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Diffuse parenchymal lung disease
SYSTEMIC AND PARENCHYMAL LUNG DISEASES
Diffuse parenchymal lung disease
some form of interstitial lung disorder and that up to 15% of respiratory clinic caseload is due to DPLD. It is likely that a general practitioner will see one or two cases of suspected DPLD per year. A range of varied conditions give rise to DPLD, including diseases with a well-defined aetiology (e.g. asbestosis, druginduced lung disease), granulomatous diseases (e.g. sarcoidosis, hypersensitivity pneumonitis (HP)), connective tissue diseases (e.g. rheumatoid arthritis, scleroderma) and diseases of unknown aetiology (e.g. IPF). Figure 1 provides a schematic for categorizing the DPLDs. A detailed discussion of all the separate DPLDs is beyond the scope of this article, which will address the investigation and diagnosis of patients with suspected DPLD and provide a brief outline of the pathogenesis, typical presentation and treatment of those more frequently encountered.
Toby M Maher
Abstract The diffuse parenchymal lung diseases (DPLDs) are a group of over 200 diverse conditions all of which affect either the alveolar space or the pulmonary interstitium. All DPLDs typically present with dyspnoea and diffuse infiltrates on chest X-ray. Achieving an exact diagnosis is frequently challenging and requires a careful history, detailed examination and assimilation of appropriate investigations. Key amongst these is high-resolution CT (HRCT) scanning. The recognition that many of the DPLDs have distinctive HRCT appearances has greatly reduced the need for lung biopsy. Understanding of the natural history of many of the DPLDs has also been greatly improved by insights derived from HRCT. Furthermore, novel treatments have been developed over the last decade and these may improve the outcome of many of the interstitial lung diseases. This article covers the key aspects to be considered in the history, examination and investigation of patients with suspected DPLD. Also covered is the classification of the idiopathic interstitial pneumonias with particular attention to pathogenesis, diagnosis and management and a brief summary of some rarer DPLDs.
Diagnosis The usual starting point for considering a diagnosis of DPLD is a patient presenting with breathlessness and diffuse shadowing on the chest X-ray. In this context it is important to exclude infection (especially in immunocompromised individuals), malignancy (particularly lymphangitis carcinomatosa) and pulmonary oedema before embarking on a full DPLD diagnostic work-up.
History General For patients with suspected DPLD, a detailed clinical history often provides important clues to diagnosis and is crucial in guiding the choice of subsequent investigations. Almost all patients present with breathlessness, most often insidious in onset and progressively worsening, but in some cases acute (e.g. acute interstitial pneumonia (AIP), hypersensitivity pneumonitis (HP)) or episodic (e.g. eosinophilic pneumonia). Cough is a common associated symptom. The onset of some DPLDs (e.g. IPF, sarcoidosis, AIP) is often heralded by a viral-like prodromal illness characterized by low-grade fever, malaise, lethargy and sweats.
Keywords idiopathic pulmonary fibrosis; interstitial lung disease; Langerhans cell histiocytosis; organizing pneumonia; sarcoidosis
Introduction The term diffuse parenchymal lung disease (DPLD) describes a diverse range of conditions affecting the pulmonary interstitium, which is the space bounded by the alveolar epithelium and the pulmonary capillary bed and including the peri-vascular and perilymphatic tissues. Also included within the term are alveolar filling diseases as these share a similar clinical and radiographic presentation. Well over 200 entities falling within the spectrum of the DPLDs have been described. These range from the relatively common, such as idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both with an annual incidence of 5e10 per 100,000 people per year, through to the exceptionally rare. As a collective group, the DPLDs are an important cause of morbidity and mortality. It is estimated that in excess of 50 million people worldwide suffer with
Past medical history A number of systemic conditions are associated with DPLD (e.g. rheumatoid arthritis and connective tissue disease). Radiotherapy for breast or thoracic malignancy can result in pulmonary fibrosis. Patients with a past history of granulomatous disease (e.g. ulcerative colitis) are at increased risk of developing sarcoidosis. Drug history A detailed drug history including prescription drugs, over-thecounter medication, herbal or homeopathic remedies, and illicit substances is important in the assessment of patients with DPLD. Numerous drugs have been reported to cause a variety of parenchymal lung diseases, ranging from acute pulmonary oedema through to eosinophilic pneumonia and diffuse fibrosis. The website www.pneumotox.com is an invaluable resource for investigating possible drug-induced lung disease.
Toby M Maher MB MSc PhD MRCP is a Consultant Respiratory Physician at the Royal Brompton Hospital and an Honorary Senior Lecturer at Imperial College, London. He qualified at Southampton University and undertook his PhD at University College London. His research interests include: biomarker discovery, clinical trials in fibrosing lung disease and studying the role of prostanoids, apoptosis and cellular senescence in the pathogenesis of IPF. Conflicts of interest: Dr Maher has received consultancy fees from GSK, Actelion, Boehringer Ingelheim and Philips Respironics. He is in receipt of an unrestricted academicindustry research grant from GSK.
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Systems review Specific attention should be paid to eliciting history suggestive of systemic disease. Raynaud’s phenomenon or arthropathy suggest
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A schematic for the general classification of the diffuse parenchymal lung diseases
Diffuse parenchymal lung disease (DPLD)
Granulomatous
Inhalational
e.g. sarcoidosis
e.g. asbestosis, hypersensitivity pneumonitis, silicosis
Connective tissue diseaseassociated DPLD
Idiopathic interstitial pneumonias
e.g. rheumatoid disease, scleroderma
Idiopathic pulmonary fibrosis (IPF)
Drug-induced DPLDs
Other diseaserelated DPLDs
e.g. bleomycin, amiodarone
e.g. systemic vasculitidies, reno-pulmonary syndromes
Other DPLDs e.g. lymphangioleiomyomatosis, Langerhans cell histiocytosis, alveolar proteinosis
Non-IPF idiopathic interstitial pneumonia
Non-specific interstitial pneumonia
Acute interstitial pneumonia
Respiratory bronchiolitis – interstitial lung disease
Desquamative interstitial pneumonia
Lymphocytic interstitial pneumonia
Cryptogenic organizing pneumonia
Figure 1
a connective tissue disease-related DPLD. Extra-thoracic symptoms may occur in sarcoidosis, systemic vasculitides or renopulmonary syndromes.
implicated in the pathogenesis of Langerhans cell histiocytosis (LCH), desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-interstitial lung disease (RB-ILD). The majority of patients with IPF are ex-smokers.
Family history Between 2 and 5% of cases of IPF occur in families. Familial IPF tends to occur at a younger age than sporadic IPF and may, in rare cases, affect children.
Examination General Finger clubbing is seen in over half of patients with IPF and is also common in fibrotic HP and DIP but is seen less in other DPLDs and is very uncommon in sarcoidosis. Palpable lymphadenopathy is unusual except in sarcoidosis.
Social history A full occupational history can provide important clues as to potential pneumotoxic exposures. The pneumoconioses are now uncommon in the UK. Occupations at greatest risk of asbestos exposure include metal plate workers, shipyard workers, vehicle body builders (including rail vehicles), plumbers, carpenters and electricians. Other occupations at risk of mineral dust exposure include miners and stone-masons. Exposure to beryllium (used in nuclear, aerospace and electronics industries) may cause a chronic, systemic granulomatous condition indistinguishable clinically from sarcoidosis. Patients should be questioned about exposure to allergens associated with hypersensitivity pneumonitis, especially birds (goose-down bedding can be a source of exposure to avian precipitins), hay and moulds. Cigarette smoking is strongly
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Respiratory In advanced DPLD, patients may be hypoxic, cyanosed and/or tachypnoeic. Respiratory examination typically discloses fine end-inspiratory crackles especially in IPF. High-pitched squawks are often heard in HP. In sarcoidosis, even with marked radiographic evidence of fibrosis, auscultation is frequently normal. More unusual findings in DPLD are of pneumothorax (especially in LCH and lymphangioleiomyomatosis (LAM)) or pleural effusion (infrequent in sarcoidosis and ChurgeStrauss syndrome and more common in rheumatoid disease and systemic lupus erythematosus).
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Cardiac Cardiovascular examination should aim to exclude pulmonary hypertension. A loud second pulmonary heart sound is an early sign and patients with more advanced disease may have a raised jugular venous pressure, pansystolic murmur of tricuspid regurgitation and peripheral oedema.
Typical high-resolution computed tomography (HRCT) appearances of the more frequently occurring diffuse parenchymal lung diseases
Other systems The remainder of the clinical examination should be directed at identifying systemic disease associated with DPLD (e.g. cutaneous or ocular lesions in sarcoidosis, joint involvement and Raynaud’s phenomenon in connective tissue disease, and cutaneous, neurological and cardiac involvement in systemic vasculitides).
Disease Idiopathic pulmonary fibrosis
Bilateral, predominantly basal and subpleural reticulation associated with traction bronchiectasis and basal honeycombing with minimal ground glass attenuation Non-specific interstitial Bilateral, basal and symmetrical, pneumonia subpleural ground glass attenuation. May be associated reticulation and only rarely honeycomb change Acute interstitial Patchy consolidation predominantly pneumonia affecting dependent areas. Associated patchy ground glass change with bronchial dilatation and architectural distortion Cryptogenic organizing Airspace consolidation e often multipneumonia focal and associated with ground glass attenuation Desquamative interstitial Widespread, patchy ground glass pneumonia attenuation with a basal and peripheral predominance. Frequently associated with reticular change Respiratory bronchiolitis- Centrilobular nodules associated with interstitial lung disease patchy ground glass attenuation and thickening of the peripheral and central airway walls. Patients frequently also have evidence of centrilobular emphysema Diffuse ground glass attenuation that Hypersensitivity may be associated with ill-defined pneumonitis centrilobular nodules and evidence of (acute) mosaic attenuation Evidence of fibrosis with reticular Hypersensitivity change, traction bronchiectasis and pneumonitis occasional honeycombing. Fibrotic (chronic) change does not tend to show any zonal predominance. In most cases the fibrosis is associated with mosaic attenuation and centrilobular nodules Langerhans cell Multiple irregular cysts with variable histiocytosis wall thickness predominantly located in the upper and mid zones. In early disease, cysts are associated with interstitial nodules Lymphangioleiomyomatosis Multiple thin-walled regular cysts of variable size distributed evenly throughout both lung fields
Investigations Serology Blood tests may occasionally be helpful in diagnosing DPLDs. A peripheral blood eosinophilia may be seen in ChurgeStrauss syndrome and in eosinophilic pneumonia. Serum calcium will be raised in 5e15% of cases of sarcoidosis. Serum angiotensinconverting enzyme (ACE), although lacking sensitivity is, when raised, useful for monitoring disease activity in sarcoidosis. Anti-neutrophil cytoplasmic antibody (ANCA) is raised in a cytoplasmic pattern in Wegener’s granulomatosis and in a peri-nuclear pattern in ChurgeStrauss syndrome. Rheumatoid factor, and an autoimmune profile should be checked for all patients with DPLD of unknown aetiology, as interstitial lung disease is occasionally the initial manifestation of connective tissue disease. Serum precipitins, although lacking in sensitivity and specificity, are occasionally useful in confirming a diagnosis of HP. Inflammatory markers are frequently raised in patients with DPLD. Lung function The majority of fibrotic DPLDs demonstrate a restrictive defect on spirometry, with reduced lung volumes and impaired gas transfer. In patients with co-existent emphysema lung volumes may be preserved. In the absence of emphysema, a mixed obstructive/restrictive defect may be seen in sarcoidosis, LAM, LCH, RB-ILD and HP. Although lung function tests are useful in confirming the presence of DPLD and are invaluable for monitoring disease progression, they do not discriminate between the different DPLDs. Radiology Since the advent of HRCT the chest X-ray has been of diminishing value in diagnosing specific DPLDs. The typical chest X-ray will show bilateral interstitial shadowing, often with reticulo-nodular change and loss of lung volumes. The distribution of changes provides some clues to potential diagnosis (upper zone e HP, ankylosing spondylitis, radiation fibrosis, sarcoidosis; lower zone e IPF, non-specific interstitial pneumonia (NSIP), druginduced DPLD, connective tissue disease-associated DPLD, asbestosis). A number of the DPLDs have a characteristic HRCT appearance (Table 1). HRCT is therefore important in the diagnostic work-up for suspected DPLD. In a significant proportion of patients HRCT appearance enables a confident diagnosis to be made, thereby obviating the need for biopsy (Figure 2).
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Typical HRCT appearance
Table 1
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SYSTEMIC AND PARENCHYMAL LUNG DISEASES
Examples of characteristic scans in diffuse parenchymal lung disease Traction bronchiectasis
aa
Honeycomb change Heart
Right
Left Aorta
Sub pleural reticular change b
R Lower lobe Thoracic bronchus vertebra
Multiple small cysts associated with parenchymal nodules throughout Right both lungs lung
L Lower lobe Traction bronchiectasis bronchus
Heart
Left lung
Right main bronchus
Thoracic vertebra
Left main bronchus Oesophagus
cc Oblique fissure
Heart Aorta Right lung
Left lung Blood vessels
Blood vessels dd
Multiple areas of consolidation
Remaining lung tissue
Multiple thin walled cysts throughout both lungs
Heart Right lung Air bronchogram
Left lung Aorta
Thoracic vertebra (a) A 65-year-old man with idiopathic pulmonary fibrosis. Scan shows bilateral, subpleural honeycomb change with marked traction bronchiectasis but minimal ground glass attenuation. (b) A 40-year-old man with early Langerhans cell histiocytosis. Scan shows multiple small cysts associated with marked parenchymal nodularity. (c) A 44-year-old female with advanced lymphangioleiomyomatosis. Scan demonstrates multiple thin-walled cystic lesions with destruction of the pulmonary parenchyma. (d) A CT scan of a 61-year-old male with organizing pneumonia showing patchy, peripheral, multi-focal consolidation with air bronchograms.
Figure 2
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Typical changes seen in broncho-alveolar lavage fluid cell differential
Disease IPF NSIP COP Sarcoidosis Hypersensitivity pneumonitis AIP Pneumoconiosis Eosinophilic pneumonia Drug-induced DPLD
Macrophages
Lymphocytes
Eosinophils
Neutrophils
Foamy appearance
[ [ [[ [[ [[[ [ [ [ [[
[ [ [ / [ [ [ [[ [[
[[ [[ [ / / [[ / / [
Inclusion particles Foamy appearance
AIP, acute interstitial pneumonia; COP, cryptogenic organizing pneumonia; DPLD, diffuse parenchymal lung disease; IPF, idiopathic pulmonary fibrosis; NSIP, non-specific interstitial pneumonia.
Table 2
Histology Histological diagnosis remains the gold standard for diagnosing diffuse parenchymal lung disease. Depending on the suspected diagnosis, tissue samples can be obtained either endobronchially (e.g. sarcoidosis), transbronchially (e.g. sarcoidosis, amyloid, cryptogenic organizing pneumonia (COP)) or surgically, by open biopsy or more usually by video-assisted thoracoscopic surgery (VATS).
aberrant wound-healing response following injury or injuries to the lung in susceptible individuals.3,4 IPF presents typically with progressive breathlessness. Patients often have finger clubbing and invariably have fine bibasal end-inspiratory crackles. In advanced disease, secondary pulmonary hypertension frequently develops. The combination of appropriate clinical history and HRCT changes (Table 1) enables a diagnosis of IPF to be made without biopsy in about 50% of cases. The histological lesion of IPF is usual interstitial pneumonia (UIP (Figure 3)). The aim of treatment in IPF is to prevent disease progression. The last decade has seen a rapid increase in clinical trials in IPF. Pirfenidone, first licensed in Europe for IPF treatment in 2011, is a novel compound with anti-fibrotic and antioxidant actions and pivotal phase III studies have found slowed progression of disease in mild to moderate IPF.5 In some individuals, use of pirfenidone is limited by adverse effects, including hepatotoxicity, photosensitive rashes and gastro-intestinal upset. The only other treatment to show an effect in IPF in a randomized, double-blind trial has been the antioxidant acetylcysteine (600 mg three times daily).6 However, a recent phase II trial of a tyrosine kinase inhibitor, BIBF 1120, has shown promising results and, subject to the outcome of ongoing phase III trials, this may become a treatment option for IPF in the future.7 Lung transplantation remains the only effective therapeutic option for patients with advanced IPF. Patients aged under 65 years with a gas transfer below 40% predicted should be offered the option of assessment at a transplant centre. Oxygen should be used for the treatment of hypoxia. There is increasing evidence that treatment of IPF-related pulmonary hypertension improves quality of life and reduces symptoms.8 For patients with end-stage disease palliative treatment of breathlessness is vital.
Other investigations Other possible investigations include bronchoscopy with broncho-alveolar lavage (BAL) to exclude co-existent infection and for analysis of the differential BAL cell count (Table 2). Echocardiography can be used to exclude co-existent pulmonary hypertension, a 6-minute walk provides an indication of prognosis, and gallium scanning is occasionally useful in confirming sarcoidosis. A 24-hour urine collection should be performed in sarcoidosis to exclude hypercalciuria e an often asymptomatic condition that may lead to renal calculi.
Idiopathic interstitial pneumonias The idiopathic interstitial pneumonias (IIPs) are the commonest group of conditions making up the DPLDs. These conditions all formerly fell under the umbrella term of cryptogenic fibrosing alveolitis e presenting as a syndrome of progressive breathlessness with diffuse interstitial infiltrates on chest X-ray and fine end-inspiratory crackles on auscultation. The separate IIPs have widely differing prognoses and distinct radiological and pathological patterns1 (Table 3). IPF is the commonest IIP and is covered in more detail below, together with NSIP, AIP and cryptogenic organizing pneumonia (COP).
Idiopathic pulmonary fibrosis IPF is a devastating, progressive fibrotic lung condition of unknown aetiology. Median survival from diagnosis is 2.8e4 years. Over 4000 people die in the UK each year from IPF and this number has been rising steadily over the last decade.2 The pathogenesis of IPF is complex but is likely to relate to an
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Non-specific interstitial pneumonia (NSIP) Clinically idiopathic NSIP is indistinguishable from IPF, usually presenting with progressive dyspnoea of insidious onset and bibasal, fine end-inspiratory crackles on auscultation. However,
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Key features of the idiopathic interstitial pneumonias as classified by the American Thoracic Society/European Respiratory Society consensus committee
Respiratory bronchiolitis- Desquamative interstitial associated interstitial pneumonia lung disease
Lymphocytic interstitial Cryptogenic organizing pneumonia pneumonia
Histological lesion Key histological features
Usual interstitial pneumonia Patchy, subpleural fibrosis with temporal and spatial heterogeneity. Fibroblastic foci, typically observed at the leading edge of fibrosis
Non-specific interstitial pneumonia Temporally homogeneous fibrosis. Often associated with mild-to-moderate interstitial inflammatory infiltrate
Respiratory bronchiolitis
Desquamative interstitial pneumonia Patchy bronchiolocentric Macrophage accumulation distribution of mild in distal airspaces with fibrosis and submucosal accompanying alveolar lymphocytic infiltrate. septal thickening and Pigmented macrophages inflammation within alveolar ducts
Lymphocytic interstitial pneumonia Dense interstitial lymphoid infiltrate, type II cell hyperplasia and occasional lymphoid follicles
Mean age of onset (years) Potential causes
65
50e55
40e50
40e50
40e50
Viral infection, wood and metal dust. Oxidative damage. Autoimmune Insidious 1:1 Intermediate
Cigarette smoking
Cigarette smoking
Insidious 2:1 Good
Insidious 2:1 Good
Immunodeficiency, lymphoid malignancy, autoimmunity Insidious 1:5 Intermediate
Viral infection, wood and metal dust, oxidative damage Rate of onset Insidious Male:female ratio 3:2 Prognosis Poor Ó 2012 Elsevier Ltd. All rights reserved.
Table 3
Acute interstitial pneumonia
Organizing pneumonia
Diffuse alveolar damage Organizing intra-luminal Initially, temporally fibrosis with patchy uniform with distribution. Underlying alveolar septal lung architecture thickening, preserved airspace filling and hyaline membranes. Later organization and fibrosis 55 50 Viral infection
Sub-acute 1:1 Good
Viral infection, autoimmune, oxidative damage Acute 1:1 Very poor
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Idiopathic pulmonary Non-specific interstitial fibrosis pneumonia
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Clinical classification
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NSIP has a better prognosis than IPF with a median survival from diagnosis of 6e7 years. Radiographically, NSIP is harder to characterize on HRCT than UIP/IPF (Table 1). Because HRCT lacks sensitivity and specificity for diagnosing NSIP, a surgical lung biopsy is frequently required to confirm the diagnosis. The histological pattern of NSIP (Figure 3) is seen in a range of conditions including connective tissue disease-associated DPLD, in some patients following recovery from acute respiratory distress syndrome (ARDS), as a sequela of cryptogenic organizing pneumonia and in some cases of chronic HP. NSIP is also the typical pattern of injury seen following drug-induced pulmonary fibrosis. The finding of NSIP on biopsy should therefore prompt careful exclusion of these conditions. The treatment of idiopathic NSIP is essentially the same as that for IPF. On the basis of the treatment response seen in patients with scleroderma-related NSIP there is some reason to believe that cyclophosphamide (600 mg/m2 i.v. every 3 weeks) may be an effective therapeutic option for progressive NSIP.9 As with IPF, consideration should be given to oxygen therapy, treatment of pulmonary hypertension, symptom palliation and referral for lung transplantation.
Haematoxylin and eosin stained low-power photomicrographs of normal and fibrotic lung tissue a
Alveolar septa
Alveolar airspace
Blood vessels
b
Cryptogenic organizing pneumonia (COP)
Dense fibrosis
Honeycomb lung
Previously also known as bronchiolitis obliterans organizing pneumonia, COP is a disease of unknown aetiology characterized on biopsy by the finding of buds of fibroproliferative tissue within alveolar spaces. The incidence is unknown. Patients typically present with rapidly progressive breathlessness over a 3e4-week period. Constitutional symptoms such as lethargy, cough, loss of appetite, and low-grade fevers are common. Clinical examination may be normal although there may be signs of consolidation, and some patients may have coarse crackles. Plain chest X-ray reveals consolidation that is frequently multi-focal. It is impossible to distinguish radiographically between the consolidation of COP and that caused by infection or malignancy. Fibreoptic bronchoscopy is therefore useful to exclude infection and to obtain trans-bronchial biopsies. When trans-bronchial biopsies are non-diagnostic, surgical biopsy should be considered. Unlike many of the other DPLDs, COP responds well to treatment with corticosteroids.10 Prednisolone is initiated at a dosage of 0.5e1.0 mg/kg and gradually tapered over 6 to 12 months. In most patients this results in full resolution, but up to one-quarter relapse and high-dose prednisolone has to be re-instituted.
Fibroblastic focus
c
Alveolar air space
Area of fibrosis
Alveolar septum thickened by fibrosis
Acute interstitial pneumonia Acute interstitial pneumonia (AIP) is essentially an idiopathic form of acute respiratory distress syndrome (ARDS). It tends to affect individuals in the fourth or fifth decade of life. Patients present with rapidly progressive breathlessness and usually develop respiratory failure within a few weeks. Pathologically, AIP is characterized by diffuse alveolar damage. No specific treatment has been shown to alter disease progression. Typical therapy consists of intravenous methylprednisolone and cyclophosphamide. Despite treatment, prognosis is poor with a greater than 50% mortality rate.
(a) Normal human lung showing regular thin-walled structure of alveoli. (b) Biopsy from a 55-year-old man with idiopathic pulmonary fibrosis shows the characteristic histological lesion of usual interstitial pneumonia (UIP). The section shows gross architectural destruction of the lung with dense fibrosis and areas of active fibroblast proliferation (high-power inset shows a fibroblastic focus – a region of highly proliferative, collagen-producing fibroblasts thought to be the advancing ‘front’ of the fibrotic process. (c) A biopsy specimen from a 49-year-old lady with scleroderma-associated non-specific interstitial pneumonia (NSIP). The section shows marked intralveolar septal thickening due to fibrosis. The histological change of NSIP is much more homogeneous than that seen in UIP (b).
Figure 3
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SYSTEMIC AND PARENCHYMAL LUNG DISEASES
progressive LAM.12 Furthermore, in individuals with chylous complications of LAM, rapamycin reduces chyle accumulation.13 For patients with severe disease, lung transplant should be considered. A
Other DPLDs Hypersensitivity pneumonitis HP (also known as extrinsic allergic alveolitis) is a syndrome caused by repeated exposure to respirable allergens. It may be acute, sub-acute or chronic in presentation. The commonest antigens causing HP in the UK are from birds (pigeons, parakeets and budgerigars) and moulds (e.g. Thermoactinomyces vulgaris e farmer’s lung). The overall incidence of HP is unknown, but it may affect as many as 10% of individuals exposed to high levels of causative antigens. Acute HP typically presents within 4e12 hours of exposure to the relevant antigen with breathlessness and cough associated with flu-like symptoms (chills, fevers and myalgia). If patients are examined during the acute phase, crackles are frequently heard. Chest X-ray shows diffuse ground glass change. Without treatment symptoms typically resolve over a few days. Identification of the causative allergen and subsequent allergen avoidance are crucial. In sub-acute and chronic disease the development of breathlessness is much more insidious and usually progressive. By the time of presentation patients have frequently developed irreversible fibrosis. Treatment consists of allergen avoidance and, in severe or progressive cases, corticosteroids. An immunosuppressant such as azathioprine should be employed as a corticosteroid-sparing agent if prolonged treatment is necessary.
REFERENCES 1 American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165: 277e304. 2 Navaratnam V, Fleming KM, West J, et al. The rising incidence of idiopathic pulmonary fibrosis in the UK. Thorax 2011; 66: 462e7. 3 Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J 2007; 30: 835e9. 4 Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: 136e51. 5 Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760e9. 6 Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353: 2229e42. 7 Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic fibrosis. N Engl J Med 2011; 365: 1079e87. 8 Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363: 620e8. 9 Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: 2655e66. 10 Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d’Etudes et de Recherche sur les Maladles “Orphelines” Pulmonaires (GERM“O”P). Am J Respir Crit Care Med 2000; 162: 571e7. 11 Ng-Cheng-Hin B, O’Hanlon-Brown C, Alifrangis C, Waxman J. Langerhans cell histiocytosis: old disease new treatment. QJM 2011; 104: 89e96. 12 McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595e606. 13 Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 2011; 154: 797e805.
Langerhans cell histiocytosis (LCH) LCH forms part of a spectrum of multi-system disorders. Pulmonary LCH occurs almost exclusively in smokers. It is thought to arise as a consequence of an aberrant immune response to cigarette smoke. LCH is rare with an estimated incidence of one to three cases per million. Up to one-quarter of individuals are detected coincidentally on chest X-ray; the remainder present with cough, exertional dyspnoea or spontaneous pneumothoraces. Examination is frequently normal. Chest X-ray shows diffuse reticulo-nodular change, often with hyper-expanded lungs. The HRCT appearance (Table 1) in combination with the clinical history is frequently sufficient to make the diagnosis. In cases where a biopsy is necessary, histology shows cystic lung destruction and CD1a-positive histiocytes. The most important aspect of management is smoking cessation. Patients with early disease who manage to quit smoking may recover fully. For patients with severe or progressive disease the purine analogue, cladribine, may be effective.11
Lymphangioleiomyomatosis (LAM) LAM is an uncommon cystic lung condition. Sporadic LAM affects only women and usually only those of child-bearing age. LAM also occurs, in both sexes, in association with the autosomal dominant neuro-cutaneous syndrome, tuberous sclerosis. Prevalence is estimated at one per million in the UK. The commonest presentation is progressive breathlessness, but patients can present with spontaneous pneumothorax or chylothorax. LAM is associated with renal angiomyolipoma (in 40e60% of cases) and meningioma (in <2%). HRCT appearance (Table 1) in the appropriate clinical setting is frequently sufficient to confirm the diagnosis. Recent multicentre trials have confirmed that the immunosuppressant rapamycin improves symptoms and lung function in
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Practice points C
C C
C
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A detailed history is critically important in the assessment of suspected diffuse parenchymal lung disease (DPLD) Drugs are an important cause of parenchymal lung disease HRCT is an important tool in the investigation of DPLD and may obviate the need for surgical lung biopsy Pirfenidone, a novel anti-fibrotic agent, has recently been licensed as a treatment for idiopathic pulmonary fibrosis
Ó 2012 Elsevier Ltd. All rights reserved.
Diffuse parenchymal lung disease
some form of interstitial lung disorder and that up to 15% of respiratory clinic caseload is due to DPLD. It is likely that a general practitioner will see one or two cases of suspected DPLD per year. A range of varied conditions give rise to DPLD, including diseases with a well-defined aetiology (e.g. asbestosis, druginduced lung disease), granulomatous diseases (e.g. sarcoidosis, hypersensitivity pneumonitis (HP)), connective tissue diseases (e.g. rheumatoid arthritis, scleroderma) and diseases of unknown aetiology (e.g. IPF). Figure 1 provides a schematic for categorizing the DPLDs. A detailed discussion of all the separate DPLDs is beyond the scope of this article, which will address the investigation and diagnosis of patients with suspected DPLD and provide a brief outline of the pathogenesis, typical presentation and treatment of those more frequently encountered.
Toby M Maher
Abstract The diffuse parenchymal lung diseases (DPLDs) are a group of over 200 diverse conditions all of which affect either the alveolar space or the pulmonary interstitium. All DPLDs typically present with dyspnoea and diffuse infiltrates on chest X-ray. Achieving an exact diagnosis is frequently challenging and requires a careful history, detailed examination and assimilation of appropriate investigations. Key amongst these is high-resolution CT (HRCT) scanning. The recognition that many of the DPLDs have distinctive HRCT appearances has greatly reduced the need for lung biopsy. Understanding of the natural history of many of the DPLDs has also been greatly improved by insights derived from HRCT. Furthermore, novel treatments have been developed over the last decade and these may improve the outcome of many of the interstitial lung diseases. This article covers the key aspects to be considered in the history, examination and investigation of patients with suspected DPLD. Also covered is the classification of the idiopathic interstitial pneumonias with particular attention to pathogenesis, diagnosis and management and a brief summary of some rarer DPLDs.
Diagnosis The usual starting point for considering a diagnosis of DPLD is a patient presenting with breathlessness and diffuse shadowing on the chest X-ray. In this context it is important to exclude infection (especially in immunocompromised individuals), malignancy (particularly lymphangitis carcinomatosa) and pulmonary oedema before embarking on a full DPLD diagnostic work-up.
History General For patients with suspected DPLD, a detailed clinical history often provides important clues to diagnosis and is crucial in guiding the choice of subsequent investigations. Almost all patients present with breathlessness, most often insidious in onset and progressively worsening, but in some cases acute (e.g. acute interstitial pneumonia (AIP), hypersensitivity pneumonitis (HP)) or episodic (e.g. eosinophilic pneumonia). Cough is a common associated symptom. The onset of some DPLDs (e.g. IPF, sarcoidosis, AIP) is often heralded by a viral-like prodromal illness characterized by low-grade fever, malaise, lethargy and sweats.
Keywords idiopathic pulmonary fibrosis; interstitial lung disease; Langerhans cell histiocytosis; organizing pneumonia; sarcoidosis
Introduction The term diffuse parenchymal lung disease (DPLD) describes a diverse range of conditions affecting the pulmonary interstitium, which is the space bounded by the alveolar epithelium and the pulmonary capillary bed and including the peri-vascular and perilymphatic tissues. Also included within the term are alveolar filling diseases as these share a similar clinical and radiographic presentation. Well over 200 entities falling within the spectrum of the DPLDs have been described. These range from the relatively common, such as idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both with an annual incidence of 5e10 per 100,000 people per year, through to the exceptionally rare. As a collective group, the DPLDs are an important cause of morbidity and mortality. It is estimated that in excess of 50 million people worldwide suffer with
Past medical history A number of systemic conditions are associated with DPLD (e.g. rheumatoid arthritis and connective tissue disease). Radiotherapy for breast or thoracic malignancy can result in pulmonary fibrosis. Patients with a past history of granulomatous disease (e.g. ulcerative colitis) are at increased risk of developing sarcoidosis. Drug history A detailed drug history including prescription drugs, over-thecounter medication, herbal or homeopathic remedies, and illicit substances is important in the assessment of patients with DPLD. Numerous drugs have been reported to cause a variety of parenchymal lung diseases, ranging from acute pulmonary oedema through to eosinophilic pneumonia and diffuse fibrosis. The website www.pneumotox.com is an invaluable resource for investigating possible drug-induced lung disease.
Toby M Maher MB MSc PhD MRCP is a Consultant Respiratory Physician at the Royal Brompton Hospital and an Honorary Senior Lecturer at Imperial College, London. He qualified at Southampton University and undertook his PhD at University College London. His research interests include: biomarker discovery, clinical trials in fibrosing lung disease and studying the role of prostanoids, apoptosis and cellular senescence in the pathogenesis of IPF. Conflicts of interest: Dr Maher has received consultancy fees from GSK, Actelion, Boehringer Ingelheim and Philips Respironics. He is in receipt of an unrestricted academicindustry research grant from GSK.
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Systems review Specific attention should be paid to eliciting history suggestive of systemic disease. Raynaud’s phenomenon or arthropathy suggest
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A schematic for the general classification of the diffuse parenchymal lung diseases
Diffuse parenchymal lung disease (DPLD)
Granulomatous
Inhalational
e.g. sarcoidosis
e.g. asbestosis, hypersensitivity pneumonitis, silicosis
Connective tissue diseaseassociated DPLD
Idiopathic interstitial pneumonias
e.g. rheumatoid disease, scleroderma
Idiopathic pulmonary fibrosis (IPF)
Drug-induced DPLDs
Other diseaserelated DPLDs
e.g. bleomycin, amiodarone
e.g. systemic vasculitidies, reno-pulmonary syndromes
Other DPLDs e.g. lymphangioleiomyomatosis, Langerhans cell histiocytosis, alveolar proteinosis
Non-IPF idiopathic interstitial pneumonia
Non-specific interstitial pneumonia
Acute interstitial pneumonia
Respiratory bronchiolitis – interstitial lung disease
Desquamative interstitial pneumonia
Lymphocytic interstitial pneumonia
Cryptogenic organizing pneumonia
Figure 1
a connective tissue disease-related DPLD. Extra-thoracic symptoms may occur in sarcoidosis, systemic vasculitides or renopulmonary syndromes.
implicated in the pathogenesis of Langerhans cell histiocytosis (LCH), desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-interstitial lung disease (RB-ILD). The majority of patients with IPF are ex-smokers.
Family history Between 2 and 5% of cases of IPF occur in families. Familial IPF tends to occur at a younger age than sporadic IPF and may, in rare cases, affect children.
Examination General Finger clubbing is seen in over half of patients with IPF and is also common in fibrotic HP and DIP but is seen less in other DPLDs and is very uncommon in sarcoidosis. Palpable lymphadenopathy is unusual except in sarcoidosis.
Social history A full occupational history can provide important clues as to potential pneumotoxic exposures. The pneumoconioses are now uncommon in the UK. Occupations at greatest risk of asbestos exposure include metal plate workers, shipyard workers, vehicle body builders (including rail vehicles), plumbers, carpenters and electricians. Other occupations at risk of mineral dust exposure include miners and stone-masons. Exposure to beryllium (used in nuclear, aerospace and electronics industries) may cause a chronic, systemic granulomatous condition indistinguishable clinically from sarcoidosis. Patients should be questioned about exposure to allergens associated with hypersensitivity pneumonitis, especially birds (goose-down bedding can be a source of exposure to avian precipitins), hay and moulds. Cigarette smoking is strongly
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Respiratory In advanced DPLD, patients may be hypoxic, cyanosed and/or tachypnoeic. Respiratory examination typically discloses fine end-inspiratory crackles especially in IPF. High-pitched squawks are often heard in HP. In sarcoidosis, even with marked radiographic evidence of fibrosis, auscultation is frequently normal. More unusual findings in DPLD are of pneumothorax (especially in LCH and lymphangioleiomyomatosis (LAM)) or pleural effusion (infrequent in sarcoidosis and ChurgeStrauss syndrome and more common in rheumatoid disease and systemic lupus erythematosus).
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Cardiac Cardiovascular examination should aim to exclude pulmonary hypertension. A loud second pulmonary heart sound is an early sign and patients with more advanced disease may have a raised jugular venous pressure, pansystolic murmur of tricuspid regurgitation and peripheral oedema.
Typical high-resolution computed tomography (HRCT) appearances of the more frequently occurring diffuse parenchymal lung diseases
Other systems The remainder of the clinical examination should be directed at identifying systemic disease associated with DPLD (e.g. cutaneous or ocular lesions in sarcoidosis, joint involvement and Raynaud’s phenomenon in connective tissue disease, and cutaneous, neurological and cardiac involvement in systemic vasculitides).
Disease Idiopathic pulmonary fibrosis
Bilateral, predominantly basal and subpleural reticulation associated with traction bronchiectasis and basal honeycombing with minimal ground glass attenuation Non-specific interstitial Bilateral, basal and symmetrical, pneumonia subpleural ground glass attenuation. May be associated reticulation and only rarely honeycomb change Acute interstitial Patchy consolidation predominantly pneumonia affecting dependent areas. Associated patchy ground glass change with bronchial dilatation and architectural distortion Cryptogenic organizing Airspace consolidation e often multipneumonia focal and associated with ground glass attenuation Desquamative interstitial Widespread, patchy ground glass pneumonia attenuation with a basal and peripheral predominance. Frequently associated with reticular change Respiratory bronchiolitis- Centrilobular nodules associated with interstitial lung disease patchy ground glass attenuation and thickening of the peripheral and central airway walls. Patients frequently also have evidence of centrilobular emphysema Diffuse ground glass attenuation that Hypersensitivity may be associated with ill-defined pneumonitis centrilobular nodules and evidence of (acute) mosaic attenuation Evidence of fibrosis with reticular Hypersensitivity change, traction bronchiectasis and pneumonitis occasional honeycombing. Fibrotic (chronic) change does not tend to show any zonal predominance. In most cases the fibrosis is associated with mosaic attenuation and centrilobular nodules Langerhans cell Multiple irregular cysts with variable histiocytosis wall thickness predominantly located in the upper and mid zones. In early disease, cysts are associated with interstitial nodules Lymphangioleiomyomatosis Multiple thin-walled regular cysts of variable size distributed evenly throughout both lung fields
Investigations Serology Blood tests may occasionally be helpful in diagnosing DPLDs. A peripheral blood eosinophilia may be seen in ChurgeStrauss syndrome and in eosinophilic pneumonia. Serum calcium will be raised in 5e15% of cases of sarcoidosis. Serum angiotensinconverting enzyme (ACE), although lacking sensitivity is, when raised, useful for monitoring disease activity in sarcoidosis. Anti-neutrophil cytoplasmic antibody (ANCA) is raised in a cytoplasmic pattern in Wegener’s granulomatosis and in a peri-nuclear pattern in ChurgeStrauss syndrome. Rheumatoid factor, and an autoimmune profile should be checked for all patients with DPLD of unknown aetiology, as interstitial lung disease is occasionally the initial manifestation of connective tissue disease. Serum precipitins, although lacking in sensitivity and specificity, are occasionally useful in confirming a diagnosis of HP. Inflammatory markers are frequently raised in patients with DPLD. Lung function The majority of fibrotic DPLDs demonstrate a restrictive defect on spirometry, with reduced lung volumes and impaired gas transfer. In patients with co-existent emphysema lung volumes may be preserved. In the absence of emphysema, a mixed obstructive/restrictive defect may be seen in sarcoidosis, LAM, LCH, RB-ILD and HP. Although lung function tests are useful in confirming the presence of DPLD and are invaluable for monitoring disease progression, they do not discriminate between the different DPLDs. Radiology Since the advent of HRCT the chest X-ray has been of diminishing value in diagnosing specific DPLDs. The typical chest X-ray will show bilateral interstitial shadowing, often with reticulo-nodular change and loss of lung volumes. The distribution of changes provides some clues to potential diagnosis (upper zone e HP, ankylosing spondylitis, radiation fibrosis, sarcoidosis; lower zone e IPF, non-specific interstitial pneumonia (NSIP), druginduced DPLD, connective tissue disease-associated DPLD, asbestosis). A number of the DPLDs have a characteristic HRCT appearance (Table 1). HRCT is therefore important in the diagnostic work-up for suspected DPLD. In a significant proportion of patients HRCT appearance enables a confident diagnosis to be made, thereby obviating the need for biopsy (Figure 2).
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Typical HRCT appearance
Table 1
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Examples of characteristic scans in diffuse parenchymal lung disease Traction bronchiectasis
aa
Honeycomb change Heart
Right
Left Aorta
Sub pleural reticular change b
R Lower lobe Thoracic bronchus vertebra
Multiple small cysts associated with parenchymal nodules throughout Right both lungs lung
L Lower lobe Traction bronchiectasis bronchus
Heart
Left lung
Right main bronchus
Thoracic vertebra
Left main bronchus Oesophagus
cc Oblique fissure
Heart Aorta Right lung
Left lung Blood vessels
Blood vessels dd
Multiple areas of consolidation
Remaining lung tissue
Multiple thin walled cysts throughout both lungs
Heart Right lung Air bronchogram
Left lung Aorta
Thoracic vertebra (a) A 65-year-old man with idiopathic pulmonary fibrosis. Scan shows bilateral, subpleural honeycomb change with marked traction bronchiectasis but minimal ground glass attenuation. (b) A 40-year-old man with early Langerhans cell histiocytosis. Scan shows multiple small cysts associated with marked parenchymal nodularity. (c) A 44-year-old female with advanced lymphangioleiomyomatosis. Scan demonstrates multiple thin-walled cystic lesions with destruction of the pulmonary parenchyma. (d) A CT scan of a 61-year-old male with organizing pneumonia showing patchy, peripheral, multi-focal consolidation with air bronchograms.
Figure 2
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Typical changes seen in broncho-alveolar lavage fluid cell differential
Disease IPF NSIP COP Sarcoidosis Hypersensitivity pneumonitis AIP Pneumoconiosis Eosinophilic pneumonia Drug-induced DPLD
Macrophages
Lymphocytes
Eosinophils
Neutrophils
Foamy appearance
[ [ [[ [[ [[[ [ [ [ [[
[ [ [ / [ [ [ [[ [[
[[ [[ [ / / [[ / / [
Inclusion particles Foamy appearance
AIP, acute interstitial pneumonia; COP, cryptogenic organizing pneumonia; DPLD, diffuse parenchymal lung disease; IPF, idiopathic pulmonary fibrosis; NSIP, non-specific interstitial pneumonia.
Table 2
Histology Histological diagnosis remains the gold standard for diagnosing diffuse parenchymal lung disease. Depending on the suspected diagnosis, tissue samples can be obtained either endobronchially (e.g. sarcoidosis), transbronchially (e.g. sarcoidosis, amyloid, cryptogenic organizing pneumonia (COP)) or surgically, by open biopsy or more usually by video-assisted thoracoscopic surgery (VATS).
aberrant wound-healing response following injury or injuries to the lung in susceptible individuals.3,4 IPF presents typically with progressive breathlessness. Patients often have finger clubbing and invariably have fine bibasal end-inspiratory crackles. In advanced disease, secondary pulmonary hypertension frequently develops. The combination of appropriate clinical history and HRCT changes (Table 1) enables a diagnosis of IPF to be made without biopsy in about 50% of cases. The histological lesion of IPF is usual interstitial pneumonia (UIP (Figure 3)). The aim of treatment in IPF is to prevent disease progression. The last decade has seen a rapid increase in clinical trials in IPF. Pirfenidone, first licensed in Europe for IPF treatment in 2011, is a novel compound with anti-fibrotic and antioxidant actions and pivotal phase III studies have found slowed progression of disease in mild to moderate IPF.5 In some individuals, use of pirfenidone is limited by adverse effects, including hepatotoxicity, photosensitive rashes and gastro-intestinal upset. The only other treatment to show an effect in IPF in a randomized, double-blind trial has been the antioxidant acetylcysteine (600 mg three times daily).6 However, a recent phase II trial of a tyrosine kinase inhibitor, BIBF 1120, has shown promising results and, subject to the outcome of ongoing phase III trials, this may become a treatment option for IPF in the future.7 Lung transplantation remains the only effective therapeutic option for patients with advanced IPF. Patients aged under 65 years with a gas transfer below 40% predicted should be offered the option of assessment at a transplant centre. Oxygen should be used for the treatment of hypoxia. There is increasing evidence that treatment of IPF-related pulmonary hypertension improves quality of life and reduces symptoms.8 For patients with end-stage disease palliative treatment of breathlessness is vital.
Other investigations Other possible investigations include bronchoscopy with broncho-alveolar lavage (BAL) to exclude co-existent infection and for analysis of the differential BAL cell count (Table 2). Echocardiography can be used to exclude co-existent pulmonary hypertension, a 6-minute walk provides an indication of prognosis, and gallium scanning is occasionally useful in confirming sarcoidosis. A 24-hour urine collection should be performed in sarcoidosis to exclude hypercalciuria e an often asymptomatic condition that may lead to renal calculi.
Idiopathic interstitial pneumonias The idiopathic interstitial pneumonias (IIPs) are the commonest group of conditions making up the DPLDs. These conditions all formerly fell under the umbrella term of cryptogenic fibrosing alveolitis e presenting as a syndrome of progressive breathlessness with diffuse interstitial infiltrates on chest X-ray and fine end-inspiratory crackles on auscultation. The separate IIPs have widely differing prognoses and distinct radiological and pathological patterns1 (Table 3). IPF is the commonest IIP and is covered in more detail below, together with NSIP, AIP and cryptogenic organizing pneumonia (COP).
Idiopathic pulmonary fibrosis IPF is a devastating, progressive fibrotic lung condition of unknown aetiology. Median survival from diagnosis is 2.8e4 years. Over 4000 people die in the UK each year from IPF and this number has been rising steadily over the last decade.2 The pathogenesis of IPF is complex but is likely to relate to an
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Non-specific interstitial pneumonia (NSIP) Clinically idiopathic NSIP is indistinguishable from IPF, usually presenting with progressive dyspnoea of insidious onset and bibasal, fine end-inspiratory crackles on auscultation. However,
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Key features of the idiopathic interstitial pneumonias as classified by the American Thoracic Society/European Respiratory Society consensus committee
Respiratory bronchiolitis- Desquamative interstitial associated interstitial pneumonia lung disease
Lymphocytic interstitial Cryptogenic organizing pneumonia pneumonia
Histological lesion Key histological features
Usual interstitial pneumonia Patchy, subpleural fibrosis with temporal and spatial heterogeneity. Fibroblastic foci, typically observed at the leading edge of fibrosis
Non-specific interstitial pneumonia Temporally homogeneous fibrosis. Often associated with mild-to-moderate interstitial inflammatory infiltrate
Respiratory bronchiolitis
Desquamative interstitial pneumonia Patchy bronchiolocentric Macrophage accumulation distribution of mild in distal airspaces with fibrosis and submucosal accompanying alveolar lymphocytic infiltrate. septal thickening and Pigmented macrophages inflammation within alveolar ducts
Lymphocytic interstitial pneumonia Dense interstitial lymphoid infiltrate, type II cell hyperplasia and occasional lymphoid follicles
Mean age of onset (years) Potential causes
65
50e55
40e50
40e50
40e50
Viral infection, wood and metal dust. Oxidative damage. Autoimmune Insidious 1:1 Intermediate
Cigarette smoking
Cigarette smoking
Insidious 2:1 Good
Insidious 2:1 Good
Immunodeficiency, lymphoid malignancy, autoimmunity Insidious 1:5 Intermediate
Viral infection, wood and metal dust, oxidative damage Rate of onset Insidious Male:female ratio 3:2 Prognosis Poor Ó 2012 Elsevier Ltd. All rights reserved.
Table 3
Acute interstitial pneumonia
Organizing pneumonia
Diffuse alveolar damage Organizing intra-luminal Initially, temporally fibrosis with patchy uniform with distribution. Underlying alveolar septal lung architecture thickening, preserved airspace filling and hyaline membranes. Later organization and fibrosis 55 50 Viral infection
Sub-acute 1:1 Good
Viral infection, autoimmune, oxidative damage Acute 1:1 Very poor
SYSTEMIC AND PARENCHYMAL LUNG DISEASES
Idiopathic pulmonary Non-specific interstitial fibrosis pneumonia
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Clinical classification
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NSIP has a better prognosis than IPF with a median survival from diagnosis of 6e7 years. Radiographically, NSIP is harder to characterize on HRCT than UIP/IPF (Table 1). Because HRCT lacks sensitivity and specificity for diagnosing NSIP, a surgical lung biopsy is frequently required to confirm the diagnosis. The histological pattern of NSIP (Figure 3) is seen in a range of conditions including connective tissue disease-associated DPLD, in some patients following recovery from acute respiratory distress syndrome (ARDS), as a sequela of cryptogenic organizing pneumonia and in some cases of chronic HP. NSIP is also the typical pattern of injury seen following drug-induced pulmonary fibrosis. The finding of NSIP on biopsy should therefore prompt careful exclusion of these conditions. The treatment of idiopathic NSIP is essentially the same as that for IPF. On the basis of the treatment response seen in patients with scleroderma-related NSIP there is some reason to believe that cyclophosphamide (600 mg/m2 i.v. every 3 weeks) may be an effective therapeutic option for progressive NSIP.9 As with IPF, consideration should be given to oxygen therapy, treatment of pulmonary hypertension, symptom palliation and referral for lung transplantation.
Haematoxylin and eosin stained low-power photomicrographs of normal and fibrotic lung tissue a
Alveolar septa
Alveolar airspace
Blood vessels
b
Cryptogenic organizing pneumonia (COP)
Dense fibrosis
Honeycomb lung
Previously also known as bronchiolitis obliterans organizing pneumonia, COP is a disease of unknown aetiology characterized on biopsy by the finding of buds of fibroproliferative tissue within alveolar spaces. The incidence is unknown. Patients typically present with rapidly progressive breathlessness over a 3e4-week period. Constitutional symptoms such as lethargy, cough, loss of appetite, and low-grade fevers are common. Clinical examination may be normal although there may be signs of consolidation, and some patients may have coarse crackles. Plain chest X-ray reveals consolidation that is frequently multi-focal. It is impossible to distinguish radiographically between the consolidation of COP and that caused by infection or malignancy. Fibreoptic bronchoscopy is therefore useful to exclude infection and to obtain trans-bronchial biopsies. When trans-bronchial biopsies are non-diagnostic, surgical biopsy should be considered. Unlike many of the other DPLDs, COP responds well to treatment with corticosteroids.10 Prednisolone is initiated at a dosage of 0.5e1.0 mg/kg and gradually tapered over 6 to 12 months. In most patients this results in full resolution, but up to one-quarter relapse and high-dose prednisolone has to be re-instituted.
Fibroblastic focus
c
Alveolar air space
Area of fibrosis
Alveolar septum thickened by fibrosis
Acute interstitial pneumonia Acute interstitial pneumonia (AIP) is essentially an idiopathic form of acute respiratory distress syndrome (ARDS). It tends to affect individuals in the fourth or fifth decade of life. Patients present with rapidly progressive breathlessness and usually develop respiratory failure within a few weeks. Pathologically, AIP is characterized by diffuse alveolar damage. No specific treatment has been shown to alter disease progression. Typical therapy consists of intravenous methylprednisolone and cyclophosphamide. Despite treatment, prognosis is poor with a greater than 50% mortality rate.
(a) Normal human lung showing regular thin-walled structure of alveoli. (b) Biopsy from a 55-year-old man with idiopathic pulmonary fibrosis shows the characteristic histological lesion of usual interstitial pneumonia (UIP). The section shows gross architectural destruction of the lung with dense fibrosis and areas of active fibroblast proliferation (high-power inset shows a fibroblastic focus – a region of highly proliferative, collagen-producing fibroblasts thought to be the advancing ‘front’ of the fibrotic process. (c) A biopsy specimen from a 49-year-old lady with scleroderma-associated non-specific interstitial pneumonia (NSIP). The section shows marked intralveolar septal thickening due to fibrosis. The histological change of NSIP is much more homogeneous than that seen in UIP (b).
Figure 3
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progressive LAM.12 Furthermore, in individuals with chylous complications of LAM, rapamycin reduces chyle accumulation.13 For patients with severe disease, lung transplant should be considered. A
Other DPLDs Hypersensitivity pneumonitis HP (also known as extrinsic allergic alveolitis) is a syndrome caused by repeated exposure to respirable allergens. It may be acute, sub-acute or chronic in presentation. The commonest antigens causing HP in the UK are from birds (pigeons, parakeets and budgerigars) and moulds (e.g. Thermoactinomyces vulgaris e farmer’s lung). The overall incidence of HP is unknown, but it may affect as many as 10% of individuals exposed to high levels of causative antigens. Acute HP typically presents within 4e12 hours of exposure to the relevant antigen with breathlessness and cough associated with flu-like symptoms (chills, fevers and myalgia). If patients are examined during the acute phase, crackles are frequently heard. Chest X-ray shows diffuse ground glass change. Without treatment symptoms typically resolve over a few days. Identification of the causative allergen and subsequent allergen avoidance are crucial. In sub-acute and chronic disease the development of breathlessness is much more insidious and usually progressive. By the time of presentation patients have frequently developed irreversible fibrosis. Treatment consists of allergen avoidance and, in severe or progressive cases, corticosteroids. An immunosuppressant such as azathioprine should be employed as a corticosteroid-sparing agent if prolonged treatment is necessary.
REFERENCES 1 American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165: 277e304. 2 Navaratnam V, Fleming KM, West J, et al. The rising incidence of idiopathic pulmonary fibrosis in the UK. Thorax 2011; 66: 462e7. 3 Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J 2007; 30: 835e9. 4 Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: 136e51. 5 Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760e9. 6 Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353: 2229e42. 7 Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic fibrosis. N Engl J Med 2011; 365: 1079e87. 8 Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363: 620e8. 9 Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: 2655e66. 10 Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d’Etudes et de Recherche sur les Maladles “Orphelines” Pulmonaires (GERM“O”P). Am J Respir Crit Care Med 2000; 162: 571e7. 11 Ng-Cheng-Hin B, O’Hanlon-Brown C, Alifrangis C, Waxman J. Langerhans cell histiocytosis: old disease new treatment. QJM 2011; 104: 89e96. 12 McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595e606. 13 Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 2011; 154: 797e805.
Langerhans cell histiocytosis (LCH) LCH forms part of a spectrum of multi-system disorders. Pulmonary LCH occurs almost exclusively in smokers. It is thought to arise as a consequence of an aberrant immune response to cigarette smoke. LCH is rare with an estimated incidence of one to three cases per million. Up to one-quarter of individuals are detected coincidentally on chest X-ray; the remainder present with cough, exertional dyspnoea or spontaneous pneumothoraces. Examination is frequently normal. Chest X-ray shows diffuse reticulo-nodular change, often with hyper-expanded lungs. The HRCT appearance (Table 1) in combination with the clinical history is frequently sufficient to make the diagnosis. In cases where a biopsy is necessary, histology shows cystic lung destruction and CD1a-positive histiocytes. The most important aspect of management is smoking cessation. Patients with early disease who manage to quit smoking may recover fully. For patients with severe or progressive disease the purine analogue, cladribine, may be effective.11
Lymphangioleiomyomatosis (LAM) LAM is an uncommon cystic lung condition. Sporadic LAM affects only women and usually only those of child-bearing age. LAM also occurs, in both sexes, in association with the autosomal dominant neuro-cutaneous syndrome, tuberous sclerosis. Prevalence is estimated at one per million in the UK. The commonest presentation is progressive breathlessness, but patients can present with spontaneous pneumothorax or chylothorax. LAM is associated with renal angiomyolipoma (in 40e60% of cases) and meningioma (in <2%). HRCT appearance (Table 1) in the appropriate clinical setting is frequently sufficient to confirm the diagnosis. Recent multicentre trials have confirmed that the immunosuppressant rapamycin improves symptoms and lung function in
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Practice points C
C C
C
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A detailed history is critically important in the assessment of suspected diffuse parenchymal lung disease (DPLD) Drugs are an important cause of parenchymal lung disease HRCT is an important tool in the investigation of DPLD and may obviate the need for surgical lung biopsy Pirfenidone, a novel anti-fibrotic agent, has recently been licensed as a treatment for idiopathic pulmonary fibrosis
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