One important difference between IPF and HPS-PF is the age of diagnosis, as the disease occurs much earlier in HPS patients [55].

Another major difference is that the survival after diagnosis differs from IPF: the survival rate is much better in HPS patients, who usually live approximately 10 years after diagnosis [55]. Treatment options for individuals with HPS include pirfenidone and lung transplantation [56].

Non-IPF Progressive Fibrotic Interstitial Lung

Diseases

Pulmonary brosis can occur in many ILDs, including those in the context of underlying systemic diseases, such as CTDs or sarcoidosis, and conditions that are limited to the lung, such as CHP, drug-induced pulmonary brosis, idiopathic non-speci c interstitial pneumonia, and IPF [57].

The natural course of IPF without anti brotic treatment is characterized by progression to respiratory failure in potentially every patient with a de nite diagnosis [14].

In contrast, about half of all patients with a diagnosis of pulmonary brosis other than IPF have stable, chronic disease or improvement with immunomodulatory agents [58].

However, despite appropriate treatment, a subgroup of patients with various non-IPF ILDs will show progressive pulmonary brosis associated with worsening respiratory symptoms, a decline in lung function, a decreased quality of life, and a risk of early death, independent of the speci c type of the ILD [59] (Fig. 32.3). Outcomes may be similar to those of IPF, especially in patients with a UIP pattern, such as those with RA–ILD and a subgroup of patients with CHP [60].

At this stage, there is no universal de nition of disease progression in patients with pulmonary brosis and various

Fig. 32.3  Interstitial lung diseases that may be associated with a progressive brosing phenotype. (Modi ed from Cottin V. Eur Respir. Rev. 2019 Oct 1;28(153):190109)

de nitions of the term “progressive” have been proposed in the context of brotic lung disease [60].

In the INBUILD study, among patients with brosing lung disease affecting >10% lung volume on HRCT, progression was de ned as satisfying at least one of the following within 24 months: (1) relative decline of FVC of 10% predicted, (2) relative decline in FVC of 5% to <10% and worsening respiratory symptoms or increased brosis on HRCT, (3) worsening respiratory symptoms and increasedbrosis on HRCT [61].

Cottin and colleagues de ned “progressive” patients with a brotic lung disease as meeting one of the following criteria within 24 months: (1) relative decline of ≥10% FVC, (2) relative decline of ≥15% DLCO, or (3) worsening symptoms or worsening radiographic appearance with ≥5–10% relative decline in FVC [57].

A recent position paper from the “Erice ILD working group” de ned progressive brosis in clinical practice as a demonstration of one or more of the following over 24 months in spite of treatment: (1) relative decline of ≥10% FVC, (2) relative decline of ≥5% FVC with a decline in DLCO of ≥15%, (3) relative decline of FVC of ≥5% with increased brosis on HRCT, (4) relative decline of FVC ≥5% with progressive symptoms, (5) progressive symptoms with increased brosis on HRCT [59].

The main challenge of such criteria includes how to measure worsening of respiratory symptoms as well as other factors that may be considered as surrogate of progression, such as a reduction in exercise capacity and a worsening quality of life.

Risk Factors for Progression

Various risk factors predispose some patients to progressive fibrosis. In fact, patients with a UIP pattern showed the greatest rate of decline and the poorest survival compared to other patients with a progressive ILD [59]. For example, patients with RA-ILD and a UIP pattern might have a similar survival to patients with IPF [33]. Similarly, patients with CHP and a UIP pattern have survival rates similar to IPF patients [62]. In CHP, also older age is considered an independent prognostic factor for poor survival [62].

Patients with extensive brotic lung disease showed also the greatest risk of disease progression. In patients with SSc-­ ILD - those with extensive disease - de ned by an ILD extent on HRCT of more than 20% or, if indeterminate on HRCT, an FVC of less than 70% of the predicted value, have more than a three-times increased risk of death than those with less extension disease [63]. Similarly, in patients with RA-ILD the HRCT disease extension is associated with poorer survival [64]. In patients with ILD, it is also hypothesized that

gastro-esophageal refux disease is associated with progressive brosis through repeated microaspiration events [65].

In patients with brotic HP, the absence of an identi ed antigen is, therefore, a risk factor for poor prognosis, with a higher risk of progressive brosis. This is an example that highlights the central importance of establishing a precise diagnosis when assessing patients with brosing ILD.

Little is known regarding which patients with non brotic ILD may progress to a brotic ILD [58, 59]. A recent study of 245 patients with brosing ILD followed at two Italian ILD referral centers found that 31% had progressive disease with iNSIP, CTD-ILD, chronic HP, and sarcoidosis most likely progressive [66]. Progression was de ned based on the INBUILD trial criteria; most of the patients met criteria for progression based on an FVC decline of ≥10%. In a similar vein, a study of pulmonologists experts in the ILD eld - reported physician estimates that 18–32% of patients with non-IPF ILD will have progressive brosis [67]. In this study, unclassi able ILD, RA-ILD, idiopathic NSIP and SSc-ILD were identi ed as the ILDs most often evolving to a progressive brotic phenotype [67].

Diagnosis

A detailed history, including environmental exposures, medication use, and extrapulmonary signs, should be carefully identi ed [6]. Serologic testing is recommended, at least for antinuclear antibodies and anti-citrullinated peptide antibodies [6]. If there is a clinical suspicion of an autoimmune condition, consultation with a rheumatologist—possibly in a multidisciplinary discussion - and more extensive serologic testing are recommended, including ANCA, rheumatoid factor, anti-ENA screen, that determines the levels of seven different autoantibodies including anti-Sm, anti-RNP, anti-SSA, anti-SSB, anti-Jo-1, anti-Scl 70, and anti-CENP-B. Each antibody (or combination of antibodies) is speci c to a different collagen disease.

Moreover, HRCT of the chest establishes the diagnosis of pulmonary brosis by revealing a UIP pattern (see radiological classi cation described by guidelines). In contrast, the most common pattern in CTD-ILDs, hypersensitivity pneumonitis, and drug-induced ILDs, together with an idiopathic clinical entity is that of NSIP, which consists of mixed reticulation and ground-glass attenuation to a varying extent, often with traction bronchiectasis, central axial distribution, and sparing of the subpleural area. Expiratory imaging may be useful, especially in CHP [28].

Lung function tests (LFTs) are useful to assess disease severity and - using serial LFTs - represents the most accurate tool for estimating ILD progression. Since FVC is highly reproducible, in the absence of major extrapulmonary restriction due to pleural disease or muscle weakness, changes in

FVC are speci c to ILD [68], together with a decreased diffusing capacity of the lung for carbon monoxide. However, normal lung function does not rule out the presence of pulmonary brosis. Bronchoalveolar lavage mainly contributes to the diagnosis of hypersensitivity pneumonitis and sarcoidosis.

A multidisciplinary approach is recommended in the diagnostic work-up of these patients. In fact, a multidisciplinary evaluation became the current diagnostic reference standard for ILD and is reported to improve diagnostic con-dence and agreement compared to individual participants of the MDD. This multidisciplinary team should require expert pulmonologists in ILD, expert ILD radiologists, rheumatologists, and histopathologists. Although a con dent diagnosis can be performed in the great majority of cases, a subgroup of ILD cases remains unclassi able even after thorough assessment [69].

Next to the MDD for diagnosis, there is a need for another multidisciplinary team that should be available for treatment and follow-up of these often complex clinical syndromes. This team should include specialists of different levels: pulmonologists rheumatologists, thoracic surgeons, cardiologists, specialist ILD nurses, physiotherapists, psychologists, and social workers [70].

Pharmacological Management

The natural history of IPF is variable and unpredictable, however, the great majority of patients experience a progressive, inexorable decline, nally leading to respiratory failure [71].

For decades, the recommended IPF treatment was the combination of steroids and immunosuppressive agents [2]. However, the PANTHER trial, designed to assess the ef - cacy of high dose prednisolone and azathioprine together with N-acetylcysteine, showed that immunosuppression was associated with a higher incidence of adverse events, including hospitalization, and death, proving de nitively that this combined regimen is deleterious [72].

In the last years, IPF therapy has considerably changed with the world-wide registration of two new anti brotic drugs, pirfenidone and nintedanib. Both drugs have been observed to reduce the annual rate of decline in forced vital capacity (FVC) in patients affected by IPF [73, 74]. In fact, FVC is considered the best surrogate for mortality in this disease. The use of both treatment options is recommended in the most recent IPF guidelines [75].

In contrast—despite the absence of “good quality” evidence coming from well-designed placebo-controlled tri- als—other forms of brotic interstitial lung disease, including iNSIP, CHP, sarcoidosis, and CTD-ILD, were still being treated with unapproved drugs - mainly systemic corticosteroids and/or immunosuppressants [76].