Idiopathic pulmonary fibrosis: clinical guidelines

List of Abbreviations

ILD - interstitial lung disease

IIP - idiopathic interstitial pneumonias

IPF - idiopathic pulmonary fibrosis

UIP – usual interstitial pneumonia

NSIP – nonspecific interstitial pneumonia

CPFE – combined pulmonary fibrosis and emphysema

PPFE – pleuroparenchymal fibroelastosis

CTD – connective tissue disease

CTD-ILD – connective tissue disease-associated interstitial lung disease

GER — gastroesophageal reflux

CT – chest computed tomography

HRCT – high-resolution chest computed tomography

CI – confidence interval

SLB – surgical lung biopsy

BAL – bronchoalveolar lavage

DAD – diffuse alveolar damage

ANA – antinuclear antibodies

CRP – C-reactive protein

RF – rheumatoid factor

ACPA – anti-citrullinated protein antibodies

MMP – matrix metalloproteinase

CK – creatine kinase

FVC – forced vital capacity

FVC – forced vital capacity

TLC – total lung capacity

RV – residual volume

DL_CO – diffusing capacity of the lungs for carbon monoxide

PAP – pulmonary artery pressure

mPAP – mean pulmonary arterial pressure

MCID – minimal clinically important difference

6MWT – 6-minute walk test

6MWD – 6-minute walk distance

GC – glucocorticosteroids

PH - pulmonary hypertension

PE – pulmonary embolism

OSA – obstructive sleep apnea

COPD – chronic obstructive pulmonary disease

CHD – coronary heart disease

LTOT – long-term oxygen therapy

SLB – surgical lung biopsy

MV – invasive mechanical ventilation

NIV – non-invasive ventilation

ARF – acute respiratory failure

MDM – multidisciplinary discussion

GRS – grade of recommendation strength

LoE – level of evidence -

OR – odds ratio

CI – confidence interval

Terms and Definitions

Interstitial lung diseases – a heterogeneous group of diseases and pathological conditions of known and unknown etiology, characterized by widespread, usually bilateral involvement of the respiratory compartments of the lungs (alveoli, respiratory bronchioles).

Idiopathic interstitial pneumonias are a group of interstitial lung diseases of unknown etiology characterized by predominant involvement of the interstitial tissue, a progressive fibrosing process in the lungs accompanied by progressively worsening dyspnea and restrictive impairment of ventilatory function over time.

Idiopathic pulmonary fibrosis is a specific form of chronic progressive fibrosing interstitial pneumonia of unknown etiology; it occurs predominantly in older adults, affects only the lungs, and is associated with the histological and/or computed tomographic pattern of usual interstitial pneumonia.

Nonspecific interstitial pneumonia is a form of idiopathic interstitial pneumonias characterized by diverse histological and computed tomographic features, often similar to idiopathic pulmonary fibrosis, but frequently demonstrating a positive response to glucocorticosteroids and a more favorable prognosis.

Honeycombing refers to clusters of air cysts ranging from 2–3 to 10 mm in diameter within the lung parenchyma, arranged in groups subpleurally, in multiple layers, with well-defined walls.

Traction bronchiectasis is the irregular dilation of bronchial and bronchiolar lumens caused by lung tissue fibrosis and the stretching (traction) of bronchial lumens resulting from progressive fibrosis.

Reticular changes represent a radiological sign on high-resolution chest computed tomography consisting of a network of relatively thin intersecting lines (thickening of the intralobular interstitium) that may form rings, polygons, or parallel lines.

“Ground-glass opacification” is a radiological sign on high-resolution chest computed tomography characterized by a mild to moderate increase in lung parenchyma attenuation, through which bronchial walls and lumens, intrapulmonary blood vessels, and any present nodules or reticular abnormalities remain visible.

Acute exacerbation of IPF is the worsening of dyspnea over the preceding 30 days with the appearance of new bilateral ground-glass opacities and/or consolidations on high-resolution chest computed tomography, after exclusion of alternative causes (such as infection).

Combined pulmonary fibrosis and emphysema is a syndrome combining features of two diseases: pulmonary fibrosis (predominantly in the lower lung zones) and emphysema (predominantly in the upper lung zones).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic progressive fibrosing interstitial pneumonia of unknown etiology that occurs predominantly in older adults, affects exclusively the lungs, and is associated with the histological and/or computed tomographic (CT) pattern of usual interstitial pneumonia (UIP) [1,2,3]. The histological pattern of UIP includes fibroblastic foci, chronic interstitial inflammation, and fibrosis predominantly distributed in bronchoalveolar junction zones and subpleural/paraseptal regions with honeycombing formation. The UIP pattern on high-resolution chest computed tomography (HRCT) includes widespread bilateral reticular abnormalities, honeycombing, and/or traction bronchiectasis with a predominance of changes in the cortical and basal lung regions.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of IPF is unknown, although several risk factors associated with IPF have been identified [4,5]:

• smoking. This is one of the most frequent risk factors with a proven reliable association with IPF. The significance of this risk factor increases in patients with a smoking history of more than 20 pack-years [6];

• non-smoking-related environmental inhalational exposures. An increased risk of developing IPF is associated with a wide range of inorganic and organic dusts, specifically metal dust (OR 2.44; 95% CI 1.74 – 3.40), wood dust (OR 1.94; 95% CI 1.34 – 2.81), and stone dust (OR 1.97; 95% CI 1.09 – 3.55). Inhalational exposure to organic dust (plant or animal origin) in agricultural or domestic settings is considered a potential risk factor (OR 1.65; 95% CI 1.20 – 2.26) [7];
• gastroesophageal reflux (GER). The relationship between GER and IPF has not been definitively established [8];
• metabolic (endocrine) disorders. Metabolic (endocrine) disorders (diabetes mellitus, hypothyroidism) occur significantly more frequently among IPF patients and are considered an independent risk factor for this disease [9,10];
• genetic factors. Approximately 5% of the overall IPF patient population has familial pulmonary fibrosis (among blood relatives). The MUC5B mutation is most frequently observed (in 34% of patients with familial pulmonary fibrosis and 38% of IPF patients) [11]; mutations in telomerase-related genes (TERT, TERC, DKC1, TINF2, RTEL1, PARN) causing telomere shortening are less common (in 25% of IPF cases and 15% of familial pulmonary fibrosis cases); mutations in surfactant protein C (SP-C) and A2 (SP-A2) genes occur in 3%, primarily in familial pulmonary fibrosis [12–16].

The pathogenesis of IPF is based on repetitive microinjuries to the alveolar epithelium accompanied by impaired regenerative mechanisms. This leads to aberrant re-epithelialization, fibroblast proliferation, and excessive extracellular matrix synthesis. As a result, normal lung parenchyma is progressively replaced by fibrous tissue [6].

1.3 Epidemiology of the Disease or Condition

It is believed that the number of IPF patients has increased in recent years. However, incidence and prevalence rates of IPF reported by various authors differ substantially, which can be explained by the lack of clear and universally accepted diagnostic criteria (both radiological and morphological), differences in study designs (different definitions of IPF, varying patient age distribution), and other factors. IPF incidence is age-dependent, with the disease occurring more frequently in the sixth and seventh decades of life. Most affected individuals are current or former smokers; men are affected slightly more often than women [17,18]. According to various sources, the incidence of IPF ranges from 6.8 to 63 cases per 100,000 population depending on the definition of IPF used [19–21].

According to preliminary data from the IPF registry in the Russian Federation, the prevalence of IPF in the Russian Federation is approximately 8–12 cases per 100,000 population, and the incidence is 4–7 cases per 100,000 population [22].

1.4 Features of Coding the Disease or Condition

Other interstitial pulmonary diseases (J84):

Other interstitial pulmonary diseases with mention of fibrosis (J84.1)

1.5 Classification of the disease or condition

There is no clinical classification of IPF. Based on the combination of specific computed tomographic and morphological patterns, the following can be distinguished:

• definite IPF (presence of a typical UIP pattern in a patient older than 60 years in the absence of clinically significant environmental and drug exposures and absence of connective tissue diseases; corresponding combination of HRCT and morphological patterns (App. D)) [23];
• probable IPF (corresponding combination of HRCT and morphological patterns (see App. D)) [23];
• combined pulmonary fibrosis and emphysema.

Example of diagnosis formulation:

a. Interstitial lung disease: idiopathic pulmonary fibrosis. Chronic hypoxemic respiratory failure.

b. Interstitial lung disease: idiopathic pulmonary fibrosis (combined pulmonary fibrosis and emphysema). Bullous emphysema of the upper lobes of both lungs. Chronic hypoxemic respiratory failure.

1.6 Clinical presentation of the disease or condition

The onset of the disease typically occurs at an age older than 50 years [18]; in patients with a family history of IPF, the disease may present at a younger age [24].

The main clinical manifestations of IPF are dyspnea, reduced exercise tolerance, and chronic cough, along with such nonspecific symptoms as fatigue, decreased appetite, and weight loss. Fever, peripheral lymphadenopathy, arthritis, myalgia, wheezing, hemoptysis, chest pain, and left heart involvement are not characteristic of IPF [23,25].

In the absence of exacerbations, the natural course of the disease is characterized by a gradual progression of symptoms over several years until the development of severe respiratory failure and complications [26].

The most frequent cause of death in IPF (60%) is progressive respiratory failure, as well as coronary artery disease (CAD), pulmonary embolism (PE), and lung cancer [27]. The median survival from the time of IPF diagnosis ranges from 2 to 3 years [1], and from the onset of initial symptoms and/or CT changes—6 years [28]. However, this figure may be higher in patients with preserved pulmonary function.

In 5–15% of patients with IPF, an acute deterioration of the clinical condition—IPF exacerbation—develops within a year [6]. The main signs of an IPF exacerbation are an unexplained worsening of dyspnea over 1 month, increased cough and sputum production, documented hypoxemia (worsened or severe gas exchange impairment), new alveolar infiltrates on chest radiography, and the absence of other causes of deterioration, such as extraparenchymal causes (pneumothorax, pleural effusion, PE) or heart failure with volume overload [26, 29–31]. The prognosis of an IPF exacerbation is generally unfavorable; in-hospital mortality reaches 65%, and within 6 months from the onset of the exacerbation—> 90% [26].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Clinical suspicion of IPF in a patient with chronic exertional dyspnea, cough, bilateral basal inspiratory crackles, and/or digital clubbing of unknown etiology should arise in the following situation: age over 60 years; absence of clinically significant environmental or drug exposures; absence of signs of systemic connective tissue diseases (CTDs) [17].

Criteria for establishing the diagnosis/condition:

1) complaints of dyspnea in the absence of obvious causes, clinically significant environmental or drug exposures; absence of signs of CTDs;

2) bilateral inspiratory crackles in the basal lung segments upon auscultation;

4) detection of a usual interstitial pneumonia (UIP) pattern on chest HRCT and/or upon pathomorphological examination of lung tissue biopsy specimens.

2.1 Complaints and Anamnesis

• When interstitial lung disease (ILD) is detected, a thorough history of medication use and environmental exposures at home, at work, and in other frequently visited places is recommended to rule out potential causes of ILD [23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5)

Comments: Clinical suspicion of IPF in a patient with chronic exertional dyspnea, cough, bilateral inspiratory crackles in the lung bases, and/or unexplained clubbing of the fingers should arise in the following scenario: age over 60 years; absence of clinically significant environmental or drug exposures; absence of signs of systemic connective tissue diseases (CTDs) [17].

• To assess dyspnea during daily physical activities in patients with IPF, the mMRC scale (App. G) is recommended [32].

GCR CLEL 4Grade of Recommendations C (Level of Evidence 4)

• To assess the severity and prognosis of IPF, the GAP scale (App. G2) is recommended [33].

GCR CLEL 4Grade of Recommendations C (Level of Evidence 4)

2.2 Physical Examination

In 40% of patients with IPF, varying degrees of digital clubbing and nail plate changes ("watch-glass nails") are detected at the initial examination. Bilateral end-inspiratory crackles («Velcro» rales) in the basal segments, detected upon auscultation, are also characteristic of patients with IPF and closely correlate with the presence of a usual interstitial pneumonia (UIP) pattern on chest HRCT [34].

• In all patients with IPF, it is recommended to evaluate the condition of the fingers and nail plates to rule out digital clubbing and nail changes.

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5)

Comments: The detection of digital clubbing and nail plate changes ("watch-glass nails") during the initial examination of a patient with IPF indicates an advanced stage of the disease and is associated with a poor prognosis [1].

• All patients with suspected IPF are recommended to undergo lung auscultation to detect bilateral crackles [34].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2)

2.3 Laboratory Diagnostics

• To rule out CTD-associated ILD (CTD-ILD), all patients with suspected IPF are recommended to undergo erythrocyte sedimentation rate (ESR) testing, blood C-reactive protein (CRP) level determination, antinuclear antibody (ANA) testing (by immunofluorescence), rheumatoid factor (RF) testing, anti-Sm antibody testing, and anti-cyclic citrullinated peptide (anti-CCP) antibody testing in the blood [23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5)

Comments: Patients with suspected IPF and symptoms of CTD require a more detailed investigation of CTD serum markers:

- if myositis is suspected: determination of blood creatine kinase activity, blood myoglobin level, blood aldolase activity, blood anticentromere antibodies, etc.;

- if systemic sclerosis is suspected: determination of antibodies to Scl-70 / topoisomerase-I in the blood, determination of anticentromere antibodies in the blood;

- if Sjögren's syndrome is suspected: determination of antibodies to SSA / Ro and SSB / La in the blood;

- if vasculitis is suspected: determination of markers for ANCA-associated vasculitis: PR3 (c-ANCA), MPO (p-ANCA).

The detection of CTD in a patient with interstitial lung changes excludes the diagnosis of IPF [1].

• All patients with IPF are recommended to regularly perform pulse oximetry ($SpO_2$) at rest and during exertion (during the 6-minute walk test [6-MWT]) to detect desaturation [1].

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5)

Comments: Detection of desaturation below 88% is an indication for oxygen therapy.

2.4 Instrumental Diagnostics

2.4.1. Radiological diagnostics

• Plain chest radiography is not recommended for patients with suspected IPF due to its low diagnostic value [37]. Grade of Recommendations C (Level of Evidence 3)
• All patients with suspected IPF are recommended to undergo chest HRCT to confirm the diagnosis of IPF [23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5)

• Chest CT with intravenous contrast is recommended for ILD patients only to rule out pulmonary embolism [23].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Technical requirements for chest HRCT in IPF patients:

- thin tomographic sections (≤1 mm) [38];

- high-spatial-resolution algorithm [39];

- images must be acquired at maximum inspiration;

- helical (volumetric) scanning;

- in case of equivocal findings in the supine position, scanning in the prone position is recommended to eliminate the "gravity effect" [40], along with expiratory CT to detect "air trapping" [41];

Changes on chest HRCT reflect morphological changes in the lungs, which in IPF present as a UIP pattern.

The main features of UIP on chest HRCT are:

- predominance of changes in the cortical and basal lung regions;

- diffuse bilateral reticular abnormalities;

- small subpleural air cysts ("honeycombing") and/or

- peripheral traction bronchiectasis or bronchiolectasis [42] (Fig. 1–3).

Ground-glass opacities may be present against the background of reticular changes and honeycombing, but should not predominate over other findings. Such ground-glass opacities are a sign of fibrosis [43].

Fig. 1. Usual interstitial pneumonia, typical HRCT pattern. a) axial section, b) coronal multiplanar reformation, c) sagittal multiplanar reformation, d) axial section in the prone position. Cortical distribution of changes with progression from the apices to the diaphragm, honeycombing, reticular changes, absence of ground-glass opacities. Examination in the prone position confirms the absence of ground-glass opacities.

Fig. 2. Usual interstitial pneumonia, typical pattern. Honeycombing on axial slice (a), with multiplanar reconstruction in coronal (b) and sagittal (c) planes.

Fig. 3. Usual interstitial pneumonia, typical pattern. Traction bronchiectasis in the cortical lung regions on oblique reconstruction (a) and axial slice (b)

Several UIP patterns are distinguished based on chest HRCT data (Table 1).

Table 1. Computed tomography diagnostic categories of UIP

Note: * - mild ground-glass opacities, reticular changes, and ossification may be present.

• In patients with a typical UIP HRCT pattern and clinical data consistent with IPF, lung biopsy (surgical, transbronchial, or cryobiopsy) and bronchoalveolar lavage (BAL) are not recommended to confirm the diagnosis [23].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: In the appropriate clinical context, the specificity of the typical UIP pattern for the diagnosis of IPF on chest HRCT reaches 94–100%, allowing a diagnosis of IPF to be established without invasive diagnostic procedures [44,45].

• In patients with suspected IPF and probable UIP, indeterminate for UIP, or alternative diagnosis patterns on chest HRCT, surgical lung biopsy is recommended to confirm the diagnosis [23].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: HRCT patterns of probable or indeterminate UIP are less specific for IPF and therefore require surgical lung biopsy for a more accurate prognosis assessment and selection of more specific therapy [23,46].

Currently, there is insufficient evidence to formulate recommendations for or against the use of other types of lung biopsy (transbronchial lung biopsy [TBLB] or cryobiopsy) in patients with suspected IPF and probable UIP, indeterminate for UIP, or alternative diagnosis patterns on chest HRCT [23].

• In patients with suspected IPF and probable UIP, indeterminate for UIP, or alternative diagnosis patterns on chest HRCT, bronchoalveolar lavage cytologic analysis is recommended for differential diagnosis with other ILDs [23].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: The cellular composition of BAL can assist in the differential diagnosis between IPF and other fibrosing ILDs. Specifically, the percentage of neutrophils in BAL is higher in IPF than in hypersensitivity pneumonitis, NSIP, and eosinophilic pneumonia; the percentage of eosinophils is lower than in eosinophilic pneumonia; the percentage of lymphocytes is lower than in NSIP, sarcoidosis, cryptogenic organizing pneumonia (COP), and lymphocytic interstitial pneumonia (LIP); the CD4 / CD ratio in BAL in IPF is lower than in sarcoidosis and higher than in NSIP [23].

• When a UIP pattern and emphysema are simultaneously identified on chest HRCT, it is recommended to specify the combination of pulmonary fibrosis and emphysema (CPFE) in the diagnosis due to the specific clinical course of this IPF phenotype [23].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: A clinical feature of the CPFE syndrome is the presence of severe dyspnea despite frequently normal spirometric values [1], as well as a high prevalence and severity of pulmonary hypertension, which significantly worsens the prognosis of the disease [47].

• Patients with suspected IPF, a UIP pattern, and signs of pleuroparenchymal fibroelastosis (PPFE) on chest HRCT should, following multidisciplinary discussion, be managed as patients with IPF due to the similar clinical course and prognosis of these conditions [23].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: PPFE is a progressive fibrosing ILD of unknown etiology. PPFE is typically characterized on chest HRCT by uneven pleural thickening and areas of subpleural pulmonary parenchyma consolidation in the upper and middle lung zones.

2.4.2. Morphological diagnostics

The cornerstone of the morphological diagnosis of IPF is the identification of the morphological UIP pattern.

• A morphological diagnosis of UIP is recommended for patients with ILD when lung tissue biopsies reveal heterogeneous architectural distortion of the lung due to areas of dense fibrosis, often with honeycombing, in combination with areas of less affected (or preserved) parenchyma and in the absence of features of an alternative lung disease [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: These histopathological changes are usually most prominent in the subpleural and paraseptal zones (Fig. 4). Interstitial inflammation is typically mild, presenting as focal infiltrates composed of lymphocytes and plasma cells. Fibrotic areas may contain so-called fibroblastic foci, consisting of proliferating fibroblasts and myofibroblasts (Fig. 5). Honeycomb changes represent cystic spaces with fibrotic walls, typically lined by bronchiolar epithelium, which may contain mucus and inflammatory cells (Fig. 6).

Fig. 4. Usual interstitial pneumonia: areas of fibrosis in subpleural and paraseptal zones

Fig. 5. Usual interstitial pneumonia: myofibroblastic focus at the transition of a respiratory bronchiole to alveoli

Fig. 6. Usual interstitial pneumonia: honeycombing

Several histological UIP patterns are distinguished (Table 2) [23].

Table 2. Histological patterns and features of UIP

Notes: * - Granulomas, hyaline membranes (differing from those seen in acute exacerbation of IPF), prominent peribronchial distribution of changes, areas of interstitial inflammation unrelated to fibrosis, marked chronic pleural fibrosis, organizing pneumonia.

# - Inflammatory cell infiltrates outside areas of honeycombing, marked lymphoid hyperplasia including secondary germinal centers, distinct peribronchial distribution of changes including extensive peribronchiolar metaplasia.

2.4.3. Functional diagnostics

Pulmonary function tests in patients with IPF typically reveal restrictive ventilatory defects with reduced lung volumes and decreased DL_CO [48].

• All patients with IPF are recommended to undergo measurement of unstimulated lung volumes and flows to determine the nature and severity of ventilatory impairment and to monitor the rate of IPF progression [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: The prognostic value of forced vital capacity (FVC) for mortality at the time of IPF diagnosis has not been definitively established; however, an absolute decline in FVC of >10% over 12 months of patient follow-up indicates disease progression and serves as a surrogate marker of mortality risk [1].

• All patients with IPF are recommended to undergo measurement of the diffusing capacity of the lungs for carbon monoxide (DLco) to detect gas exchange impairment in the lungs [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: A DLCO value <40% of predicted at the time of IPF diagnosis is a reliable risk factor for death [35]. A decrease in DLco in absolute values by >15% (with or without a concomitant decrease in FVC) over 12 months of follow-up, in the absence of alternative causes, indicates disease progression and is a surrogate marker of mortality risk [1]. In the early stages of IPF, an isolated decrease in DL_CO may be detected with normal lung volumes. A progressive isolated decrease in DLco during disease monitoring requires exclusion of pulmonary vascular pathology, primarily pulmonary hypertension [49].

• All patients with IPF are recommended to perform the 6-minute walk test (6MWT) to objectively assess their functional status, need for oxygen therapy, prognosis, and the efficacy of pulmonary rehabilitation [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Several 6MWT parameters have prognostic value: distance walked, desaturation < 88%, and heart rate recovery rate at the end of the test [50-52]. The 6MWT makes it possible to predict mortality in IPF patients awaiting lung transplantation [53,54]. The 6MWT is not indicated for patients in whom walking is limited by other causes (e.g., musculoskeletal pathology) and for patients with advanced stages of IPF [55].

2.5 Other Procedures

• Multidisciplinary discussion (MDD) is recommended for all patients with suspected IPF to confirm the diagnosis of IPF and discuss treatment strategy [17,24].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: MDD is essential for all patients with fibrotic ILD to establish a diagnosis, determine the need for lung biopsy and other diagnostic procedures, and select optimal therapy. The multidisciplinary team of specialists must necessarily include a pulmonologist, a radiologist, and a pathologist experienced in the diagnosis of ILD; participation of a rheumatologist, an occupational health physician, and in certain cases, a clinical geneticist, is also possible. The discussion may be conducted via telemedicine communication [24].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Conservative management

3.1.1. Pharmacotherapy

Currently, systemic corticosteroid monotherapy is not recommended for the treatment of IPF [56-60].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: According to retrospective studies, systemic corticosteroid monotherapy does not affect the survival of IPF patients [56,57]. Long-term corticosteroid therapy may be accompanied by serious side effects [58,59,60].

• Currently, antineoplastic therapy (cytotoxic agents), either as monotherapy or in combination with systemic corticosteroids, is not recommended for the treatment of IPF [2].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Currently, there is no convincing evidence of improved survival in IPF patients receiving antineoplastic agents (cytotoxic drugs) (nitrogen mustard analogues: cyclophosphamide** (ATX code: L01AA01), other immunosuppressants: azathioprine** (ATX code: L04AX01)) either as monotherapy or in combination with systemic corticosteroids [1]. Antineoplastic therapy (cytotoxic agents) may be accompanied by the development of serious side effects.

• Acetylcysteine** monotherapy (ATX code: R05CB01) is not recommended to be routinely prescribed to all IPF patients [2,61].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Acetylcysteine** monotherapy did not reliably improve any patient-important outcomes, including survival [62,63]. Acetylcysteine** therapy may be effective in IPF patients with certain genetic polymorphisms (e.g., the TT genotype of TOLLIP), as well as in patients with interstitial pneumonia with autoimmune features (in the presence of a CT or histological UIP pattern and positive ANAs) [64].

• Combination therapy with acetylcysteine**, azathioprine**, and prednisolone** (ATX code: H02AB06) ("triple therapy") is not recommended for the treatment of IPF [2].

GCR CLOE 5Grade of Recommendation C; Level of Evidence 5.

Comments: Combination therapy with oral acetylcysteine**, azathioprine**, and prednisolone** ("triple therapy") has no significant effect on functional parameters, mortality, and the frequency of IPF exacerbations [65,66].

• Ambrisentan** (ATX code: C02KX02) is not recommended for the treatment of IPF, regardless of the presence or absence of pulmonary hypertension [2].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: If an IPF patient with pulmonary hypertension is taking ambrisentan**, treatment should be discontinued due to progressive decline in pulmonary function during ambrisentan therapy in IPF patients [67]

• Sildenafil (ATX code: G04BE03), bosentan** (ATX code: C02KX01), and macitentan** (ATX code: C02KX04) are not recommended for the treatment of IPF [2].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Sildenafil, bosentan**, and macitentan** are not recommended for the treatment of IPF due to the lack of positive clinical outcomes and a high incidence of serious side effects [2]. Sildenafil may be used in IPF patients for other indications, such as pulmonary hypertension or other variants of right ventricular dysfunction [2]. Bosentan** and macitentan** do not have a positive effect on pulmonary hemodynamics in IPF patients even in the presence of pulmonary hypertension [2].

• Warfarin** (ATX code: B01AA03) is not recommended for the treatment of IPF [2].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: The use of oral warfarin** for the treatment of IPF is associated with an increased risk of death [68]. If an IPF patient has indications for anticoagulant therapy, such as deep vein thrombosis of the lower extremities or atrial fibrillation, warfarin may be used as an anticoagulant in accordance with existing clinical guidelines for the treatment of these conditions. This recommendation does not apply to the use of other anticoagulants prescribed for other indications [2].

• Proton pump inhibitors are recommended in the treatment of IPF patients in the presence of clinically significant GERD [69, 70].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: A number of studies have found that the addition of proton pump inhibitors to IPF therapy increases FVC, reduces the frequency of exacerbations [69], and improves the survival of IPF patients [70]. Patients receiving pirfenidone** (ATX code: L04AX05) should not be treated with omeprazole** (ATX code: A02BC01) due to an undesirable drug-drug interaction, whereas other proton pump inhibitors may be used concomitantly with pirfenidone** [70].

• All IPF patients are recommended treatment with antineoplastic agents and other immunosuppressants (antifibrotic drugs) – nintedanib** or pirfenidone** [71].

GCR BLOC 1Grade of Recommendation B (Level of Evidence 1)

Comments: Currently, clinical efficacy in the treatment of IPF has been proven for only two drugs registered in the Russian Federation: nintedanib** (ATX code: L01XE31) and pirfenidone** (ATX code: L04AX05).

Therapy with nintedanib** or pirfenidone** helps to slow the rate of FVC decline, reduce the risk of IPF exacerbations, and decrease the risk of death [72,73]. Similar efficacy of nintedanib** and pirfenidone** has been demonstrated in patients with varying severity of functional impairment [77,84]. Since the goal of treatment is to slow disease progression, the duration of treatment is not defined [69].

In phase 2-3 clinical trials, nintedanib** demonstrated a 47% reduction in the frequency of exacerbations [77]; the mean survival in patients treated with nintedanib** based on Weibull distribution was 11.6 (95% CI 9.6 - 14.1) years [72]. In phase 3 trials, nintedanib** was studied in patients with a HRCT pattern of probable UIP without surgical lung biopsy, with FVC >90% predicted, with normal FEV1/FVC ratio values, as well as in patients over 80 years of age [83].

Recommendations on the use of different drug groups in the treatment of IPF are summarized in Table 4.

Table 4. Recommendations for pharmacological therapy of IPF

• Management of IPF patients with chronic cough should be carried out according to the principles adopted for the management of other patients with chronic cough [85].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• In IPF patients with chronic cough, proton pump inhibitors are recommended to be prescribed only in the presence of GERD [85].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• For patients with chronic cough that is refractory to standard therapy and disrupts the patient's daily activity, when other treatment methods are ineffective, the prescription of opioid analgesics as part of palliative care is recommended [84].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: When prescribing opioid analgesics, a thorough assessment of efficacy and side effects is required after 1 week of treatment and then monthly during their use [85].

There are no proven methods of therapy for acute exacerbation of idiopathic pulmonary fibrosis (IPF), including glucocorticosteroid medicinal products. Therefore, it is currently impossible to provide specific recommendations on doses, routes of administration, and duration of therapy with GCS or other medicinal products during an IPF exacerbation [69].

3.1.2. Non-pharmacological treatment

Long-term oxygen therapy (LTOT)

• LTOT is recommended for patients with IPF and clinically significant resting hypoxemia (resting SpO2 less than 88% while breathing ambient air) [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Indirect evidence regarding the benefits of LTOT in IPF is based on data obtained from patients with chronic obstructive pulmonary disease (COPD). Similar to patients with COPD, when prescribing LTOT to patients with IPF, its duration should be at least 15–17 hours per day, including the period of nocturnal sleep [86,87].

Non-invasive positive pressure ventilation

• The use of non-invasive positive pressure ventilation (NIV) is recommended in patients with IPF and hypercapnia during inpatient pulmonary rehabilitation [69], as well as in patients with acute respiratory failure (ARF) against the background of an IPF exacerbation [88].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Nocturnal NIV with inspiratory positive pressure in patients with interstitial lung disease (ILD), including IPF, and hypercapnia improved exercise tolerance and quality of life [89].

A positive effect in the form of reduced ARF mortality and intubation risk was achieved in a small number (44–45%) of patients, although the absence of NIV did not affect the prognosis of deceased patients [88].

Mechanical ventilation (MV)

• Mechanical ventilation is not recommended for the majority of patients with IPF, except for cases where lung transplantation is planned [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Several small studies of mechanical ventilation in patients with IPF and respiratory failure have been published, all showing high in-hospital mortality [90-92], although the studies carried a risk of systematic bias.

3.2. Surgical treatment

Lung transplantation

• Lung transplantation is recommended for patients with IPF in the presence of appropriate indications (Table 5) [93].

LoE CGoE 4Level of evidence C; grade of recommendation 4.

Comments: Individual studies have shown a reduction in the 5-year mortality risk after transplantation in patients with IPF [93], but exact data on the most optimal timing of transplantation in this disease are lacking [69]. A systematic review of 54 studies showed better survival after bilateral lung transplantation compared to single lung transplantation, but these results may be related to patient selection criteria for single versus bilateral lung transplantation [93].

Table 5. Indications for lung transplantation in IPF [69].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Pulmonary rehabilitation is recommended for all patients with IPF, the scope of which is determined by the severity of the patient's condition [94].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2)

Comments: Pulmonary rehabilitation for patients with IPF should include aerobic training of skeletal and respiratory muscles, patient education, nutritional status correction, and psychological support. These measures can reduce dyspnea, improve exercise tolerance in daily activities, and enhance quality of life regardless of the severity of functional impairment [94].

5. Prevention and Dispensary Observation

Monitoring of patients with IPF is necessary for the active detection of progressive disease, assessment of symptom dynamics, and identification of treatment complications [1].

• Measuring FVC and DL_CO is recommended for all patients with IPF to monitor disease progression in routine clinical practice at intervals of 3–6 months [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Several cohort clinical studies have confirmed that a 10% decline in absolute FVC values (with or without a concurrent decline in DL_CO) or a 15% decline in absolute DL_CO values (with or without a concurrent decline in FVC) is a surrogate marker of mortality and, in the absence of other explanations, a marker of disease progression [35,95]. Disease progression may also be reflected by a smaller (5-10%) but steady decline in FVC [96].

• Resting oxygenation should be assessed using a pulse oximeter at every visit of a patient with IPF [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Oxygenation via pulse oximetry should be assessed at rest and during exertion in all patients, regardless of symptoms, to identify the need for oxygen therapy. Such measurements should be performed initially and every 3–6 months of follow-up.

• With rapid deterioration of respiratory symptoms, IPF exacerbation and other potential causes such as pulmonary embolism, pneumothorax, respiratory infection, and aspiration should be ruled out [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Patients with IPF may develop comorbid conditions such as pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease, which affect survival. However, the role of routine screening for the diagnosis of these conditions and diseases in patients with IPF (e.g., annual HRCT for early lung cancer detection) has not been studied.

6. Organization of Medical Care

Routine management of a patient with IPF is carried out in primary specialized (outpatient) medical care settings.

Indications for hospital admission to a medical organization:

1) planned hospital admission is carried out to confirm the diagnosis of IPF (performing a surgical lung biopsy);

2) emergency hospital admission is carried out in case of an IPF exacerbation (increasing dyspnea, worsening oxygenation) or the development of IPF complications (pulmonary embolism, acute lower respiratory tract infection).

Indications for discharging a patient from a medical organization:

1) stabilization of the clinical condition;

2) blood oxygen saturation of at least 93% at rest while breathing ambient air or during oxygen therapy.

7. Additional Information

Due to age—60 years and older—patients with IPF often have numerous comorbid conditions that complicate the course and treatment of IPF and negatively affect the prognosis.

Lung Cancer

Peripheral lung cancer, most commonly adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, develops in 12–14% of patients with IPF [97,98]. These diseases share common risk factors and pathogenetic mechanisms. However, due to the low frequency of this combination, evidence-based information on the treatment of IPF combined with lung cancer is lacking. At the same time, the combination of IPF and lung cancer significantly increases the mortality risk compared to patients with IPF without lung cancer [99].

Pulmonary hypertension

Pulmonary hypertension (PH)—an increase in mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg according to right heart catheterization—is the most common complication of IPF (20–84%, according to various authors). The development of PH leads to increased dyspnea, reduced physical reserves of the patient, and increases the risk of mortality [1].

• Specific drugs for the treatment of PH are not recommended for the majority of patients with IPF with PH, but in individual patients, such therapy may improve pulmonary hemodynamics and exercise tolerance [1].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: In general, long-term home oxygen therapy remains the most well-founded method of treating PH in lung diseases. In patients with severe PH (mPAP > 35 mmHg) confirmed by right heart catheterization, a trial of sildenafil therapy is possible, which may improve pulmonary hemodynamics and exercise tolerance without worsening oxygenation [100-102]. There are also isolated data on the positive effects of inhaled iloprost (ATX code: B01AC11) [103] and bosentan [104]. Dedicated clinical trials on PH therapy in patients with IPF are needed.

Gastroesophageal Reflux

GER is accompanied by microaspiration of gastric contents and can be considered as a trigger for alveolar damage and a factor worsening the course of IPF, although it is often asymptomatic.

• Medical treatment of GER is recommended for the majority of patients with IPF with asymptomatic GER, although in individual patients it is inappropriate [1].

LoR CLE 5Level of Recommendation C (Level of Evidence 5)

• Lifestyle modifications (eating small meals, elevating the head of the bed) are recommended for patients with IPF with GER, and fundoplication is recommended for clinically significant GER not controlled by medical therapy with objective confirmation of severe acid reflux [105].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Evidence has been published demonstrating that medical or surgical treatment of GERD can stabilize pulmonary function and slow down the progression of IPF [105-108]. Laparoscopic Nissen fundoplication, which reduces both acid and non-acid reflux as well as microaspiration, improves survival in patients with IPF [109]. Lifestyle modifications (eating small meals, elevating the head of the bed, etc.) are justified recommendations for patients with IPF and symptoms of GERD [105].

Obstructive sleep apnea (OSA)

OSA occurs in 20–68% of patients with IPF, defined as an increase in the apnea-hypopnea index > 15 episodes per hour [110]. OSA-associated hypoventilation worsens hypoxemia and pulmonary hypertension [111].

• All patients with IPF are recommended to undergo screening for nocturnal desaturation followed by diagnostic evaluation for OSA [111].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• Patients with IPF and nocturnal desaturation are recommended to receive oxygen therapy during nocturnal sleep as a palliative treatment [110].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Diagnosing OSA in patients with IPF is challenging because daytime somnolence and fatigue are characteristic of both conditions. At the same time, nocturnal desaturation is quite common in IPF. According to isolated studies, CPAP therapy in patients with IPF improves quality of life but does not affect mortality [111].

Criteria for Evaluating the Quality of Medical Care

ICD-10 code(s): J84.1

References

Appendix A1. Working Group Composition

Conflict of interest:

None of the working group members have any conflicts of interest related to the development and implementation of these clinical guidelines into clinical practice.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for evidence collection/selection:

electronic database searching.

Description of methods used for evidence collection/selection:

the evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE, and MEDLINE databases. The search depth was 10 years.

Methods used to assess the quality and strength of evidence:

• Expert consensus;
• Assessment of significance in accordance with the rating scale.

Target audience for these clinical guidelines:

1. General practitioners

2. General practitioners (family physicians)

3. Pulmonologists

4. Radiologists

5. Pathologists

6. Physical medicine and rehabilitation doctors

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Chuchalin A.G., Avdeev S.N., Aisanov Z.R., Belevskiy A.S., Demura S.A., Ilkovich M.M., Kogan E.A., Samsonova M.V., Speranskaya A.A., Tyurin I.E., Chernyaev A.L., Chernyak B.A., Chernyak A.V., Shmelev E.I. Diagnosis and treatment of idiopathic pulmonary fibrosis. Federal Clinical Guidelines. Pulmonologiya 2016; 26(4): 399-419.

2. Idiopathic pulmonary fibrosis. Clinical Guidelines. / Available at: https://spulmo.ru/obrazovatelnye-resursy/federalnye-klinicheskie-rekomendatsii/ Idiopathic Pulmonary Fibrosis. Clinical Guideline. Available at: https://spulmo.ru/obrazovatelnye-resursy/federalnye-klinicheskie-rekomendatsii/

3. Instructions for medical use of Vargatef® /electronic resource/ Available at: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=89d81e79-6176-4356-8184-1cd22b600c7a&t= date of last review 19.03.2021 / Vargatef. Prescription Drug Leaflet. Available at: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=89d81e79-6176-4356-8184-1cd22b600c7a&t=. Accessed on 19.03.2021.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Idiopathic pulmonary fibrosis is a lung disease characterized by damage to and thickening of the walls of the pulmonary alveoli. Alveoli are tiny "sacs" through whose walls oxygen from the air enters the bloodstream. When alveoli are damaged, the lung tissue becomes dense (fibrotic), leading to an irreversible, progressive decline in lung function. Synonyms for idiopathic pulmonary fibrosis include: idiopathic fibrosing alveolitis, fibrosing alveolitis. Typically, the disease manifests at over 40 years of age. Unfortunately, the exact cause of this condition remains unknown.

Who is at risk for developing idiopathic pulmonary fibrosis?

Risk groups include:

- smokers;

- individuals working in hazardous occupational environments;

- patients with a positive family history (if close relatives have idiopathic pulmonary fibrosis).

Symptoms of idiopathic pulmonary fibrosis

Typically, the disease begins slowly and imperceptibly for the patient. Idiopathic pulmonary fibrosis is characterized by the following symptoms:

- exertional dyspnea (initially during heavy exertion, later also at rest).

- dry cough;

- fatigue;

- dizziness;

- anxiety;

- weight loss.

To confirm the diagnosis, the physician must rule out lung diseases with a known etiology that can also present with cough and progressive dyspnea. If a thorough investigation fails to identify the cause of these symptoms, the disease is considered idiopathic (of unknown origin).

When idiopathic pulmonary fibrosis is suspected, the minimum diagnostic workup includes:

- blood test;

- pulmonary function testing (spirometry, and when possible, body plethysmography and diffusing capacity of the lungs), which helps to more accurately determine the cause of dyspnea that may also accompany other lung diseases;

- computed tomography (CT) of the lungs. Currently, CT of the lungs is one of the most accurate diagnostic methods for idiopathic pulmonary fibrosis.

If the doctor still has doubts about the diagnosis after a thorough interview, physical examination, and diagnostic tests, a lung biopsy is performed. A biopsy is a procedure in which a surgeon surgically obtains a small tissue fragment (in this case, lung tissue). The obtained sample is then examined under a microscope by a pathologist to look for signs of a specific disease.

Treatment of idiopathic pulmonary fibrosis

Only two medications have proven efficacy in the treatment of IPF: nintedanib** and pirfenidone**. These drugs can slow down disease progression and potentially prolong the patient's life. In case of rapid deterioration or a sudden increase in dyspnea, you must contact your doctor immediately. Such situations often require hospitalization. To prevent exacerbations, your attending physician may recommend annual influenza vaccination and a single pneumococcal vaccination (to prevent pneumonia).

The most effective treatment for idiopathic pulmonary fibrosis is lung transplantation − a surgical procedure to replace damaged lungs with those of a healthy donor.

Patients with idiopathic pulmonary fibrosis need to:

- strictly stop smoking (including passive smoking), as it contributes to disease progression;

- participate in pulmonary rehabilitation programs. A physical therapy instructor will guide you through various breathing exercises that help reduce dyspnea and general weakness;

- treat gastroesophageal reflux disease if present. Gastroesophageal reflux disease is a condition in which a small amount of acidic stomach contents refluxes into the esophagus and then into the respiratory tract. It has been proven that this condition contributes to the progression of idiopathic pulmonary fibrosis. Treatment of gastroesophageal reflux disease will help reduce lung damage in idiopathic pulmonary fibrosis;

- regularly take the medications prescribed by your attending physician. In recent years, there has been active development of new drugs for patients with idiopathic pulmonary fibrosis. Ask your physician about the possibility of follow-up and treatment at a large research institution, where modern medications may be available;

- undergo long-term oxygen therapy. Over time, idiopathic pulmonary fibrosis leads to hypoxemia (low blood oxygen levels), which is corrected by long-term oxygen inhalation from a concentrator.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

G1. British Medical Research Council (MRC) Dyspnea Scale

Source: Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 1988 Mar;93(3):580-6. doi: 10.1378/chest.93.3.580. PMID: 3342669.

Type (underline):

• rating scale
• index
• questionnaire
• other (specify):

Purpose: to assess the severity of dyspnea during daily physical activity

Content (template):

Key (interpretation): a higher score corresponds to more severe dyspnea during daily physical activity

Notes: the MRC scale is used for the initial assessment of a patient's clinical status and monitoring their condition during treatment.

Appendix 2. GAP scale

Source: Ley B., Ryerson C.J., Vittinghoff E., Ryu J.H., Tomassetti S., Lee J.S., Poletti V., Buccioli M., Elicker B.M., Jones K.D., King T.E. Jr., Collard H.R. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012 May 15;156(10):684-91. doi: 10.7326/0003-4819-156-10-201205150-00004.

Type (underline):

• rating scale
• index
• questionnaire
• other (specify):

Purpose: assessment of severity and prognosis of IPF course

Content (template):

Key (interpretation): a higher score corresponds to a more severe clinical course and a poorer prognosis in IPF. The total score (ranging from 0 to 8) is used to classify patients into stage I (0-3 points), stage II (4-5 points), or stage III (6-8 points) based on 1-, 2-, and 3-year mortality prognosis.

Notes: the GAP scale is used to assess the risk of mortality in patients with IPF.