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Idiopathic interstitial pneumonias 

Idiopathic interstitial pneumonias
Chapter:
Idiopathic interstitial pneumonias
Author(s):

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

DOI:
10.1093/med/9780198703860.003.0030
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date: 26 October 2021

Overview

Definition

The idiopathic interstitial pneumonias (IIPs) comprise a group of diffuse lung diseases of unknown aetiology that primarily involve the pulmonary interstitium—the area between the alveolar epithelium and capillary endothelium, as well as the septal and bronchovascular tissues that make up the fibrous framework of the lung. These primarily interstitial processes, however, frequently also involve the airways, vasculature, and alveolar airspaces. The underlying pathological process is one of varying degrees of inflammation and fibrosis.

The terminology used to describe the IIPs may be confusing; these conditions have been subject to much reclassification, reflecting the lack of understanding of their underlying aetiology and pathogenesis. Idiopathic pulmonary fibrosis (IPF; previously termed cryptogenic fibrosing alveolitis) is the commonest IIP and is characterized by the radiological and histological pattern of usual interstitial pneumonia (UIP). The other IIPs are distinct disease entities and are all rare. They all represent a subgroup of interstitial (or diffuse parenchymal) lung diseases.

Diagnosis

Made from a multidisciplinary approach, taking into account the combination of clinical, HRCT, and histological features—distinguish from other causes of diffuse lung disease (see Idiopathic interstitial pneumonias p. [link]). Histological patterns are often considered to be the most specific but must be interpreted in the context of clinical and radiological features. Surgical lung biopsy is recommended for many cases of suspected IIP, with the exception of patients exhibiting typical clinical and HRCT features of IPF. TBBs have a very limited role due to the generally patchy distribution of the IIPs, although they may be useful in the diagnosis of acute interstitial pneumonitis (AIP) and organizing pneumonia (OP), as well as the exclusion of other causes of diffuse lung disease (e.g. sarcoidosis).

The conditions currently included within the classification of IIPs, together with their key clinical, imaging, and histological features and prognosis, are presented in Table 30.1 (see Idiopathic interstitial pneumonias p. [link]) (in order of frequency) and discussed in detail in the remainder of this chapter.

Table 30.1 Idiopathic interstitial pneumonias: summary of key features

Idiopathic pulmonary fibrosis (IPF) (previously cryptogenic fibrosing alveolitis (CFA))

  • Onset Over months to years

  • HRCT Fibrosis, honeycombing, subpleural, basal distribution, minimal ground glass

  • Histology Usual interstitial pneumonia (UIP): areas of interstitial fibrosis (made up of foci of proliferating fibroblasts) interspersed with normal lung (temporal and spatial heterogeneity), minimal inflammation

  • Prognosis Poor

Non-specific interstitial pneumonia (NSIP)

  • Onset Over months to years

  • HRCT Ground glass, fine reticulation, often basal distribution, minimal honeycombing

  • Histology Varying degrees of inflammation and fibrosis, more uniform appearance than UIP

  • Prognosis Variable, can be good

Cryptogenic organizing pneumonia (COP) (previously idiopathic bronchiolitis obliterans organizing pneumonia, BOOP)

  • Onset Over months

  • HRCT Areas of consolidation, basal, subpleural, peribronchial predominance

  • Histology Alveolar spaces ‘plugged’ with granulation tissue ± extension into bronchioles

  • Prognosis Generally good

Acute interstitial pneumonia (AIP)

  • Many similarities to ARDS

  • Onset Over days

  • HRCT Diffuse ground-glass and patchy consolidation

  • Histology Diffuse alveolar damage: interstitial oedema, intra-alveolar hyaline membranes, followed by fibroblast proliferation and interstitial fibrosis

  • Prognosis Poor

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)

  • Onset Over years

  • Symptoms usually mild

  • HRCT Centrilobular nodules, ground glass, thick-walled airways

  • Histology Pigmented macrophages in bronchioles

  • Prognosis Good

Desquamative interstitial pneumonia (DIP)

  • Onset Over weeks to months

  • HRCT Ground glass

  • Histology Pigmented macrophages in alveolar airspaces (perhaps a more extensive form of RB-ILD), temporally uniform appearance

  • Prognosis Good

Lymphoid interstitial pneumonia (LIP)

  • Onset Over years

  • HRCT Ground glass, often reticulation, cysts

  • Histology Diffuse interstitial lymphoid infiltrates

  • Prognosis Variable

Further information

British Thoracic Society. Interstitial lung disease guideline. Thorax 2008;63(suppl. V):v1–58.Find this resource:

Idiopathic pulmonary fibrosis (IPF): diagnosis

Definition

Chronic interstitial pneumonia of unknown cause characterized histologically by temporal and spatial heterogeneity, with areas of fibrosis and architectural distortion interspersed with areas of normal lung. This occurs as different areas of lung are in varying stages of evolution of the pathological process. The term UIP refers to the radiological (HRCT) and histological appearance of IPF (previously known as CFA). Note that the UIP pattern is non-specific and can be seen in other conditions, e.g. connective tissue disease, asbestosis.

Epidemiology

Prevalence figures vary from 6 to 14/100, 000, although prevalence may be 175/100, 000 in patients >75 years old. Slightly more common in ♂. Median age at presentation 66. Familial form well described but very rare.

Causes and pathophysiology

The development of fibrosis was previously thought to reflect a response to chronic inflammation, although this has been questioned in light of the observations that inflammation is not a major feature of pathological specimens and that responses to ‘anti-inflammatory’ treatment with steroids are poor. An alternative, currently favoured theory is that repeated alveolar epithelial injury leads directly to aberrant wound healing, with activation of mesenchymal cells and the formation of fibroblastic and myofibroblastic foci that secrete excessive extracellular matrix, primarily collagens. The nature of the lung injury remains obscure; postulated triggers include inhalation of metal dust and wood dust, smoking, gastro-oesophageal reflux, or exposure to herpesviruses. Cytokine production (e.g. plasminogen activator inhibitors, matrix metalloproteinases, transforming growth factor-β‎) by alveolar epithelial cells may play an important role in the development of fibrosis. Host genetic factors are also likely to be important in the pathogenesis of fibrosis, e.g. MUC5B and ELMOD2 gene polymorphisms and telomerase mutations.

Clinical features

  • Typically presents with gradual-onset exertional breathlessness and cough; average of 9 months of symptoms prior to presentation

  • 5% of patients are said to be asymptomatic, although this is likely to be an underestimate

  • Fine basal late inspiratory crackles

  • Clubbing in up to 50%

  • Cyanosis and cor pulmonale in severe disease.

Investigations

  • Blood tests Raised ESR and CRP and mild anaemia may occur; positive RhF and/or ANA may occur at low titres in the absence of associated connective tissue disease

  • PFTs Typically restrictive pattern with reduced VC and transfer factor; reduced gas transfer with preserved lung volumes is suggestive of PHT or coexisting emphysema. O2 saturations are frequently reduced, particularly on exertion; ABGs may demonstrate type I respiratory failure

  • CXR Peripheral and basal reticular shadowing, may extend to other zones, sometimes with honeycombing; rarely may be normal

  • HRCT Features include bilateral, peripheral, and subpleural reticulation, with honeycombing, traction bronchiectasis, architectural distortion, and minimal or no ground-glass change. Predominantly basal initially, more extensive later in disease course. Extent of disease on CT correlates with physiological impairment. Predominant ground-glass appearance suggests an IIP other than IPF—consider lung biopsy

  • BAL is not routinely required and is rarely helpful. Typically shows neutrophilia, sometimes mild eosinophilia. Marked eosinophilia (>20%) or lymphocytosis (>50%) should raise possibility of alternative diagnosis

  • Lung biopsy (via VATS or thoracotomy) if there is diagnostic doubt

  • Transthoracic echo to estimate the PAP in selected patients.

Histology

UIP, a fibrosing pattern characterized by temporal and spatial heterogeneity; patches of active fibroblastic foci (reflecting acute injury) are interspersed with honeycombing/architectural distortion (reflecting chronic scarring) and areas of normal lung, reflecting varying stages of evolution of the disease process in different areas of lung. Interstitial inflammation is minimal. Significant inter-observer disagreement between expert pathologists regarding the presence of a UIP pattern on lung biopsy has been reported, and an overall diagnosis taking into account clinical, radiological, and histological features is recommended.

Diagnosis

can be confidently made in most cases on the basis of clinical and HRCT findings. Lung biopsy is not generally recommended in patients with typical clinical and HRCT features of IPF but should be considered in the presence of unusual features (e.g. predominant ground glass/nodules/consolidation/upper lobe involvement on HRCT, or young patient). When required, biopsies should be obtained at VATS or thoracotomy; TBBs are not recommended, as they provide smaller samples, which are rarely diagnostic.

Differential diagnosis

  • LVF (a common clinical misdiagnosis in IPF, and patients are often prescribed inappropriate diuretics)

  • Fibrotic NSIP and other IIPs

  • Asbestosis (may mimic clinically and radiologically, with UIP pattern on histology; occupational history and presence of pleural plaques may suggest this diagnosis)

  • Connective tissue disease (may mimic clinically and radiologically, with UIP pattern on histology—particularly in RA; lung involvement may precede extrapulmonary manifestations of disease)

  • Chronic HP (suggested by typically upper/mid-zone predominance, micronodules, ground glass, areas of reduced attenuation, lymphocytic BAL fluid; uncommonly, it may be associated with a UIP pattern)

  • Chronic sarcoidosis

  • Drug-induced lung disease (refer to Idiopathic interstitial pneumonias http://www.pneumotox.com).

IPF: management

Clinical trials of therapy

in IPF are particularly challenging. Older studies were hindered by inclusion of a heterogeneous patient group, but, even within groups of patients with well-defined IPF, there remains significant heterogeneity in clinical course. Furthermore, some relatively recent large studies of IPF have been poorly designed, e.g. failing to include a placebo group. There is ongoing debate as to optimal trial design and end points, including the definition of minimally important clinical difference in FVC.

Drug treatments that are not recommended, based on previous studies, include: corticosteroid monotherapy, combination ‘triple therapy’ (with prednisolone, azathioprine, and acetylcysteine), azathioprine, cyclophosphamide, colchicine, ciclosporin, imatinib, interferon gamma-1b (INSPIRE study), bosentan (BUILD-3 study), ambrisentan, etanercept, and warfarin. Specific points of note from these studies include:

  • Prior to the reclassification of IIPs, studies suggested that corticosteroids might improve lung function and symptoms. However, these studies almost certainly included patients with conditions other than IPF that are associated with a better treatment response and prognosis (e.g. NSIP)

  • Combination of oral prednisolone, azathioprine, and acetylcysteine was initially reported to confer a small improvement in lung function when compared with prednisolone and azathioprine alone (IFIGENIA trial, 2005), and, despite the lack of a placebo arm, this study led to widespread use of such ‘triple therapy’. Interim analysis of the PANTHER-IPF study in 2012 demonstrated that this combination was, however, associated with higher mortality and hospitalization rates than placebo, and consequently the use of azathioprine or triple therapy should be avoided

  • Although a small, open-label, placebo-controlled study suggested a possible survival benefit from anticoagulation, a subsequent study (ACE-IPF trial, 2012) reported an increased mortality and serious adverse event rate with warfarin; anticoagulation is not recommended.

Management

Treatment options should be considered in the context of the individual patient’s clinical condition, comorbidity, and wishes, particularly in view of the often unpredictable disease course, unknown efficacy of treatment, and high frequency of serious side effects. Principles of treatment are as follows:

  • Supportive treatment Consider use of home O2 concentrator if limited by breathlessness and persistent resting PaO2 <7.3kPa or <8kPa in the setting of clinical features of PHT. Use of ambulatory O2 may improve exercise tolerance. Encourage pulmonary rehabilitation programme. Gastro-oesophageal reflux disease is common in IPF and may drive lung fibrosis; symptomatic patients should be treated with PPIs ± pro-motility agents (e.g. domperidone); treatment of asymptomatic GORD is recommended in the ATS 2011 guidelines, although there is currently little direct evidence to support this. Cough may be troublesome; consider oral codeine. Opioids are frequently required for palliation of severe breathlessness

  • Drugs should be considered in a closely observed trial of therapy. Patients should be offered inclusion in clinical trials where possible. Monotherapy with oral acetylcysteine (an antioxidant and antifibrotic) at a dose of 600mg tds is of unproven efficacy (the final analysis of the PANTHER-IPF trial should resolve this question) but unlikely to cause significant harm, and it is widely used. Treatment with pirfenidone (antifibrotic, inhibits collagen synthesis, and reduces fibroblast proliferation) has been associated with a small beneficial effect on rate of FVC decline (CAPACITY trials 1 and 2) but is often limited by side effects; it has recently been approved by NICE for use in the UK for patients with FVC between 50% and 80% predicted although should be discontinued if there is evidence of ongoing disease progression (decrease in FVC by 10% or more within 12 months)

  • Studies do not support treatment with steroids in IPF, and NICE guidance recommends that steroids should not be used in an attempt to modify disease progression (except in acute exacerbations where benefit is possible but unproven; see Box 30.1). Despite this, oral prednisolone is still sometimes used in practice, particularly when specifically requested by an informed patient, for attempted symptom control (e.g. cough), or when there is diagnostic uncertainty (may be of benefit in patients with other IIPs misdiagnosed as IPF). Significant side effects of steroid treatment (e.g. hyperglycaemia necessitating insulin, osteoporosis, myopathy, peptic ulcer disease, cataracts, raised intraocular pressure, psychosis) are very common in this patient group

  • Monitoring Disease progression and response to treatment are best assessed by serial measurements of FVC and TLCO; document them at each clinic attendance. Absolute changes in FVC or TLCO of 10–15% or more are considered significant in terms of assessing disease progression. Note that a realistic aim of disease-modifying treatment in IPF is to slow progression, rather than improve lung function. Changes in symptoms, such as exercise tolerance and cough frequency/severity, may also be useful

  • Lung transplantation Patients with IPF are often referred for consideration of transplantation too late, and many die whilst on the waiting list (which is around 12 months in the UK). Guidelines recommend referral of all suitable patients with histological or radiographic evidence of UIP, irrespective of VC and without delaying for trials of treatment. These are not widely applied in the UK, and, in practice, referral is often considered in symptomatic patients aged <65y, with TLCO <40% predicted, fall in FVC ≥10%, or in TLCO ≥15% over 6 months, O2 desaturation <88% on 6min walk, and/or honeycombing on HRCT.

IPF: prognosis and future developments

Prognosis

is highly variable; many patients remain stable or decline slowly over years, whilst a subgroup declines more quickly (‘accelerated variant’, mainly male smokers), and between 5 and 20% experience a very rapid decline after a period of relative stability (‘acute exacerbation’ of IPF; see Box 30.1); prognosis is difficult to predict in individual patients. Mean survival from diagnosis is 2.9–5y. Poor prognostic factors include TLCO <40% at presentation, O2 desaturation <88% during 6min walk, and fall of ≥10% in FVC or ≥15% in TLCO in the first 6–12 months. The presence of PHT is associated with a particularly poor prognosis. More extensive fibroblastic foci on lung biopsy have also been shown to correlate with shorter survival. Death is commonly due to respiratory failure and/or infection. Increased risk of developing lung cancer, particularly in peripheral fibrotic areas of lung.

Future developments

There is significant current interest in clinical trial design for IPF and specifically the development of robust outcome measures. Only relatively few trials to date have included patients with advanced disease. The development of biomarkers to identify subgroups of patients with differing responses to treatment or outcomes is another area of interest. Therapeutic agents currently under evaluation include:

  • A controlled trial of sildenafil (a PDE-5 inhibitor) in advanced IPF (STEP-IPF trial) reported no effect on the 1° outcome of significant increase in 6min walk distance, although small, but significant, improvements in 2° outcomes (oxygenation, gas transfer, degree of dyspnoea, and QoL) were noted in the sildenafil group; trials are ongoing

  • Silent GORD appears to be common in IPF, and episodes of micro-aspiration may drive lung fibrosis; clinical trials of treatment of asymptomatic GORD are in progress

  • Treatment with the tyrosine kinase inhibitor BIBF 1120 (which targets growth factor receptors involved in lung fibrosis) in a phase 2 trial was associated with a reduced frequency of acute exacerbations and a trend towards a reduction in the decline of FVC; a phase 3 clinical trial is in progress

  • A small single-centre study of thalidomide reported an improvement in cough and respiratory QoL in patients with IPF; a larger trial is awaited

  • A trial of co-trimoxazole reported no effect on lung function but a possible mortality benefit, which may be partly explained by attenuation of increased mortality related to immunosuppression; side effects were common, particularly nausea and rash

  • Trials of the CCL2-specific monoclonal antibody CNTO 888 are underway

  • Stem cell therapy aimed at repairing lungs injured by fibrosis is an area of future research.

Non-specific interstitial pneumonia (NSIP)

Definition

The term NSIP is a description of a histological pattern, rather than a specific clinical entity. This form of IIP is particularly poorly understood, and the histological pattern of NSIP probably encompasses several distinct clinical/radiological conditions—indeed, a proposed subclassification divides NSIP into three clinicoradiological syndromes: NSIP with an IPF-like profile/overlap (NSIP/IPF), NSIP with an organizing pneumonia profile (NSIP/OP), and NSIP with a hypersensitivity profile (NSIP/HP). The clinical utility of this subclassification is uncertain. Patients with NSIP on lung biopsy have a generally better prognosis and greater response to steroids when compared with patients with IPF. NSIP may be idiopathic or occur in association with other systemic conditions, most notably connective tissue diseases.

Epidemiology

Typically affects younger patients than IPF, with age of onset 40–50y. May rarely affect children.

Causes/associations

  • Idiopathic

  • Connective tissue disease (NSIP may be the first manifestation of disease)

  • Drugs

  • Infection

  • Immunodeficiency (including HIV, post-bone marrow transplant, chemotherapy).

Clinical features

There are few specific clinical features that help distinguish NSIP from other IIPs. Described features include:

  • Breathlessness, cough

  • Weight loss is common

  • Onset gradual or subacute; typical symptom duration before diagnosis varies 0.5–3y

  • Crackles at lung bases, later more extensive

  • Clubbing in a small proportion of patients.

Investigations

  • HRCT frequently shows ground-glass change, often in a basal distribution, with or without reticulation and traction bronchiectasis. The appearance is usually more confluent and homogeneous than the patchy heterogeneous distribution seen in IPF. Honeycombing is rare

  • PFTs Typically restrictive pattern, but impaired gas transfer in only 50%. Desaturation on exertion is common

  • BAL Lymphocytosis common

  • Lung biopsy is often required

  • Investigations to exclude underlying disease (see under Causes/associations).

Histology

Variable, ranging from a predominantly ‘cellular’ pattern (mild to moderate interstitial inflammation, no fibrosis) to a ‘fibrotic’ pattern (interstitial fibrosis, more homogeneous appearance than in UIP and lack of fibroblastic foci or honeycombing; lung architecture may be relatively preserved). NSIP may be subclassified, based on the relative proportions of inflammation and fibrosis: NSIP 1 (primarily inflammation, termed ‘cellular’), NSIP 2 (inflammation and fibrosis), and NSIP 3 (primarily fibrosis). Features of both NSIP and UIP are sometimes seen on biopsies from the same individual—in such cases, the diagnosis is considered to be IPF (indicating a poor prognosis).

Diagnosis

Clinical and HRCT features are non-specific, and surgical lung biopsy is often required for diagnosis. An exception is NSIP in the setting of connective tissue disease, when histological confirmation is not usually required. Biopsy evidence of NSIP should be interpreted in the context of clinical and radiological findings, using a multidisciplinary approach in order to assign to the ‘best fit’ NSIP syndrome (NSIP/IPF, NSIP/OP, or NSIP/HP).

Management

Treatment is with corticosteroids, with a typical prednisolone dose of 0.5mg/kg. Consider routine use of bisphosphonate, PPI, and co-trimoxazole prophylaxis (960mg three times/week) against PCP. As with IPF, disease progression and response to treatment are best assessed by serial measurements of FVC and TLCO, with absolute changes of 10–15% or more considered significant. Additional immunosuppressive treatments may be considered in patients who fail to respond to corticosteroids alone.

Prognosis

Variable. Most patients improve or remain stable on treatment. ‘Cellular’ pattern on biopsy is associated with a good prognosis. Fibrotic NSIP is associated with a markedly better prognosis than IPF (5y survival >50% in fibrotic NSIP, compared with 10–15% in IPF).

Cryptogenic organizing pneumonia (COP)

Definition

COP is a disease of unknown cause, characterized by ‘plugging’ of alveolar spaces with granulation tissue that may also extend up into the bronchioles. In addition to the ‘cryptogenic’ form, OP may also occur in the context of other diseases (see under Causes of OP). Use of the term ‘bronchiolitis obliterans organizing pneumonia (BOOP)’ is no longer recommended, as it erroneously suggests a primarily airways disease and is easily confused with bronchiolitis obliterans, a distinct disease entity.

Epidemiology

More common in non-smokers. Mean age of onset 55y although can affect any age. ♂ = ♀.

Causes of OP

  • Cryptogenic (COP)

  • OP 2° to:

    • Infection (including pneumonia, lung abscess, bronchiectasis)

    • Drug reaction or radiotherapy

    • Connective tissue disease (particularly myositis, RA, Sjögren’s)

    • Diffuse alveolar damage

    • IBD

    • Haematological malignancy

    • Post-bone marrow transplant

    • Lung malignancy or airways obstruction

    • Pulmonary infarction.

Clinical features

  • Typically short (<3 months) history of breathlessness and dry cough, often with malaise, fevers, weight loss, and myalgia. Often presents as a ‘slow-to-resolve chest infection’, frequently after several courses of antibiotics

  • Breathlessness is usually mild, although a minority of patients experience severe breathlessness with rapid onset of respiratory failure and sometimes death (‘fulminant COP’)

  • Examination may be normal or reveal crackles. Clubbing is absent.

Investigations

  • Blood tests Raised CRP and ESR, neutrophilia

  • PFTs Mild to moderate restrictive pattern is typical, although mild airways obstruction may also be seen in smokers. Mild hypoxaemia is common

  • CXR classically shows patchy consolidation, sometimes with nodular shadowing. May present as a solitary mass on CXR

  • HRCT Areas of consolidation with air bronchograms, sometimes with associated ground glass or small nodules. Often basal, subpleural, and peribronchial. May migrate spontaneously. Reticulation may suggest poor response to treatment. Less common appearance is as a solitary mass that may cavitate and that is often mistaken radiologically for a lung cancer. Septal thickening may occur

  • TBB often confirms diagnosis, but there is concern that the relatively small samples may not effectively exclude associated diseases. TBB is usually adequate in patients with typical clinical and HRCT features who are subsequently followed up closely. Surgical lung biopsy (at VATS) is otherwise required

  • BAL, if performed, shows lymphocytosis, neutrophilia, and eosinophilia.

Histology

Alveolar spaces ‘plugged’ with granulation tissue (fibrin, collagen-containing fibroblasts, often with inflammatory cells), sometimes with extension up into the bronchiolar lumen. Patchy. Lack of architectural distortion. Examine for evidence of underlying cause, e.g. infection, vasculitis.

Diagnosis

Usually made on the basis of clinical and HRCT features and TBB. Surgical lung biopsy may be required in atypical cases or if an underlying disease is suspected. Remember that the histological finding of ‘OP’ is non-specific, and search for 2° causes (see under Causes of OP). Lung cancers may be surrounded by patches of OP, and biopsy of these areas in patients with a solitary lung mass may give misleading results.

Differential diagnosis

  • Infective consolidation

  • Connective tissue disease, vasculitis

  • Lymphoma, alveolar cell carcinoma

  • Lung cancer (when OP presents as lung mass).

Management

Steroids are the mainstay of treatment. Optimal dose and duration unknown. Typical initial dose of oral prednisolone is 1–1.5mg/kg daily for 3 months, before slowly weaning the dose over a total period of 6–12 months. In fulminant disease, use pulsed IV methylprednisolone 750mg–1g on 3 consecutive days, followed by maintenance therapy with 0.5–1mg/kg/day of prednisolone. Additional treatment with azathioprine or cyclophosphamide may be considered in patients with minimal response to steroids; IV pulses of cyclophosphamide may be tried in critically ill patients if failure to respond 5–7 days after steroid treatment.

Prognosis

Generally good. Most patients respond to steroids and improve within a week of starting treatment. Consider alternative diagnosis (e.g. lymphoma) if no improvement on steroid doses >25mg/day. Relapse is common on reduction of steroid dose, and treatment courses of 6–12 months are usually required. A minority improves spontaneously. Lack of steroid response and progressive respiratory failure and death are rare but well documented.

Acute interstitial pneumonia (AIP)

Definition

Rapidly progressive form of interstitial pneumonia, characterized histologically by diffuse alveolar damage. May be considered as an idiopathic form of ARDS. Formerly known as Hamman–Rich syndrome.

Epidemiology

Poorly described. Mean age of onset is 50 but may occur at any age. Patients often previously healthy.

Clinical features

  • Often preceded by ‘viral’-type illness, with systemic symptoms, e.g. fevers, tiredness, myalgia, arthralgia

  • Rapid onset (over days) of breathlessness; usually presents <3 weeks after symptom onset

  • Widespread crackles on examination.

Investigations

  • CXR Bilateral diffuse airspace shadowing with air bronchograms, progressing to widespread reticulation and ground glass; often spares costophrenic angles, heart borders, and hila

  • HRCT Bilateral diffuse ground glass and patchy airspace consolidation in early stages; later traction bronchiectasis, cystic change, reticulation

  • PFTs Restrictive, reduced gas transfer. Often profound hypoxia and respiratory failure

  • BAL Increased total cells, red blood cells, and haemosiderin. Non-diagnostic but may be useful in excluding infection

  • Lung biopsy required for diagnosis. TBB may be diagnostic; the risk of pneumothorax is higher in mechanically ventilated patients (about 10%). Surgical lung biopsy is otherwise required.

Histology

Diffuse alveolar damage: hyaline membranes, oedema, interstitial inflammation, and alveolar septal thickening, progressing to organizing fibrosis and sometimes honeycombing.

Diagnosis

Based on lung biopsy and exclusion of causes of ARDS.

Differential diagnosis

See Idiopathic interstitial pneumonias p. [link]. Consider, in particular, the possibility of drug-induced pneumonitis or AIP occurring as a manifestation of antisynthetase syndrome (see Idiopathic interstitial pneumonias p. [link]).

Management

No treatment demonstrated to be of benefit. In practice, treat infection (including consideration of unusual organisms), and consider high-dose steroids (e.g. IV methylprednisolone 750mg–1g on 3 consecutive days, followed by maintenance therapy with 0.5–1mg/kg/day of prednisolone). There is a suggestion that outcome may be better following early use of high-dose steroids, although robust evidence is lacking. Clinical and radiological features may be indistinguishable from fulminant COP, which is likely to be more steroid-responsive. High-flow O2. ITU admission and mechanical ventilatory support usually required.

Prognosis

Overall mortality at least 50%, although difficult to predict outcome in individuals. Survivors may stabilize, develop chronic progressive ILD, or experience recurrent exacerbations.

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)

Definition

‘Respiratory bronchiolitis’ is a pathological term referring to the accumulation of bronchiolar pigmented macrophages in cigarette smokers and is asymptomatic in nearly all cases. A minority of smokers with respiratory bronchiolitis, however, develop a form of ILD known as RB-ILD. The exact relationship between RB-ILD and DIP is unclear—they may be considered as different forms of the same underlying disease, with DIP associated with a more extensive accumulation of macrophages throughout alveolar spaces.

Epidemiology

Invariably occurs in current or previous smokers, typically >30 pack years. ♂:♀ ≈ 2:1. Usual age of onset 30–40y.

Clinical features

  • Usually mild breathlessness and cough

  • Small proportion have severe dyspnoea and respiratory failure

  • Often crackles on examination.

Investigations

  • PFTs Often show restrictive or combined obstructive and restrictive picture, with mildly impaired gas transfer

  • CXR Thick-walled bronchi, reticular or ground-glass change, may be normal

  • HRCT Centrilobular nodules, ground-glass change, thick-walled airways, often with associated centrilobular emphysema

  • BAL Typically reveals pigmented alveolar macrophages.

Histology

Accumulation of pigmented brown macrophages in terminal bronchioles. Patchy bronchiolocentric distribution. These findings are frequently incidental in healthy smokers, and the diagnosis of RB-ILD is usually made on the basis of clinical and HRCT features; BAL and lung biopsy may be of value in excluding other conditions.

Management

Smoking cessation is the mainstay of treatment. Corticosteroids are occasionally used, with uncertain benefit.

Prognosis

Available data are limited; prolonged survival is common, although improvements in symptoms or physiology appear to occur in only a minority of patients.

Desquamative interstitial pneumonia (DIP)

Definition

ILD that occurs in smokers and is associated with the pathological finding of abundant pigmented macrophages located diffusely throughout alveolar airspaces. It may represent a more extensive form of RB-ILD, in which macrophages are restricted to peribronchiolar regions. The term DIP is misleading, as desquamation of epithelial cells is not responsible for the histological findings, as previously thought; a more accurate term is ‘alveolar macrophage pneumonia’, although this is not in widespread use.

Epidemiology

Very rare. Majority of patients are smokers, although may also occur following inhalation of inorganic dusts, including passive inhalation of cigarette smoke. Typically occurs aged 30–50.

Clinical features

Onset of breathlessness and cough over weeks to months is typical. Clubbing is common.

Investigations

  • PFTs Mild restrictive pattern common, sometimes with reduced gas transfer

  • CXR May be normal or may demonstrate reticular or ground-glass pattern, particularly affecting lower zones

  • HRCT Ground glass seen in all cases, typically lower zone or peripheral predominance. Reticulation and honeycombing may be present although tend to be mild

  • BAL Increase in pigmented macrophages.

Histology

Diffuse accumulation of pigmented macrophages in alveolar airspaces. Changes are uniform.

Diagnosis

Clinical and HRCT features are non-specific, and surgical lung biopsy is often required for diagnosis.

Management

Smoking cessation. Corticosteroids are often used, with high response rates reported in retrospective cohorts.

Prognosis

Usually good prognosis. Improvement in ground glass on HRCT may correlate with response to treatment. Survival 70% after 10y. Fluctuating course with remissions, and relapses may occur.

Lymphoid interstitial pneumonia (LIP)

Definition

Interstitial pneumonia characterized by diffuse lymphoid infiltrates and often lymphoid hyperplasia. Previously considered to be a precursor to pulmonary lymphoma and difficult to distinguish from lymphoma histologically; it is now considered a distinct entity and is thought to only rarely undergo malignant transformation. Only a minority of cases are idiopathic; actively investigate for an underlying cause (see under Causes/associations).

Epidemiology

Very rare. Commoner in women. May occur at any age.

Causes/associations

  • Idiopathic

  • Connective tissue disease—particularly Sjögren’s syndrome, also RA, SLE

  • Immunodeficiency, particularly HIV and common variable immunodeficiency

  • Infection, e.g. PCP, hepatitis B

  • Autoimmune disease, e.g. haemolytic anaemia, Hashimoto’s thyroiditis, pernicious anaemia, chronic active hepatitis, primary biliary cirrhosis, myasthenia gravis

  • Drugs, e.g. phenytoin.

Clinical features

Gradual-onset breathlessness and cough over several years. Fever, weight loss may occur. Crackles may be heard on examination.

Investigations

  • Blood tests Mild anaemia may occur; poly- or monoclonal increase in serum immunoglobulins is common

  • CXR Lower zone alveolar shadowing or diffuse honeycombing

  • HRCT Predominant ground-glass change, often with reticulation and cysts, and sometimes honeycombing and nodules

  • BAL Non-clonal lymphocytosis

  • Investigations to identify underlying cause (see under Causes/associations).

Histology

Diffuse interstitial lymphoid infiltrates, predominantly involving alveolar septa, sometimes with lymphoid hyperplasia or honeycombing. Cellular NSIP, follicular bronchiolitis, and lymphoma may give similar appearances.

Management

Steroids are frequently used and often appear to improve symptoms.

Prognosis

Progression to extensive fibrosis occurs in around one-third of patients.