What are the types, clinical presentations, diagnosis, and treatment options, including off-label treatments, for interstitial lung diseases (ILDs)?

Interstitial Lung Diseases: Types, Clinical Presentations, Diagnosis, and Treatment

Interstitial lung diseases (ILDs) require a multidisciplinary diagnostic approach involving pulmonologists and rheumatologists for accurate diagnosis and optimal treatment outcomes, with early intervention being crucial to prevent irreversible fibrosis and reduce mortality. 1

Types of Interstitial Lung Diseases

1. Idiopathic Interstitial Pneumonias (IIPs)

• Idiopathic Pulmonary Fibrosis (IPF): Characterized by usual interstitial pneumonia (UIP) pattern on HRCT/biopsy
• Nonspecific Interstitial Pneumonia (NSIP)
• Desquamative Interstitial Pneumonia (DIP)
• Respiratory Bronchiolitis with Interstitial Lung Disease (RBILD)
• Acute Interstitial Pneumonia (AIP)
• Cryptogenic Organizing Pneumonia (COP)
• Lymphoid Interstitial Pneumonia (LIP) 2

2. Known-Cause ILDs

• Connective Tissue Disease-associated ILD (CTD-ILD): Accounts for ~25% of ILD cases
  • Systemic sclerosis-related ILD (SSc-ILD)
  • Rheumatoid arthritis-related ILD (RA-ILD)
  • Idiopathic inflammatory myopathy-related ILD (IIM-ILD)
  • Other CTD-ILDs (Sjögren's, lupus, mixed connective tissue disease)
• Hypersensitivity Pneumonitis (HP): Accounts for ~15% of ILD cases
• Pneumoconioses: Occupational dust exposures
• Drug-induced ILD
• Radiation-induced ILD 2, 3

3. Other ILDs

• Sarcoidosis
• Eosinophilic Pneumonia
• Diffuse Alveolar Hemorrhage (DAH)
• Alveolar Proteinosis 2

Clinical Presentations

Common Symptoms

• Dyspnea on exertion: Primary symptom in most ILD patients
• Chronic cough: Present in approximately 30% of patients
• Fatigue: Common and often debilitating
• Bibasilar inspiratory crackles: Key physical examination finding
• Clubbing: May be present, especially in IPF 2, 3

Disease-Specific Presentations

• IPF: Typically presents in patients >60 years with progressive dyspnea, dry cough, and bibasilar crackles
• CTD-ILD: May present with extra-pulmonary manifestations of underlying CTD (joint pain, skin changes, muscle weakness)
• Hypersensitivity Pneumonitis: Often associated with environmental exposures with symptom flares after exposure
• Sarcoidosis: May present with hilar lymphadenopathy, erythema nodosum, and multi-organ involvement 2

Clinical Course Patterns

• Acute/subacute onset: AIP, acute eosinophilic pneumonia, acute hypersensitivity pneumonitis
• Chronic progressive: IPF, chronic HP, CTD-ILD
• Acute exacerbations: Can occur in any ILD but particularly common in IPF 2

Diagnosis

Diagnostic Algorithm

1. Clinical evaluation:

   • Detailed history (occupational/environmental exposures, medication use, symptoms of CTD)
   • Physical examination (crackles, clubbing, extra-pulmonary signs of CTD)

2. High-Resolution CT (HRCT):

   • Gold standard for confirming ILD diagnosis (~91% sensitive, 71% specific)
   • Pattern recognition crucial (UIP, NSIP, HP patterns)
   • UIP pattern: Peripheral, basal predominant reticular abnormalities with honeycombing 2, 3

3. Pulmonary Function Tests (PFTs):

   • Restrictive pattern (reduced FVC, normal FEV1/FVC ratio)
   • Reduced DLCO
   • Baseline and follow-up measurements essential to assess progression 1

4. Laboratory testing:

   • CTD serologies when clinically indicated
   • Specific antibody testing for HP when suspected

5. Bronchoalveolar Lavage (BAL):

   • Useful for specific ILD patterns:
     • Lymphocytosis >25%: Suggests granulomatous disease (sarcoidosis, HP)
     • Lymphocytosis >50%: Suggests HP or cellular NSIP
     • Neutrophilia >50%: Suggests acute lung injury
     • Eosinophilia >25%: Diagnostic of eosinophilic pneumonia
     • CD4/CD8 ratio >4: Highly specific for sarcoidosis 2

6. Lung Biopsy:

   • Surgical Lung Biopsy (SLB):

     • Recommended for patients with HRCT patterns of probable UIP, indeterminate for UIP, or alternative diagnosis
     • Not recommended for patients with definite UIP pattern on HRCT 2

   • Transbronchial Lung Cryobiopsy (TBLC):

     • Alternative to SLB with fewer complications
     • Suggested for patients at higher risk of surgical complications 2

7. Multidisciplinary Discussion (MDD):

   • Essential for final diagnosis
   • Involves pulmonologists, radiologists, pathologists, and rheumatologists 2, 4

Treatment

General Approach

• Treatment goals: Reduce symptoms, slow disease progression, improve quality of life
• Treatment selection based on specific ILD diagnosis, disease severity, and progression rate

Disease-Specific Treatments

1. Idiopathic Pulmonary Fibrosis (IPF)

• Antifibrotic therapy:
  • Pirfenidone: Slows FVC decline by 44-57% 5, 3
  • Nintedanib: Slows FVC decline by 44-57% 3
• Supportive care: Oxygen therapy, pulmonary rehabilitation
• Lung transplantation: For advanced disease 3

2. CTD-ILD

• First-line options:

  • Mycophenolate mofetil: Strong evidence for treatment of SSc-ILD
  • Cyclophosphamide: Alternative first-line option
  • Rituximab: Especially for patients with active inflammatory arthritis
  • Tocilizumab: For progressive SSc-ILD 1

• Adjunctive treatments:

  • Short-term glucocorticoids: Limited to ≤3 months
  • Caution: Avoid long-term steroids in SSc-ILD due to risk of scleroderma renal crisis 1

• Antifibrotic therapy:

  • Nintedanib: Approved for SSc-ILD and progressive fibrosing ILDs
  • Pirfenidone: Consider for progressive RA-ILD 1, 3

3. Hypersensitivity Pneumonitis

• Antigen avoidance
• Corticosteroids for acute/inflammatory disease
• Consider immunosuppressants for chronic/fibrosing disease

4. Sarcoidosis

• Corticosteroids for symptomatic or progressive disease
• Steroid-sparing agents (methotrexate, azathioprine) for maintenance

Treatment Monitoring and Adjustment

• PFTs every 3-6 months for the first year (more frequent in severe/progressive disease)
• HRCT when clinically indicated or to assess treatment response
• Ambulatory oxygen desaturation testing every 3-12 months
• Regular symptom assessment 1

Treatment for Progressive Disease

If progression occurs despite first-line therapy:

1. Add or switch to alternative agent (rituximab, cyclophosphamide, nintedanib, pirfenidone, tocilizumab)
2. Consider combination therapy
3. Early referral for lung transplantation evaluation 1

Supportive Care

• Oxygen therapy: For patients who desaturate below 88% on exertion
• Pulmonary rehabilitation: Improves exercise capacity and quality of life
• Comorbidity management: Treat GERD, pulmonary hypertension
• Vaccination: Influenza and pneumococcal vaccines 1, 3

Pitfalls and Caveats

• Delayed diagnosis leads to irreversible fibrosis; maintain high suspicion for ILD
• ILD can be asymptomatic in early stages; screening HRCT recommended in high-risk patients (e.g., SSc)
• Avoid long-term corticosteroids in SSc-ILD due to risk of scleroderma renal crisis
• Methotrexate has uncertain benefit for ILD and is not recommended as first-line treatment
• TNF inhibitors may be harmful or ineffective for RA-ILD
• Regular monitoring is crucial; a 5% decline in FVC over 12 months is associated with doubled mortality 1, 3