Article about diffuse parenchymal lung disease which is a term that refers to a diverse group of conditions which affect the interstitial tissue of the lung and/or the alveolar lumen. The symptoms, features and progression of these conditions may differ widely, but they are often grouped together because they share similar symptoms, physical signs, pulmonary function abnormalities and radiological changes. High resolution CT scanning has become the important first step in the investigation of diffuse parenchymal lung disease, indicating the diagnosis or directing further investigation. A range of conditions may mimic interstitial lung disease. This article uses technical medical terminology.
The nomenclature of diffuse parenchymal lung disease has caused a great deal of confusion, with the use of complicated histopathological terms not always corresponding exactly to clinico-radiological entities.
‘Cryptogenic fibrosing alveolitis’—Hamman and Rich first described a presentation of rapidly progressive fatal diffuse parenchymal lung disease in which the cardinal histological features were interstitial inflammation and fibrosis. A typical clinical picture was defined, consisting of progressive dyspnoea, bilateral predominantly basal crackles on auscultation, reticulonodular predominantly basal abnormalities on chest radiography, and a restrictive ventilatory defect on lung function testing. This clinical entity was termed ‘cryptogenic fibrosing alveolitis’ (CFA) or ‘idiopathic pulmonary fibrosis’, but it has become clear that the outcome associated with this presentation—termed the ‘CFA clinical syndrome’—is highly heterogeneous.
Diffuse parenchymal lung diseases can be subdivided into five major groupings: (1) idiopathic interstitial pneumonias; (2) diseases associated with systemic conditions, including rheumatological disease; (3) diseases caused by environmental triggers or drug ingestion; (4) granulomatous diseases; and (5) other diffuse lung diseases.
Classification—this is based on recognition of clinical, radiological, and histopathological patterns, as opposed to the purely histopathological terminology. The following are recognized: (1) usual interstitial pneumonia (UIP); (2) nonspecific interstitial pneumonia (NSIP); (3) desquamative interstitial pneumonia (DIP); (4) respiratory bronchiolitis–interstitial lung disease (RBILD); (5) diffuse alveolar damage (DAD); (6) lymphocytic interstitial pneumonia (LIP); and (7) cryptogenic organizing pneumonia.
Diagnosis—is complicated by the large number of disorders grouped within the diffuse parenchymal lung diseases. A systematic diagnostic algorithm, based upon careful clinical evaluation and a logical sequence of tests, is essential. This approach can be broken down into two phases: (1) clinical history, clinical examination, chest radiography, pulmonary function tests, and selective blood tests; and (2) high-resolution CT, bronchoalveolar lavage (in some cases), and lung biopsy (in a few cases).
Clinical patterns of disease—the chronic diffuse parenchymal lung diseases can be broadly subclassified into five patterns of longitudinal disease behaviour, based upon cause, severity, the relative degree of inflammation and fibrosis, and observed change in the short term. Each clinical pattern is associated with a separate approach to management:
- Self-limited inflammation—usually caused by an extrinsic agent, usually responds to withdrawal of an offending agent, and other therapy is unnecessary.
- Stable fibrotic disease—most commonly encountered in sarcoidosis, following drug-induced lung disease, and in patients with formerly active rheumatological disorders. Treatment is not required, but monitoring of serial pulmonary function tests is needed.
- Major inflammation, with or without supervening fibrosis—often a feature of drug-induced lung disease, and also of some patients with cryptogenic organizing pneumonia, DIP, hypersensitivity pneumonitis, sarcoidosis, and aggressive inflammatory disease in rheumatological disease. Treatment with corticosteroids is usual, initially at high dosage.
- Slowly progressive fibrotic disease, in which stabilization is a realistic goal—frequently seen in sarcoidosis, hypersensitivity pneumonitis, rheumatological conditions, and in many patients with fibrotic NSIP. Aggressive initial treatment is usually warranted to ensure optimal control of disease activity. Long-term therapy is often required.
- Inexorably progressive fibrotic disease—the hallmark of IPF, but an IPF-like course is sometimes observed in idiopathic fibrotic NSIP, rheumatological disease, and in a few patients with chronic hypersensitivity pneumonitis. Long-term treatment may slow disease progression, but initial high-dose therapy achieves nothing in known IPF and may cause unnecessary drug toxicity.
The nomenclature of diffuse parenchymal lung disease has caused a great deal of confusion. There have been too many complicated histopathological terms, not always corresponding exactly to clinico-radiological entities. The free use of synonymous terms—e.g. extrinsic allergic alveolitis and hypersensitivity pneumonitis; idiopathic pulmonary fibrosis (IPF) and cryptogenic fibrosing alveolitis (CFA)—has added to difficulties faced by general and respiratory physicians in coming to terms with a difficult group of idiopathic diseases. Before the recent reclassification of the idiopathic interstitial pneumonias, the use by clinicians of the ‘umbrella term’ CFA/IPF to group idiopathic diseases with a common clinical presentation was an understandable attempt to simplify terminology. However, attempts to lump disorders together according to their clinical presentation contributed to imprecision in defining individual diseases.
Diffuse parenchymal lung disease was formerly known as interstitial lung disease. The change of terminology reflects the fact that disease processes involve the lung parenchyma, but also in many cases the air-space components of the acini. Infective pneumonias, pulmonary oedema, and some malignancies involve the acinar regions of the lung but are not, by convention, grouped with the diffuse parenchymal lung diseases, although they may present with similar clinical and radiological findings and should be considered in the formulation of a differential diagnosis.
In this introduction, a broad approach to the classification of the diffuse lung diseases and their diagnosis and investigation is discussed.
Diffuse parenchymal lung diseases can be subdivided into five major groupings:
- 1 idiopathic interstitial pneumonias
- 2 diseases associated with systemic conditions, including rheumatological disease
- 3 diseases caused by environmental triggers or drug ingestion
- 4 granulomatous diseases
- 5 other diffuse lung diseases
In most patients with environmentally induced and drug-induced lung disease, granulomatous lung disease, or lung disease complicating systemic disease, the cause and thus the diagnosis is immediately apparent, or is rapidly disclosed by standard investigations detailed below. By contrast, diagnosis is less straightforward when a cause is not immediately apparent. By definition, most patients can be categorized as having one of the idiopathic interstitial pneumonias, discussed in detail in the remainder of this chapter. Bullet list 1 lists diseases of known and unknown cause falling within the broad headings above, and disorders that present more acutely are shown in Bullet list 2.
Idiopathic interstitial pneumonias
The diseases grouped as the ‘idiopathic interstitial pneumonias’ give rise to particular confusion, largely because terms used to describe histopathological patterns have been used interchangeably but inaccurately with disease ‘labels’. In 1944, Hamman and Rich first described a presentation of rapidly progressive fatal disease, in which the cardinal histological features were interstitial inflammation and fibrosis. It subsequently became clear that chronic insidiously progressive fibrosing disease was much more common. A typical clinical picture was defined, consisting of progressive dyspnoea, bilateral predominantly basal crackles on auscultation, reticulonodular predominantly basal abnormalities on chest radiography, and a restrictive ventilatory defect on lung function testing. This clinical entity was termed ‘cryptogenic fibrosing alveolitis’ or ‘idiopathic pulmonary fibrosis’. However, it became clear that the outcome associated with this presentation, hereafter termed the ‘CFA clinical syndrome’, was highly heterogeneous. Although most patients progressed inexorably to a fatal outcome, usually within 3 to 4 years, a more insidious course was seen in a significant minority, and in 10 to 15% of cases there was a response to corticosteroid therapy and, usually, a good long-term outcome.
Histological patterns of disease encountered in the CFA clinical syndrome were first classified by Liebow in 1975 as usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), bronchiolitis obliterans with UIP, lymphocytic interstitial pneumonia (LIP), and giant-cell interstitial pneumonia. However, it subsequently became clear that these patterns of disease were also present outside an idiopathic setting. The most frequent, UIP, was occasionally found in connective tissue disease, drug-induced lung disease, and chronic hypersensitivity pneumonitis, and LIP was most commonly associated with rheumatological disease and, more recently, AIDS-related disease. Giant-cell interstitial pneumonia was seldom idiopathic but was caused by exposure to hard metals (cobalt, tungsten carbide, titanium salts). It also became apparent that the historical histological pattern of UIP did, in fact, encompass separate patterns of UIP and nonspecific interstitial pneumonia (NSIP), which denoted a better outcome.
These considerations led to a revision of Liebow’s classification. The interstitial pneumonias of known cause were removed (although smoking-related disorders were retained). The revised classification, constructed by a nomenclature committee of the American Thoracic Society and European Respiratory Society (ATS/ERS), included UIP, NSIP, DIP, respiratory bronchiolitis–interstitial lung disease (RBILD), diffuse alveolar damage (DAD), LIP, and cryptogenic organizing pneumonia (Table 1). In this classification, disease nomenclature incorporates clinical, radiological, and histopathological patterns, as opposed to the purely histopathological terminology used previously. The term ‘cryptogenic fibrosisng alveolitis’ is now synonymous with IPF, requiring an underlying histological pattern of UIP or compatible high-resolution CT appearances, and should not be confused with the nonspecific CFA clinical syndrome. The other idiopathic interstitial pneumonias, all commonly presenting with the CFA clinical syndrome, are reviewed briefly below.
Bullet list 1 Diffuse parenchymal lung diseases
- ◆ Rheumatological:
- • Systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis
- ◆ Vasculitis:
- • Wegener’s granulomatosis, Churg–Strauss granulomatosis, microscopic polyangiitis, pulmonary–renal syndrome (including Goodpasture’s syndrome), capillaritis, Behçet’s syndrome
- ◆ Vascular:
- • Primary pulmonary hypertension, idiopathic pulmonary haemosiderosis, pulmonary veno-occlusive disease, antiphospholipid syndrome
- ◆ Hypersensitivity pneumonitis: fungal, bacterial, avian, chemical
- ◆ Fibrogenic inorganic dusts: asbestosis, silica, hard metal alloyberyllium, coal, aluminium
- ◆ Therapeutic agents,a illicit drugs, radiation, pesticides, oxygen and other inhaled gases
- ◆ Sarcoidosis, hypersensitivity pneumonitis, berylliosis, Langerhans’ cell histiocytosis, Wegener’s granulomatosis, Churg–Strauss syndrome, lymphomatoid granulomatosis, bronchocentric granulomatosis
- ◆ Idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis–interstitial lung disease, acute interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia
- ◆ Inherited disorders: tuberous sclerosis, neurofibromatosis, Hermansky–Pudlak syndrome, lipid storage disorders, familial idiopathic pulmonary fibrosis
- ◆ Pulmonary eosinophilia: known causes (fungi, parasites, drugs), acute idiopathic, chronic idiopathic
- ◆ Lymphangioleiomyomatosis
- ◆ Alveolar proteinosis
- ◆ Alveolar microlithiasis
- ◆ Amyloidosis
- ◆ Chronic aspiration
a See http://pneumotox.com for full listing of drug related lung disease.
Bullet list 2 Acute presentations of diffuse parenchymal lung disease: differential diagnosis
- ◆ Acute interstitial pneumonia
- ◆ Acute exacerbations of idiopathic pulmonary fibrosis
- ◆ Diffuse alveolar haemorrhage due to vasculitis or coagulopathy
- ◆ Fulminant cryptogenic and secondary organizing pneumonia
- ◆ Acute pneumonitis due to rheumatological disease
- ◆ Hypersensitivity pneumonitis
- ◆ Acute pulmonary eosinophilia
- ◆ Drug-induced lung disease
- ◆ Left ventricular failure
- ◆ Other causes of pulmonary oedema, including mitral stenosis
- ◆ Lung manifestation of uraemia
- ◆ Infection, especially opportunistic with pneumocystis
- ◆ Extensive, rapidly progressive metastatic malignancy
|Table 1 American Thoracic Society/European Respiratory Society nomenclature of idiopathic interstitial pneumonias|
|Clinical diagnosis||Pathological pattern|
||Usual interstitial pneumonia|
||Desquamative interstitial pneumonia|
|Respiratory bronchiolitis–interstitial lung disease||Respiratory bronchiolitis–interstitial lung disease|
|Acute interstitial pneumonia||Diffuse alveolar damage|
|Cryptogenic organizing pneumonia||Organizing pneumonia|
|Lymphocytic interstitial pneumonia||Lymphocytic interstitial pneumonia|
Desquamative interstitial pneumonia
The cardinal histological feature is diffuse accumulation of alveolar macrophages in airspaces in a uniform pattern, variably associated with minor interstitial inflammation and fibrosis. DIP is almost exclusively found in smokers and is now a rare disorder. Typical high-resolution CT appearances comprise patchy ground-glass attenuation which is often extensive. The disease presents with the features of the CFA clinical syndrome but, unlike IPF and NSIP, a response to corticosteroids is usual (although not invariable) and the treated outcome is usually good.
Respiratory bronchiolitis–interstitial lung disease
As in DIP, the histological features of RBILD are dominated by the presence of pigmented macrophages, but unlike DIP these accumulate in the air spaces around the bronchioles (respiratory bronchiolitis), often with associated peribronchiolar interstitial inflammation and fibrosis. The most frequent high-resolution CT findings are bronchial wall thickening, poorly defined centrilobular nodules, and patchy ground-glass attenuation. RBILD is found only in current or former smokers, and in many patients there is overlap in histological features between RBILD and DIP. The histological appearances in RBILD are identical to those of asymptomatic respiratory bronchiolitis, which is always present in current smokers. The distinction between RBILD and respiratory bronchiolitis is based upon disease severity, as defined by symptoms, the severity of lung function impairment, and the extent of disease on high-resolution CT. RBILD is diagnosed when a clinically significant diffuse lung disease is considered to be present. The disorder usually has a good outcome and often regresses with smoking cessation, but (on the basis of limited data) corticosteroid therapy is seldom efficacious.
Acute interstitial pneumonia
Diffuse alveolar damage is rare but seen in the adult respiratory distress syndrome and in acute interstitial pneumonia (AIP, commonly viewed as idiopathic adult respiratory distress syndrome, ARDS). Diffuse alveolar damage is characterized by hyaline membranes lining damaged alveoli and buds of organization in the alveoli of those acini that have been damaged and are undergoing the healing process. There is widespread ground-glass consolidation, often with traction bronchiectasis, and dependent consolidation on high-resolution CT. AIP probably equates to the Hamman–Rich syndrome and is fatal in 80 to 90% of cases. Although high-dose corticosteroid therapy and immunosuppressive agents are commonly given, there is no evidence that treatment influences outcome in most cases.
Lymphocytic interstitial pneumonia
The histopathological pattern of LIP is most commonly found in patients with rheumatological disease and in immunodeficiency syndromes, but can also occur as an idiopathic disorder. The histological findings consist of diffuse interstitial lymphocytic infiltration, variably associated with follicular bronchiolitis. The high-resolution CT features consist of patchy and sometimes extensive ground-glass attenuation with a variable nodular component. Corticosteroid and immunosuppressive therapy is effective in over 50% of cases.
Nonspecific interstitial pneumonia
NSIP is the least satisfactory entity amongst the idiopathic interstitial pneumonias. Histologically, there is variable interstitial inflammation and fibrosis but, unlike UIP—the pattern with which it is most likely to be confused—disease is uniform throughout biopsy specimens, both in severity and in the age of fibrosis. Fibroblastic foci, the cardinal finding in UIP, are absent or sparse. The radiological and clinical manifestations of NSIP are diverse. In a few cases inflammation predominates and the treated outcome is uniformly good, but in most patients with fibrotic NSIP, fibrosis is as at least as prominent as inflammation. Certain clinico-radiological profiles are increasingly recognized in NSIP. Most commonly patients present with the CFA clinical syndrome, the basal distribution of disease on high-resolution CT is similar to that of IPF, but unlike IPF there is prominent ground-glass attenuation and no honeycombing. A similar profile is typically present in pulmonary fibrosis associated with systemic sclerosis. In a second large subgroup, predominating in reports from South Korea and Japan, the clinical and radiological features resemble organizing pneumonia with fibrosis and there is a prominent lymphocytosis on bronchoalveolar lavage. Another group of patients are likely to have a form of hypersensitivity pneumonitis, based upon exposure histories and high-resolution CT features, despite the absence of granulomas in biopsy tissue. Corticosteroid and immunsosuppressive therapy are often effective in producing regression or stabilization of disease, but in a few cases, largely confined to those presenting with the CFA clinical syndrome, there is inexorable progression to a fatal outcome despite treatment.
Diagnosis is complicated by the large number of disorders grouped within the diffuse parenchymal lung diseases. A systematic diagnostic algorithm, based upon careful clinical evaluation and a logical sequence of tests, is essential. This approach can be broken down into in two phases, as shown in Bullet list 3.
In most patients, the presentation is insidious dyspnoea, variably accompanied by cough which is usually nonproductive. The duration of dyspnoea is diagnostically important: an acute presentation narrows the differential diagnosis considerably (see Bullet list 2).
Wheeze is a useful discriminatory symptom, as the presence of an airway-centred component informs the differential diagnosis. Disorders with variable but sometimes prominent wheeze include extrinsic allergic alveolitis, sarcoidosis, lymphangioleiomyomatosis, and Langerhans’ cell histiocytosis. Other less frequent respiratory symptoms are also diagnostically useful. Pleuritic chest discomfort often occurs in the rheumatological diseases and occasionally in drug-induced disease, but never in idiopathic pulmonary fibrosis or extrinsic allergic alveolitis. Haemoptysis, which may be trivial even when haemorrhage is severe, may be indicative of diffuse alveolar haemorrhage due to capillaritis, occurring in a number of disorders. A history of pneumothorax should prompt suspicion of cystic lung disease, especially Langerhans’ cell histiocytosis and lymphangioleiomyomatosis.
Bullet list 3 Diagnostic algorithm for diffuse parenchymal lung diseases
- 1 Clinical history
- 2 Clinical examination
- 3 Chest radiography
- 4 Pulmonary function tests
- 5 Selective blood tests
- 1 High resolution CT
- 2 bronchoalveolar lavage
- 3 Lung biopsy
The patient’s previous medical history may provide crucial information, including diagnoses of rheumatological disease or other relevant systemic diseases (including vasculitis). Even when no previous systemic diagnosis has been made, the nature of preceding systemic symptoms may point strongly to a hitherto undiagnosed rheumatological disorder. Knowledge of underlying cardiac and malignant disease is also essential as cardiac failure and disseminated malignancy may both simulate diffuse parenchymal lung disease, clinically and radiologically. A detailed list of medications serves to alert the clinician to the possibility of drug-induced lung disease. The agents most frequently responsible include nitrofurantoin, methotrexate and bleomycin, but a long list of other drugs occasionally cause lung disease. The comprehensive website http://pneumotox.com provides a rapid and fruitful means of checking possible pulmonary toxicities.
The occupational history should include all occupations from leaving school onwards: diseases caused by some exposures (including asbestos exposure) manifest decades later. Environmental conditions in which pneumoconioses most commonly arise include sawing, grinding, and drilling. Hypersensitivity pneumonitis arises from the inhalation of organic dusts including fungal contaminates of hay (as in farmer’s lung) and avian proteins found on the bloom and in the excreta of domestic birds. Many other organic antigens can give rise to hypersensitivity pneumonitis, with over 200 causes now recognized.
Other relevant historical information includes foreign travel, which may raise the possibility of parasitic infection as an explanation of pulmonary eosinophilia. A history of cigarette smoking identifies a predisposition to Langerhans’ cell histiocytosis, DIP, and RBILD, and is also a risk factor for exacerbations of pulmonary vasculitis. Paradoxically, smoking appears to protect against the development of sarcoidosis and hypersensitivity pneumonitis.
Digital clubbing is common in IPF and NSIP, not infrequent in hypersensitivity pneumonitis, but unusual in the other diffuse parenchymal lung diseases. Predominantly basal fine end-inspiratory crackles are a cardinal feature of the CFA clinical syndrome, are expected in IPF, and variably present in the other idiopathic interstitial pneumonias. Sporadic crackles are heard in many diffuse parenchymal lung diseases, but are seldom present in sarcoidosis. Expiratory wheeze is indicative of airway disease. Inspiratory squawks are strongly predictive of hypersensitivity pneumonitis or obliterative bronchiolitis. In advanced disease, clinical evidence of secondary pulmonary hypertension should be sought, as oxygen supplementation may have a pivotal role in management.
Relevant systemic findings include ocular disease (in sarcoidosis or vasculitis), skin disease (in sarcoidosis or rheumatological disease), musculoskeletal signs (in rheumatological disease), and neurological abnormalities (mononeuritis multiplex in sarcoidosisis, rheumatological disease and vasculitis; a wide variety of central and peripheral signs in sarcoidosis).
Chest radiography was formerly a central part of the diagnostic evaluation of diffuse parenchymal lung disease. Although high-resolution CT has now supplanted chest radiography in routine diagnosis, the chest radiograph continues to provide useful information.
Radiographic findings suggestive of pulmonary fibrosis are a required feature of the CFA clinical syndrome. Patients with fibrosing lung diseases tend have reduced lung volumes. If other clinical features are indicative of IPF, normal-sized or large lungs on chest radiography are suggestive of the coexistence of emphysema and pulmonary fibrosis, a frequent association in cigarette smokers with IPF. Large or normal-sized lungs on chest radiography, in association with nodular or reticular shadowing, also occur in Langerhans’ cell histiocytosis, lymphangioleiomyomatosis (a disorder involving smooth muscle proliferation arising in premenopausal women), and the closely related disorder tuberous sclerosis. Idiopathic bronchiectasis or cystic fibrosis, with increased radiographic volumes due to hyperinflation, can also be mistaken radiologically for diffuse parenchymal lung disease, although the clinical profile of chronic purulent sputum production is usually discriminatory.
The distribution of disease is often helpful. Primary fibrosing disorders, including IPF, fibrotic NSIP, pulmonary fibrosis in rheumatological disease, and asbestosis, produce predominantly basal reticular or reticulonodular abnormalities, which may also be overtly peripheral when disease is not advanced. By contrast, granulomatous disorders, including sarcoidosis and hypersensitivity pneumonitis (as well as tuberculosis and allergic bronchopulmonary asbestosis) most often have a predominantly upper and mid zone distribution. In the correct clinical setting, chest radiographic findings typical of sarcoidosis (predominantly upper zone fibrotic change, variably associated with lymphadenopathy and hilar retraction towards the apices) often suffice for a confident diagnosis.
The size and shape of abnormalities is sometimes diagnostically useful, although this aspect of radiological evaluation has largely been supplanted by high-resolution CT. Shadows of more than 5 mm in diameter are often present in Wegener’s granulomatosis, lymphoma, and other malignancies. Cavitating nodules are a frequent feature in Wegener’s granulomatosis, but necrotizing carcinomas and multiple staphylococcal abscesses should also be considered. The presence of nodules of differing size and shape is strongly suggestive of metastatic malignancy. An alveolar filling pattern, consisting of widespread confluent shadowing, usually denotes the presence of life-threatening disease. The differential diagnosis includes pulmonary oedema (due to left ventricular failure or mitral stenosis), diffuse alveolar haemorrhage, uraemia, drug-induced lung disease (and other forms of diffuse alveolar damage), infection (especially opportunistic infection in immunosuppressed patients), and alveolar proteinosis. When widespread confluent shadowing is chronic, alveolar cell carcinoma, lymphoma, and pulmonary eosinophilia should also be considered.
Inspection of previous chest radiographs is often highly revealing, especially in the patient presenting with multifocal consolidation. Waxing and waning of consolidation effectively excludes malignant disease and is strongly suggestive of immunologically mediated disorders, including cryptogenic organizing pneumonia, vasculitis, and pulmonary eosinophilia. Fixed consolidation may occur in all of these disorders but should also prompt suspicion of lymphoma, alveolar cell carcinoma and chronic infection.
Pleural thickening, with or without effusion, occurs commonly in rheumatological disease, rheumatoid arthritis, and systemic lupus erythematosus. Pleural abnormalities also occur commonly in asbestosis, Churg–Strauss syndrome, and Wegener’s granulomatosis. The presence of pleural disease should always prompt consideration of a second disease process, including malignancy, heart failure, tuberculosis, pulmonary embolism, and drug-induced lung disease. Pleural involvement is not a feature of uncomplicated hypersensitivity pneumonitis or IPF and is seldom present in the other idiopathic interstitial pneumonias, although occasionally encountered in sarcoidosis and cryptogenic organizing pneumonia.
Symmetrical hilar lymphadenopathy is usually indicative of sarcoidosis, but tuberculosis, lymphoma, and other malignancies should always be considered, especially if the changes are unilateral. Lymphadenopathy is seldom visible on chest radiography in other diffuse lung diseases, with the exception of silicosis. Hilar calcification occurs in sarcoidosis, silicosis, and tuberculosis.
Pulmonary function testing
In most patients with diffuse parenchymal lung disease, there is a restrictive ventilatory defect with reduced gas transfer (D L CO). Arterial oxygen tensions (PaO 2) are normal or mildly reduced until disease is advanced, although the alveolar-arterial oxygen gradient is often widened in associated with PaCO 2 levels that are at the lower end of the normal range. In early disease, maximal exercise testing may unmask abnormalities or, when normal, may reassure the clinician that the disease is not clinically significant. In IPF, maximal exercise testing typically leads to a fall in the PaO 2 and widening of the alveolar–arterial oxygen gradient (A–a gradient), reflecting ventilation–perfusion mismatch and, at maximal exercise, impairment of diffusion. The anatomical dead space to tidal volume ratio (V D/V T) normal falls on exercise in the healthy individual but is unchanged or increases in restrictive lung disease. Striking rises in the V D/V T ratio are strongly suggestive of disproportionate pulmonary vascular limitation.
A mixed (restrictive–obstructive) ventilatory defect is seen in disorders in which airway involvement is associated with diffuse parenchymal lung disease. This ventilatory pattern most commonly occurs in hypersensitivity pneumonitis, sarcoidosis, and rheumatological disorders. The coexistence of pulmonary fibrosis and emphysema, usually found in cigarette smokers with IPF or fibrotic NSIP, may also give rise to a mixed ventilatory defect, but more commonly there is spurious preservation of lung volumes and a disproportionate reduction in D L CO.
Routine haematological and biochemical tests have little discriminatory value in the diffuse lung diseases. A peripheral blood eosinophilia (>1.5 × 109/litre) is a prerequisite for diagnosis of Churg–Strauss vasculitis and may also be indicative of pulmonary eosinophilia (although not always present in that disorder). An increased level of serum angiotensin converting enzyme (ACE) is a helpful ancillary diagnostic finding in some patients with sarcoidosis and may also confirm ongoing disease activity. Routine immunoglobulin estimation may disclose hypogammaglobulinaemia in undiagnosed granulomatous disorders, but has no diagnostic value in other diffuse lung disorders.
Autoantibody testing is an essential part of routine evaluation. The presence of a positive antinuclear antibody, with specific extractable nuclear antigen profiles, or rheumatoid factor, may disclose an occult systemic rheumatological condition. The autoantibody profile is sometimes indicative of the likely pattern of pulmonary involvement. In systemic sclerosis the anti-DNA topoisomerase autoantibody is often associated with clinically significant pulmonary fibrosis, whereas the anticentromere antibody is linked to pulmonary vascular disease. Anti-t-RNA synthetase autoantibodies occur when polymyositis is associated with diffuse parenchymal lung disease. Other common associations include anti-Sm in systemic lupus erythematosus, SS-A and SS-B in Sjögren’s syndrome, and the anti-RNP autoantibody in mixed connective tissue disease. Mild increases in antinuclear antibody and rheumatoid factor titres are commonly found in IPF and idiopathic fibrotic NSIP but appear to have no clinical significance. Increased antineutrophil cytoplasmic antibodies (ANCA) with a cytoplasmic pattern are strongly suggestive of Wegener’s granulomatosis or microscopic polyangiitis: the perinuclear (P-ANCA) pattern is less discriminatory.
The presence of specific precipitins to organic antigens is often diagnostically useful in hypersensitivity pneumonitis. However, positive precipitins are not diagnostic in isolation, confirming only the presence of immunological recognition. Avian precipitins, for example, are often present in healthy pigeon breeders. Moreover, the absence of precipitins does not exclude a diagnosis of hypersensitivity pneumonitis: avian proteins causing disease in an individual may be species specific or even specific to a single bird.
High-resolution CT provides a three-dimensional anatomical reconstruction of both lungs, with careful evaluation of the distribution and pattern of disease resulting in improved diagnostic accuracy compared to chest radiography. A number of high-resolution CT patterns can now be viewed as pathognomonic of particular diseases (Bullet list 4), and high-resolution CT is often diagnostic in other patients when the findings are integrated with clinical information. A detailed review of the rapidly enlarging high-resolution CT literature lies beyond the scope of this chapter and the reader is referred to sources listed in the ‘Further reading’ section.
High-resolution CT is much more sensitive than chest radiography, leading to the earlier diagnosis of limited disease. While this is sometimes highly advantageous, the sensitivity of high-resolution CT can cause problems. The detection of limited abnormalities in cigarette smokers, or when high-resolution CT is used as a screening tool in rheumatological disorders, sometimes leads to difficulty in assigning clinical significance to the findings. In this context pulmonary function tests have a pivotal role, but they are sometimes difficult to interpret when functional impairment is minor, due to the wide normal range: an FVC 75% of predicted can equally represent a minor fall or a major reduction from premorbid values of 80% and 120% of predicted, respectively. Absence of oxygen desaturation on maximal exercise testing is especially helpful in this scenario in excluding clinically significant disease.
Bullet list 4 Diffuse parenchymal lung disease with characteristic high-resolution CT features
- ◆ Cryptogenic fibrosing alveolitis
- ◆ Extrinsic allergic alveolitis
- ◆ Sarcoidosis
- ◆ Langerhans’ cell histiocytosis
- ◆ Lymphangioleiomyomatosis
- ◆ Alveolar proteinosis
A simple high-resolution CT diagnostic algorithm can be usefully be applied to apparently idiopathic diffuse lung disease. Confirmation of fibrosing disease is readily demonstrated by the presence of reticular abnormalities, anatomical distortion or, when ground-glass attenuation predominates, traction bronchiectasis. The essential preliminary question is whether high-resolution CT appearances are typical of IPF (i.e. predominantly basal reticular abnormalities, with or without honeycombing, with little ground-glass attenuation). If not, it is appropriate to look for the high-resolution CT features of fibrotic NSIP, sarcoidosis, hypersensitivity pneumonitis, and organizing pneumonia with fibrosis, disorders which—along with IPF—account for up to 95% of diagnoses in apparently idiopathic disease. When high-resolution CT appearances are not typical of one of these disorders and disease is progressive, IPF with atypical high-resolution CT features is the most frequent diagnosis made at surgical biopsy.
High-resolution CT imaging has a number of other advantages. Even when the high-resolution CT diagnosis is uncertain, signs of fibrosis often make it clear that disease is irreversible. The identification of reversible disease is less straightforward. Prominent ground-glass attenuation often denotes inflammation, but only when there is no admixed reticular pattern or traction bronchiectasis. High-resolution CT is also invaluable in allowing the thoracic surgeon to select optimal sites for biopsy, by which means the full range of morphological abnormalities and disease severity can be sampled. Serial high-resolution CT is sometimes useful in monitoring changes in disease severity, especially when pulmonary function trends are inconclusive, although it should be used for this purpose only in order to cast light on clinically important questions and not performed rigidly by protocol.
Finally, high-resolution CT is often revealing when disease processes are admixed. In rheumatological disorders and in smoking-related disease, patterns of functional impairment are often complex and an assessment of the extent of interstitial disease allows a better understanding of the presence and likely functional impact of emphysema and airway disease. The complications of diffuse lung disease are often disclosed by high-resolution CT. Lung malignancy is increased in prevalence in fibrosing lung disease but can sometimes be difficult to detect on chest radiography when interstitial fibrosis is extensive. Infection is also sometimes masked by extensive disease, and this applies especially to aspergillomas which tend to develop in fibrobullous sarcoidosis.
Bronchoalveolar lavage (BAL)
When first employed, it was hoped that BAL might replace diagnostic surgical biopsy or provide accurate prognostic information, and that serial BAL might disclose important changes in disease activity. These expectations were eventually shown to be baseless and the role of BAL has now been downgraded. However, BAL has an ancillary diagnostic role in diffuse lung diseases and is also sometimes helpful in excluding infection. Granulomatous and drug-induced lung diseases are characterized by an excess of lymphocytes with or without granulocytes. The presence of a BAL lymphocytosis is occasionally pivotal in alerting the clinician to the possibility that a fibrosing process may be due to hypersensitivity pneumonitis or sarcoidosis. BAL can also be diagnostic in some rare lung disorders, including alveolar proteinosis (milky effluent; PAS-positive material), Langerhans’ cell histiocytosis (increased numbers of Langerhans’ cells identified by CD1a staining), alveolar haemorrhage (iron-laden macrophages) and hard metal lung disease (bizarre multinuclear giant cells). By contrast, a BAL neutrophilia is an expected finding when pulmonary fibrosis is moderately extensive and has little diagnostic value. It appears increasing likely, based on recent data, that the observed linkage between disease progression and a BAL neutrophilia in rheumatological disease reflects the presence of more severe disease, which is itself more likely to progress.
BAL is an essential part of the diagnostic algorithm in patients presenting acutely with widespread interstitial abnormalities. Diffuse alveolar haemorrhage does not always manifest with haemoptysis but is readily disclosed by BAL. In patients receiving immunosuppressive drugs, increased treatment may be urgently required in the hope of reversing disease progression, but acute decompensation due to opportunistic infection can be confidently excluded only with BAL.
Assessment of a surgical biopsy offers the important advantage that further investigation is unlikely to clarify the situation and a final diagnosis must now be made, integrating all clinical, radiological, and histological information. A confident diagnosis leads to more confident management, with a more accurate evaluation of the balance of risk and benefit with suggested treatments. Clinicians are better able to inform the patient of the likely natural history and treated course of disease. However, in many patients a firm diagnosis can be made from clinical and high-resolution CT data such that a surgical biopsy is redundant, and in other cases a biopsy is contraindicated by the severity of disease, major comorbidity, or the wishes of the patient.
Transbronchial biopsies are used to diagnose some airway-centred disorders. In sarcoidosis and lymphangitis carcinomatosis the histological appearances are sufficiently characteristic to allow a confident diagnosis to be made from very small biopsy specimens. However, for most diffuse lung diseases, including the idiopathic interstitial pneumonias, the overall pattern of disease cannot be meaningfully evaluated without a larger surgical biopsy. The acquisition of biopsies from more than one lobar site increases the likelihood of obtaining representative tissue. The limited thoracotomy approach used historically has now been largely supplanted by video-assisted thoracoscopic surgical procedures, which are less invasive, provide equivalently sized samples, and are associated with less morbidity.
The morbidity and mortality associated with diagnostic surgical biopsy are low provided that pulmonary reserve is adequate. However, postoperative mortality increases significantly when disease is extensive and approached 15% in one IPF series in which the average level of functional impairment were severe. Thus, if the D L CO level is less than 30% of predicted, a surgical biopsy should be performed only if considered indispensable. The histological diagnosis is, in any case, less prognostically useful in advanced disease. Mortality is very similar in IPF and fibrotic NSIP when D L CO levels are less than 35%, despite striking differences in survival when disease is less severe.
Key clinical issues
Although a surgical biopsy was once viewed as definitive in diffuse parenchymal lung disease, it is now widely accepted that all clinical, radiological, and histopathological data must be integrated into the final diagnosis. The limitations of a purely histological diagnosis are now better understood. ‘Sampling error’ consists of the acquisition of nonrepresentative tissue, e.g. in some patients with IPF there are lung regions with the histological appearances of fibrotic NSIP, but this finding has no prognostic significance. Sampling error can be minimized by ensuring that large samples are taken, by sampling more than one site, and by selecting the sites of biopsy to sample the full range of disease morphology and severity based on high-resolution CT appearances. However, diagnostic variation between pathologists remains problematic, with less agreement than documented with many clinically useful tests. Moreover, in some cases there is ‘appropriate’ interobserver variation, reflecting the fact that histological appearances occasionally lie intermediate between classical entities. To complicate matters further, the diagnostic significance of a histological pattern is critically dependent upon the clinical context. For example, UIP is the required histological pattern in IPF but has a better outcome when occurring in patients with rheumatological disorders, drug-induced lung disease, or hypersensitivity pneumonitis.
The ‘gold standard’ for diagnosis of diffuse parenchymal lung disease is now a multidisciplinary diagnosis, with participation by clinicians, radiologists, and—when applicable—histopatholologists. As a useful rule of thumb, in nonbiopsied cases the clinical and high-resolution CT evaluation is, on average, equally influential, and careful clinical assessment should not be curtailed because of the ready availability of high-resolution CT. In patients undergoing surgical biopsy, clinical and high-resolution CT findings are usually inconclusive and the histological features tend to carry the most diagnostic weight. However, it is accepted that the final diagnosis will differ from the histological diagnosis in a few patients when all available information is integrated.
Principles of management
The chronic diffuse parenchymal lung diseases can be broadly subclassified into five patterns of longitudinal disease behaviour, based upon cause, severity, the relative degree of inflammation and fibrosis, and observed change in the short term. Each clinical pattern is associated with a separate approach to management.
The schema below is proposed to capture key thought processes and to serve as a rationale for treatment and monitoring decisions. The idiopathic interstitial pneumonias can each be broadly assigned to one clinical pattern or another. In many cases the pattern of disease behaviour is evident at presentation, but in other instances careful short-term observation is highly informative.
This is usually caused by an extrinsic agent (as in drug-induced disease, hypersensitivity penumonitis, and RBILD), but may also be idiopathic as in a subset of patients with sarcoidosis. Disease usually responds to withdrawal of an offending agent, therapy is often unnecessary, and monitoring consists of confirming that disease has regressed.
This is most commonly encountered in sarcoidosis, following drug-induced lung disease, and in patients with formerly active rheumatological disorders. Treatment is not required but monitoring is needed to ensure that disease is truly stable, usually with serial pulmonary function tests until a long-term ‘track record’ of disease stability has been established.
This is often a feature of drug-induced lung disease, and this category also applies to some patients with cryptogenic organizing pneumonia, DIP, hypersensitivity pneumonitis, sarcoidosis, and aggressive inflammatory disease in rheumatological disease. High-dose therapy is usual, often with corticosteroids, and the short term response is quantified, often at 4 to 6 weeks. Once inflammation is controlled and the residual level of functional impairment has been quantified, treatment is gradually reduced with monitoring centred around serial pulmonary function tests, usually at 3- to 4-monthly intervals. In this way, the minimum dose of immunosuppression required to maintain control of disease is established.
This is frequently seen in sarcoidosis, hypersensitivity pneumonitis, rheumatological conditions, and in many patients with fibrotic NSIP. In this scenario long-term therapy is often required, and long-term monitoring with serial pulmonary function tests—often at increasing time intervals—is needed to ensure that stabilization has been achieved and maintained. Aggressive initial treatment is usually warranted to ensure optimal control of disease activity.
This is the hallmark of IPF, but an IPF-like course is sometimes observed in idiopathic fibrotic NSIP, rheumatological disease, and in a small subset of patients with chronic hypersensitivity pneumonitis. Long term treatment may slow disease progression, as suggested by a recent trial of anti-oxidant therapy in IPF. However, in known IPF, initial high-dose therapy achieves nothing and may cause unnecessary drug toxicity. The early realization that fibrotic disease is relentlessly progressive, either because IPF is diagnosed or because disease continues to progress despite treatment, is especially important when lung transplantation is realistic. Monitoring is performed to quantify disease progression, usually at three to four monthly intervals.
When should a surgical biopsy be performed?
A broad classification of disease behaviour also serves as a rationalization of when to recommend diagnostic surgical biopsy. This is usually warranted, disease severity and comorbidity permitting, when the underlying diagnosis is uncertain and the clinician is unable to assign likely disease behaviour such that management is difficult. However, if the diagnosis is uncertain but the pattern of disease behaviour is already clear, a diagnostic biopsy is much less likely to inform management. For example, when it is already known from previous investigations that fibrotic abnormalities are long-standing and wholly stable, a histological diagnosis is unlikely to change management.
When considering whether or not to recommend biopsy, it is useful to construct scenarios in which long-term management may differ significantly depending upon histological findings. It is important to reach an early decision. The empirical approach of initiating treatment, with recourse to biopsy if the response is unsatisfactory, has serious flaws. Modification of the histological appearances by treatment may make diagnosis more difficult and, more importantly, deterioration during the interim period may make the biopsy more hazardous, as well as increasing the likelihood of side effects to treatment, including postoperative infection and impaired wound healing. Thus, if biopsy is to be performed, the best time is shortly after presentation before treatment is instituted.