Diffuse lung disease is common, and its diagnosis is frequently challenging. This chapter describes a diagnostic approach, based on clinical features, imaging, and other investigations; more detailed descriptions of the diseases themselves are presented later in the book. The term ‘diffuse lung disease’ is used here to describe any widespread pulmonary disease process. Patients typically present with breathlessness and bilateral CXR shadowing. The rate of onset and severity of breathlessness are extremely variable, however, and presentations range from an asymptomatic patient with long-standing radiological changes to an acute onset of breathlessness over a period of days, leading rapidly to respiratory failure and death.
Anatomy of diffuse lung disease
An understanding of lung anatomy is helpful when considering the causes of diffuse lung disease and their appearance on HRCT. Many diffuse lung diseases primarily affect the interstitium (‘interstitial lung disease’, also described as ‘diffuse parenchymal lung disease’), a poorly defined term that refers to the connective tissue fibrous framework of the lung. Centrally, connective tissue surrounds bronchovascular bundles (each consisting of a bronchus and its accompanying pulmonary artery) that originate at the hila. Peripherally, these connective tissue sheaths are in continuity with fibrous interlobular septa, which organize the lung into units called ‘2° pulmonary lobules’, polyhedral structures with approximately 2cm sides (see Fig. A4.4, p. [link]). Interlobular septa, which define and separate 2° pulmonary lobules, contain lymphatics and venules. A 2° pulmonary lobule contains around 5–12 acini and is supplied at its centre by a bronchiole and pulmonary arteriole.
The term ‘interstitial lung disease’ is potentially confusing, because many primarily interstitial processes also involve the airways, vasculature, and alveolar airspaces. Disease processes that primarily affect the airways (e.g. bronchiectasis), vessels (e.g. vasculitis), or airspaces (e.g. pneumonia) may also present with diffuse CXR shadowing.
There are several hundred causes of diffuse lung disease, and it is useful to divide these into groups, based on their rate of onset and aetiology/disease mechanism (see Table 6.1).
Table 6.1 Causes of diffuse lung disease
Examples (common conditions in bold)
Bacterial (pneumococcal, staphylococcal, Gram-negative, anaerobic, TB, atypical), viral (influenza, parainfluenza, adeno, respiratory syncitial virus (RSV), cytomegalovirus (CMV), measles, varicella, hanta), fungal (aspergillosis, histoplasmosis, PCP)
Adult respiratory distress syndrome (ARDS), acute interstitial pneumonia (AIP), acute HP
Acute or chronic
Immunosuppressants (methotrexate, azathioprine, cyclophosphamide); treatment of connective tissue disease (gold, penicillamine, sulfasalazine); cytotoxics (chlorambucil, melphalan, busulfan, lomustine, carmustine, bleomycin, mitomycin); antibiotics (nitrofurantoin, cephalosporins); anti-arrhythmics (amiodarone); illicit (cocaine inhalation, heroin, methadone, talc)
Radiotherapy, high-concentration O2, paraquat
Wegener’s granulomatosis, Churg–Strauss syndrome, Goodpasture’s syndrome, SLE, MPA, idiopathic haemosiderosis
Pulmonary venous hypertension
Cardiogenic pulmonary oedema, pulmonary veno-occlusive disease
Sarcoidosis, organizing pneumonia (OP), eosinophilic pneumonia, lipoid pneumonia
Idiopathic interstitial pneumonias (IIPs)
IPF, non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), lymphocytic interstitial pneumonia (LIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)
Asbestosis, coal worker’s pneumoconiosis, silicosis, metals, e.g. cobalt, aluminium
Hypersensitivity pneumonitis, e.g. bird fancier’s lung, farmer’s lung
Connective tissue disease
RA, SLE, scleroderma, poly- and dermatomyositis, ankylosing spondylitis, Sjögren’s syndrome, Behçet’s disease
Lymphangitis carcinomatosa, bronchoalveolar cell carcinoma, pulmonary lymphoma
Bronchiectasis, Langerhans cell histiocytosis (LCH), amyloidosis, lymphangioleiomyomatosis (LAM), alveolar proteinosis, microlithiasis
Clinical features may provide useful clues to the underlying diagnosis. Key points in the history are:
• Breathlessness is the most common symptom, and its rate of onset may be useful diagnostically (see Table 6.1)
• Causes of truly episodic breathlessness and CXR shadowing include eosinophilic pneumonia, vasculitis, alveolar haemorrhage, Churg–Strauss syndrome, HP, cryptogenic organizing pneumonia (COP), allergic bronchopulmonary aspergillosis (ABPA), and pulmonary oedema
• Cough may occur, although its diagnostic value is uncertain; it may be a prominent symptom in IPF, lymphangitis carcinomatosis, HP, OP, sarcoid, and eosinophilic pneumonia. Chronic production of purulent sputum suggests bronchiectasis. Bronchorrhoea (production of large volumes of sputum) may occur with bronchoalveolar cell carcinoma. Haemoptysis suggests alveolar haemorrhage, malignancy, or pulmonary venous hypertension
• Wheeze may occur in asthma associated with eosinophilic pneumonia or Churg–Strauss syndrome
• Weight loss and fever are non-specific symptoms associated with many diffuse lung diseases.
Other medical conditions,
e.g. malignancy, connective tissue disease, HIV infection, other immunosuppression.
• Delays of months, or even years, may occur between starting the drug and developing lung involvement
• Illicit drug abuse (crack cocaine or heroin—pulmonary oedema, eosinophilic pneumonitis, diffuse alveolar haemorrhage, interstitial pneumonia; IV drug use—IV talcosis, septic emboli)
• Oily nose drops (lipoid pneumonia).
Occupation, lifestyle, hobbies, and pets
• May involve inhalation of inorganic or organic dusts. Document lifelong employment history, including probable exposure levels, use of protective equipment, and names of employers
• Inorganic dusts associated with development of diffuse lung disease include asbestos, silica, cobalt, beryllium, aluminium, isocyanates, copper sulfate, iron, tin, barium, and antimony
• HP may result from inhalation of organic dusts, such as Thermoactinomycetes in mouldy hay (farmer’s lung), avian proteins or feathers (bird fancier’s lung), mushroom compost, mouldy cheese, cork or sugar cane, and isocyanates
• Smoking history (LCH, RB-ILD, DIP, and Goodpasture’s syndrome are more common in smokers).
Evidence of extrapulmonary disease
Manifestations of connective tissue disease, vasculitis, sarcoidosis, e.g. arthralgia, skin rash or thickening, ocular symptoms, muscular pain and weakness, Raynaud’s, nasal/sinus disease, sicca symptoms, haematuria. Infertility in ♂ (immotile cilia syndrome, CF).
TB, pulmonary eosinophilia from parasites (tropics), histoplasmosis (north and central USA, parts of South America and Africa), hydatid disease (Middle East, Australasia, Mediterranean).
• Cyanosis and signs of cor pulmonale in severe disease
• Clubbing (IPF, asbestosis, bronchiectasis)
• Basal crackles (IPF, asbestosis, connective tissue disease, pulmonary oedema, lymphangitis, drugs); crackles in bronchiectasis are characteristically coarse
• Absence of crackles, despite a significant CXR abnormality, may be suggestive of sarcoidosis, pneumoconiosis, HP, or LCH
• Squeaks suggest the presence of bronchiolitis and may occur in HP
• Skin, joint, and eye disease (connective tissue disease, sarcoidosis, vasculitis).
is an essential test although is rarely diagnostic. Up to 10% of patients with biopsy-proven diffuse lung disease have a normal CXR. Previous CXRs are helpful in assessing disease duration and progression.
is more sensitive and specific than CXR for diagnosing diffuse lung disease (for HRCT diagnosis, see pp. [link]–[link] and Appendix 4). HRCT is often, in itself, diagnostic and should always precede biopsy in the investigation of diffuse lung disease. HRCT also enables assessment of disease extent and optimal biopsy site, if required. HRCT appearance correlates to some extent with disease activity in the interstitial pneumonias: a predominantly ‘ground-glass’ appearance may signify a steroid-responsive inflammatory state, whereas reticulation and honeycombing are often associated with fibrosis, poor response to treatment, and a worse prognosis.
HRCT (and, to a limited extent, CXR) appearances can be classified, according to the pattern and distribution of disease and the presence of additional features (see also Appendix 4).
Reticular (or linear) pattern
• Interstitial pulmonary oedema
• UIP (reticular shadowing is typically patchy, subpleural, and basal; other features include loss of architecture of 2° pulmonary lobules, honeycombing, traction bronchiectasis)
• Asbestosis (similar features to UIP, often with pleural plaques)
• Connective tissue disease associated fibrosis (similar features to UIP)
• Chronic HP (often associated with regions of ground-glass change, air trapping on expiration, and centrilobular micronodules)
• Drug-induced fibrosis
consists of numerous discrete, round opacities 0.1–1cm in diameter.
• Interstitial processes result in nodularity within interlobular septa, around bronchovascular bundles, and subpleurally (e.g. sarcoidosis, which may demonstrate associated perihilar reticular shadowing and lymphadenopathy)
• Airspace diseases may lead to affected acini becoming visible as nodules (e.g. HP, miliary TB, COP, malignancy).
is an increase in lung density through which pulmonary vasculature is still visible (compare the lung density with that of air within the bronchi). May occur as a result of airspace or interstitial disease and may be patchy or diffuse. Causes include:
• Pulmonary oedema or haemorrhage, ARDS
• Certain IIPs (NSIP, RB-ILD, DIP, AIP)
• Bronchoalveolar cell carcinoma
• Alveolar proteinosis.
appearance may be artefactual, the increased density resulting from breath-holding during expiration. It may also be confused with ‘mosaic perfusion’ where densities vary in different regions of the lung as a result of either variable perfusion (e.g. in chronic thromboembolic disease) or gas trapping (small airways disease).
(or airspace shadowing) is an increase in attenuation, characterized by air bronchograms (air-filled bronchi superimposed against opacified alveoli) and the loss of visibility of adjacent vessels. It occurs as disease processes infiltrate and fill alveolar airspaces, e.g. with water, blood, pus, malignant cells, or fibrous tissue. Causes include:
• Pulmonary oedema or haemorrhage, ARDS
• Bronchoalveolar cell carcinoma, lymphoma
• Other rare conditions (e.g. eosinophilic pneumonia, alveolar proteinosis).
refers to well-defined airspaces with a thin wall. Causes include:
• LCH (bizarrely shaped cysts and nodules, apical predominance)
• UIP (subpleural honeycombing)
• Septic emboli
• LAM (thin-walled cysts, otherwise normal lung)
• Centrilobular emphysema may simulate cystic disease, but there is absence of a well-defined wall.
Interlobular septal thickening
occurs as a result of processes affecting the lymphatics or venules within interlobular septa such as:
• Pulmonary oedema (smooth thickening)
• Lymphangitis carcinomatosis (irregular, nodular thickening of interlobular septa and bronchovascular bundles, no architectural distortion)
• Upper zone: silicosis, pneumoconiosis, chronic sarcoidosis, HP, ankylosing spondylitis, TB, LCH
• Lower zone: UIP, connective tissue diseases, asbestosis
• Mid-zone: sarcoidosis, pulmonary oedema, PCP
• Peripheral: UIP, eosinophilic pneumonia, drugs (amiodarone), COP
• Sharp borders: radiation pneumonitis.
Urine and blood tests
Consider the following investigations:
• Urine dipstick and microscopy for detection of renal disease associated with vasculitis/connective tissue disease
• ESR, CRP, FBC (look specifically at the eosinophil count), renal and liver function, CK (?myositis), calcium (increased in >10% of patients with sarcoidosis)
• Autoantibodies (RhF, ANA, ENAs (Ro, La, RNP, Scl-70, Jo-1, Sm))
• ANCA (vasculitis), anti-GBM (Goodpasture’s syndrome)
• Serum precipitins (to antigens in HP; poor specificity)
• Serum ACE levels may be increased in sarcoidosis, but this is a non-specific and relatively insensitive test and is unhelpful diagnostically
• HIV testing.
• Cytology may be diagnostic in bronchoalveolar cell carcinoma
• Induced sputum may be useful in the diagnosis of PCP and TB.
• Useful in assessing progression and severity of disease and response to treatment, but often unhelpful diagnostically
• Typically show restrictive pattern with reduced vital capacity (VC) and transfer factor. Normal values do not exclude mild, early lung disease
• Obstructive pattern rare but may be seen in sarcoidosis, LCH, and LAM; may see mixed picture if coexisting COPD
• Transfer factor may be increased transiently (days) in alveolar haemorrhage. Reduced transfer factor with preserved lung volumes is suggestive of pulmonary vascular disease (pulmonary arterial hypertension (PAH) or vasculitis) or coexistent emphysema
• Disease progression and response to treatment are best assessed by serial measurements of vital capacity and transfer factor
• Check O2 saturation, and consider ABGs. A fall in O2 saturation on simple exercise may be performed in the clinic setting and is a useful clue to underlying lung disease in patients with normal saturation and lung function at rest and an unremarkable CXR.
• ECG Conduction abnormality in sarcoidosis; cardiogenic pulmonary oedema is unusual in the presence of a completely normal ECG
• Echo Assess LV and valvular function if cardiac pulmonary oedema suspected, and measure pulmonary arterial pressure (PAP) (e.g. in scleroderma or suspected pulmonary veno-occlusive disease). The presence of a tricuspid regurgitation jet is required in order to assess PAP on echo.
• Most useful in diagnosis of opportunistic infection (bacterial or fungal pneumonia, TB, PCP), eosinophilic pneumonia, malignancy, alveolar proteinosis, and alveolar haemorrhage
• BAL differential cell counts usually unhelpful diagnostically, although BAL lymphocytosis is typical of HP, sarcoidosis, and LIP, and eosinophilic BAL occurs in eosinophilic pneumonia or drug-induced lung disease.
Which patients need a lung biopsy?
In cases of uncertain aetiology, despite clinical assessment and HRCT, lung biopsies often provide a definitive diagnosis. Ideally, they should be taken before treatment is started. The decision to biopsy varies amongst clinicians and should take into account the individual patient’s clinical condition and wishes, and the likely benefit of a definitive diagnosis in terms of predicting treatment response and prognosis. Some take a pragmatic approach when a diagnosis (or group of diagnoses with the same treatment) is likely, but not biopsy-proven, and treat empirically. In some cases, the patient may be too unwell for biopsy and require empirical treatment. Lung biopsy is not usually recommended in patients with typical clinical and HRCT features of IPF, and biopsy of end-stage fibrosis is in general unhelpful in eliciting an underlying aetiology.
provides small samples but relatively high diagnostic yield in diseases with a ‘centrilobular’ distribution, e.g. sarcoidosis, HP, malignancy, infection (fungi, TB), and OP. Take 4–6 samples. Additional blind endobronchial biopsies may be diagnostic in sarcoidosis.
Open lung biopsy
via thoracotomy or video-assisted thoracoscopic (VATS) biopsy provides larger samples than TBB and have diagnostic yields of at least 90%. Both require general anaesthesia. VATS probably has a lower morbidity and is generally preferred in stable patients; open biopsy is required in ventilator-dependent patients. Open or VATS biopsy is required for histological confirmation of IIPs, vasculitis, lymphoma, LAM, and LCH—the yield of TBB in these conditions is very low.
The management of patients presenting with diffuse lung disease—particularly ILD—and acute respiratory failure is challenging. These patients are often critically ill with rapidly progressive disease, and a variety of diverse conditions can underlie the typically non-specific presentation with breathlessness, hypoxia, raised inflammatory markers, and diffuse ground-glass infiltrates on HRCT. There is little evidence to guide management, which needs to be on a case-by-case basis. Assessment is largely as outlined earlier in this chapter but with particular emphasis on prompt identification and treatment of reversible causes and early consideration of appropriate ceilings of care/ICU admission.
• Diffuse infection (community-acquired pneumonia (CAP)—including ‘atypical’, PCP, other fungi, viral, TB)
• Drug-induced pneumonitis
• Diffuse alveolar haemorrhage/vasculitis
• Fulminant OP
• Acute exacerbation of previously subclinical IPF
• Acute HP
• Acute eosinophilic pneumonia
Key points in assessment and treatment
• Have a low threshold for treating infection, which, in practice, is difficult to distinguish from many non-infectious causes. Consider PCP. Subacute presentations of infection, such as fungal disease or TB, may rarely mimic ILD
• Look for evidence of extrapulmonary disease, particularly involving kidneys (urine dipstick and microscopy), heart, eyes, ENT, skin, muscles, joints. Active disease in these sites may, in some cases, provide a safer biopsy target than the lungs, if histology is required
• Actively consider drug-induced lung disease (see http://www.pneumotox.com): review current and previous medications carefully, and discontinue potentially offending drugs
• Bloods FBC (?eosinophilia), renal and liver function, CRP, ESR, CK, urgent immunology (RhF, ANA, ENA profile—including antisynthetase antibodies (anti-Jo-1 (see p. [link]), ANCA (vasculitis), anti-GBM (Goodpasture’s), serum precipitins (to antigens in HP)), HIV testing
• The presence of an antisynthetase antibody, in combination with one or more of interstitial pneumonitis, myositis, and arthritis, is characteristic of antisynthetase syndrome. Fever, Raynaud’s phenomenon, and mechanic’s hands (thick, cracked skin on palms and fingers) may also occur, or pneumonitis may be the sole clinical manifestation. Check anti-Jo-1, which may be positive in myositis-associated acute pneumonitis, even in the setting of a negative ANA. Other antisynthetase antibodies, such as anti-PL-7 and anti-PL-12, and anti-CADM-140 may underlie rapidly progressive pneumonitis, with or without myositis, but are not yet routinely available
• Consider echo to assess LV and valvular function if cardiac pulmonary oedema suspected
• Further imaging PEs may coexist with ILD, and CTPA with HRCT slices is usually the radiological investigation of choice
• BAL is useful in excluding infection but may decompensate seriously ill, hypoxic patients; it is often safer to wait and perform after patients are ventilated. TBBs may increase diagnostic yield, but risk probably outweighs benefit in the majority of patients. Surgical lung biopsy may yield a diagnosis that alters management in carefully selected individuals, particularly those with de novo lung disease. It can be performed in the ICU on mechanically ventilated patients
• Consider empirical high-dose steroids (e.g. IV methylprednisolone 750mg–1g on 3 consecutive days, followed by maintenance therapy with 0.5–1mg/kg/day prednisolone). Fulminant COP is frequently steroid-responsive, and, although robust evidence is lacking, the outcome in AIP may be more favourable following early use of high-dose steroids. Assess the response to steroids over 5–7 days, and then consider further immunosuppression, particularly if there is any suggestion of underlying connective tissue disease: IV cyclophosphamide 600–650mg/m2 is usually favoured because of relatively rapid onset (often <1 week), with mesna protection against bladder toxicity if total dose exceeds 1g; a second dose can be given 7–10 days later (depending upon white blood count) or 2-weekly. Empirical ‘upfront’ treatment with cyclophosphamide, alongside initial IV methylprednisolone, increases the infection risk but may be indicated in severe disease or in suspected severe vasculitis/Wegener’s. Rituximab (a monoclonal antibody that targets peripheral B lymphocytes) or tacrolimus may be of benefit in severely ill patients with connective tissue disease-associated interstitial pneumonitis, particularly antisynthetase syndrome
• Consider ceiling of care. High-flow O2 is almost always needed, and ICU admission and mechanical ventilatory support are usually required. ICU admission is usually appropriate for patients with de novo ILD, and it is appropriate to support patients with mechanical ventilation whilst awaiting a possible response to steroids/immunosuppression. Note that mechanical ventilation is usually considered an absolute contraindication to lung transplantation in the UK. The outcome of mechanical ventilation in patients with IPF is typically very poor, and ICU admission is rarely appropriate in the setting of underlying IPF/extensive fibrotic change.