Diffuse parenchymal lung disease in older adults

Definition. Diffuse parenchymal lung disease (DPLD), or interstitial lung disease, is a heterogeneous group of disorders characterised by inflammation and/or fibrosis of the alveolar interstitium, alveoli and small airways, producing a restrictive ventilatory defect with impaired gas transfer — reduced TLC, FVC and DLCO with a preserved or raised FEV /FVC ratio.

Epidemiology in older adults. DPLD is predominantly a disease of later life. Idiopathic pulmonary fibrosis (IPF) has a median age at diagnosis of about 65–70, a male predominance and rising incidence with each decade; it is rare below 50. Interstitial lung abnormalities are found incidentally on CT in up to 10% of older people and a proportion progress. In India, hypersensitivity pneumonitis and connective tissue disease-associated ILD form a larger share than in Western registries, and post-tubercular fibrosis is an important mimic.

Pathogenesis. Modern understanding of IPF is of repetitive micro-injury to a genetically susceptible, aged alveolar epithelium rather than primary inflammation. Ageing mechanisms are central — telomere shortening, cellular senescence, mitochondrial dysfunction, impaired autophagy and defective epithelial repair. Injured type II pneumocytes drive aberrant fibroblast activation and myofibroblast proliferation with excess extracellular matrix deposition and formation of fibroblastic foci. Risk factors: smoking, gastro-oesophageal reflux with micro-aspiration, dusts and metals, viral infection, and gene variants (MUC5B promoter polymorphism, telomerase TERT/TERC mutations, surfactant protein genes). In hypersensitivity pneumonitis the mechanism is an immune response to inhaled organic antigen.

Classification.

Clinical features. Insidious exertional breathlessness and a persistent dry cough. In older adults symptoms are frequently attributed to ageing, deconditioning, heart failure or COPD, causing years of diagnostic delay. Signs: fine bibasal end-inspiratory "Velcro" crackles (an early and important sign in IPF), finger clubbing (about 50% of IPF), and later cyanosis, cor pulmonale and right heart failure. Look for extrapulmonary clues to CTD — arthritis, Raynaud phenomenon, sclerodactyly, mechanic's hands, rash, dry eyes and mouth. Take a meticulous occupational, environmental, avian, mould and drug history.

Investigations — imaging is central. Chest radiograph shows reduced lung volumes with reticulonodular shadowing but is insensitive. High-resolution CT is the key investigation. The usual interstitial pneumonia (UIP) pattern — subpleural, basal-predominant reticulation with honeycombing and traction bronchiectasis, and no significant ground-glass — is diagnostic of IPF in the right clinical setting and removes the need for biopsy. Other patterns: ground-glass with subpleural sparing (NSIP); mosaic attenuation with air trapping and centrilobular nodules (hypersensitivity pneumonitis); peripheral consolidation (organising pneumonia); upper-zone perilymphatic nodules and hilar nodes (sarcoidosis).

Other investigations. Full pulmonary function tests — restrictive pattern with reduced FVC, TLC and DLCO; DLCO is the most sensitive early marker and the best correlate of prognosis. Six-minute walk test with oximetry to document exertional desaturation. Serology — ANA, rheumatoid factor, anti-CCP, ENA, myositis panel, ANCA; serum precipitins for hypersensitivity pneumonitis; serum ACE and calcium for sarcoidosis. Bronchoalveolar lavage for lymphocytosis (hypersensitivity pneumonitis, sarcoidosis) and to exclude infection. Echocardiography for pulmonary hypertension. Surgical lung biopsy is high-risk in the elderly and is largely avoided; transbronchial lung cryobiopsy is a lower-risk alternative in selected patients. The diagnosis should be made by a multidisciplinary discussion of clinician, radiologist and pathologist — this is the accepted gold standard.

Management — general and non-pharmacological. Remove the cause — antigen avoidance in hypersensitivity pneumonitis, stopping the culprit drug, smoking cessation. Pulmonary rehabilitation improves exercise capacity and quality of life. Ambulatory and long-term oxygen for resting or exertional hypoxaemia. Vaccination (influenza, pneumococcal, COVID-19, RSV). Treat comorbidities that materially affect outcome — gastro-oesophageal reflux, obstructive sleep apnoea, pulmonary hypertension, ischaemic heart disease, depression, deconditioning and osteoporosis. Manage cough and breathlessness symptomatically, with low-dose opioids where refractory.

Management — pharmacological. IPF: antifibrotic therapy with nintedanib (a triple tyrosine kinase inhibitor; adverse effects diarrhoea, deranged LFTs, bleeding risk with anticoagulants) or pirfenidone (nausea, photosensitivity, weight loss) — both slow the rate of FVC decline. Corticosteroids and immunosuppression are harmful in IPF (the PANTHER-IPF trial showed increased mortality with prednisolone + azathioprine + N-acetylcysteine) and must not be used. Non-IPF ILD: corticosteroids ± mycophenolate, azathioprine or rituximab for CTD-ILD and hypersensitivity pneumonitis; nintedanib is licensed for the progressive pulmonary fibrosis phenotype (INBUILD trial) and for systemic sclerosis-ILD (SENSCIS). Lung transplantation is the only curative option but age over 65–70 with frailty and comorbidity usually precludes it.

Prognosis and natural history. IPF has the worst prognosis — median survival about 3–5 years from diagnosis, comparable to many cancers. The course is variable: slow decline, rapid decline, or stability punctuated by acute exacerbations. Acute exacerbation of IPF — new ground-glass on a background of UIP without infection, heart failure or PE — carries an in-hospital mortality above 50%. Prognostic tools: the GAP index (Gender, Age, Physiology — FVC and DLCO), and a decline in FVC of ≥ 10% or DLCO of ≥ 15% over 6–12 months. NSIP, COP and sarcoidosis carry a much better prognosis than IPF. Because trajectory is poor, early advance care planning, symptom control and palliative care must run in parallel with disease-modifying therapy in older patients.

Progressive pulmonary fibrosis is now a treatable entity in its own right. The 2022 ATS/ERS/JRS/ALAT guideline formally defined PPF as at least two of — worsening respiratory symptoms, physiological progression (absolute FVC decline ≥ 5% or DLCO decline ≥ 10% within one year), or radiological progression — occurring in a patient with non-IPF fibrotic ILD. On the basis of the INBUILD trial, nintedanib is recommended for PPF regardless of the underlying ILD, so the modern question at the bedside is no longer only "which ILD?" but "is this fibrosis progressive?"

Nerandomilast — the first new antifibrotic class in a decade. The phase III FIBRONEER-IPF and FIBRONEER-ILD trials (NEJM 2025) showed that nerandomilast, an oral preferential phosphodiesterase-4B (PDE4B) inhibitor, significantly reduced the decline in FVC at 52 weeks in both IPF and progressive pulmonary fibrosis, at both 9 mg and 18 mg twice daily, and whether given alone or added to background nintedanib or pirfenidone. Longer follow-up of FIBRONEER-ILD also showed reduced risk of death. It is under regulatory review and represents the first successful new mechanism in pulmonary fibrosis since the antifibrotics.