on identifying the underlying known causes of ILD. If a speci c diagnosis is not made, then an MDD focused on clinicalndings, HRCT features, and, as appropriate, lung biopsy may help in determining or excluding IPF diagnosis.

Clinical Diferential Diagnosis of the UIP

Pattern

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary brosis is the most common type of idiopathic interstitial pneumonia. It is de ned as a speci c form of chronic, progressive brosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP [13]. However, as discussed previously, a UIP pattern is not synonymous with IPF and the differential diagnosis with other ILDs showing a UIP pattern may be hard, requiring the thorough exclusion of all known causes of pulmonary brosis [14].

The disease should be suspected particularly in male, current or ex-smokers, about 60 years of age, with unexplained dry cough and exertional dyspnea and should be discussed

during an MDD. An integrated approach is particularly necessary in cases of discordant radiological and/or histopathological abnormalities (e.g., HRCT inconsistent with UIP, but SLB suggestive of UIP) [14]. Differentiating between IPF and “secondary” UIP has well-de ned therapeutic and prognostic implications.

In the next paragraphs, we will describe the ILDs showing a UIP pattern and the potential ndings useful for a differential diagnosis with IPF.

Chronic Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is an interstitial lung disease that results from repeated inhalation and sensitization to various antigens [15], and appears to be driven by cell-­ mediated immunity. HP is classi ed clinically as acute, subacute and chronic.

Alternatively, Vasakova and colleagues proposed a new classi cation method, including two main categories based on clinical-radiologic-pathologic correlation: an acute/ infammatory HP and a chronic/ brotic HP, avoiding the term “subacute” [16] (Fig. 32.2). The acute/infammatory HP form shows symptom duration usually within 6-months,

Fig. 32.2  Novel classi cation of hypersensitivity pneumonitis. (Modi ed from [16]). HP hypersensitivity pneumonitis, HRCT high-resolution computed tomography, NOS not otherwise speci ed, NSIP nonspeci c interstitial pneumonia, UIP usual interstitial pneumonia

is often reversible, and is characterized by infammatory radiologic and histopathologic patterns. In contrast, the chronic/ brotic HP, is usually non-reversible and can show radiologic and/or histopathologic patterns including organizing pneumonia (OP), nonspeci c interstitial pneumonia (NSIP), and usual interstitial pneumonia (UIP).

At HRCT of the chest, honeycombing is frequent in CHP, although it has frequently a patchy, mid-upper predominance [16, 17]. Ground glass opacities and mosaic attenuation, indicating “air trapping”, are clues useful to differentiate CHP from IPF.

Speci c histological features of a UIP pattern in CHP include some “ancillary ndings,” such as centrilobular and bridging brosis, organizing pneumonia, bronchiolitis, granulomas, and giant cells [18]. Recent HP diagnostic criteria have been described in recent guidelines [19].

The prognosis of CHP is related to its histopathological patterns: cases of CHP with a UIP-like pattern tend to have the worst prognosis, and a course similar to that observed in IPF patients [20]. Similarities between IPF and CHP can result in clinically indistinguishable diseases and the latter can be misdiagnosed, particularly when the causative agent appears as unidenti able. This could be a frequent opportunity as can be observed in up to 50% of patients with brotic HP [16, 17].

Therefore, in the differential diagnosis between CHP and IPF, a very detailed clinical history is of paramount importance. Speci c questionnaires to identify potentially relevant exposures for HP have been proposed, but have not yet been validated [21].

Laboratory tests include the detection of precipitins or speci c IgG. However, positivity to these tests indicates exposure, but not necessarily disease. In contrast, negativity is not discriminatory, as they disappear with time [21].

Bronchoalveolar lavage (BAL) lymphocytosis has been proposed as a diagnostic criterion for HP diagnosis [22]. However, the ability of BAL fuid lymphocyte analysis to discriminate between HP from other ILDs, including sarcoidosis and IPF, is unknown, as is the optimal threshold

BAL lymphocyte count to diagnose HP [10–12]. A recent systematic review showed that—although the percentage of BAL fuid lymphocytes is higher in CHP than in IPF or sar- coidosis—a threshold that distinguishes HP from IPF or sarcoidosis with both high sensitivity and high speci city was not identi ed [23].

Connective Tissue Disease

Connective tissue diseases (CTDs), also referred to as collagen vascular diseases, are a group of diseases characterized by circulating autoantibodies and systemic manifestations considered to be related to autoimmune-mediated organ damage [24]. The spectrum of CTDs encompasses rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), infammatory idiopathic myopathy (dermatomyositis, polymyositis, myositis associated with anti-synthetase antibodies), and mixed CTD, each of them with international consensus diagnostic criteria [25].

Interstitial lung disease (ILD) can occur in any CTD with different frequencies and severity [26, 27]. The only current classi cation of CTD-ILD is the histological classi cation of idiopathic interstitial types of pneumonia (IIP) [24]. All histological patterns are seen in IIP [28], including the UIP pattern, are also reported to occur in CTD-ILD [29] (Table 32.1). However, in various CTD-ILDs, NSIP is the most prevalent histological pattern, including in ILD associated with SSc [30], polymyositis–dermatomyositis [31], and pSS [32]. In contrast, a UIP pattern may be prevalent in patients with RA [33] and less frequently in SSc [25]. Furthermore, in these disorders, whether the histological distinction between UIP and NSIP has prognostic importance is unclear [24]. In SSc-­ ILD, a histological pattern of UIP was not associated with a worse outcome in the largest histological series of 78 patients [30], although this conclusion has been questioned in one small series, in which UIP was associated with a very poor outcome [34].

In contrast, various data suggest that UIP is more prevalent than NSIP in RA; moreover, UIP appears to have a worse prognosis than NSIP in some series [35, 36].

Patients with RA-ILD with a histologic UIP pattern are usually older, male, and smokers or former smokers compared with patients with RA-related ILD with a non-UIP pattern [37] and showed a poorer prognosis compared with patients with an RA-ILD showing a non-UIP pattern [24].

ILD may be detected at any point in the natural history of a CTD [25]. This complexity explains the potentially dif cult differential diagnosis with IPF. In fact, ILD may develop in the context of an already diagnosed CTD with characteristic manifestations. However, ILD may be therst presenting manifestation of a CTD, the features of which may not yet have been identi ed, the ILD may be initially diagnosed as an IIP, including IPF if a UIP pattern is detected, and CTD diagnosis may be challenging, mainly because systemic symptoms may be absent or subtle. There is no standardized approach to the assessment for underlying CTD in patients initially diagnosed as affected by IIPs. However, in clinical practice, detailed history and physical examination are required, together with testing for circulating autoantibodies. In this context, when clinical exams and laboratory testing arise suspicion of an underlying CTD, a multidisciplinary approach represents the diagnostic “gold standard.” Therefore ILD might be the rst sign of a yet uncovered CTD: in this case a followup is crucial.

Moreover, patients with interstitial pneumonia can present with some aspects of CTD, but not enough to diagnose a speci c CTD diagnosis. These patients, in whom it seems that the lung is the only or most clinically important manifestation of an occult CTD, are suspected of having a systemic autoimmune disease. The latter might be identi ed by the presence of circulating autoantibodies, speci c histopathological features on surgical lung biopsy samples, or subtle extra-thoracic manifestations these patients are classi ed as having an “interstitial pneumonia with autoimmune features” (IPAF), rather than an idiopathic disease. IPAF however is a research tool, rather than an established diagnosis at the present moment [38]. In this speci c setting, a multidisciplinary discussion may con rm the absence of criteria to de ne a speci c CTD and decide on the speci c treatment and follow-up [39].

Drug-Induced Lung Diseases

Many drugs have been related to the possible onset of ILD, showing that ILDs represent between 1.8% and 2.1% of the total number of ILDs in Italy, 2.6% in Germany and between 1.9%, and 3.5% of total ILDs in the USA [40]. However,

there are no de nitive data and the real incidence of drug-­ induced ILDs is probably still underestimated.

A paradigmatic drug in inducing pulmonary toxicity is amiodarone, which is an antiarrhythmic agent commonly used to treat supraventricular and ventricular arrhythmias. Although the broad heterogeneity of the clinical and radiological picture of amiodarone-induced pulmonary toxicity, irreversible pulmonary brosis and ARDS are the most serious manifestations of amiodarone-induced lung toxicity [41].

In various publications describing patients affected by amiodarone pneumonitis, septal thickening, non-speci c infammation and interstitial brosis in combination with the presence of lipids within interstitial, endothelial and alveolar cells have been described [41, 42].

Amiodarone pneumonitis is more frequent in male patients and is unusual in patients who are younger than 40. The risk of developing pulmonary toxicity in patients taking amiodarone increases with age, and, on average, with daily dosage of the drug [43].

The prevalent histological and radiological pattern of amiodarone-induced pulmonary brosis is classi ed as a NSIP type [42, 44]. However, interstitial reticular opacities, and traction bronchiectasis with subpleural and basal predominance have been observed on HRCT in cases of pulmonary brosis [41, 43]. Honeycombing is unusual at the time of diagnosis [43]. Amiodarone-induced pulmonary brosis is irreversible, response to corticosteroids is very limited or of short duration, and the disease adversely impacts life expectancy [43]. Amiodarone-induced pulmonary brosis appears milder and slowly progressive compared to IPF [41]. The histopathologic features of amiodarone-induced pulmonary brosis showed thickened alveolar septa, type II cell hyperplasia/dysplasia, and the accumulation of foamy alveolar macrophages [43]. Alveolar foam cells are seen, depending on the time from biopsy to discontinuation of the drug.

In conclusion, although amiodarone is characterized by various clinical entities, pulmonary brosis may occur; the most frequent pathological and radiological pattern is considered NSIP, but also—in a few cases—a UIP pattern may be identi ed with a need for a differential diagnosis also with IPF.

Radiation Pneumonitis

The lung is susceptible to radiation damage more than any other organ and then it tends to be easily damaged by radiation beams. The functional unit that is highly sensitive to ionizing radiation is the alveolar-capillary barrier [45]. In lung cancer, it is estimated that about 5% to nearly 40% of lung cancer patients will develop radiation-induced lung injury.

Radiation-induced lung disease following radiotherapy is separated into two phases: an acute phase, characterized by lung infections and pneumonitis, that usually occurs during the rst 6-months, and a permanent phase, in which the prominent radiological feature is characterized by pulmonary brosis and occurs at least 6-months after radiotherapy [46] and it is characterized by a tissue repair response triggered by chronic infammation. It can continuously progress for several years.

Although the opacities of radiation pneumonitis can gradually resolve without radiologic sequelae when the injury to the lung is limited, in cases of more severe injury there is usually a progression to brosis [46]. Radiation brosis manifests at HRCT as a well-de ned area of volume loss, linear scarring, consolidation, and traction bronchiectasis. Consolidation usually coalesces and typically has a relatively sharp border that conforms to the treatment portals rather than to anatomic boundaries [47]. Occasionally, thesendings are associated with ipsilateral displacement of the mediastinum and adjacent pleural thickening or effusion [47]. With the evolution of radiation brosis, the demarcation between normal and irradiated lung parenchyma often becomes more sharply de ned [47].

Currently, there are no approved treatment options for patients with radiation-induced pulmonary brosis partly due to the absence of effective targets [48].

Asbestosis

Asbestos is related to a group of naturally occurring bers composed of hydrated magnesium silicates that are commercially valuable due to its strength, fexibility, and resistance to electrical, thermal, and chemical degradation. Two categories of asbestos exist serpentine, long, curly bers; and amphibole—long straight rod-like structures. Chrysotile is the only signi cant commercially used serpentine ber. Amphibole bers include crocidolite, amosite, anthophylite, actinolite, and tremolite. Chrysotile ber use is more common, whereas amphibole bers are considered more toxic [49]. In addition to its association with lung cancer, mesothelioma, small airways disease, and pleural disease, asbestos exposure can lead to asbestosis, a form of interstitial lung disease often indistinguishable from IPF [50].

As discussed above, the diagnostic work-up of any patient with ILD includes a comprehensive history, high-resolution chest CT scan, and pulmonary function testing. Biopsies are not routinely required [51].

Given the long latency between exposure and disease, clinicians should consider present and past jobs and employers, as well as the presence of disease among co-workers.

Whereas asbestosis CT scans may appear indistinguishable from IPF patients, the presence of certain radiographic

clues may be particularly helpful in patients who have indeterminate or unknown asbestos exposure. Such clues include the presence of pleural diseases such as pleural plaques and pleural thickening. Bilateral pleural plaques are very speci c for asbestos exposure [51].

For the asbestosis patient, a strong exposure history in the presence of brotic lung disease on HRCT is suf cient for diagnosis and does not require further investigation. Therefore, histopathologic con rmation is not usually required.

In the absence of a de nitive UIP CT scan, surgical lung biopsy should be considered. Whereas histopathologic ndings in advanced asbestosis usually show a UIP pattern, early asbestosis features may show only a bronchiolocentric disease. In contrast to UIP, broblastic foci are less prominent, whereas mild brosis of the visceral pleura is more commonly seen [51].

Hermansky-Pudlak Syndrome

The Hermansky-Pudlak syndrome (HPS) is a group of autosomal-­recessive disorders characterized by tyrosinase-­ positive oculocutaneous albinism, bleeding diatheses, and, in selected individuals, neutropenia, granulomatous colitis, and early onset accelerated pulmonary brosis, the latter occurring only in HPS-1, HPS-2, and HPS-4 [52]. So far, 10 genetically distinct subtypes (HPS-1 to HPS-10) exist [52].

Patients affected by HPS generally develop ILD in the third decade of life [53] but some reports indicate the presence of symptomatic lung disease in late adolescence [53]. The diagnosis of ILD is established with a chest HRCT scan because lung biopsy is not recommended for ILD diagnosis in HPS patients, because the risk of bleeding is considerable and the pretest likelihood that brotic changes are very high in HPS patients [53]: for all these reasons surgical lung biopsy is usually not recommended. Chest HRCT in general shows reticular opacities, thickened interlobular septa, and groundglass in ltrates in addition to traction bronchiectasis and honeycombing [54]. These imaging ndings progress over time. The severity of changes in HRCT has been shown to correlate with a decline in lung function and mortality [54].

When available, lung tissue from HPS patients with pulmonary brosis has shown changes that are similar to the UIP pattern characteristic of IPF. Additional characteristic changes are foamy swelling of alveolar macrophages and epithelial cells.

Similar to IPF, pulmonary brosis in the framework of HPS is characterized by progressive diseases, ultimately leading to death from respiratory failure [55]. similarly to IPF, including increased dyspnea initially manifesting only on exertion and subsequently progressing to dyspnea at rest and the need for supplemental oxygen over time.