Role of Corticosteroids in Respiratory Diseases

1. Introduction

2. Mechanism of Action

Molecular Mechanism

• Upregulation of beta-2 adrenergic receptors
• Increased production of anti-inflammatory mediators (lipocortin-1, IL-10, IL-12)
• Upregulation of beta-2 adrenergic receptor sensitivity

• Suppression of pro-inflammatory cytokines: IL-1, IL-4, IL-5, IL-6, IL-8, IL-13, TNF-alpha
• Inhibition of phospholipase A2 (via lipocortin-1), reducing arachidonic acid release
• Suppression of NF-kB (the primary immunosuppressive mechanism)
• Decreased expression of COX-2, iNOS, adhesion molecules

The clinical effects of glucocorticosteroids are delayed for several hours after administration, reflecting the time needed to influence gene transcription.

Airway-Specific Effects

• Increase number and responsiveness of beta-2 adrenergic receptors
• Decrease mucus production and secretion
• Decrease bronchial hyperresponsiveness
• Reduce the number of mucosal mast cells
• Enhance eosinophil apoptosis
• Decrease airway edema and vascular permeability
• Inhibit the allergen-induced late-phase response (but NOT the immediate phase)

3. Classification and Available Preparations

A. Inhaled Corticosteroids (ICS)

• High receptor-binding affinity and long pulmonary retention = greater efficacy
• Low oral bioavailability: Ciclesonide, fluticasone, and mometasone undergo extensive first-pass hepatic metabolism (<1% oral bioavailability)
• High protein binding: Ciclesonide and mometasone are 99% protein bound
• Prodrug advantage: Beclomethasone 17,21-dipropionate is hydrolyzed in the lungs to the more active beclomethasone 17-monopropionate; ciclesonide is hydrolyzed from inactive prodrug to active desisobutyryl-ciclesonide in the lungs

B. Systemic Corticosteroids

• Oral: Prednisolone, prednisone, methylprednisolone, dexamethasone
• Parenteral (IV/IM): Hydrocortisone, methylprednisolone, dexamethasone

C. Combination Products (ICS + LABA)

• Salmeterol/fluticasone (Advair/Seretide)
• Formoterol/budesonide (Symbicort)
• Formoterol/mometasone (Dulera)
• Vilanterol/fluticasone furoate (Breo Ellipta)

4. Role in Specific Respiratory Diseases

4.1 Bronchial Asthma

• Recommended for all patients with persistent asthma (mild, moderate, or severe)
• GINA (Global Initiative for Asthma) guidelines mandate ICS as the foundational controller
• ICS reduces: symptom frequency, frequency of exacerbations, need for reliever medication, bronchial hyperresponsiveness, and hospitalizations
• Beclomethasone, budesonide, ciclesonide, and fluticasone propionate are FDA-approved for twice-daily administration; mometasone furoate for once or twice daily; fluticasone furoate once daily

• Used for acute severe exacerbations (status asthmaticus): IV hydrocortisone 100-200 mg 6-hourly or IV methylprednisolone
• Short courses of oral prednisolone (40 mg/day x 5-7 days) for moderate-to-severe exacerbations
• Reduce airway inflammation, prevent biphasic response, and hasten recovery
• Consider IV magnesium sulfate in severe exacerbations not responding to initial treatment (current GINA guidelines)

• A subset of patients have reduced glucocorticoid responsiveness
• Associated with microRNA modifications (miR-155-5p) that modify NF-kB transrepression by corticosteroids
• Phosphoinositide-3-kinase-delta (PI3K-delta) activation (by oxidative stress, in smokers) reduces histone deacetylase-2 (HDAC2) activity, impairing corticosteroid sensitivity
• Theophylline reverses corticosteroid resistance in COPD and some asthmatic patients through HDAC2 restoration

4.2 Chronic Obstructive Pulmonary Disease (COPD)

• Not first-line monotherapy - ICS monotherapy is not recommended in COPD (unlike asthma)
• GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommends ICS in combination with long-acting bronchodilators (LABA or LAMA) for patients with:
  • GOLD Grade D (more symptoms + more exacerbations)
  • Blood eosinophil count ≥ 300 cells/µL (strong predictor of ICS benefit)
  • 2 or more moderate exacerbations or 1 severe exacerbation per year
• Threshold eosinophil counts (rather than specific targets) are associated with beneficial effect

• Oral prednisolone (40 mg/day x 5 days) recommended for acute exacerbations requiring hospitalization
• Shortens hospital stay, improves FEV1, and reduces treatment failure
• Longer courses (>5 days) do not provide added benefit (REDUCE trial)
• Patients requiring corticosteroid therapy for exacerbations are at increased risk for additional exacerbations in the following year

• Increased risk of pneumonia (especially with fluticasone)
• Increased risk of nontuberculous mycobacterial (NTM) infection
• Diabetes - modestly increases risk; associated comorbidity in COPD patients on long-term ICS
• ICS should not be used routinely in bronchiectasis unless for comorbid asthma or COPD

4.3 Interstitial Lung Diseases (ILD)

4.4 Tuberculosis

• TB meningitis: Reduces mortality and neurological sequelae (dexamethasone 0.4 mg/kg/day, tapered over 6-8 weeks)
• Pericardial TB: Prednisolone reduces pericardial constriction and mortality
• Hypoxic TB pleuritis with large effusion: Facilitates resolution
• Adrenal TB (Addison's disease): Replacement therapy
• Paradoxical reactions on TB treatment in HIV patients
• NOT routinely used in pulmonary TB

4.5 Pneumonia

• Dexamethasone 6 mg/day x 10 days is standard of care for patients requiring supplemental oxygen or mechanical ventilation (RECOVERY trial, 2020)
• Reduces mortality in ventilated patients by ~35%
• NOT beneficial (may be harmful) in patients not requiring oxygen

• Adjunctive corticosteroids (methylprednisolone or hydrocortisone) may reduce treatment failure and mortality in severe CAP
• Benefit primarily in patients with high inflammatory burden (elevated CRP)

• Adjunctive prednisolone when PaO2 < 70 mmHg or A-a gradient > 35 mmHg
• Reduces risk of respiratory failure and mortality by ~50%

4.6 Allergic Bronchopulmonary Aspergillosis (ABPA)

• Systemic corticosteroids are the treatment of choice: prednisolone 0.5 mg/kg/day for 2 weeks, then on alternate days, gradually tapered over 6-12 months
• Prevents progressive lung damage and bronchiectasis
• Antifungal agents (itraconazole) used as steroid-sparing agents

4.7 Allergic Rhinitis (Upper Airway)

• Intranasal corticosteroids (fluticasone, mometasone, budesonide, triamcinolone) are first-line treatment
• More effective than antihistamines for nasal congestion, rhinorrhea, and sneezing
• Inhibit allergen-induced late response; no effect on immediate response
• Minimal systemic absorption at therapeutic doses

4.8 Other Respiratory Conditions

5. Adverse Effects

A. Inhaled Corticosteroids (Local)

• Oropharyngeal candidiasis (thrush) - minimized by spacer use and rinsing mouth
• Dysphonia (hoarseness) - myopathy of laryngeal muscles
• Cough and throat irritation
• Minimized by using prodrugs (ciclesonide) and small-particle formulations

B. Inhaled Corticosteroids (Systemic, dose-dependent)

• Adrenal suppression - especially at high doses
• Reduced bone mineral density - osteoporosis risk with long-term use
• Growth suppression in children (at high doses)
• Skin thinning and bruising
• Increased risk of pneumonia in COPD patients
• Modest risk of cataracts and glaucoma
• Modest increase in diabetes risk and glucose intolerance

C. Systemic Corticosteroids

• Hypothalamic-Pituitary-Adrenal (HPA) axis suppression - Cushing's syndrome with prolonged use
• Metabolic: Hyperglycemia, dyslipidemia, central obesity, fluid retention
• Musculoskeletal: Osteoporosis, avascular necrosis of femoral head, proximal myopathy
• Cardiovascular: Hypertension, edema
• Gastrointestinal: Peptic ulcer disease (especially with NSAIDs), pancreatitis
• Neuropsychiatric: Euphoria, mood swings, depression, psychosis, insomnia
• Ocular: Posterior subcapsular cataracts, glaucoma
• Immunosuppression: Increased susceptibility to infections (bacterial, fungal, viral, TB reactivation)
• Dermatological: Skin atrophy, striae, delayed wound healing, acne

6. Corticosteroid-Sparing Agents

• Methotrexate - most studied steroid-sparing agent
• Cyclosporine
• Azathioprine
• Biologics (omalizumab, mepolizumab, dupilumab) in severe eosinophilic/allergic asthma
• Macrolides (azithromycin) in COPD for exacerbation prevention

7. Practical Considerations for Optimizing Steroid Use

1. ICS delivery: Use spacers/valved holding chambers with MDIs to reduce oropharyngeal deposition; rinse mouth after use to prevent candidiasis
2. Dose titration: Titrate to the lowest effective dose
3. Monitoring: Bone density (DEXA), blood glucose, blood pressure, and eye pressure in long-term systemic use
4. Prophylaxis: Co-prescribe proton pump inhibitors in high-risk patients; calcium + Vitamin D supplementation; bisphosphonates for osteoporosis prevention
5. Steroid cards: Patients on long-term steroids should carry steroid alert cards; supplemental doses needed during surgery or stress
6. Never abruptly stop: Taper systemic steroids to avoid adrenal insufficiency

8. Summary Table

Key Exam Points to Remember

1. Corticosteroids act via nuclear glucocorticoid receptors - effects are delayed (hours)
2. ICS are the cornerstone of asthma management at all but the mildest severity
3. In COPD, ICS are recommended only for high-risk patients (GOLD D, eosinophilia ≥300)
4. ICS increase pneumonia risk in COPD - especially fluticasone
5. Ciclesonide and beclomethasone are prodrugs activated in the lung
6. Dexamethasone is corticosteroid of choice in TB meningitis and COVID-19
7. Corticosteroids are NOT recommended in IPF and may worsen prognosis
8. HPA suppression is the key systemic danger; never abruptly stop after prolonged use
9. ICS side effects are mainly local: oral candidiasis, dysphonia
10. Systemic steroids in asthma exacerbation act primarily on the late-phase response

• Fishman's Pulmonary Diseases and Disorders (Chapter 144 - Pulmonary Pharmacotherapy)
• Goldman-Cecil Medicine International Edition
• Lippincott Illustrated Reviews: Pharmacology (Chapter 41)
• Murray & Nadel's Textbook of Respiratory Medicine
• Katzung's Basic and Clinical Pharmacology, 16th Edition
• Scott-Brown's Otorhinolaryngology Head & Neck Surgery, Vol. 1 & 2