Interstitial lung diseases

Interstitial lung diseases (ILDs) are a diverse group of rare, highly morbid pulmonary disorders characterized by inflammation and progressive scarring (fibrosis) of the lungs. The most common types of ILD are idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis, and smoking-related ILD. Cough and progressive exertional dyspnea are the most common symptoms. Bibasilar inspiratory crackles or rales are typically heard on auscultation. While most forms of ILD have similar clinical features, different types of ILD have unique epidemiological and radiographic features. A multidisciplinary approach is ideal for distinguishing IPF from other types of ILD, based on a thorough medical history and HRCT findings. Bronchoscopy or surgical lung biopsy is sometimes necessary to confirm the diagnosis. Smoking cessation, removal of exposures, symptom management, and advance care planning are central to the management of all forms of ILD. Long-term treatment of IPF may include antifibrotic agents. Corticosteroids should only be used to treat select cases of acute exacerbations of IPF. For other causes of ILD, treatment may involve systemic immunomodulators targeting the underlying cause (e.g., rheumatoid arthritis). Advanced stages of ILD can result in pulmonary hypertension and right heart failure. Lung transplantation is the only curative treatment.

• Interstitial lung diseases (ILDs)
  • A term encompassing a heterogeneous group of disorders characterized by inflammation and progressive fibrosis of the lungs
  • Cough and progressive exertional dyspnea are the most common symptoms [1]
• Idiopathic interstitial pneumonias (IIPs): a group of interstitial lung diseases of unknown cause, also described as diffuse parenchymal lung diseases (DPLDs), characterized by inflammation and fibrosis of the pulmonary interstitium but frequently also affect the airspaces, peripheral airways, and vessels
• Pneumoconioses: a group of restrictive interstitial lung diseases caused by the inhalation of certain substances (mainly dusts) that often affect miners and agricultural workers

Idiopathic interstitial pneumonias (IIPs)

• Idiopathic pulmonary fibrosis (IPF)
• Other IIPs
  • Acute interstitial pneumonia (AIP)
  • Cryptogenic organizing pneumonia (COP)
  • Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)
  • Desquamative interstitial pneumonia (DIP)
  • Nonspecific interstitial pneumonia (NSIP)
  • Lymphoid interstitial pneumonia (LIP)
  • Idiopathic pleuroparenchymal fibroelastosis

Secondary to a known cause

Exposure-related (environmental and occupational)

• Hypersensitivity pneumonitis (extrinsic allergic alveolitis)
  • Farmer's lung
  • Pigeon breeder's lung
  • Chemical worker's lung
• Pneumoconioses
  • Coal worker's lung
  • Asbestosis
  • Silicosis
  • Berylliosis
• Radiation pneumonitis
• Substance-induced ILD
  • Chemotherapeutic agents
    • Bleomycin
    • Busulfan
    • Methotrexate
  • Other medications
    • Amiodarone
    • Nitrofurantoin (see “Nitrofurantoin-induced lung disease”)
    • Phenytoin
    • Penicillamine
  • Other substances
    • Cocaine
    • Heroin

Secondary to underlying disease

• Connective tissue diseases
  • Systemic sclerosis
  • Polymyositis-dermatomyositis
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Mixed connective tissue disease
• Granulomatous diseases: sarcoidosis
• Vasculitis
  • Granulomatosis with polyangiitis
  • Eosinophilic granulomatosis with polyangiitis
• Hypersensitivity reactions: eosinophilic pneumonia
• Alveolar filling diseases
  • Anti-glomerular basement membrane antibody (Goodpasture syndrome)
  • Idiopathic pulmonary hemosiderosis
  • Pulmonary alveolar proteinosis
• Infectious diseases
  • Tuberculosis
  • Legionellosis
• Miscellaneous
  • Pulmonary Langerhans cell histiocytosis
  • Amyloidosis
  • Lymphangioleiomyomatosis (LAM)

Idiopathic pulmonary fibrosis (IPF)

• Definition: most common type of ILD, characterized by irreversible pulmonary fibrosis and impaired pulmonary function
• Epidemiology
  • Incidence: 10:100,000 cases per year [2]
  • Affects mostly men 50–70 years of age
• Diagnosis [3]
  • Requires the absence of other known causes of interstitial lung disease (e.g., medication, environmental exposures, CTD-ILD)
  • Presence of usual interstitial pneumonia (UIP) pattern on HRCT or histopathologic studies
    • Honeycomb appearance with or without traction bronchiectasis
    • Ground-glass opacification with superimposed reticular abnormalities
    • Bibasal subpleural distribution
• Prognosis: Respiratory failure usually occurs within 3–7 years.

Acute interstitial pneumonia (AIP)

• Definition: a severe, acute ILD that can rapidly progress to respiratory failure
• Epidemiology: most commonly affects individuals without preexisting lung conditions
• Diagnostics: histologically characterized by diffuse alveolar damage

Cryptogenic organizing pneumonia (COP)

• Definition: a rare, type of ILD characterized by inflammation of the bronchioles, alveolar ducts, and alveolar walls
• Epidemiology
  • Incidence: 1–3 per 100,000 hospital admissions [4]
  • Affects mostly individuals 40–50 years of age
• Diagnostics: histologically characterized by the presence of Masson bodies (granulation tissue buds made of foamy macrophages, mononuclear cells, and fibrous tissue) and chronic patchy interstitial inflammation without fibrosis

Nonspecific interstitial pneumonia (NSIP)

• Definition: a type of ILD characterized by a mild to moderate chronic interstitial inflammation, without specific histopathologic findings that characterize UIP
• Epidemiology: affects nonsmoker women 50–60 years of age
• Etiology: associated with connective tissue diseases (e.g., systemic sclerosis), HIV infection, and hypersensitivity pneumonitis
• Diagnostics
  • Immediate subpleural sparing on imaging studies is considered specific for NSIP.
  • Histological findings include interstitial thickening due to fibrosis and/or inflammatory cells

Desquamative interstitial pneumonia (DIP)

• Definition: a rare type of ILD characterized by lung inflammation due to intraalveolar mononuclear infiltration
• Epidemiology: affects men 40–50 years of age with a history of smoking
• Diagnostics
  • Imaging studies show ground-glass opacities in the lower pulmonary lobes, usually without peripheral reticular opacities
  • Histologically characterized by intraalveolar accumulation of macrophages and thickening of alveolar septa

Respiratory bronchiolitis-interstitial lung disease (RB-ILD)

• Definition: a rare, mild ILD characterized by bronchiolar inflammation
• Epidemiology: affects individuals 30–50 years of age with a history of smoking
• Diagnostics: histologically characterized by accumulation of brown pigmented macrophages and bronchiolar submucosal inflammation

Lymphocytic interstitial pneumonia (LIP)

• Definition: a rare ILD characterized by lymphocytic infiltration of the alveolar and alveolar septa
• Epidemiology: affects adults (especially women) of all ages
• Etiology: Associated with autoimmune (e.g., Sjögren disease, SLE) disorders, lymphoproliferative disorders, and HIV infection
• Diagnostics: histologically characterized by diffuse alveolar and interstitial infiltration with plasma cells and polyclonal lymphocytes

Idiopathic pleuroparenchymal fibroelastosis (IPPFE)

• Definition: a rare ILD characterized by pleural and subpleural fibrosis
• Epidemiology: affects nonsmoker individuals between 50 and 60 years of age
• Diagnostics
  • Imaging studies show pleural and subpleural thickening of the upper pulmonary lobes on imaging studies
  • Histological findings include intraalveolar fibrosis and elastosis of the alveolar walls

Although coal is mined from under the earth, the upper lobes of the lungs are primarily affected.

• General
  • All types of ILDs share the same basic pathophysiology.
  • Repeated cycles of tissue injury in the lung parenchyma with aberrant wound healing → collagenous fibrosis → remodeling of the pulmonary interstitium [18]
• Pneumoconiosis: inhalation of dust particles →; phagocytosis by alveolar macrophages → destruction of alveolar macrophages, inflammatory reaction → scarring, granuloma formation

Features

• Progressive dyspnea
  • Exertional dyspnea that progresses to dyspnea at rest
  • Patients may present with high-frequency, shallow breathing to compensate for dyspnea. [19]
• Persistent nonproductive cough
• Bibasilar, inspiratory crackles or rales (velcro-like rales) on auscultation
• Fatigue
• Fever is common in hypersensitivity pneumonitis and sarcoidosis, but otherwise uncommon.
• Findings suggestive of connective tissue disease, sarcoidosis, or vasculitis

Advanced disease

• Digital clubbing due to chronic hypoxia
• Cyanosis
• Loud inspiratory wheeze

Approach [3][20][21]

• Perform a thorough clinical evaluation.
  • Past medical history and family history for pulmonary and/or autoimmune conditions [3]
  • Physical examination, including evaluation for signs of connective tissue disorders
• Obtain HRCT of the chest to evaluate for IPF and other alternative diagnoses. [22]
• Obtain laboratory studies to screen for CTD-ILD.
• Perform pulmonary function tests to assess disease severity and treatment response.
• If diagnosis remains unclear, consider:
  • Additional laboratory studies based on clinical suspicion
  • Invasive testing

Multidisciplinary care helps increase diagnostic accuracy. [3][23]

High-resolution CT (HRCT) chest [3][24][25]

Usual interstitial pneumonia (UIP) pattern is highly specific for IPF.

• Typical UIP pattern findings
  • Honeycombing: multiple cystic lesions within the lung parenchyma due to fibrosis
  • Irregular thickening of intralobular septa
  • Reticular pattern and mild ground glass opacity (GGO)
  • Traction bronchiectasis (irreversible dilatation of the bronchi and bronchioles due to fibrosis) or bronchiolectasis
  • Pulmonary ossification may be seen.
• Other findings may be classified into:
  • Probable UIP: some findings that support a diagnosis of IPF, e.g., a reticular pattern and traction bronchiectasis, but no honeycombing
  • Indeterminate for UIP: nonspecific fibrosis that neither supports a diagnosis of IPF nor any alternative diagnosis
  • Alternative diagnosis, e.g., hypersensitivity pneumonitis or sarcoidosis, can be made based on HRCT findings
• Interpretation
  • If UIP pattern is present, a definitive diagnosis can be made without histopathologic confirmation.
  • If other patterns are present, further evaluation is required to determine the cause.

In patients with IPF, the extent of abnormalities on HRCT correlates with the severity of functional impairment. [26]

Laboratory evaluation for CTD-ILD [3][23]

• Obtain in all patients:
  • Autoantibodies: ANA, rheumatoid factor and anti-CCP; , myositis-specific antibodies (e.g., anti-Jo-1 antibodies)
    • May be elevated depending on underlying disease
    • Consider additional studies on a case-by-case basis.
  • Inflammatory markers: ↑ CRP, ↑ ESR
• Obtain in patients with clinical features of myositis: muscle enzymes, e.g., ↑ aldolase

All patients should be screened for rheumatic and autoimmune diseases. [3][23]

Pulmonary function tests (PFTs)

PFTs can help assess disease severity but do not identify a specific cause of ILD. [22]

• Restrictive lung disease pattern
  • ↓ Total lung capacity and ↓ vital capacity
  • Normal or ↓ FEV₁
  • ↓ FVC
  • Normal or ↑ FEV₁:FVC ratio
• Decreased diffusing capacity for CO (DL_CO): highly sensitive parameter

Additional studies

X-ray chest [21]

Findings are not sufficient for a diagnosis but can raise clinical suspicion for ILD. [21]

• Normal in approx. 10% of patients
• Predominantly basilar increase in reticular opacities (sign of fibrosis)
• Patients may have nodular or mixed patterns.

Additional laboratory studies [21][22][24]

• CBC with differential
  • Anemia, e.g., anemia of chronic disease or due to occult pulmonary hemorrhage
  • Eosinophilia, e.g., due to hypersensitivity pneumonitis or drug toxicity
• Liver enzymes: ↑ GGT, ↑ ALT, and/or ↑ AST may be consistent with sarcoidosis, amyloidosis, or polymyositis
• BMP: ↑ creatinine may be seen in CTD-ILD, pulmonary-renal syndromes, sarcoidosis, and amyloidosis
• Urinalysis: RBC casts, and/or dysmorphic RBCs may be seen in vasculitis and pulmonary-renal syndromes
• ABG: nonspecific findings in patients with ILD
  • ↑ Alveolar-arterial oxygen gradient
  • ↓ PaO₂
• Serum biomarkers for IPF: not recommended [3]

Invasive testing [21][27]

Obtain invasive testing if the diagnosis remains unclear and results will affect management.

• Bronchoscopy with bronchoalveolar lavage (BAL): Cellular analysis may help identify an underlying cause of ILD and exclude IPF. [3]
• Surgical lung biopsy [21][28]
  • Obtain if the diagnosis remains unclear after BAL.
  • Biopsy findings may show a histopathologic pattern of definite, probable, or indeterminate UIP ; or an alternative diagnosis.

If HRCT shows a pattern of definite UIP, invasive testing is not usually necessary for diagnostic confirmation. [3]

Approach [24][29]

• Offer supportive management, including preventive measures.
• Refer all patients to pulmonology for:
  • Pharmacological therapy depending on the cause of ILD
  • Evaluation for lung transplantation
• Identify and treat common comorbidities, e.g., GERD, pulmonary hypertension, major depressive disorder. [24][25][30]
• Initiate early advance care planning while patients are still able to participate in decision-making. [31]

ILD is a chronic, progressive, life-limiting condition. Encourage advance care planning and early engagement with palliative care. [29]

Supportive management [24]

• Encourage measures to prevent exacerbations and slow disease progression:
  • Counsel on smoking cessation and treat tobacco-related disorders.
  • Ensure recommended vaccinations are administered.
  • Recommend avoidance of triggers for secondary causes of ILD.
• Offer pulmonary rehabilitation. [32][33]
• Supplementary oxygen therapy as needed
• Symptom management
  • Consider cough suppressants and referral for multimodal speech therapy.
  • Consider palliative pharmacotherapy for dyspnea as indicated, e.g., palliative anxiolysis. [31][34][35]

Treatment of IPF [24]

• Pharmacological therapy
  • Antifibrotic agents may reduce mortality and acute exacerbations and slow the decline in FVC. [36][37][38]
    • Pirfenidone: inhibits TGF-β-stimulated collagen synthesis
    • Nintedanib: inhibits tyrosine kinases that target fibrogenic growth factors, e.g., VEGF, PDGF, and fibroblast growth factor receptor
  • Immunosuppressive therapy is not indicated.
• Lung transplantation: Refer for evaluation at the time of diagnosis. [39]

Do not start patients with IPF on immunosuppressive therapy; immunomodulation may worsen outcomes. [29]

Treatment of non-IPF ILD

• Pharmacological therapy: depending on the cause of ILD [24]
  • Treat the underlying condition if possible, e.g.:
    • Specific management for patients with CTD-ILD
    • Antibiotics if bacterial interstitial pneumonia is suspected
  • Consider corticosteroids and/or systemic immunomodulators, e.g., for COP or NSIP, in consultation with a specialist.
• Lung transplantation [39]
  • In patients with fibrotic NSIP, refer for evaluation at the time of diagnosis.
  • Refer patients with other types of non-IPF ILD and:
    • Progression to respiratory failure
    • ILD refractory to disease-specific therapies

Lung transplantation is the only curative option for ILD.

Management of acute exacerbation of IPF (AE-IPF) [40][41]

AE-IPF is characterized by acute respiratory deterioration accompanied by new widespread alveolar abnormalities and it may be idiopathic or triggered. [41]

• Clinical features may include: [40]
  • Worsening cough with increased sputum production
  • Fever
  • Hypoxemia
• Diagnose AE-IPF if all four clinical diagnostic criteria are present : [41]
  • Known diagnosis of IPF
  • Worsening dyspnea for < 1 month
  • New bilateral ground-glass opacities and/or consolidation over a background of UIP on HRCT chest
  • Symptoms are not explained by an alternative diagnosis.
• Management [40][41]
  • Admit to hospital.
  • Consider ICU admission and mechanical ventilation to bridge eligible patients to lung transplantation.
  • Offer supportive care, e.g., supplemental oxygen, palliative treatment for dyspnea.
  • High-dose systemic corticosteroids and/or antibiotic therapy may be considered.
  • Consult the patient's pulmonologist as soon as possible.
  • Discuss goals of care and consult palliative care if indicated.

AE-IPF has an in-hospital mortality rate of ∼ 50%. An elevated APACHE score, the need for mechanical ventilation, and hypoxemia are all associated with increased mortality in hospitalized patients with ILD. [42]

• Pulmonary hypertension
• Cor pulmonale
• Respiratory failure: initially partial respiratory failure (↓ pO₂), followed by global respiratory failure (↑ pCO₂) in advanced stages

We list the most important complications. The selection is not exhaustive.