • ARDs causes low ventilation, low O₂;     (in contrast, pulmonary embolism causes low Q, perfusion);
   • Gas exchange diminishes.
   • Shock will occur (definition of shock is not enough oxygenated blood flow to tissues, leading to
     • organ failure, brain symptoms are usually first, anxiety, confusion, loss of consciousness,
3. Lack of O₂, means cells resort to anaerobic cellular respiration
   • (creating a lot of lactate as well as carbonic acid) leading to respiratory acidosis.
   • This can contribute to cardiac arrythmias (plus lack of O2)

• • Respiratory Insufficiency occurs when blood gases are abnormal (O₂ low and CO2 high) but cell function can continue, though this is a rapidly life-threatening condition.
  • Respiratory Failure: (worse) when PaO2 < 50mmHg and/or PaCO2 > 50mmHg…  leads to resp. arrest, which leads to cardiac arrest
    • Often associated with multiple organ dysfunction or failure

• Death rate of ARDS = 90% in untreated;  50% in treated
• If person survives, the damaged pneumocytes are replaces with collagen fibers that form scars, creating fibrosis and further reducing elasticity and functionality of lungs.
  • Often called “stiff lung”.

Signs and symptoms of ARDS:

• Rapid Onset
• Severe dyspnea, rales, productive cough, cyanosis; hypoxemia
• Rapid, shallow respiration; ↓ tidal vol. & vital capacity
• Increased heart rate
• Restlessness, anxiety, and then lethargy & confusion and decreasing levels of consciousness
• Combination of respiratory and metabolic acidosis

Treatment of ARDS:

• Treatment of underlying cause (e.g. antibiotics)
• Supportive respiratory therapy (mechanical ventilator & supplemental O2)
• If survives, fluid accumulation may develop pneumonia → treatment