Essential respiratory medicine. Shanthi Paramothayan

Chapter 7. Diffuse parenchymal lung disease

Learning objectives

■ To understand the classification of diffuse parenchymal lung diseases (DPLD)

■ To appreciate the aetiology and pathophysiology of DPLD

■ To be aware of the clinical presentation of DPLD

■ To understand the investigations required to make the diagnosis of a specific type of DPLD

■ To appreciate the differential diagnosis of DPLD

■ To understand the clinical presentation, diagnosis, and management of Idiopathic Pulmonary Fibrosis (IPF)

■ To understand the clinical presentation, diagnosis, and management of Non-specific Interstitial Pneumonia (NSIP)

■ To understand the clinical presentation, diagnosis, and management of sarcoidosis

■ To have a basic understanding of the diagnosis and management of other, rarer DPLD

■ To understand the differences in prognosis of the different types of DPLD

Abbreviations

ABPA allergic bronchopulmonary aspergillosis

ACE angiotensin converting enzyme

AIP acute interstitial pneumonia

ARDS acute respiratory distress syndrome

ATS American Thoracic Society

BAL bronchoalveolar lavage

BCG Bacilli Calmette-Guérin

BHL bilateral hilar lymphadenopathy

BOOP bronchiolitis obliterans organizing pneumonia

BTS British Thoracic Society

COP cryptogenic organising pneumonia

CRP C-reactive protein

CTD connective tissue disease

CXR chest X-ray

DIP desquamative interstitial pneumonia

DPLD diffuse parenchymal lung disease

EAA extrinsic allergic alveolitis

EBUS endobronchial ultrasound

ECMO extracorporeal membrane oxygenation

ERS European Respiratory Society

ESR erythrocyte sedimentation rate

FEV₁ forced expiratory volume in one secnd

FVC forced vital capacity

GM-CSF granulocyte-macrophage colony-stimulating factor

HIV human immunodeficiency virus

HLA human leukocyte antigen

HP hypersensitivity pneumonitis

HRCT high-resolution computed tomography scan

IFN interferon

IIP idiopathic interstitial pneumonia

IL interleukin

ILD interstitial lung disease

IPF idiopathic pulmonary fibrosis

LAM lymphangioleiomyomatosis

LDH lactate dehydrogenase

LIP lymphoid interstitial pneumonia

MCTD mixed connective tissue disease

MHC major histocompatibility complex

NAC N-acetyl cysteine

NSIP non-specific interstitial pneumonia

OCS oral corticosteroids

PAP pulmonary alveolar proteinosis

PAS periodic acid Schiff

PLCH pulmonary Langerhans cell histiocytosis

RB-ILD respiratory bronchiolitis interstitial lung disease

SLE systemic lupus erythematosus

TBLB transbronchial lung biopsy

TLCO transfer factor for carbon monoxide

TNF tumour necrosis factor

TSC tuberous sclerosis complex

UIP usual interstitial pneumonia

VATS video-assisted thoracoscopic surgery

VEGF-D vascular endothelial growth factor

VC vital capacity

Introduction

Diffuse parenchymal lung diseases (DPLDs) are a heterogeneous group of about 200 different nonneoplastic conditions characterised by inflammation and fibrosis of the alveoli, the distal airways, and interstitium from a variety of insults. In the early stages, the inflammatory alveolitis may be responsive to corticosteroids, but if untreated, most of these conditions will progress to irreversible lung fibrosis that is not responsive to corticosteroid therapy. These conditions are all restrictive lung diseases characterised by a reduction in forced vital capacity (FVC), an increase in the FEV₁/FVC ratio, and a reduction of the transfer factor for carbon monoxide (TLCO). These conditions present with parenchymal radiological abnormalities, and the distribution of these changes may point to the diagnosis. Histology of samples taken from transbronchial biopsy, video-assisted thoracoscopic surgery (VATS), or surgical lung biopsy is usually required to make a definitive diagnosis. The treatment and prognosis vary considerably for the different types of DPLD, so it is essential to make the correct diagnosis.

In the historical terminology used to classify interstitial lung diseases, ILD and DPLD are imprecise terms based on clinical, radiological, or histological features. These terms are still used interchangeably in old text books and can be confusing. The new classification aims to correlate the clinical presentation more accurately with the radiological and histological findings. Box 7.1 lists the common DPLD.

Diagnosis of DPLD

In the following section, an approach to a patient presenting with a possible DPLD will be outlined. Patients with a DPLD will present with a history of worsening breathlessness, cough, and other symptoms according to the underlying condition. It is important to obtain a detailed history and to conduct a thorough examination as this is likely to give clues as to the aetiology and the possible diagnosis. Box 7.2 summarises the important points to elicit in the history and Box 7.3 presents the important features to note on clinical examination.

Box 7.1 Classification of common diffuse parenchymal lung diseases.

Figure 7.1 shows the classification of DPLD:

• Eosinophilic pneumonias

• Hypersensitivity pneumonitis (extrinsic allergic alveolitis)

• Idiopathic interstitial pneumonias (IIP)

• Lymphangioleiomyomatosis (LAM)

• Langerhans cell histiocytosis (histiocytosis X)

• Pulmonary alveolar proteinosis

• Pulmonary amyloidosis

• Sarcoidosis

A comprehensive occupational history is essential as exposure to inorganic dusts, organic dusts, and toxins is a common cause of alveolar damage. Lung damage secondary to occupational, recreational, and environmental exposure is discussed in more detail in Chapter 17. Drugs commonly associated with DPLD are listed in Box 7.4.

Investigations in a patient suspected of a DPLD

All patients with a suspected DPLD will require some basic investigations, including a chest X-ray, a high-resolution CT scan of the thorax (HRCT), blood tests (which may include autoantibodies, serum angiotensin converting enzyme (ACE), and serum precipitins) and full lung function tests, including transfer factor for carbon monoxide (TLCO). In some cases, depending on the differential diagnosis and the results of the HRCT, patients may need a bronchoscopy with bro choalveolar lavage (BAL) to exclude infection and to determine the differential cell count. HRCT changes can be diagnostic in chronic eosinophilic pneumonia, acute eosinophilic pneumonia, sarcoidosis, and allergic bronchopulmonary aspergillosis (ABPA).

Box 7.2 History of patient presenting with DPLD.

• Duration of symptoms (acute, subacute, chronic)

• Full occupational history, particularly exposure to asbestos, silica, mouldy hay

• Pets, especially pigeon, parakeet, budgerigar

• Drugs

• Exposure to radiation

• Toxins, for example, paraquat

• Symptoms suggestive of collagen vascular disease

• HIV

• Family history of interstitial lung disease

____

Box 7.3 Clinical examination of a patient suspected of DPLD.

• Respiratory rate

• Finger clubbing

• Fine, late inspiratory, bibasal crackles

• Features of autoimmune disease

• Signs of cor pulmonale in advanced disease

• Oxygen saturation at rest and on exertion

____

Box 7.4 Drugs associated with DPLD.

• Amiodarone

• Chemotherapy agents

• Methotrexate

• Naproxen

• Nitrofurantoin

• Sulphonamides

The pulmonary side effects of some of these commonly used drugs are discussed in Chapter 3. A full list of drugs that affect the lungs can be found on www.pneumotox.com.

____

A histological diagnosis will be required in many cases to make a definite diagnosis which will determine the management and prognosis. Small pieces of lung tissue obtained by a transbronchial biopsy may be sufficient to make a diagnosis of sarcoidosis, but a VATS lung biopsy taken from different lobes may be required when other conditions, for example, non-specific interstitial pneumonia (NSIP) or pulmonary amyloidosis, are suspected. In advanced disease, histology may be unhelpful as it will only show non-specific lung fibrosis without any clues as to the aetiology. In some cases, for example, in a patient presenting with typical clinical and radiological features of idiopathic pulmonary fibrosis (IPF), histology will not be necessary.

Patients with DPLD will have opacities on their CXR. The differential diagnosis, therefore, always includes infection, malignancy, and heart failure. The common DPLDs (see Box 7.1) have different aetiologies, management, and prognosis and will be discussed in more detail. In 10% of cases, the DPLDs remain unclassified, even with extensive investigations. This makes it difficult to treat and predict the prognosis. As with all DPLDs, careful monitoring over time is required to see how the condition progresses.

Idiopathic interstitial pneumonias (IIP)

Idiopathic interstitial pneumonias (IIP) constitute a group of inflammatory and fibrotic lung diseases, often of unknown aetiology. The classification used is that adopted by the American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus and the British Thoracic Society and is listed in Box 7.5. The prognosis of the idiopathic interstitial pneumonias varies according to the specific type of IIP. While some respond well to immunosuppression, many have a severe and relentless course, progressing to type 1 respiratory failure and death (Figure 7.2).

Pathophysiology

The interstitium, which is the space between the epithelial and endothelial basement membranes, becomes infiltrated by inflammatory cells which can also affect the airspaces, the peripheral airways, the blood vessels, and their respective epithelial and endothelial linings. This can result in abnormal collagen deposition and proliferation of fibroblasts. It is postulated that the host’s immune system plays an important role in the development of an IIP.

Box 7.5 Classification of idiopathic interstitial pneumonias.

• Idiopathic pulmonary fibrosis (IPF)

• Non-specific interstitial pneumonia (NSIP)

• Cryptogenic organising pneumonia (COP)

• Acute interstitial pneumonia (AIP)

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

• Desquamative interstitial pneumonia (DIP)

• Lymphoid interstitial pneumonia (LIP)

_____

Idiopathic pulmonary fibrosis (IPF)

IPF, previously called cryptogenic fibrosing alveolitis, is a distinctive type of chronic fibrosing interstitial pneumonia of unknown aetiology which is limited to the lungs. The incidence of IPF is 7—16/100000 per year, with a prevalence of 14—40/100 000 which increases with age, approaching 175/100 000 in those over 75 years. It is rare in patients younger than 50 years old and is twice as common in men as in women. It accounts for 25% of all ILD.

The aetiology of IPF is unknown, but an association with previous exposure to environmental dusts, such as metal and wood, has been found in some epidemiological studies. There is also an association with smoking. Immunological factors may be important, and it appears to run in some families. Several gene mutations, including mutations in the promoter region of a mucin gene (MUC 5B) and the telomerase and surfactant genes, are associated with sporadic and familial pulmonary fibrosis. Some 30% of patients with IPF have autoantibodies, such as rheumatoid factor, in their serum. This suggests that IPF is a form of connective tissue disease primarily affecting the lungs.

There is no cure for IPF, which progresses relentlessly to respiratory failure, with a median survival of 2.8 years from diagnosis. Approximately 2500 people die of IPF each year in the UK. There is some evidence that IPF increases the risk of lung cancer. It is essential to exclude other IIP such as NSIP which may respond better to treatment with corticosteroids and which may have a better prognosis.

Figure 7.2 Pathophysiology of pulmonary fibrosis.

Clinical presentation of IPF

Patients with IPF present with progressively worsening breathlessness, initially on exertion, then at rest. They may have a dry cough and complain of fatigue, malaise, and weight loss. These symptoms are non-specific and could apply to any of the IIPs or DPLDs. Symptoms suggestive of a connective tissue disease, such as Raynaud’s, joint paints, rashes, and dysphagia, point to NSIP.

In IPF, clinical examination will reveal tachyp- noea, clubbing in 50% of patients and fine, late- inspiratory, basal crackles on auscultation. Crackles are usually first audible at the lung bases in the posterior axillary line. In advanced disease, patients may develop clinical signs of cor pulmonale, which includes a raised jugular venous pressure, a parasternal heave, a loud P2, peripheral oedema, and low oxygen saturation.

Investigations in IPF

A chest X-ray will show reduced lung volumes with reticulonodular shadowing at the lung bases (Figure 7.3). An HRCT will typically show areas of reticulation, predominantly at the lung bases in a sub-pleural distribution with evidence of honeycombing, traction bronchiectasis, and architectural distortion (Figure 7.4, Figure 7.5). In IPF, there is minimal evidence of ground glass opacities although these can develop during acute exacerbations. The HRCT is atypical in 30% of cases and a lung biopsy will be required to confirm the diagnosis.

A lung function test will show a restrictive pattern with decreased vital capacity, increased FEV1/ FVC ratio and a reduced TLCO. Bronchoalveolar lavage will reveal a neutrophilia, the extent of which corresponds to the reticular changes on HRCT. This is indicative of, but not diagnostic of, IPF.

Blood tests should be sent for full blood count, urea and electrolytes and autoimmune profile.

Figure 7.3 CXR of idiopathic pulmonary fibrosis (IPF).

Figure 7.4 HRCT thorax showing bibasal fibrosis of idiopathic pulmonary fibrosis (IPF).

 

Figure 7.5 HRCT thorax showing fibrosis and honeycombing in advanced idiopathic pulmonary fibrosis (IPF).

If there is clinical evidence of pulmonary hypertension, then an ECG and an echocardiogram should be conducted. A six-minute shuttle test is an objective way to determine the degree of oxygen desaturation on exertion and is used as a primary end-point in trials looking at treatments for IPF.

With advanced disease, arterial blood gas sampling will confirm type 1 respiratory failure with hypoxia (PaO₂ < 8 kPa) and normo or hypocapnoea (PaCO₂ < 6 kPA). The alveolar-arterial gradient will be increased. (The calculation is described in Chapter 13.)

The diagnosis of IPF is usually made on the clinical history, clinical examination, and HRCT. The British Thoracic Society (BTS) guidelines recommend that if the history and HRCT are consistent with a diagnosis of IPF, then histology is not required. In patients with established IPF, histology is unlikely to be helpful as it will only show end- stage fibrotic changes with no clues as to the aetiology. If there are any unusual features in the presentation, for example, the patient is younger than 50 years old, or the radiological appearance is atypical, then a lung biopsy is recommended.

The histological appearance in IPF is described as ‘usual interstitial pneumonia’ (UIP) (Figure 7.6). The lung parenchyma will have a heterogeneous appearance with patchy areas of normal lung, areas of mild interstitial inflammation, fibrosis, and honeycombing. Fibroblast activation results in the formation of fibroblastic foci at the margins of normal lung composed of dense collagen. Areas of honeycombing are composed of cystic, fibrotic air spaces lined by bronchiolar epithelium filled with mucin, and associated with smooth muscle hyperplasia. The areas of interstitial inflammation are patchy and consist of lymphocytes, plasma cells and histiocytes associated with hyperplasia of type 2 pneumocytes.

Figure 7/6 Histology of lung showing usual interstitial pneumonia (UIP) in IPF.

Management and prognosis in IPF

The prognosis in IPF is poor with no curative treatment. Most patients die of type 1 respiratory failure within five years. A multidisciplinary approach to diagnosis and management is important and suitable patients should be referred for participation in multicentre trials.

For decades, patients with IPF were treated with corticosteroids, azathioprine, and N-acetyl cysteine (triple therapy) but the PANTHER trial was stopped early because the results showed that patients in the triple therapy arm had increased mortality compared to the control group. Glutathione, a pulmonary antioxidant, is reduced in the bronchoalveolar fluid of patients with IPF. N- acetyl cysteine (NAC), a glutathione precursor with antioxidant properties, has been shown to replace glutathione levels in bronchoalveolar lavage fluid in patients with IPF. The IFEGENIA trial showed that the addition of NAC attenuated decline in FVC and TLCO compared to prednisolone and azathioprine, but more recent trial data (PANTHER) has shown no improvement with NAC compared to placebo. The current recommendation is that patients with IPF are not commenced on triple therapy, although those established on it can continue if they are stable.

Pirfenidone has anti-fibrotic, anti-inflammatory, and antioxidant properties in vitro. In recent trials (CAPACITY and ASCEND), pirfenidone has been shown to reduce the decline in vital capacity by 45% over a period of 24—72 weeks, amounting to about 120 ml of vital capacity over a year. Pirfenidone reduced the risk of disease progression and death by 43% and there was an increase in the number of patients with stable FVC. Pirfenidone has significant side effects, including nausea and photosensitivity, but these were tolerated by most patients. NICE has recommended the use of pirfenidone for patients with mild to moderate IPF and FVC of 50—80% predicted, but only in certain regional centres in the UK.

Nintedanib, an orally active tyrosine kinase inhibitor, has been shown in multi-centre trials (INPULSIS 1 and 2) to halt the decline in FVC and may delay the time to first exacerbation. It is indicated in patients with IPF who have a vital capacity of between 50% and 80% predicted. Nin- tedanib has significant side effects, including diarrhoea, nausea, abdominal pain, and weight loss. As with pirfenidone, it can only be prescribed in regional centres.

Several other drugs are currently being trialled for the treatment of IPF. These include IFN-y, anti-TGF-β therapies, relaxin, lovastatin, ACE inhibitors, leukotriene receptor antagonists, endothelin receptor antagonists, and anti-TNF-a therapies. There is some evidence that microaspiration may play a role in the development of IPF and that treatment with a proton pump inhibitor increases survival. Although a preliminary study suggested benefit with warfarin, a recent study has suggested increased mortality in patients on warfarin, so this is no longer recommended. A lung transplant, either a double or single, may be considered in a patient younger than 60 years.

Patients with IPF can have acute exacerbations, with a sudden decline in vital capacity (VC) and development of severe hypoxaemia requiring high flow oxygen. In these patients, infection should be excluded and those with bacterial infection should receive intravenous antibiotics. Pneumothorax can be a cause of sudden deterioration. Acute exacerbations may be responsive to intravenous pulsed methylprednisolone given over three days, followed by a high dose of oral corticosteroids (OCS). Patients with advanced IPF should be offered palliative care, which includes long term oxygen therapy and opiates for severe breathlessness and cough.

Asbestosis, pulmonary fibrosis secondary to inhalation of asbestos fibres, can present with similar clinical and radiological features, but it is important to make the correct diagnosis as patients with asbestosis may be eligible for compensation. This is discussed in Chapter 15.

Non-specific interstitial pneumonia (NSIP)

NSIP is called ‘non-speciftc because the histological features differ from those of the other idiopathic interstitial pneumonias. It occurs equally in men and women, typically in the fifth and sixth decade of life. NSIP is distinct radiologically and pathologically from IPF and has a better prognosis than IPF (Figure 7.7).

Some 88% of patients with NSIP have clinical features of an undifferentiated connective tissue disease, including sicca symptoms, arthralgia, dysphagia, Raynaud’s symptoms, and gastrooesophageal reflux. These patients may also have positive serological tests for rheumatoid factor, antinuclear antibodies, or antibodies to SSA, SSB, RNP, Jo-1 and SCL-70, although NSIP may precede a diagnosis of a collagen vascular disease by several months or years. Radiologically, NSIP may resemble hypersensitivity pneumonitis (HP) or cryptogenic organising pneumonia (COP). Box 7.6 shows the aetiology of NSIP.

Figure 7.7 Prognosis in UIP NSIP, and other fibrotic lung diseases.

Box 7.6 Aetiology of NSIP.

Connective tissue diseases

• Ankylosing spondylitis

• Behçet’s disease

• Dermatomyositis

• Human immunodeficiency virus (HIV) infection

• Microscopic polyangiitis

• Mixed connective tissue disease (MCTD)

• Polymyositis

• Rheumatoid arthritis

• Sjogren’s syndrome

• Systemic lupus erythematosus (SLE)

• Systemic sclerosis

Drugs associated with NSIP

• Amiodarone

• Carmustine

• Chlorambucil

• Flecanide

• Methotrexate

• Nitrofurantoin

• Statin

____

Clinical presentation of NSIP

Patients present with progressively worsening breathlessness, cough, and pleuritic chest pain, which develop over weeks to months. About a third of patients with NSIP may describe flu-like symptoms, including myalgias. They may report symptoms suggestive of a CTD, such as rashes, arthralgia, fatigue, sicca syndrome (dry eyes and mouth), and weight loss.

Clinical examination may reveal tachypnoea, bibasal crackles, and features of an underlying CTD. Clubbing is rare. Patients may be hypoxic or desaturate on exertion.

Investigations in NSIP

The CXR may appear normal in the early stages, but bilateral interstitial opacities will eventually develop (Figure 7.8). HRCT will show abnormalities, even when the CXR appears normal, typically diffuse, bilateral, basal, and subpleural ground glass changes (Figure 7.9). A minority of patients with NSIP will develop irregular, linear, reticular opacities, traction bronchiectasis, and volume loss. Honeycombing, which is a feature of UIP, is rare and may suggest advanced disease which is less responsive to treatment. The differential diagnosis for ground glass opacification is wide, therefore a surgical lung biopsy taken from several lobes is recommended.

Figure 7.8 CXR of non-specific interstitial pneumonia (NSIP) showing interstitial shadowing.

Figure 7.9 HRCT thorax showing ground glass changes of non-specific interstitial pneumonia (NSIP).

NSIP is characterised by inflammatory changes in the lung parenchyma resulting in the ground glass changes seen on HRCT, and there is good correlation between the HRCT changes and the histological features. NSIP can be sub-classified into fibrotic or cellular types. In cellular NSIP there is interstitial infiltration of mononuclear cells with minimal fibrosis on lung biopsy and a better response to immunosuppression. BAL will show a non-specific lymphocytosis (50%) with an increase in the number of neutrophils and eosinophils. Dendritic cells, which play a role in the immune response through antigen presentation, are found in greater numbers in biopsies of patients with NSIP compared to UIP, and are found close to CD4 and CD8 lymphocytes. Fibrotic NSIP resembles UIP, is less responsive to immunosuppression than cellular NSIP, and has a worse prognosis.

Lung function shows a restrictive pattern with reduced vital capacity and a decrease in gas transfer. FVC and TLCO can predict the prognosis and can be useful in monitoring disease progression and response to treatment.

NSIP can resemble hypersensitivity pneumonitis (HP) clinically, radiologically, and histologically, although HP typically has granulomata and multi- nucleated giant cells. Focal areas resembling the changes seen in cryptogenic organising pneumonia (COP) can also occur.

Management of NSIP

If an underlying cause is found, for example, a drug, then this should be stopped. Infection should always be excluded by taking a BAL. Evidence for hypersensitivity pneumonitis should be sought by BAL and serum precipitins. Investigations to diagnose an underlying CTD should be conducted. In idiopathic NSIP, fewer than 20% of patients will improve or stabilise without therapy, but these patients will need careful monitoring with serial lung function and HRCT, initially every three months.

NSIP is more responsive to immunosuppressive treatment than IPF and has a better prognosis. Oral prednisolone at 1 mg kg^-1 day^-1 should be started in patients who do not improve spontaneously. Patients with severe symptoms and worsening lung function can be treated with pulsed intravenous methylprednisolone, 1000 mg day^-1 for three days, followed by oral prednisolone, 40—60 mg daily. The steroids should be gradually tapered, aiming to reach 5—10 mg day^-1 on alternate days by the end of 12 months. Up to a third of patients will relapse when the steroids are stopped.

High doses of corticosteroids have significant side effects, and these should be considered (see Chapter 3).

Azathioprine, starting at 50 mg day^-1, and increasing by 25 mg increments every 7—14 days up to 200 mg day^-1, can be given additionally to those who need a steroid-sparing agent or who have an incomplete response to steroids. Cyclophosphamide can be considered for those with severe lung disease secondary to CTD or those who have progressed despite steroids+/azathioprine. Oral cyclophosphamide can be given at a dose of 1.5—2 mg kg^-1 day^-1 up to a maximum of 200 mg day^-1 as a single dose. Cyclophosphamide has significant side effects which limits its use in the long term. Mycophenolate mofetil can also be used for interstitial lung disease secondary to a connective tissue disorder and Rituximab is used as a rescue therapy in NSIP. A lung transplant can be considered with severe NSIP that is progressive despite immunosuppressive therapy. Patients on immunosuppressive therapy should have regular monitoring of their full blood count and a liver function test. Pneumocystis jiroveci infection is common in immunosuppressed individuals, so prophylactic co-trimoxazole is recommended.

Prognosis in NSIP

The overall response to therapy and prognosis in NSIP is good compared to UIP, with a median survival of 56 months compared to a median survival of 33 months in UIP. Some 66% will improve or remain stable after five years of treatment with a 15—25% mortality at five years.

Serial pulmonary function testing gives better prognostic information than imaging or histopathology, with the TLCO being the most sensitive prognostic indicator.

Cryptogenic organising pneumonia (COP)

Cryptogenic organising pneumonia (COP) is also called bronchiolitis obliterans organising pneumonia (BOOP). It occurs equally in men and women, with a peak incidence in the mid-fifties, and is commoner in smokers compared to non-smokers. The exact incidence and prevalence are unknown.

Patients often present after a lower respiratory tract infection with cough, malaise, fever, and dyspnoea, which can persist for several weeks and months. These patients are often diagnosed as having community acquired pneumonia and are treated with antibiotics despite the lack of evidence of a bacterial pneumonia. Symptoms can progress, with patients developing myalgias, weight loss, worsening breathlessness, and respiratory failure. Clinical examination may reveal crackles in the lungs, but clubbing is rare.

CXR and the HRCT thorax show unilateral or bilateral areas of patchy consolidation in 90% of cases (Figure 7.10, Figure 7.11). Less common findings include nodules with air bronchograms, reticulonodular shadowing or ground glass shadowing which can resemble NSIP. Blood tests may show a raised ESR and a neutrophilia, and a BAL will show 40% lymphocytes with an increase in the proportion of neutrophils and eosinophils. Transbronchial biopsy or open lung biopsy may be required if the diagnosis is in doubt and will show alveolar ducts and alveoli with intraluminal polyps and intra-alveolar buds of organising fibrosis.

Figure 7.10 CXR in cryptogenic organising pneumonia (COP) showing areas of consolidation.

Figure 7.11 CT thorax showing extensive areas of consolidation in cryptogenic organising pneumonia (COP).

The differential diagnosis of COP includes pneumonia, sarcoidosis, bronchoalveolar cell carcinoma (adenocarcinoma in situ), eosinophilic pneumonia, NSIP, and atypical infection. In COP, no pathogen will be identified from a BAL and there will be no clinical or radiological improvement with antibiotics. Most patients with COP show a dramatic improvement with oral corticosteroids, although it is common for relapse to occur when the dose of steroids is reduced, so six months of treatment may be required. Stronger immunosuppression may be required in some cases.

Desquamative interstitial pneumonia (DIP)

DIP is relatively rare, accounting for about 8% of ILD, although the exact incidence and prevalence are unknown. It was called ‘desquamative’ as it was thought to be due to desquamation of alveolar macrophages on lung biopsy. However, it is now known to be due to the accumulation of intra-alveolar macrophages. It mainly affects smokers in the fourth and fifth decades and is twice as common in men as in women. It is unclear whether those exposed to passive smoking have an increased risk. There is also an association with connective tissue diseases. Patients present with breathlessness and a dry cough which develops over weeks and months and can progress to respiratory failure. Some 50% of patients develop clubbing.

A lung function test will reveal a mild reduction in lung volumes but a moderate reduction in transfer factor. The CXR may be normal in 20% of cases and the HRCT will show ground glass shadowing, predominantly in the lower zones with a peripheral distribution. In one-third of cases, the HRCT will progress to honeycombing (Figure 7.12). A BAL will show increased alveolar macrophages with granules of ‘smoker’s pigment’ consisting of intracellular yellow, golden, brown, or black smoke particles. Histology will show macrophage accumulation in the distal airspaces and infiltration of alveolar septae with plasma cells and eosinophils.

Figure 7.12 CT thorax of desquamative interstitial pneumonia (DIP) showing areas of fibrosis.

Figure 7.13 CT thorax of respiratory bronchiolitisinterstitial lung disease (RBILD).

The differential diagnoses include RB-ILD, sarcoidosis, hypersensitivity pneumonitis (HP), and pneumocystis jiroveci infection. The prognosis is good with smoking cessation and oral corticosteroids, with a 70—80% 10-year survival.

Respiratory bronchiolitis interstitial lung disease (RB-ILD)

RB-ILD and DIP are similar clinically, radiologically, and pathologically and have a similar prognosis, although RB-ILD affects the lung in a more diffuse manner than DIP. Many consider RB-ILD to be an early form of DIP. Although the exact incidence and prevalence are unknown, it accounted for about 20% of biopsy-proven ILD cases in the Mayo Clinic. RB-ILD occurs most commonly in the fourth and fifth decades in smokers with a greater than 30-pack a year history, and is twice as common in men as in women.

Patients, usually smokers, present with dyspnoea and cough, and the CXR will show fine reticulonodular shadowing at the lung bases in 80% of cases (Figure 7.13). A lung biopsy will show pigmented, intraluminal macrophages within the respiratory bronchioles which contain iron-rich, granular, golden-brown particles. These macrophages are surrounded by peribronchiolar infiltrate of lymphocytes and histiocytes containing coarse, black pigment. As with DIP, RB-ILD is responsive to steroids and has a good prognosis in those who stop smoking.

Lymphoid interstitial pneumonia (LIP)

LIP is a rare form of ILD, considered to be a pulmonary lymphoproliferative disorder, often associated with HIV infection, hypogammaglobulinaemia, severe combined immunodeficiency, and collagen vascular diseases, particularly rheumatoid arthritis and Sjogren’s. LIP is commoner in females in their fifth decade. Patients present with cough and dyspnoea which develops over months. Systemic symptoms include fever, weight loss, chest pain, and arthralgia. Clinical examination may reveal crackles in the lungs.

LIP is characterised by a diffuse lymphocytic interstitial infiltrate. It can be difficult to distinguish between lymphoma and LIP histologically, but immunocytochemistry and molecular analysis can separate neoplastic infiltrates from LIP. Blood tests often show mild anaemia and dysproteinaemia, with polyclonal increase in gammaglobulins or monoclonal increase in IgG or IgM in 75% of cases. The CXR shows alveolar shadowing at the lung bases or diffuse honeycombing. The HRCT shows ground glass opacities with perivascular cysts, perivascular honeycombing, reticular opacities, and lung nodules. The BAL will show lymphocytosis, and a lung biopsy will reveal dense lymphoid infiltrates. Corticosteroids may improve symptoms, but there is little evidence that it can reverse pulmonary fibrosis.

Acute interstitial pneumonia (AIP)

AIP, also called Hamman-Rich syndrome, is an aggressive form of ILD characterised by rapidly progressive diffuse alveolar damage. It is indistinguishable from ARDS secondary to sepsis and shock (see Chapter 17) and has a similar poor prognosis. Exacerbation of IPF can also present in a similar way, although in that case there will be underlying histological features of UIP. AIP has equal sex preponderance and can occur at any age, with a mean age of 50. The exact incidence and prevalence are unknown. Genetic and immunological factors may be important.

AIP is often preceded by a short history (three weeks) of upper respiratory tract viral infection, with patients presenting with cough, severe breathlessness, myalgia, malaise, and fever. Clinical examination will reveal widespread, diffuse crackles, signs of consolidation, and worsening hypoxaemia. The CXR and the CT thorax will show bilateral patchy airspace opacification with air bronchograms, ground-glass changes, bronchial dilatation, and architectural distortion, especially in the later organising stage of the disease. Lung function will show a restrictive pattern with reduced transfer factor. The BAL will show an increase in total cells, with haemorrhage secondary to alveolitis and hyaline membrane formation as seen in ARDS. A lung biopsy will reveal extensive fibroblast proliferation with thickening of the alveolar septa, the proliferation of atypical type 2 pneumocytes, and hyaline membrane formation within the alveolar walls.

AIP has a high mortality of more than 50%, with patients progressing rapidly to respiratory failure within one to three months of onset of illness. As in ARDS, treatment is with ventilatory support and prevention of secondary infection. Corticosteroids have not been shown to alter the natural history of the disease. ECMO may have a role in supporting oxygenation and preventing further damage to the lungs. Survivors usually progress to pulmonary fibrosis. Recurrence of AIP can occur.

Eosinophilic lung disease

Eosinophils predominantly dwell in tissues with a mucosal epithelial interface, such as the lungs, the gastrointestinal system, and the genitourinary system. The usual eosinophil count in peripheral blood is <0.4 x 10⁹ l^-1 which accounts for 1.3% of the circulating white cell count. The peripheral eosinophil count does not indicate the extent of eosinophilic infiltration of organs. Eosinophils are not found in the lungs of healthy individuals, so a finding of an eosinophilia of greater than 10% on a BAL is pathological.

Pulmonary eosinophilic diseases are a group of disorders which present with breathlessness, productive cough, and wheeze secondary to infiltration of the lung parenchyma by eosinophils which secrete inflammatory cytokines which damage the alveoli. In some cases, patients can develop systemic symptoms of fever, night sweats, weight loss, and myalgia. Some of these conditions may be associated with a peripheral blood eosinophilia, although in several serious eosinophilic conditions, the peripheral eosinophil count may be normal.

As with all the DPLD, it is essential to obtain a detailed history of any new drugs, including recreational drugs, occupational exposure to toxins and chemicals, travel to areas where parasitic diseases are endemic, and any history of allergy or atopy. Bacterial pneumonia is a serious consideration in these patients as it presents with the same symptoms and can be radiologically difficult to rule out, but pneumonia usually results in a neutrophilia and an eosinopenia secondary to the elevated endogenous corticosteroid levels.

In eosinophilic lung diseases, the chest X-ray is often normal, but may show parenchymal infiltrates, usually in a bilateral and peripheral distribution (Figure 7.14). The term ‘infiltrate’ implies areas of consolidation within the parenchyma. The HRCT is much more sensitive at detecting subtle ground glass and other parenchymal changes, although in most cases of pulmonary eosinophilic diseases, the radiological appearances are non-specific. The differential diagnoses for the radiological appearances of eosinophilic pulmonary disease include IPF, sarcoidosis, HP, and COP (Figure 7.15).

Figure 7.14 CXR of eosinophilic pneumonia showing interstitial shadowing.

Figure 7.15 CT thorax of eosinophilic pneumonia showing areas of consolidation.

Sputum samples can be helpful in determining the presence of eosinophils, which implies lung involvement, and in detecting larvae of parasites. BAL fluid should always be sent for microbiological analysis to exclude bacterial, fungal, and parasitic infections and for cytology to look for an underlying malignant cause, such as bronchoalveolar cell carcinoma (adenocarcinoma in situ). A diagnosis of eosinophilic pneumonia is likely if the differential cell count of BAL shows >10% eosinophils. A transbronchial biopsy may not yield samples that are adequate, so either a VATS or open lung biopsy may be necessary to demonstrate eosinophilic infiltration.

Measurement of total serum immunoglobin E (IgE) may be helpful when asthma or ABPA are likely, as IgE-mediated eosinophil production is induced by leukotrienes, histamine, and IL5, which are released by mast cells and basophils. Aspergillus-specific IgE and IgG measurement is recommended if the clinical and radiological features suggest ABPA. Auto-antibody testing should be done, as an underlying connective tissue disease is always a possibility with this presentation. Serum antifilarial IgG should be measured if the clinical features suggest helminth infection.

Table 7.1 lists the differential diagnosis of eosinophilic pulmonary diseases and describes the typical features of each of these.

Allergy to drugs, atopic diseases, and malignancy are the commonest causes of peripheral eosinophilia in the UK. Worldwide, parasitic infections account for most cases of peripheral eosinophilia. Appendix 7.A lists some of the commonly implicated drugs. Toxins and inhaled recreational drugs can also be associated with eosinophilia and are discussed in Chapter 15. ABPA is discussed in more detail in Chapter 6 and EGPA is discussed in more detail in Chapter 11.

Management of pulmonary eosinophilia depends on the severity of symptoms and the exact diagnosis. Infection must be excluded prior to commencing corticosteroids which are very effective in reducing the peripheral eosinophil count within hours. Therefore, if an eosinophilic condition is suspected, investigations should be carried out prior to starting corticosteroid treatment.

Sarcoidosis

Sarcoidosis is a multisystem disease characterised by the development of non-caseating granulomatous lesions in the affected organs. It is the commonest diffuse parenchymal lung disease worldwide and affects men and women in the third to fifth decades. The prevalence is 3/100 000 in Caucasians, 47/100 000 in African Americans and rises to 64/100 000 in Scandinavians. The markedly different prevalence between races, familial clustering, and a significantly increased incidence in monozygotic twins suggest a genetic predisposition. Studies have suggested linkage to a section within MHC on the short arm of chromosome 6. HLA Dr11, 12, 14, 15 and 17 confer susceptibility to the disease, whereas HLA DR1 and DR4 are protective.

It is postulated that sarcoidosis results from an abnormal immunological reaction to a poorly degradable antigen, with granulomas forming around the antigen to prevent dissemination. The frequent involvement of the lungs suggests that the antigen enters the body through inhalation. The ACCESS study, a case-control aetiological study of sarcoidosis, found some evidence that the antigen may be a remnant of microbial organisms, including Mycobacterium species, Propionibacterium acnes, and herpes. There is also some evidence implicating organic dusts, metals, minerals, solvents, pesticides, and wood stoves. There appears to be an association with tuberculosis and lymphoma.

Table 7.1 Causes of eosinophilia.

In sarcoidosis, there is accumulation of CD4 lymphocytes within the organs involved, with a corresponding depletion in CD4 ceIIs peripherally. This anergy results in a delayed type 4 hypersensitivity response. Patients with sarcoidosis will have a negative reaction to tuberculin testing, even when they have had a previous Bacilli Calmette-Guerin (BCG) vaccination.

IL-2, IL-12 and IFN-y activate T helper cells and have been shown to result in granuloma formation and exacerbation of sarcoidosis. High levels of IL-12, which is known to play an important role in the immunological response to intracellular organisms, have been found in the bronchial washings of patients with sarcoidosis. Genetic defects in IL-12 receptor decrease granuloma formation and increase the susceptibility to atypical mycobacterial infections. TNF-a is a non-specific, but potent, pro-inflammatory cytokine in sarcoidosis.

Clinical presentation of sarcoidosis

Sarcoidosis can present acutely or chronically. In many cases the diagnosis is made incidentally in an asymptomatic patient.

Acute sarcoidosis (Lofgren’s syndrome)

Acute sarcoidosis typically occurs in young patients in their twenties and thirties. This type of presentation is more likely to occur in women, particularly in those of Irish and Nordic descent, and has a good prognosis. Box 7.7 lists the symptoms and signs of acute sarcoidosis (Figure 7.16, Figure 7.17). The differential diagnosis for this presentation is wide and includes viral or bacterial infection, mycobacterium tuberculosis infection, lymphoma, and autoimmune conditions.

Chronic sarcoidosis

Chronic sarcoidosis presents more insidiously and can affect one or several organs. The lungs are affected in 90% of cases, and in 50% of cases only the lungs are affected. In 10% of cases, there is only cutaneous involvement. Symptoms of pulmonary sarcoidosis include breathlessness, reduced exercise tolerance, cough, fatigue, anorexia, and weight loss. Examination of the chest will reveal reduced lung expansion consistent with a restrictive process and crackles in 20% of patients. The differential diagnosis includes any of the diffuse parenchymal lung diseases.

Figure 7.16 Erythema nodosum.

Figure 7.17 Anterior uveitis with arrow showing hypopyon.

The finding of an abnormal chest X-ray with bilateral hilar lymphadenopathy (BHL) in an asymptomatic individual is a common presentation of sarcoidosis. Other common presentations of sarcoidosis include hypercalcaemia and abnormal liver function tests.

Sarcoidosis can affect several organs in the upper respiratory tract, including the larynx, the pharynx, sinuses, and the post-nasal space, causing nasal obstruction, rhinosinusitis, nasal crusting, anosmia, epistaxis, and nasal polyposis. The differential diagnosis includes granulomatous polyangiitis (see Chapter 11) and asthma (see Chapter 6).

Multisystem sarcoidosis

Sarcoidosis can affect most of the organs in the body. Box 7.8 lists the organs involved.

Investigations

A comprehensive history, including a full occupational history and family history, should be ascertained. The diagnosis of sarcoidosis is made with a correlation between clinical presentation, radiological, and histopathological features.

Radiology

The lungs are involved in 90% of cases, so the CXR will be abnormal in the majority. Box 7.9 shows the different stages of pulmonary sarcoidosis (Figure 7.18, Figure 7.19, Figure 7.20, Figure 7.21, Figure 7.22, Figure 7.23, Figure 7.24, Figure 7.25).

Box 7.9 Radiological staging of pulmonary sarcoidosis.

Chest X-ray stage
Stage 0	Normal chest X-ray (5-10%)
Stage 1	Bilateral hilar lymphadenopathy (45-65%)
Stage 2	BHL and pulmonary infiltrates (25-30%)
Stage 3	Pulmonary infiltrates without BHL (15%)
Stage 4	Pulmonary fibrosis

Box 78 Organs involved in multisystem sarcoidosis.

• Skin: lupus pernio in 25%, maculopapular eruption, plaques, nodules, and scar infiltration

• Lymph nodes: palpable in 30%

• Eyes: 26-50% develop anterior uveitis, posterior uveitis, retinal vasculitis, keratoconjunctivitis, conjunctival follicles

• Muscle and joints: 10-15% develop joint pain and swelling, muscle pain

• Liver: hepatomegaly in 12%, resulting in abnormal liver function test and granulomas

• Spleen: splenomegaly in 7%

• Heart: cardiomyopathy, third degree heart block, arrhythmias, sudden death

• Bone: bone cysts affecting hands and feet, dactylitis, osteolytic or osteosclerotic lesions

• Salivary glands: parotid and submandibular gland involvement in 4%

• Lacrimal glands: involvement in 1%

• Kidneys: nephrocalcinosis, renal calculi, acute nephritis

• Gastrointestinal system, including pancreas: involvement in 1%

• Reproductive system: although rare, involvement of testes can cause infertility. Sarcoidosis can become active after pregnancy

• Central nervous system: neurosarcoidosis can present with granulomatous meningitis (elevated lymphocyte count in cerebrospinal fluid), cranial and/or peripheral nerve palsies, seventh nerve palsy, space-occupying lesion resulting in obstructive hydrocephalus and seizures. Posterior pituitary involvement may cause diabetes insipidus

____

Figure 7.18 CXR of stage 1 pulmonary sarcoidosis showing BHL.

Figure 7.19 CT thorax of stage 1 pulmonary sarcoidosis showing bilateral hilar lymphadenopathy (BHL).

Figure 7.20 CXR of stage 2 pulmonary sarcoidosis with BHL and pulmonary infiltrates.

 

Figure 7.21 CT thorax of stage 2 pulmonary sarcoidosis with BHL and pulmonary infiltrates.

The differential diagnosis of bilateral hilar lymphadenopathy (BHL) includes mycobacterium tuberculosis infection and lymphoma. Rarer differentials in those with occupational exposure include silicosis and berylliosis (see Chapter 15). Coccidioidomycosis and histoplasmosis can occur in endemic areas in North America.

The HRCT scan of the thorax is more sensitive than a CXR and may show interstitial changes, even when the CXR appears normal. Typical HRCT features, which occur in 60—70% of cases, include nodules (called ‘beading’) in a perilymphatic or bronchovascular distribution, forming along the subpleural surface, along fissures and interlobular septae. The lung parenchyma in the upper and middle zones is affected, with sparing of the lung bases. Lymph nodes in the hilar and paratracheal region may be enlarged and calcified.

In stages 3 and 4 sarcoidosis, progressive pulmonary fibrosis results in reticulonodular shadowing, with volume loss of the upper lobes, displacement of the interlobar fissure, hilar elevation, architectural distortion, and traction bronchiectasis. A lymphocytic pleural effusion will occur in fewer than 5% of cases. Pneumothorax and chylothorax are very rare presentations of sarcoidosis.

Figure 7.22 CXR of stage 3 pulmonary sarcoidosis showing pulmonary fibrosis.

Figure 7.23 CT thorax of stage 3 pulmonary sarcoidosis showing pulmonary fibrosis.

Figure 7.24 CXR of stage 4 pulmonary sarcoidosis showing extensive, chronic fibrosis.

 

Figure 7.25 CT thorax of stage 4 pulmonary sarcoidosis showing extensive, chronic fibrosis.

A minority of patients may require further radiological investigations to confirm the extent of organ involvement. Gallium scanning is expensive and exposes the patient to significant radiation, but can be helpful in assessing disease activity, especially when an MRI scan is not possible. ⁶⁷Gallium, which is taken up preferentially by granulomas, can detect lesions not seen on a CT scan, particularly in the mediastinum, spleen, and salivary glands. Bilateral, symmetrical involvement of lymph nodes and salivary glands is typical of sarcoidosis with the characteristic ‘lambda’ sign where there is paratracheal and bilateral hilar uptake of ⁶⁷Ga and the ‘panda’ sign when there is uptake in the lacrimal and parotid glands. Magnetic resonance imaging (MRI) is required to investigate a patient suspected of neurosarcoidosis.

Blood tests

The serum ACE level is elevated in two-thirds of patients with active sarcoidosis, but lacks sensitivity and specificity so is of limited value in the diagnosis of sarcoidosis. Serum ACE levels do not correlate with the radiological stage of the disease and serial measurements are not recommended in the guidelines. Full blood count, corrected serum calcium, liver function tests, and 24-hour urine calcium levels should be measured in all patients with sarcoidosis. Mild leucopenia, mild anaemia, and a slight increase in transaminases can occur. C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and serum immunoglobulin levels may be elevated in acute sarcoidosis, and immune complexes are often present. Hypercalcaemia can occur in 10—20% of patients with sarcoidosis due to dysregulation of the calcium metabolism. Macrophages within granulomas in lungs and lymph nodes synthesise calcitriol (1, 24 dihydroxy vitamin D) which results in increased calcium absorption from the gastrointestinal tract and increased bone resorption.

Some 30—50% of patients with sarcoidosis develop hypercalciuria which, if not treated, can progress to renal calculi, nephrocalcinosis, and renal failure.

Lung function test

The lung function test will be abnormal in 20% of patients with stage 1 sarcoidosis, and in the majority of those with stages 2, 3 and 4 sarcoidosis. The lung function test will show a restrictive defect, with reduction in FVC, TLC, and TLCO. There may be an obstructive element when there is significant endobronchial disease. The severity of the restrictive changes does not correlate well with the HRCT changes, and the baseline lung function does not predict the long term outcome. Serial lung function measurements can be used to monitor disease progression and response to treatment, with the vital capacity (VC) and TLCO being the most sensitive measures in predicting steroid-responsiveness.

Histological diagnosis of sarcoidosis

Histological confirmation is essential to rule out lymphoma, Mycobacterium tuberculosis, and other parenchymal lung diseases in those presenting with BHL. Biopsies should be obtained from the most accessible site. Most patients will have a bronchoscopy with a bronchoalveolar lavage (BAL) and a transbronchial lung biopsy (TBLB). The HRCT may be helpful in guiding which lobe to biopsy. Lymph nodes can be sampled through an endobronchial ultrasound-guided biopsy (EBUS). At bronchoscopy, endobronchial lesions may be seen which can be biopsied. A transbronchial biopsy is often diagnostic and is a relatively safe procedure with a < 10% risk of a pneumothorax. The BAL will show an increase in the CD4 and T-helper cells and raised CD4:CD8 T cell ratio. In all cases, bronchial fluid and biopsies should be sent for microscopy and culture to exclude infection, particularly mycobacterium tuberculosis infection.

Biopsies can also be taken from mediastinal lymph nodes via a mediastinoscopy, which is a surgical procedure requiring a general anaesthetic. A VATS lung biopsy or surgical open lung biopsy may be necessary in patients presenting with an atypical HRCT or those with pulmonary nodules where malignancy may be of concern. If other organ involvement is suspected, then biopsies can be obtained from these, for example, skin, liver, and bone.

Histology will show non-caseating granuloma but no acid-fast bacilli. Granulomas consist of a central area of macrophages that differentiate into epithelioid cells and fuse to form multi-nucleated giant cells surrounded by lymphocytes. The multi- nucleated cells have cytoplasmic inclusions, including asteroid bodies, Schaumann bodies, and birefringent crystalline particles. There is accumulation of CD4 T-helper cells within the granulomas with CD8 T cells around the periphery (Figure 7.26). The Kveim test, a diagnostic test used in the past, is no longer used because of the risk of infection.

Other investigations

Tuberculin skin testing, which is negative in sarcoidosis, can be useful in excluding Mycobacterium tuberculosis, except in patients who have HIV. Patients suspected of having cardiac involvement of sarcoidosis should have an ECG, an echocardiogram, and a cardiac MRI, before proceeding to a cardiac biopsy if necessary.

Figure 7.26 Histology of sarcoid lung showing granuloma with multinucleate giant cells, lymphocytes and histiocytes.

Management and prognosis of sarcoidosis

The natural history of sarcoidosis is variable and unpredictable, with spontaneous remissions and relapses. Acute sarcoidosis has a good prognosis: it is usually self-limiting with spontaneous resolution occurring in the majority, although relapses are common. For symptomatic patients (fatigue, fever, night sweat, and joint pains), a short course of oral corticosteroids (OCS) given for three and six months is recommended. Patients with eye symptoms should be referred to the ophthalmologist and are usually prescribed steroids eye drops.

The clinical course and prognosis in pulmonary sarcoidosis vary according to the radiological stage of the disease and the ethnicity of the patient. Overall, for all stages, two-thirds are in remission within 10 years but one-third progress, resulting in significant organ damage. Some 1—5% of patients die secondary to respiratory failure, cardiac arrhythmias, or neurosarcoidosis.

Spontaneous remission occurs in 55—90% of patients with stage 1 disease, 40—70% with stage 2 disease, and 10—20% with stage 3 disease, with most remissions occurring in the first six months of diagnosis. Treatment is not indicated for asymptomatic patients with stage 1 disease as the rate of spontaneous remission is so high. A “wait and watch” policy is recommended in this group.

Treatment with OCS for 6—24 months is indicated for symptomatic patients with stages 2 and 3 disease and abnormal lung function. A dose of 0.4 mg kg^-1 ideal body weight is recommended, usually 20—40 mg day^-1. The dose of OCS should be tapered according to clinical response and improvement in CXR and lung function. Most patients will improve with steroids, but 50% will relapse when the dose is reduced or stopped. There is little evidence for the use of inhaled corticosteroids in pulmonary sarcoidosis, although those with cough secondary to significant endobronchial disease and obstruction on lung function may benefit.

OCS treatment is indicated for patients with multisystem sarcoidosis and involvement of other organs. OCS are particularly effective in treating hypercalcaemia and hypercalciuria secondary to sarcoidosis.

In patients with refractory disease and in those who have significant side effects with corticosteroids, steroid-sparing agents, such as methotrexate, mycophenolate mofetil, and azathioprine should be considered. TNF-a inhibitors, such as infliximab and pentoxifylline, have not been shown in trials to be particularly effective in patients with chronic sarcoidosis and have significant side effects. Hydroxycholoroquine is often used for cutaneous sarcoid lesions and in chronic sarcoidosis. Low- dose thalidomide may also be beneficial in cutaneous sarcoidosis. In patients with refractory hypercalciuria, chloroquine, hydroxychloroquine, and ketoconazole can be used.

Multisystem sarcoidosis, particularly neurosarcoidosis and cardiac sarcoidosis, can be life-threatening and may require high doses of intravenous cyclophosphamide. There is some evidence that a combination of infliximab and mycophenolate mofetil is effective in neurosarcoidosis. Patients with multisystem sarcoidosis and those with significant organ involvement are often managed in specialist centres.

Many of these drugs are contraindicated in women of child-bearing age because of teratogenicity. These drugs can also cause significant side effects, particularly bone marrow suppression, so will need to be carefully monitored.

Patients with refractory pulmonary sarcoidosis and advanced fibrotic disease should be considered for lung transplantation before they develop respiratory failure, although there are reports of recurrence of disease in the transplanted organ. For those patients who do not respond to any treatment and develop pulmonary hypertension, cor pulmonale, and respiratory failure, long term oxygen therapy and palliative care should be offered.

Hypersensitivity pneumonitis (HP)

Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis (EAA), can be classified as acute, sub-acute, or chronic depending on the frequency, length, and intensity of exposure and the duration of the illness. It is not a single disease but can be caused by exposure to microorganisms (fungal, bacterial, protozoan), animal or insect proteins, agricultural dusts, bio-aerosols, and certain reactive chemical species. The exact prevalence of HP is unknown because over 300 different aetiological agents have been identified and because there are no uniform diagnostic criteria. Prevalence and incidence vary depending on the intensity of exposure to inciting antigens, geographical conditions, and different methods of collecting data.

HP is an immunologically mediated type 3 hypersensitivity lung disease. It is postulated that both environmental and host factors are important in developing HP. The inhalation of antigens by an individual who has already been sensitised provokes a complex immune response involving antibody reactions, immune complex formation, complex activation, and cellular response, resulting in alveolitis. Only a small proportion of exposed individuals develop clinically significant HP.

Common causes of HP include thermophilic spores of saprophytic fungi and bird droppings. Farmer’s lung, caused by thermophilic actinomycetes and saccharopolyspora rectivirgula, is one of the most common forms of HP, affecting 0.4— 7% of the farming population. The prevalence varies by region, climate, and farming practices, being higher in humid areas (9%) and lower in drier climates (3%). When hay is harvested and stored in damp conditions, it becomes mouldy and generates heat that encourages the growth of fungi. Thermophilic actinomycetes are present in the atmosphere throughout the year and cause disease when individuals are exposed to large numbers of particles. The numbers of actinomycetes spores increase with temperature and humidity and can contaminate a wide variety of vegetables, wood bark, air-conditioning systems, and humidifiers.

Avian-related HP develops in pigeon fanciers and in those keeping budgerigars, parakeets, and chickens. The reported prevalence is 20-20 000/100 000 persons at risk. The prevalence of HP is higher among bird fanciers than farmers because contact with the inciting avian antigen is less limited by season or geographic location.

Table 7.2 lists some other known causes of HP. Cigarette smoking reduces antibody response to inhaled antigens so is associated with a decreased risk of developing HP, although once the disease is established, smoking does not appear to attenuate its severity and may predispose to a more chronic and severe course.

Acute hypersensitivity pneumonitis

Patients present with fever, rigors, chest pains, malaise, breathlessness, and cough which can occur within hours of exposure. The intensity of the reaction is proportional to the amount of inhaled antigen and the duration of exposure. Many patients with HP are misdiagnosed as suffering from viral illnesses or asthma as the CXR could be normal in the early stages and an occupational history is not taken by the doctor. Physical examination may reveal tachypnoea and diffuse fine crackles on auscultation of the lungs. In severe cases, the patient may become profoundly breathless and hypoxic and progress to type 1 respiratory failure.

HP is characterised by inflammation of the alveoli with a lymphocytic infiltration and minimal fibrosis. Blood tests will show a non-specific inflammatory picture with elevated ESR, CRP, and lactate dehydrogenase (LDH). If an occupational history is suspected, then serum-precipitating IgG antibodies against the causative antigen are usually detectable, but only indicate exposure as these are also present in 10-15% of exposed but asymptomatic individuals. False negative results can also occur. Bronchial washings are required to exclude infection. A differential cell count from the BAL will show an increase in CD8 T cells.

Table 7.2 Some causes of hypersensitivity pneumonitis.

Name of disease	Antigen	Source of antigen
Farmer’s lung	Thermophilic actinomycetes Saccharaplyspora rectivirgula Micropolyspora faeni Aspergillus Species	Mouldy hay
Bird fancier’s lung	Feather and bird droppings	Pigeon, budgerigars, parakeets, chicken
Malt worker’s lung	Aspergillus fumigatus, Aspergillus clavatus	Mouldy barley
Coffee worker’s lung	Coffee bean protein	Coffee bean
Detergent worker’s lung	Bacillus subtilis enzymes	Detergent
Bagassosis	Thermoactinomyces vulgaris	Mouldy sugar cane
Humidifier lung	Thermoactinomyces vulgaris	Contaminated water in reservoirs or air conditioning systems
Hot tub lung	Mycobacterium avium	Mist from hot tubs
Cheese-washer’s lung	Aspergillus clavatus, Pénicillium casei	Mouldy cheese
Chemical worker’s lung	Isocyanates	Spray paints, glues

The CXR may show early interstitial changes in the middle and upper zones of the lungs. An HRCT is more sensitive and will reveal ground glass shadowing with areas of decreased attenuation and air trapping on expiratory scans. A lung function test will reveal a restrictive pattern. If histology is sought from a lung biopsy, it typically shows poorly formed, non-caseating, interstitial granulomas or mononuclear cell infiltration in a peribronchial distribution, often with prominent giant cells. The main differential diagnosis is sarcoidosis.

The symptoms and radiological changes of acute hypersensitivity pneumonitis can resolve rapidly when the antigen is removed. In those who are symptomatic and hypoxic, a course of oral corticosteroids can improve the symptoms and radiological changes. Steroids may be required for three to six months in a tapering course and relapse is common when the steroids are stopped. Re-exposure to the antigen will also cause a relapse.

Sub-acute hypersensitivity pneumonitis

The sub-acute form of HP is more insidious, developing over weeks and months. Patients present with progressively worsening dyspnoea, cough, anorexia, and weight loss. Clinical examination may reveal finger clubbing and inspiratory crackles.

The CXR may be normal, as in acute HP, or may show micronodular or reticular opacities, most prominent in the middle to upper lung zones. The HRCT will show diffuse micronodules, ground glass changes, focal air trapping, and mild fibrotic changes. A lung biopsy will show well- formed non-caseating granulomas in the interstitium, bronchiolitis with or without organising pneumonia, and interstitial fibrosis. The main clinical, radiological, and histological differential diagnosis of sub-acute HP is sarcoidosis.

Chronic hypersensitivity pneumonitis

The chronic form develops over months and can progress to pulmonary fibrosis and respiratory failure. Patients with advanced disease develop clubbing and will have clinical signs of volume loss, particularly in the upper zones, with fine crackles on auscultation. The CXR shows ground-glass changes and reticulation (Figure 7.27). The HRCT may show parenchymal micronodules, interstitial pneumonia, bronchiolitis obliterans, and fibrosis with honeycombing. It can be difficult to differentiate this from IPF and stage 4 sarcoidosis. A BAL will show an increase in neutrophils, which is a non-specific finding, but fluid should be sent for microbiology and culture to exclude infection, including pneumocystis jiroveci infection (Figure 7.28).

Management of HP

Antigen avoidance is the most important advice to give to patients diagnosed with HP. This will result in rapid resolution of symptoms over hours and days and avoid the need for corticosteroid treatment. This may be difficult for some if it is their hobby or occupation, in which case, measures to reduce antigen exposure, including wearing protective masks, head covering, and protective clothes should be advocated. Respirators can be used, although their efficacy in reducing exposure is unknown. Changes in the handling and storage of material, for example, hay, reducing the humidity of a building to below 60%, reducing stagnant water, and preventing the re-circulation of water in heating, ventilation, and air conditioning systems are essential measures. Wetting compost before handling it can reduce the dispersion of actinomy- cetes spores, and the use of antimicrobial solutions in sugar cane processing can reduce fungal growth and the development of bagassosis.

Figure 7.27 CXR of hypersensitivity pneumonitis (HP).

Figure 7.28 CT thorax of chronic hypersensitivity pneumonitis (HP) showing ground glass changes and fibrosis.

Corticosteroids are usually given to those with significant and persistent symptoms, those with hypoxaemia, those with reduced diffusing capacity on the lung function test and those with extensive radiological changes. Oral prednisolone given at a moderately high dose of 1 mg kg^-1 day^-1 (up to a maximum of 60 mg day^-1) for two weeks, with a reducing regime over the next two to four weeks, will improve the symptoms of fever, chest pain, and dyspnoea, and improve the radiological changes of acute and sub-acute hypersensitivity pneumonitis. Relapse can commonly occur when the dose of steroids is reduced or stopped.

However, there is no evidence of long term benefit with corticosteroids which are less effective in chronic hypersensitivity pneumonitis and established pulmonary fibrosis. Steroid-sparing agents, such as methotrexate, can be considered for those who require immunosuppression for a longer period or for those who have significant side effects with steroids.

Prognosis of HP

Most patients with acute and sub-acute hypersensitivity pneumonitis recover completely with antigen avoidance, although it may take up to two years for the lung function to recover completely. Those presenting acutely generally do better than those with a chronic presentation and established pulmonary fibrosis. Older age, digital clubbing at presentation, and honeycombing and traction bronchiectasis on HRCT confer a worse prognosis.

About 50% of patients with farmer’s lung develop mild chronic lung impairment, usually obstructive in nature, often with emphysematous changes on HRCT. Bird fancier’s lung carries a worse prognosis than farmer’s lung, possibly due to the higher degree of exposure to antigens and the persistence of avian antigens at home despite attempts at decontamination. Mortality was 29% at five years in Mexican patients with chronic pigeon breeder’s lung. Those with histological changes resembling NSIP or COP had a better prognosis than those with UIP-like changes. The prognosis of HP secondary to other aetiologies is less well described.

Lymphangioleiomyomatosis (LAM)

Pulmonary LAM is a rare condition occurring in women of child-bearing age. It is commoner in the Caucasian population, but the exact incidence and prevalence of LAM are unknown. Many cases of LAM are associated with germ line mutations in the tuberous sclerosis complex (TSC). Some 30% of women with TSC are affected by pulmonary LAM. Sporadic pulmonary LAM is associated with somatic mutations in the TSC1 or TSC2 genes in the lungs. LAM has been reported in men in association with the TSC complex. Oestrogen may be implicated in the development of clinically apparent LAM in genetically predisposed individuals.

LAM is a benign mesenchymal tumour characterised by the proliferation of atypical pulmonary smooth muscle and epithelioid cells, called LAM cells, around bronchovascular structures, resulting in the formation of multiple, small cysts in the distal airspaces. These cysts can vary in size from 0.1 cm to several centimetres in diameter. Rupture of the dilated and tortuous venules can result in haemosiderin deposition in the cysts. The thoracic duct can also be enlarged and thickened. Extra-pulmonary manifestations of LAM include renal angiomyolipomas and mediastinal, retroperitoneal, and pelvic lymphangioleiomyomas.

Although LAM is often classified as a DPLD, it has more similarities to asthma or emphysema clinically and radiologically, and can present with significant airflow obstruction. Patients present with progressive breathlessness, spontaneous pneumothorax, haemoptysis, and chylo- thorax. Patients presenting late may have evidence of pulmonary hypertension. Diagnosis is made on HRCT which shows multiple (usually between 2 and 10), small, thin-walled cysts (Figure 7.29, Figure 7.30). A chylous pleural effusion secondary to rupture of the thoracic duct can occur. If the radiological features are typical, then a tissue biopsy is not required. If a tissue biopsy is needed, then a lung biopsy can be obtained via TBLB, VATS or open lung biopsy, although an increased risk of pneumothorax must be taken into consideration.

Figure 7.29 CXR of lymphangioleiomyomatosis (LAM) showing hyperinflation.

Figure 7.30 HRCT thorax of lymphangiomyomatosis (LAM) showing multiple cysts in both lungs.

A lung function test will be normal in 57% of cases but will show an obstructive picture, with an increase in TLC and RV compatible with hyperinflation, a marked reduction in TLCO, and reversibility to bronchodilators in the rest. A six-minute walk test will be abnormal in severe disease and is often used to monitor patients. The A-a gradient will be increased.

The differential diagnosis of LAM includes asthma, emphysema, and alpha-1 antitrypsin deficiency (see Chapter 6). Measurement of vascular endothelial growth factor (VEGF-D), which is elevated in LAM, may be helpful as a screening test if LAM is suspected, but is not commonly available.

There is no specific treatment for LAM, but the effectiveness of mTOR inhibitors sirolimus and everolimus is currently being evaluated in trials. Some studies have demonstrated disease stabilisation and modest improvement with progestational and anti-oestrogen agents, but it should be noted that long term treatment with progesterone increases the risk of venous thromboembolism and meningiomas. Symptomatic treatment of LAM includes the use of bronchodilators, oxygen therapy in those who are hypoxic, and pulmonary rehabilitation. Oestrogen therapy should be avoided. The prognosis is good, with survival of 29 years from the onset of symptoms. Patients who present with a spontaneous pneumothorax may require pleurodesis or pleurectomy. Patients who progress towards respiratory failure may be eligible for lung transplantation.

Pulmonary Langerhans cell histiocytosis (PLCH)

Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon interstitial lung disease that affects young adults, particularly cigarette smokers. The true incidence and prevalence are unknown, but it is commoner in men and was diagnosed in about 5% of lung biopsies in a study at the Mayo Clinic. Systemic LCH is commoner in young children between the ages of 1 and 3 where it can present with severe disseminated disease involving multiple organs, including bone, skin, lymph nodes, liver, spleen, lung, CNS, and oral mucosa.

The Langerhans cell is a differentiated cell of the macrophage-monocyte line which is usually found in the dermis, the reticulo-endothelial system, the lungs, and the pleura. The Langerhans cell has a pale-staining cytoplasm, a large nucleus, large nucleoli and Birbeck granules on electron microscopy. Langerhans cells have CD1 antigen on the cell surface and demonstrate positive immunohistochemical staining for S100 protein. An increase in Langerhans cells can be found in healthy smokers and in idiopathic pulmonary fibrosis. In PLCH, these cells are found in larger numbers in clusters, although there is no consensus as to the numbers of these cells required to make a diagnosis of PLCH.

Pulmonary involvement is seen in 10% of cases, and patients present with progressive breathlessness, dry cough, chest pain, and spontaneous pneumothorax, which can be recurrent in 15—25%. The HRCT will demonstrate characteristic cysts and nodules, predominantly in the upper zones (Figure 7.31, Figure 7.32). If the radiological picture is not typical, lung biopsy can be performed to make the diagnosis. Lung function tests demonstrate reduced lung volumes and diffusing capacity and, in advanced disease, patients develop airflow obstruction. Hypercalcaemia is a common finding in patients with PLCH due to increased production of calcitriol.

The emphasis in adults presenting with pulmonary LCH is smoking cessation and symptomatic treatment with bronchodilators and oxygen if required. Lung transplantation should be considered in young patients with progressive disease.

Figure 7.31 CXR of pulmonary Langerhans cell histiocytosis (PLCH).

Figure 7.32 HRCT thorax of pulmonary Langerhans cell histiocytosis (PLCH) showing multiple cysts in both lungs.

Pulmonary alveolar proteinosis (PAP)

PAP occurs due to accumulation of amorphous, periodic acid-Schiff (PAS)-positive lipoproteinaceous material composed of phospholipid surfactant and surfactant apoprotein in the distal air spaces of the lungs. There is no lung inflammation and the lung architecture is preserved. Congenital PAP occurs in neonates due to mutations in surfactant or mutations in the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, resulting in reduced or absent function of the GM-CSF receptor β-chain on mononuclear cells.

Secondary PAP can occur after inhalation of silica, aluminium dust, or titanium and after allogenic bone marrow transplantation for myeloid malignancy. It can be associated with haematological malignancies, haemolytic anaemia, polymyalgia rheumatica, ulcerative colitis, and granulomatosis with polyangiitis. Alveolar macrophage dysfunction due to altered GM-CSF function, impaired secretion of surfactant transport vesicles, impaired phagocytosis, and phagolysosome fusion results in an increased risk of opportunistic infections such as Nocardia, pneumocystis jiroveci, and mycobacterium tuberculosis.

The typical age of presentation for secondary PAP is 30—50 years, and it is twice as common in men as in women. PAP presents with insidious onset of dyspnoea in 55—80%, dry cough and expectoration of ‘chunky’ gelatinous material. Patients may also develop constitutional symptoms of fatigue, low grade fever, and weight loss. A third of affected patients are asymptomatic despite infiltration of the alveolar spaces. Physical examination is often normal, but 25% develop clubbing and cyanosis, and 50% develop crackles.

CXR of PAP shows bilateral, symmetric alveolar opacities located centrally in mid and lower zones, often in a bat-wing distribution (Figure 7.33). Segmental atelectasis can occur due to bronchiolar obstruction by thick, lipoproteinaceous material. In chronic cases, fibrosis can occur in foci or become extensive.

HRCT reveals ground-glass opacification in a homogeneous distribution, thickened intralobular structures and interlobular septa in typical polygonal shapes referred to as ‘crazy paving’ (Figure 7.34). The differential diagnosis for these radiological findings includes acute respiratory distress syndrome (ARDS), lipoid pneumonia, acute interstitial pneumonia (AIP), drug-related hypersensitivity reactions, and diffuse alveolar damage superimposed on usual interstitial pneumonia.

Lung function tests may show a restrictive ventilatory defect or an isolated decrease in diffusing capacity. Hypoxaemia and compensated respiratory alkalosis can worsen with exercise and suggest a right-to-left shunt.

Figure 7.33 CXR of pulmonary alveolar proteinosis (PAP) showing extensive shadowing.

Figure 7.34 CT thorax in pulmonary alveolar proteinosis (PAP) showing extensive ground-glass changes.

The absolute diagnosis of PAP is made at bronchoscopy. A BAL will have a milky appearance due to lipoproteinaceous material which will settle on standing and contain lamellar bodies composed of phospholipids. which are derived from type 2 alveolar epithelial cells and contain high levels of anti- GM-CSF. Transbronchial and open lung biopsies will reveal terminal bronchioles and alveoli filled with macrophages that are engorged with PAS-positive material, large acellular eosinophilic bodies in a background of eosinophilic granules and cholesterol crystals. Transbronchial biopsy will show thickened alveolar septa due to type 2 epithelial cell

hyperplasia with little or no inflammatory cell infiltration. Special stains to exclude infection, particularly fungal and protozoal, should always be done. Serum anti-GM-CSF level will be elevated, as will serum lactic dehydrogenase (LDH), which correlates with disease severity.

The treatment depends on the severity of symptoms and gas exchange abnormalities. Asymptomatic patients with minimal physiological impairment can be observed carefully, even if there are radiological changes. For those with mild symptoms, supplemental oxygen and close follow-up is recommended. For those with severe dyspnoea and hypoxaemia, whole lung lavage via a double-lumen endotracheal tube under general anaesthetic is indicated.

Administration of GM-CSF subcutaneously or by inhalation for idiopathic PAP is experimental, but is an option for adults who cannot undergo lung lavage or in those in whom lung lavage has failed. Glucocorticoids are contra-indicated in PAP. Other therapies include lung transplantation and plasmapheresis.

Pulmonary amyloidosis

Pulmonary amyloidosis results from the deposition of fibrils composed of low molecular weight subunits of 5—25 kD in the lungs. Amyloid deposits can infiltrate the trachea and the bronchial tree, causing hoarseness and airway obstruction. If severe, it can result in stridor and dysphagia from oesophageal compression. Some 1—2% of patients with systemic amyloidosis can develop persistent pleural effusions, caused either by pleural infiltration with amyloid deposits or secondary to amyloid-induced cardiomyopathy, and it can be difficult to differentiate between these. Parenchymal nodules (amyloidomas) can present as solitary pulmonary nodules. Rarely, pulmonary hypertension can occur due to amyloidosis.

A diagnosis of pulmonary amyloid is made with a lung biopsy which stains congo red and shows the typical apple-green birefringence with polarised microscopy. Management includes bronchoscopic laser resection or surgical resection of the areas involved. Management of amyloid- induced pleural effusions includes pleurodesis and bevacizumab, but persistent effusions confers a poor prognosis.

■ Diffuse parenchymal lung diseases (DPLD) are a heterogenous group of more than 300 disorders.

■ DPLD present with progressively worsening breathlessness, cough, and systemic symptoms.

■ DPLD can occur due to a variety of lung insults; so a detailed history, including duration of symptoms, occupational, social, and travel history will need to be elicited.

■ Patients presenting with a suspected DPLD will require HRCT, a BAL, and often a lung biopsy to make the diagnosis.

■ The diagnosis is made by careful correlation of the clinical features with the radiological and histological findings.

■ The management and prognosis of the individual DPLDs vary considerably, so it is essential to make the correct diagnosis.

■ Idiopathic pulmonary fibrosis (IPF) has a poor prognosis with a median survival of 2.8 years.

■ There is evidence that treatment of IPF with pirfenidone slows the rate of decline of the disease and stabilises it, but this drug has significant side effects.

■ Nintedanib also slows disease progression of IPF but has significant side effects.

■ NSIP is often secondary to CTD, but infection and HP need to be excluded.

■ NSIP responds to immunosuppression, and has a better prognosis than IPF, with a median survival of 4.5 years.

■ Sarcoidosis is the commonest DPLD worldwide and involves the lungs in 90% of cases.

■ Sarcoidosis can present acutely, with chronic symptoms or as an incidental finding in an asymptomatic patient.

■ Overall, pulmonary sarcoidosis has a good prognosis in stage 1 disease, with spontaneous resolution in most cases.

■ Patients with multisystem sarcoidosis, who do not improve with corticosteroids, or those who have significant side effects, may require steroid-sparing agents such as methotrexate, azathioprine or my- cophenalate mofetil.

■ Hypersensitivity pneumonitis develops due to the inhalation of antigens and can present acutely or more insidiously.

■ The management of HP includes removal of the antigen and, in some cases, immunosuppression with corticosteroids.

■ There are several different types of eosinophilic pulmonary diseases, most of which respond to corticosteroids.

■ Not all pulmonary eosinophilic diseases present with a peripheral eosinophilia.

■ The commonest causes of peripheral eosinophilia in the UK include asthma, allergy, and drugs.

■ LAM is a rare pulmonary disease that is associated with the tuberous sclerosis complex.

■ LAM is more common in women, and oestrogen is implicated in its development.

■ Patients with LAM often present with spontaneous pneumothorax.

■ PLCH is commoner in men and in smokers.

■ PLCH can present with spontaneous pneumothorax.

■ Smoking cessation is the most important intervention in the management of PLCH.

■ Pulmonary alveolar proteinosis is a rare condition which can be congenital or secondary to haematological malignancies and abnormalities of GM-CSF function.

■ PAP can be treated with whole lung lavage and/or GM-CSF.

■ Pulmonary amyloidosis is a rare cause of pulmonary nodules and can cause airway obstruction if it involves the main bronchi or trachea.

■ Pulmonary amyloidosis affecting the main airways can be treated with laser or surgical resection.

MULTIPLE CHOICE QUESTIONS

7.1 Which of the following radiological features suggest a diagnosis of IPF?

A Bilateral patchy consolidation

B Ground glass opacification

C Middle and upper zone distribution

D Perivascular beading

E Subpleural honeycombing

Answer: E

IPF is characterised by bilateral, basal, subpleural areas of reticulation and honeycombing. Patchy consolidation is seen with cryptogenic organising pneumonia, ground glass changes are seen most commonly with NSIP or HP and perivascular beading is seen in sarcoidosis.

7.2 What treatments have been shown in multicentre trials to have some positive effects in IPF?

A Cyclophosphamide

B Etanercept

C Methylprednisolone

D N -acetyl cysteine

E Pirfenidone

Answer: E

Pirfenidone has been shown in trials to reduce decline in FVC with disease stabilisation.

7.3 Which of the following DPLDs, have the best prognosis without treatment?

A Alveolar proteinosis

B Hypersensitivity pneumonitis

C Idiopathic pulmonary fibrosis

D Non-specific interstitial pneumonia

E Sarcoidosis

Answer: E

Sarcoidosis has the best prognosis overall, with most patients showing spontaneous remission within 2 years. IPF has the worst prognosis with a median survival of 2.8 years.

7.4 A 35-year-old woman presenting with tiredness and Stage 1 pulmonary sarcoidosis should be managed as follows

A Inhaled corticosteroid therapy

B Methotrexate

C Oral corticosteroids for six months

D Oral corticosteroids for two years

E Wait and watch policy

Answer: E

Some 55—90% of patients with Stage 1 pulmonary sarcoidosis will have spontaneous remission of their disease, so immediate treatment is not indicated.

7.5 Which of the following statements about Hypersensitivity Pneumonitis (HP) is true?

A Acute HP has a good prognosis if the antigen is removed

B The presence of serum precipitins is diagnostic of HP

C Farmer’s lung has a worse prognosis than pigeon fancier’s lung

D Chronic HP responds well to immunosuppression

E HP mainly affects the lung bases

Answer: A

Removal of antigen results in rapid symptomatic and radiological improvement in acute HP. The presence of serum precipitins (IgG) is not diagnostic as it merely indicates exposure to the antigen. Bird fancier’s lung has a worse prognosis than farmer’s lung because there is greater exposure in the former. Chronic HP, which presents with pulmonary fibrosis, does not respond well to immunosuppression. HP affects the mid and upper zones of the lungs.

7.6 Which of the following statements about COP is true?

A Clubbing is present in the majority with COP

B There is Eosinophilia in bronchoalveolar lavage

C HRCT shows basal honeycombing

D Improvement is seen with oral corticosteroids

E Symptoms resolve with intravenous antibiotics

Answer: D

Clubbing is not a feature of COP and BAL will usually show a lymphocytosis. HRCT will show patchy areas of consolidation and basal honeycombing is seen with IPF. COP does not respond to antibiotics, but will improve with corticosteroids.

7.7 Which of the following statements regarding eosinophilic lung disease is true?

A Eosinophilic lung disease is always associated with a peripheral eosinophilia

B The commonest cause of peripheral eosinophilia in the UK is acute eosinophilic pneumonia

C The diagnosis can be made from characteristic radiological features in most cases

D Most pulmonary eosinophilic conditions respond to corticosteroids

E Chronic eosinophilic pneumonia affects the lungs, heart and gastrointestinal system

Answer: D

Not all eosinophilic lung diseases result in peripheral blood eosinophilia, so tissue biopsy or a BAL is necessary if lung involvement is suspected. The commonest causes of a peripheral blood eosinophilia in the UK are asthma, allergy, and certain drugs. The features on a CXR or HRCT are not specific. Most eosinophilic conditions respond well to oral corticosteroids, therefore investigations must be done prior to treating with corticosteroids. Chronic eosinophilic pneumonia only affects the lungs.

7.8 Which of the following statements about lymphangioleiomyomatosis (LAM) is true?

A LAM occurs most commonly in young men

B LAM is strongly associated with cigarette smoking

C LAM is characterised by the deposition of thick, lipoproteinaceous material in the alveoli

D LAM predisposes to spontaneous pneumothorax

E Lung function demonstrates a restrictive process with reduced TLC

Answer: D

LAM is commoner in young women. There is no association with cigarette smoking. It is characterised by the development of thin- walled cysts, which is made worse by oestrogen. This increases the risk of a spontaneous pneumothorax. Although classified as a DPLD, LAM is more like emphysema and lung function tests show hyperinflation with increased TLC and RV.

7.9 Which of the following statements about pulmonary Langherhans cell histiocytosis (PLCH) is true?

A PLCH is associated with smoking

B PLCH is characterised by Schaumann bodies

C PLCH is characterised by abnormal surfactant production

D PLCH can be effectively treated with oestrogen therapy

E The condition will progress despite smoking cessation

Answer: A

PLCH is strongly associated with smoking and will improve with smoking cessation. It is characterised by Birbeck granules. Schaumann bodies are found in sarcoidosis and abnormal surfactant is seen in pulmonary alveolar proteinosis.

7.10 The treatment of choice for a symptomatic patient with secondary pulmonary alveolar proteinosis who has a diffusion capacity of 30% predicted is

A Inhaled GM-CSF

B Intravenous cyclophosphamide

C Lung transplantation

D Oral corticosteroids

E Whole lung lavage

Answer: E

Immunosuppression is contra-indicated in patients with PAP and GM-CSF is as yet only experimental therapy. Although lung transplantation can be considered in patients who have not responded to other treatments, whole lung lavage is currently the treatment of choice.

Appendix 7A Drugs that cause peripheral eosinophilia

■ ACE inhibitors

■ Aminosalicylates

■ Amiodarone

■ Ampicillin

■ Anticonvulsants

■ Antidepressants

■ Antimalarial drugs

■ Antituberculous medication

■ Betablockers

■ Bleomycin

■ Cephalosporins

■ Contrast given for radiology

■ H2-receptor antagonists

■ Methotrexate

■ Minocycline

■ Nitrofurantoin

■ NSAID

■ Proton pump inhibitor

■ Sulphonamides

■ Tetracycline

This lists some of the common drugs associated with a peripheral eosinophilia. See www. pneumotox.com for a comprehensive list of medications causing eosinophilia.

FURTHER READING

American Thoracic Society (ATS) (2017) ATS official documents: statements, guidelines and reports. [online] Available at: http://www.thoracic.org/ about

American Thoracic Society American Thoracic Society/European (ATS) and European Respiratory Society (2002). Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. American Journal of Respiratory and Critical Care Medicine 165 (2): 277-304.

ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis, Raghu, G., Collard, H.R. et al. (2011). An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. American Journal of Respiratory and Critical Care Medicine 183 (6): 788-824.

Barnard, J., Rose, C., Newman, L. et al. (2005). Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS). Journal of Occupational and Environmental Medicine 47 (3): 226-234.

Bradley, B., Branley, H., Egan, J. et al. (2008). Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 63 (Supplement 5): v1-v58.

Collard, H.R., Moore, B.B., Flaherty, K.R. et al. (2007). Acute exacerbations of idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 176 (7): 636-643.

Gibson, G.J., Prescott, R.J., Muers, M.F. et al. (1996). British Thoracic Society Sarcoidosis study: effects of long-term corticosteroid treatment. Thorax 51 (3): 238-247.

Hunninghake, G.W., Costabel, U., Ando, M. et al. (1999). Statement on sarcoidosis: Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ER. American Journal of Respiratory and Critical Care Medicine 160 (2): 736-755.

King, T.E. Jr. (2005). Clinical advances in the diagnosis and therapy of the interstitial lung diseases. American Journal of Respiratory and Critical Care Medicine 172 (3): 268-279.

King, T.E. Jr., Bradford, W.Z., Castro-Bernardini, S. et al. (2014). A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England Journal of Medicine 370 (22): 2083-2092.

Liebow, A. (1975). Definition and classification of interstitial pneumonias in human pathology. Progress in Respiratory Research 8: 1-33.

Martinez, FJ., de Andrade, J.A., Anstrom, K.J. et al. (2014). Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. The New England Journal of Medicine 370 (22): 2093-2101.

Noble, P.W., Albera, C., Bradford, W.Z. et al. (2011). Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377 (9779): 1760-1769.

Paramothayan, S. and Jones, P. (2002). Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. Journal of the American Medical Association 287 (10): 1301-1307.

Richeldi, L., du Bois, R.M., Raghu, G. et al. (2014). Efficacy and safety of Nintedanib in idiopathic pulmonary fibrosis. New England Journal of Medicine 370 (22): 2071-2082.

Schwartz, M.I., King, T.E. Jr., and Raghu, G. (2003). Approach to the evaluation and diagnosis of interstitial lung disease. In: Interstitial Lung Disease, 4e (ed. M.I. Schwartz and T.E. King), 1-30. USA, Shelton, CT: People’s Medical House Publishing.

The Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu, G., Anstrom, K.J. et al. (2012). Prednisone, azathioprine and N-acetylcysteine for pulmonary fibrosis. New England Journal of Medicine 366 (21): 1968-1977.