CHAPTER 7 Diffuse parenchymal lung diseases (DPLDs) are a heterogeneous group of about 200 different non‐neoplastic 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. 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. 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. 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 bronchoalveolar 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). 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) 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). Figure 7.2 Pathophysiology of pulmonary fibrosis. 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. 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 7–16/100 000 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. 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 tachypnoea, 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. 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. 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). 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. 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. 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. Nintedanib 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‐α therapies. There is some evidence that micro‐aspiration 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. NSIP is called ‘non‐specific’ 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). Figure 7.7 Prognosis in UIP, NSIP, and other fibrotic lung diseases. Some 88% of patients with NSIP have clinical features of an undifferentiated connective tissue disease, including sicca symptoms, arthralgia, dysphagia, Raynaud’s symptoms, and gastro‐oesophageal 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. 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. 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 multinucleated giant cells. Focal areas resembling the changes seen in cryptogenic organising pneumonia (COP) can also occur. 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. 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) 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. 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. 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. 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. Figure 7.13 CT thorax of respiratory bronchiolitis‐interstitial lung disease (RBILD). 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 Sjögren’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. 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. 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 × 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. Table 7.1 Causes of eosinophilia. 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 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. In sarcoidosis, there is accumulation of CD4 lymphocytes within the organs involved, with a corresponding depletion in CD4 CElls 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‐Guérin (BCG) vaccination. IL‐2, IL‐12 and IFN‐γ 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‐α is a non‐specific, but potent, pro‐inflammatory cytokine in sarcoidosis. Sarcoidosis can present acutely or chronically. In many cases the diagnosis is made incidentally in an asymptomatic patient. 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. Figure 7.16 Erythema nodosum. Figure 7.17 Anterior uveitis with arrow showing hypopyon.
Diffuse parenchymal lung disease
Abbreviations
Introduction
Diagnosis of DPLD
Investigations in a patient suspected of a DPLD
Idiopathic interstitial pneumonias (IIP)
Pathophysiology
Idiopathic pulmonary fibrosis (IPF)
Clinical presentation of IPF
Investigations in IPF
Management and prognosis in IPF
Non‐specific interstitial pneumonia (NSIP)
Clinical presentation of NSIP
Investigations in NSIP
Management of NSIP
Prognosis in NSIP
Cryptogenic organising pneumonia (COP)
Desquamative interstitial pneumonia (DIP)
Respiratory bronchiolitis interstitial lung disease (RB‐ILD)
Lymphoid interstitial pneumonia (LIP)
Acute interstitial pneumonia (AIP)
Eosinophilic lung disease
Condition
Clinical presentation
Onset
Peripheral blood
Eosinophilic lung involvement
Skin involvement
Other organ involvement
Radiological changes
Allergic asthma, common Good prognosis
Dyspnoea
Wheeze
Weeks to months
Mild eosinophilia
Raised IgE
None
None
None
Hyperinflated
Allergy, common Good prognosis
Dyspnoea
Wheeze
Hours to days
Eosinophilia
Raised IgE
Positive RAST to allergen
None
Positive skin prick tests to allergens, rash
Upper airways
Skin
Gastrointestinal tract
Normal
ABPA, relatively common Usually not fatal but difficult to eradicate
Dyspnoea Wheeze Cough Systemic symptoms
Weeks to months
Eosinophilia, Raised IgE, Raised aspergillus IgG, Positive aspergillus skin prick test
None
Positive skin prick to aspergillus
None
Proximal bronchiectasis with bronchial wall thickening, mucous plugging, and areas of atelectasis.
Eosinophilic granulomatosis with polyangiitis (EGPA) previously called Churg‐Strauss Syndrome. Significant morbidity and mortality if untreated
Breathlessness Wheeze Rhinitis
Fever
Malaise Weight loss
Weeks to months
Eosinophilia
Eosinophilic lung infiltration
Eosinophilic infiltration resulting in rash, palpable purpura, and nodules
Eosinophilic infiltration of upper airways, kidneys, gastrointestinal tract, heart, and peripheral nervous system
Bilateral, peripheral pulmonary infiltrates, pleural effusion
Hypereosinophilic Syndrome (HES). Rare, some associated with an abnormality of the tyrosine kinase fusion protein. Fatal if untreated. OCS effective. Mepolizumab if associated with genetic abnormality Splenectomy
Fever
Weight loss Cough
Dyspnoea
Night sweats Pruritis
Weeks to months
Very high peripheral eosinophil count (>1.5 × 109 l−1
High eosinophils, some of which are abnormal with a decrease in number and size of granules
Eosinophilic infiltration of skin
Eosinophilic tissue infiltration of many organs: heart, peripheral nervous system, and spleen. Increased risk of thromboembolic disease
Patchy ground glass opacities and areas of consolidation
Acute Eosinophilic Pneumonia. Idiopathic, can cause diffuse alveolar damage and progress to ARDS and respiratory failure. Responds to corticosteroids
Severe dyspnoea
Non‐productive cough
Fever
Hypoxia Myalgia
Rapid onset, over a few days
Normal peripheral eosinophil count initially, but may increase over time
Very high eosinophils in sputum and BAL (>25%)
None
None
Non–specific ground glass opacification with areas of consolidation, interlobular septal thickening, and pleural effusion
Chronic Eosinophilic Pneumonia. Idiopathic, commoner in women and non‐smokers, may be commoner in those who have had radiotherapy for breast cancer. Responds to corticosteroids but can be recurrent
Dyspnoea Productive cough, Haemoptysis Wheeze
Fever
Weight loss Night sweats. In 50% asthma‐like symptoms precede development of eosinophilia
Weeks to months
Peripheral eosinophilia in 80%
High eosinophils in sputum or BAL (> 40%). Nodular mucosal lesions with necrotising eosinophilic inflammation
None
None
Characteristic bilateral, consolidative, and ground glass areas which are peripheral and in the middle and upper zones. Pleural changes can occur
Tropical pulmonary eosinophilia occurs in those who have travelled abroad. Secondary to immune response to the parasites Wucheria bancrofti and Brugia Malayi, endemic in Asia and South America. Characterised by remissions and relapses. Successfully treated with diethylcarbamazine
Dyspnoea Productive cough
Wheeze
Chest pain Haemoptysis
Fever
Fatigue
Weight loss
Weeks to months.
Significant peripheral eosinophilia > 3 × 109 l−1. Serum IgE> 1000 kU l−1 and increase titres of antifilarial IgG
Eosinophils in sputum and BAL
None
Gastrointestinal tract
Normal in 70% but showing diffuse reticulonodular opacities and mediastinal lymphadenopathy in 30%
Simple pulmonary eosinophilia (Löffler’s syndrome), now used to describe acute onset pulmonary eosinophilia. Originally described in cases secondary to parasitic infection with Ascaris lumbricoides, strongyloidis stercoralis, ancyclostoma duodenale or necator americanus. Treatment with antihelminth drugs
Cough
Malaise Anorexia Rhinitis
Night sweats Fever
Dyspnoea Wheeze
Over days to weeks
Low level peripheral eosinophilia
Sputum may be blood‐tinged and show eosinophils, larvae, and Charcot‐Leyden crystals
None
Gastrointestinal system
Flitting opacities ranging in size from a few mm to a few cm.
Clear spontaneously after several weeks
Drug‐induced
Cough Dyspnoea Hypoxia
Hours to days of taking new drug
Peripheral eosinophilia
None
Skin rash, infiltration of skin
None
Normal
Sarcoidosis
Clinical presentation of sarcoidosis
Acute sarcoidosis (Löfgren’s syndrome)
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