Hypersensitivity pneumonitis: Clinical Guidelines

List of Abbreviations

BAL – bronchoalveolar lavage

CT – computed tomography

HP – hypersensitivity pneumonitis

CI – confidence interval

LTO – long-term oxygen therapy

MV – invasive mechanical ventilation

ILD – interstitial lung disease

IPF – idiopathic pulmonary fibrosis

6MWT – 6-minute walk test

NIV – non-invasive ventilation

NSIP – nonspecific interstitial pneumonia

UIP – usual interstitial pneumonia

TBB – transbronchial biopsy

TBLC – transbronchial lung cryobiopsy

PE – pulmonary embolism

FVC – forced vital capacity

SLB – surgical lung biopsy

COPD – chronic obstructive pulmonary disease

GRS – grade of recommendation strength

LCE – level of confidence of evidence

DL_CO – diffusing capacity of the lungs for carbon monoxide

IgG – immunoglobulin G

SpO₂ – peripheral capillary oxygen saturation

Terms and Definitions

Bronchiectasis – irreversible dilatation of the bronchial lumina.

Air trapping – local retention of air in the distal airways and alveoli.

Hypersensitivity pneumonitis – an inflammatory and/or fibrosing disease of the lung parenchyma and small airways occurring in susceptible individuals as a result of an immune-mediated reaction to inhaled antigens.

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 – a group of interstitial lung diseases of unknown etiology, characterized by similar features: predominant involvement of the alveoli and interstitial tissue, development of an inflammatory and/or fibrosing process in the lungs accompanied by progressive dyspnea and restrictive impairment of ventilation capacity over time.

Idiopathic pulmonary fibrosis – a specific form of chronic progressive fibrosing interstitial pneumonia of unknown etiology, occurring primarily in older adults, affecting exclusively the lungs, and associated with a histological and/or computed tomographic pattern of usual interstitial pneumonia.

Ground-glass opacity – a hazy increase in lung density («semi-transparent» lung) through which pulmonary vessels and bronchial walls remain visible.

Mosaic attenuation – uneven lung attenuation on inspiratory scans (inspiratory CT) manifesting as regional differences in lung parenchymal lucency; characterized by the alternation of areas with visually different attenuation (varying shades of gray) measuring 1–2 cm

Nonspecific interstitial pneumonia – one of the forms of idiopathic interstitial pneumonias characterized by diverse histological and computed tomographic features, often resembling idiopathic pulmonary fibrosis, but frequently showing a positive response to systemic corticosteroids and a more favorable prognosis.

Honeycomb lung – cystic transformation of the lung parenchyma characterized by multiple small (usually 0.3–1.0 cm in diameter) thick-walled air spaces, often arranged in multiple layers.

Reticular changes – linear and ring-like structures in the lung parenchyma forming a network, caused by thickening of interlobular septa (meshes <1 cm) or intralobular septa (meshes >1 cm).

Traction bronchiectasis – a type of bronchiectasis resulting from volume loss (shrinkage and architectural distortion) of the surrounding lung tissue and the mechanical pulling (traction) of small bronchi or bronchioles with weakly developed cartilaginous support.

Centrilobular nodules – multiple small (usually up to 5 mm) opacities in the lung located at a distance from the visceral pleura.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrosing disease of the lung parenchyma and small airways that occurs in susceptible individuals as a result of an immune-mediated reaction to inhaled antigens [1]. This disease was previously called extrinsic allergic alveolitis. If the causative antigen cannot be identified, the terms «cryptogenic HP» or «HP of undetermined etiology» are used.

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

HP develops in susceptible individuals following repeated antigen exposure. Etiologic antigens may include fungi, microorganisms, animal and bird proteins, low-molecular-weight inorganic chemicals, and drugs [1] encountered by the patient at home, in the workplace, or in other environments. In many cases, such exposure cannot be identified.

Repeated exposure to the etiologic antigen leads to the development of humoral (type III hypersensitivity reaction) and cellular (type IV hypersensitivity reaction) immune responses with predominantly lymphocytic inflammation and granuloma formation [2].

An important role in the development of the immune-mediated reaction to external exposure is played by the patient's genetic profile, in particular, polymorphisms of HLA class II histocompatibility genes (Human Leukocyte Antigens), proteasomes, protein transporters, and tissue inhibitors of matrix metalloproteinases [3–6], which are associated with aberrant fibroblast activity and the development of the fibrotic HP phenotype [7].

1.3 Epidemiology of the Disease or Condition

HP is most commonly diagnosed at 50–60 years of age [8], although young adults and children can also be affected [9].

The prevalence of HP varies across different regions of the world from 0.3 to 0.9 cases per 100,000 population, reaching up to 54.6 per 100,000 in high-risk groups [8, 10–12].

Sporadic outbreaks of HP have been described in various risk groups, such as indoor pool workers, automotive mechanics handling polyurethane, and office workers exposed to fungi and microorganisms contaminating air conditioning and humidification systems [1].

1.4 Features of Coding the Disease or Condition

Hypersensitivity pneumonitis due to organic dust (J67):

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

1.5 Classification of the disease or condition

HP is divided into acute (disease duration less than 6 months) and chronic (disease duration more than 6 months). Acute and chronic HP differ in their clinical and radiological manifestations and reflect the specific disease course (Appendix A3). The term «subacute HP» is not recommended because this condition lacks clear diagnostic criteria.

Currently, chronic HP is recommended to be classified into fibrotic and non-fibrotic phenotypes based on the predominant pathological findings on high-resolution computed tomography (HRCT) of the chest and/or histological examination of lung tissue biopsies (see sections 2.4.1, 2.4.2), as this classification directly correlates with prognosis [13].

For fibrotic HP, it is recommended to specify the presence or absence of progression, as treatment strategies depend on this determination [13]. Progression is defined by the rate of worsening clinical symptoms, decline in lung function, and increase in fibrotic changes on chest HRCT over 1 year based on the following criteria (Fig. 1) [14, 15]:

• relative decline in forced vital capacity (FVC) of ≥ 10% of predicted;

• relative decline in FVC of 5% ≤ FVC < 10% of predicted combined with worsening respiratory symptoms;

• relative decline in FVC of 5% ≤ FVC < 10% of predicted combined with increased extent of fibrosis on HRCT;

• worsening respiratory symptoms combined with increased extent of fibrosis on chest CT

Fig. 1. Classification of HP [1, 15]

Examples of diagnosis formulation:

Acute hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis, fibrotic progressive phenotype.

Chronic hypersensitivity pneumonitis, non-fibrotic phenotype.

1.6 Clinical presentation of the disease or condition

The main symptoms of both non-fibrotic and fibrotic HP include dyspnea, nonproductive cough, weight loss, fatigue, and low-grade fever [16–18]. The disease may present acutely over several days or weeks (more typical of non-fibrotic HP) [19, 20] or insidiously over months or years (more typical of chronic HP) [17, 21], although symptom duration does not strictly correlate with the fibrotic or non-fibrotic phenotype [17].

The course of HP can be relapsing. Elimination of contact with the causative antigen may lead to stabilization or complete regression of symptoms; however, the progressive fibrotic phenotype carries a poor prognosis, leading to respiratory failure and death [22].

2. Diagnostics, medical indications and contraindications for diagnostic methods

HP should be suspected in patients presenting with recurrent symptoms as described above, a history of exposure to a suspected antigen, inspiratory crepitations, occasionally high-pitched dry inspiratory crackles (squeaks) upon lung auscultation, and weight loss [17, 23].

The diagnosis of HP is established based on medical history (environmental exposure), physical examination, laboratory data, chest high-resolution computed tomography (HRCT), pulmonary function tests, pathomorphological examination of lung biopsy (surgical) material, and cytological analysis of bronchoalveolar lavage (BAL) fluid.

Criteria for establishing the diagnosis/condition [24]:

• complaints of dyspnea and/or cough;

• bilateral inspiratory crackles in the basal lung fields upon lung auscultation;

• history of exposure to a suspected antigen or detection of serum IgG antibodies to a suspected antigen;

• identification of an HP pattern on chest CT.

2.1 Complaints and Anamnesis

The main symptoms of HP are exertional dyspnea and cough; complaints of general fatigue, weight loss, and low-grade fever are less common (the latter are more typical of the acute form of HP) [17, 23].

Pathognomonic symptoms of HP are absent.

For patients with clinically suspected HP, a thorough history taking is recommended to identify external exposures that could be etiological factors of the disease [17, 21-23, 25].

To identify external exposures in the history of patients with chronic HP, a questionnaire can be used (Appendix G1). The absence of a history of contact with a potential etiotropic antigen does not rule out the diagnosis of HP.

2.2 Physical Examination

Upon lung auscultation in patients with HP, inspiratory crackles and/or high-pitched inspiratory wheezes ("squeaks") are most frequently heard [16, 17, 20, 21, 26, 27].

High-pitched inspiratory wheezes may be heard in

interstitial lung disease (ILD) involving the distal airways, but are more common in HP [16, 17, 20, 21, 27].

Inspiratory crackles can be considered as a factor increasing the probability of an HP diagnosis (odds ratio 4.5, 95% confidence interval (CI) 1.8 – 11.7) [17, 26].

2.3 Laboratory Diagnostics

• For patients with suspected HP, testing for serum IgG antibodies to the suspected etiotropic antigen is recommended to confirm the diagnosis and eliminate contact with the etiotropic antigen [16, 28-33].

Strength of recommendation _C_ (level of evidence – _3_)

Comments: currently, there is no standardization for measuring serum IgG against potential antigens associated with the development of HP. Different methods used to determine specific IgG have varying sensitivity and specificity, which complicates the interpretation of results [1]. In one-third of patients with HP, the etiotropic antigen cannot be identified [34].

2.4 Instrumental Diagnostics

2.4.1. Radiological diagnostics

• For patients with suspected HP, plain chest radiography is not recommended for diagnosis verification due to its low diagnostic value [35-39].

Strength of recommendation A__ (level of evidence – _3_)

Comments: Plain radiography is inferior to chest CT in sensitivity and specificity for detecting lung abnormalities in patients with suspected HP [40]. However, radiography makes it possible to identify patients whose lung changes resemble the pattern of HP and to justify referring these patients for chest CT [41].

It should be borne in mind that chest radiography is the most frequent type of diagnostic X-ray imaging and is also often used for screening latent diseases. Therefore, the detection of signs compatible with HP is of great importance in the modern diagnosis of the disease (Appendix A3).

• For patients with suspected HP, chest CT is recommended to determine the nature of changes in the lung parenchyma, confirm the diagnosis of HP, and perform differential diagnosis with other ILDs [35-37].

Strength of recommendation B__ (level of evidence – _3_)

Comments: There are technical requirements for performing chest CT in patients with HP (Appendix A34).

Various combinations of radiological signs form the CT picture (pattern) of HP. Currently, it is accepted to distinguish three main CT patterns of HP—typical, probable, and indeterminate, which differ between the non-fibrotic and fibrotic phenotypes (Appendix A3).

A typical HP pattern includes at least one sign of lung parenchyma abnormality and one sign of small airway abnormality [1]:

• Parenchyma: ground-glass opacity, mosaic attenuation of the lung parenchyma

• Small airways: poorly defined centrilobular nodules, air trapping

• Distribution: diffuse +/- less pronounced in the basal segments

A probable HP pattern includes less characteristic features described in HP

• Parenchyma: patchy or mild ground-glass opacity, consolidation, air cysts

• Diffuse distribution, including predominant basal and peribronchovascular distribution

A typical fibrotic HP pattern includes characteristic features of HP and signs of lung tissue fibrosis: reticular abnormalities distorting the lung architecture (normal arrangement of vessels and visible bronchi) and/or traction bronchiectasis; +/- honeycombing; random distribution of fibrotic changes (without distinct predominance) or mid-lung zone predominance (at the level of the hilar regions), with prominent airiness of the lower lung zones characteristic

A probable fibrotic HP pattern includes isolated signs of fibrosis and inflammation that may be observed in HP [1].

2.4.2. Morphological diagnostics

Lung biopsy often plays a key role in establishing the diagnosis of HP.

• A morphological diagnosis of HP is recommended to be established in patients with clinically suspected HP when specific features are identified in any lung tissue biopsy samples (Appendix A3) [1, 42, 43].

GGR BLEL 3Grade of Recommendation B (Level of Evidence 3)

Comments: Non-fibrotic HP is characterized by the following findings in lung tissue biopsies (Fig. 2) [1, 44-46]:

1) cellular interstitial pneumonia with a bronchiolocentric distribution combined with

2) cellular chronic bronchiolitis;

3) granulomatous inflammation;

4) in the absence of histological signs of an alternative disease.

Fig. 2.Histological signs of non-fibrotic HP:a.Cellular interstitial pneumonia, peribronchiolar infiltration, and granulomas with multinucleated giant cells.b.Peribronchiolar interstitial inflammation, fibroblastic foci in the wall of the terminal bronchiole.c.Peribronchiolar infiltration, organizing pneumonia.d.Granuloma in the wall of the terminal bronchiole, consisting of histiocytes and lymphocytes.

Cellular interstitial pneumonia is represented by infiltration predominantly of small lymphocytes, but a small number of plasma cells and occasionally eosinophils are also present. There may be foci of organizing pneumonia located exclusively peribronchiolarly.

Granulomas in HP are typically small, loose (poorly formed), comprising histiocytes and multinucleated giant cells, located predominantly in the peribronchiolar interstitium. Sporadically lying multinucleated giant cells are frequent and may contain various inclusions in their cytoplasm, such as Schaumann bodies, asteroid bodies, or needle-like cholesterol structures [42, 44].

Diagnostic criteria for HP are applicable to both non-fibrotic and fibrotic variants, the difference lying in the absence or presence of fibrotic changes.

Fibrotic HP is characterized by the presence of chronic interstitial pneumonia and/or bronchiolitis combined with fibrosis in the presence of signs of granulomatous inflammation (Fig. 3) [1, 45, 47, 48].

Fig. 3.Histological signs of fibrotic HP:a. Chronic interstitial pneumonia, UIP pattern with micro-honeycombing.b.Chronic interstitial pneumonia, NSIP pattern.c."Bridging" fibrosis.d.Peribronchiolar metaplasia with smooth muscle proliferation, obliterating "purse-string" bronchiolitis, multinucleated giant cells, and cholesterol clefts in micro-honeycomb spaces.

• For patients with suspected HP, cytological examination of bronchoalveolar lavage (BAL) fluid is recommended to confirm the diagnosis of HP and perform differential diagnosis with other ILDs [49-54].

GRL ALEL 2Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendations A (level of evidence 2).

Comments: The most typical result of BAL cytology in HP is pronounced lymphocytosis. A threshold level of more than 30% lymphocytes of the total BAL cell count is considered a diagnostic criterion [52, 55-57]. At the same time, in non-fibrotic HP, the proportion of lymphocytes in BAL is on average higher (more than 30-40%) than in fibrotic HP (about 20%) [49; 58].

Determination of the CD4+/CD8+ ratio can be useful in the differential diagnosis of HP and sarcoidosis. In HP, the CD4+/CD8+ ratio is less than 1, whereas in sarcoidosis it is greater than 2 [59].

Different variants of lung biopsy (surgical lung biopsy [SLB], cryobiopsy, transbronchial lung biopsy [TBLB]) have different diagnostic value and risk levels. The harm from the procedure must be weighed against the potentially useful information that can be obtained, especially when non-fibrotic HP or fibrotic HP with pronounced fibrosis is suspected.

• Patients with suspected non-fibrotic HP are recommended to undergo transbronchial lung biopsy (TBLB) with pathomorphological examination of lung tissue biopsy material to confirm the diagnosis of HP and perform differential diagnosis with otherILDs [60-64].

GCR BLOCE 2Grade of Recommendation B (Level of Evidence 2)

Comments: according to a meta-analysis by experts from the European and Japanese Respiratory Societies and the American and Latin American Thoracic Societies, the overall diagnostic yield of TBLB in ILD is 41 - 68%, but is significantly higher in non-fibrotic HP than in fibrotic HP [1]. Reported side effects include pneumothorax (7% frequency) and pulmonary hemorrhage (4%) [1]. No fatal cases or HP exacerbations associated with TBLB have been registered [1].

• For patients with suspected non-fibrotic HP in whom a definitive diagnosis is not reached using alternative diagnostic methods, SLB with pathomorphological examination of lung tissue biopsy material is recommended to confirm the diagnosis of HP and perform differential diagnosis with other ILDs [1, 65-75].

LoE AGoE 2Level of Evidence A (Grade of Recommendation 2)

Comments: the diagnostic yield of SLB in both fibrotic and non-fibrotic ILDs, including HP, is 96-98%, while the diagnosis of HP in suspected cases was confirmed in 91% of patients [1]. At the same time, one should take into account the high rate of complications, including mortality, associated with SLB [76-78].

• For patients with suspected fibrotic HP in whom a definitive diagnosis is not reached using alternative diagnostic methods, SLB with pathomorphological examination of lung tissue biopsy material is recommended to confirm the diagnosis of HP and perform differential diagnosis with other ILDs [1, 53, 79-83].

GCR ALEL 3Level of Recommendation A (Level of Evidence 3)

Comments: the diagnostic yield of SLB in patients with unclassified ILDs who previously underwent TBLB and BAL reaches 100% [75], with postoperative complication rates ranging from 7% [75] to 15% [81] and postoperative mortality from 0% [75] to 4% [81].

• For patients with suspected fibrotic HP, lung cryobiopsy with pathomorphological examination of lung tissue biopsy material is recommended to confirm the diagnosis of HP and perform differential diagnosis with other ILDs [1, 84].

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

Comments: Considering the lower diagnostic yield of TBLB compared to non-fibrotic HP and the high risk of postoperative complications with SLB, lung cryobiopsy may be considered a more preferred method of histological verification of the diagnosis in patients with suspected fibrotic HP [1].

2.4.3. Functional diagnostics

Pulmonary function tests in patients with non-fibrotic HP may reveal obstructive ventilation disorders or be within normal limits; however, diffusing capacity for carbon monoxide (DLCO) may be the only reduced pulmonary function parameter [85]. In fibrotic HP, restrictive pulmonary ventilation disorders develop with decreased lung volumes and reduced DLCO [38, 85].

• All patients with HP are recommended to undergo spirometry (unprovoked respiratory volumes and flows) to clarify the nature and severity of pulmonary ventilation disorders, as well as to monitor the rate of IPF progression [38, 85-94].

GCR BLOCE 3Grade of Recommendation B (Level of Evidence 3)

• All patients with fibrotic HP are recommended to perform the 6-minute walk test (6MWT) to objectively assess their functional status, need for oxygen therapy, determine prognosis, and evaluate the effectiveness of pulmonary rehabilitation [95-99].

GCR ALEL 1Grade of Recommendation A (Level of Evidence 1)

Comments: Studies involving patients with various fibrotic ILDs, including HP, have shown that a decrease in the distance walked in the 6MWT to <300 m, as well as a decrease in oxygen saturation below 85% by the end of the 6MWT, are prognostic factors for mortality [99, 100]. The 6MWT can be used to evaluate the effectiveness of pulmonary rehabilitation in patients with fibrotic ILDs, including HP [99].

2.4.4. Pulse oximetry

• All patients with HP are recommended to regularly perform pulse oximetry to measure blood oxygen saturation (SpO2) and determine the significance of blood desaturation both at rest and during physical exertion, such as in the 6MWT [19, 95, 100, 101].

GRL BLEL 4Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendations B (level of evidence 4)

Comments: Detection of desaturation below 88% during physical activity is an unfavorable prognostic sign and an indication for prescribing oxygen therapy [100].

2.5 Other Procedures

• A multidisciplinary discussion is recommended for all patients with suspected HP to confirm the diagnosis of HP and discuss treatment tactics [1, 102].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: A multidisciplinary discussion is necessary for all patients with fibrotic HP to establish a diagnosis, determine the need for SLB, and select optimal therapy. The multidisciplinary team of specialists must necessarily include a pulmonologist, a radiologist, and a pathologist with experience in diagnosing HP, and participation of an occupational health physician is also possible. The discussion can be conducted via telemedicine communication [1]. The HP diagnostic algorithm is given in Appendix B.

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

3.1. Conservative management

• All patients with HP are recommended to eliminate contact with the suspected or confirmed etiological antigen to reduce the risk of a progressive course and unfavorable outcome of HP [33, 88, 103-105].

Level of Evidence AGrade of Evidence 3Level of Recommendations A (Grade of Evidence – 3)

Comments: Elimination of contact with the suspected or confirmed antigen is a key point in the treatment of HP, although quite a few cases of spontaneous regression or lack of HP progression have been described while continuing contact with the etiological antigen and, conversely, a progressive course of HP when contact with the antigen is eliminated [106, 17, 108]. Presumably, more complex relationships between the human body and environmental factors play a role in the development of a specific HP phenotype [107].

3.1.1. Pharmacotherapy

• Patients with acute and chronic non-fibrotic HP are recommended to be prescribed systemic corticosteroids to reduce the risk of progressive HP and improve survival prognosis [31, 88, 109, 1110, 111].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: therapy with systemic corticosteroids can reduce the severity of symptoms, improve pulmonary function, and slow the progression of non-fibrotic HP [31, 88, 109]. Regarding fibrotic HP, there is no consensus on the effect of systemic corticosteroids on disease outcomes [31, 88, 109-112]. During an exacerbation of fibrotic HP, the use of systemic corticosteroids should be considered [113, 114].

• In case of inefficacy or pronounced side effects of systemic corticosteroids in patients with HP, it is recommended to consider the use of oral #mycophenolic acid** at 1-3 g per day in divided doses for up to 24 months (ATX code: L04AA06) or #azathioprine** (ATX code: L04AX01) orally at 100-150 mg [115, 116] per day in divided doses for up to 24 months, or #rituximab** (ATX code: L01FA01) administration at 500-1000 mg intravenously as an infusion on days 0, 6, and 12 of therapy [117] or administration at 1000 mg intravenously as an infusion on days 0 and 14 of treatment [118].

GCR CLOE 4Grade of Recommendation C (Level of Evidence – 4

Comments: Currently, there are no data to develop unambiguous recommendations for or against the use of the listed medications in HP [111]; isolated studies with contradictory results have been published [109, 111].

• Patients with a progressive course of fibrotic HP are recommended to be prescribed nintedanib to slow the progressive decline in pulmonary function [94, 119].

GRL ALEL 2Grading of Recommendations Assessment, Development and Evaluation (GRADE) level of recommendations A (level of evidence – 2

Comments: Currently, it has been demonstrated that in interstitial lung disease (ILD) with a progressive fibrotic phenotype, including fibrotic hypersensitivity pneumonitis (HP), nintedanib significantly slows the rate of decline in pulmonary function (FVC, DL_CO) regardless of the presence or absence of a usual interstitial pneumonia (UIP) HRCT pattern [94, 119]. There is evidence of a potential increase in life expectancy in patients with progressive fibrosing ILD, including fibrotic HP, receiving nintedanib therapy of up to 3.5 years compared with placebo [119].

3.1.2. Non-pharmacological treatment

Long-term oxygen therapy (LTOT) is the inhalation administration of medicinal products and oxygen.

• Patients with fibrotic HP and clinically significant resting hypoxemia (resting SpO2 less than 88% while breathing ambient air) are recommended to undergo LTOT [119].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: Indirect evidence regarding the benefits of LTOT in HP is based on data obtained from patients with chronic obstructive pulmonary disease (COPD). Similar to patients with COPD, when prescribing LTOT to patients with fibrotic HP and chronic respiratory failure, its duration should be at least 15–17 hours per day, including nocturnal sleep [121, 122].

Non-invasive positive pressure ventilation

• The use of non-invasive positive pressure ventilation (NIPPV) is recommended for patients with fibrotic HP and chronic respiratory failure when ongoing LTOT is insufficiently effective [122–126].

LoR CLE 3Level of Recommendation C (Level of Evidence 3)

Comments: NIPPV with inspiratory and expiratory positive airway pressure during daily physical activity in patients with fibrosing ILDs, including fibrotic HP, improved saturation to a greater extent than oxygen therapy [121].

Mechanical ventilation (MV)

Currently, there is insufficient data to formulate recommendations for or against the use of mechanical ventilation in the event of acute respiratory failure in patients with fibrotic HP [127, 128].

Published studies included patients with various fibrosing ILDs, including fibrotic HP, who developed acute respiratory failure. In a systematic analysis by J.A. Huapaya et al., mortality in patients with fibrosing ILDs on mechanical ventilation ranged from 27% to 100% [127]. Furthermore, mechanical ventilation in fibrosing ILDs is associated with increased one-year mortality (odds ratio 5.18; 95% CI 1.18–22.75) [127]. At the same time, the use of specific mechanical ventilation modes, in particular achieving a target plateau pressure within the first 3 hours of MV initiation (odds ratio 0.23; 95% CI 0.07–0.7; p = 0.016) and a higher PaO₂ / FiO₂ ratio in the first 3 and 48 hours of MV initiation (odds ratio 0.98; 95% CI 0.96–0.99; p = 0.002 and 0.98; 0.97–0.99; p = 0.018, respectively), may reduce mortality in this category of patients [128].

3.2. Surgical treatment

Lung transplantation

• Patients with fibrotic HP who meet the relevant indicators may be recommended for lung transplantation [129, 130].

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

Comments: Lung transplantation is a life-saving procedure, albeit with a high risk of mortality [129]. Nevertheless, the survival rate of patients with HP after lung transplantation is 96% at 1 year and 89% at 5 years, which is significantly higher than that of patients with idiopathic pulmonary fibrosis (IPF); the average life expectancy after lung transplantation is 3.6 years [131].

Indications for lung transplantation in HP have not been established; therefore, experts from the Russian Respiratory Society recommend using the indications developed for patients with IPF in accordance with the clinical guidelines of the Russian Transplant Society [129]:

• a decrease in FVC by 10% or more over 6 months of follow-up;

• a decrease in DL_CO by 15% or more over 6 months of follow-up;

• a decrease in SpO₂ below 88% or a distance of less than 250 meters in the 6-minute walk test (6MWT), or a negative trend in the 6MWT distance of more than 50 meters over 6 months of follow-up;

• presence of pulmonary hypertension according to right heart catheterization or echocardiography;

• repeated hospitalizations for respiratory failure.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients with fibrotic HP are recommended to undergo pulmonary rehabilitation, the scope of which is determined by the severity of the patient's condition [96].

GCR ALEL 1Grade of Recommendation A (Level of Evidence 1)

Comments: Pulmonary rehabilitation for patients with fibrotic HP should include aerobic training of skeletal and respiratory muscles, patient education programs, nutritional status correction, and psychological support. These measures can reduce dyspnea, improve exercise tolerance, and enhance quality of life regardless of the severity of functional impairment [96].

• To assess the effectiveness of pulmonary rehabilitation and exercise tolerance in patients with fibrotic HP, the MRC scale (Appendix G2) is recommended [97, 98].

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

Comments: According to several authors, the MRC scale reliably reflects changes in dyspnea during daily physical activity in patients with various ILDs undergoing pulmonary rehabilitation [97, 98].

5. Prevention and Dispensary Observation

Monitoring of patients with HP is necessary for the active detection of progressive disease, assessment of symptom dynamics, and identification of therapy complications [90, 91, 93].

• All patients with HP are recommended to have FVC and DL_CO measured (e.g., once every 3–6 months) for annual assessment of disease prognosis and timely treatment adjustment [90, 91, 93].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: Certain clinical studies have confirmed that a 10% decrease in absolute FVC values is a marker of progressive HP, which warrants the initiation of antifibrotic therapy [90, 91, 93].

• At every scheduled visit, patients with HP are recommended to have their resting SpO₂ assessed using a pulse oximeter [132, 133].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: SpO₂ should be assessed using a pulse oximeter 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.

• In all patients with HP presenting with a rapid worsening of respiratory symptoms, it is recommended to rule out acute exacerbation of the disease and other potential causes, such as pulmonary embolism, pneumothorax, respiratory infection, and aspiration [124, 125].

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

Comments: Patients with HP may develop comorbid conditions such as pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease, which affect survival [125].

6. Organization of Medical Care

Routine management of patients with HP is carried out in an outpatient specialized healthcare setting.

Indications for hospital admission to a medical organization:

1) planned hospital admission is performed to confirm the diagnosis of HP (via transbronchial lung biopsy [TBLB] or surgical lung biopsy [SLB]);

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

Indications for patient discharge from a medical organization

1) stabilization of the clinical condition;

2) SpO₂ of at least 93% at rest while breathing ambient air or during oxygen therapy.

7. Additional Information

No additional information available

Criteria for Evaluating the Quality of Medical Care

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. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

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

Table 3. Scale for grading grades of recommendation (GR) 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 on 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. Avdeev S.N. Hypersensitivity pneumonitis. Pulmonologiya. 2021; 31 (1): 88-99. https://doi.org/10.18093/0869-0189-2021-31-1-88-99.

2. Avdeev S.N., Chikina S.Yu., Tyurin I.E. et al. Chronic fibrosing interstitial lung diseases with a progressive fibrosing phenotype: resolution of the Interdisciplinary Expert Council. Pulmonologiya. 2021; 31 (4): 505 – 510. https://doi.org/10.18093/0869-0189-2021-31-4-505-510.

3. Vargatef® SmPC (Instructions for medical use) /Electronic resource/ Available at: https://lk.regmed.ru/Register/EAEU_SmPC

Characteristics of acute and chronic HP

Source: Vasakova M., Morell F., Walsh S. et al. Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am. J. Respir. Crit. Care Med. 2017;196:680–689.

Avdeev S.N. Hypersensitivity pneumonitis. Pulmonology. 2021;31(1):88-99. DOI: 10.18093/0869-0189-2021-31-1-88-99. (In Russ.)

Radiographic features of HP at different stages of the disease

Source: Glazer CS, Rose CS, Lynch DA. Clinical and radiologic manifestations of hypersensitivity pneumonitis. J Thorac Imaging. 2002;17 (4): 261-72

Technical requirements for chest CT in patients with HP

Source: [1, 33]

- thin tomographic slices, collimation ≤1.5 mm), submillimeter slices improve the quality of multiplanar reformations;

- high-spatial-resolution algorithm;

- helical (volumetric) scanning

- scanning range: 2-3 cm above the lung apices down to the costophrenic angles;

- caudocranial scanning direction (from the diaphragm to the apices) to reduce artifacts from involuntary respiratory movements;

- scanning on a relaxed (non-forced) breath-hold;

- expiratory scanning (expiratory CT) is usually not required, but may be performed to clarify lung tissue abnormalities seen on standard scans, specifically to assess the mosaic attenuation pattern;

- prone scanning is usually not required, but is performed by the radiologist for differential diagnosis of abnormalities in gravitationally dependent lung regions;

- intravenous contrast is usually not required, except for clinically justified suspected pulmonary embolism\

CT diagnostic categories of non-fibrotic HP

Source: Raghu G., et al. Am. J. Respir. Crit. Care Med. 2020; V. 202, Iss. 3: pp e36–e69.

CT diagnostic categories of fibrotic HP

1. Source: Raghu G., et al. Am. J. Respir. Crit. Care Med. 2020; V. 202, Iss. 3: pp e36–e69.

Histological diagnostic categories of non-fibrotic HP

Source: Raghu G., et al. Am. J. Respir. Crit. Care Med. 2020; V. 202, Iss. 3: pp e36–e69.

Histological diagnostic categories of fibrotic HP

Source: Raghu G., et al. Am. J. Respir. Crit. Care Med. 2020; V. 202, Iss. 3: pp e36–e69.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Hypersensitivity pneumonitis is a lung disease resulting from an exaggerated immune response to repeated exposure of the human respiratory system to various allergens and other adverse environmental factors. With a favorable course of hypersensitivity pneumonitis, upon elimination of adverse exposures and/or treatment, the disease resolves with complete recovery; in some cases, more often with continued adverse exposure or delayed initiation of treatment, the disease may progress and lead to lung tissue thickening (fibrosis) and an irreversible progressive decline in pulmonary function, primarily the lungs' ability to deliver oxygen to all organs. Hypersensitivity pneumonitis most commonly develops in the second half of life, but can also occur at a younger age.

Factors associated with the risk of developing hypersensitivity pneumonitis include:

- contact with bird feathers, including pillow feathers, feather and down products, poultry farming;

- contact with farm and other animals (fur, hides, livestock farming);

- contact with mold, including humidifiers, air conditioners, swimming pools, jacuzzis, moldy hay, vegetable and grain storage facilities, compost, soil, woodworking waste, wind instruments, CPAP devices, yeast, cheese, wine, and beer production, etc.;

- contact with organic dust (plant dust, shellfish processing, fish scales, flour, soy, etc.);

- contact with certain types of bacteria that multiply in humid environments and contaminate swimming pools, jacuzzis, air conditioners, air humidifiers, sewage, etc.;

- contact with inorganic compounds (household chemicals, hairspray, dental materials, acrylic, epoxy resins, metals, etc.).

Symptoms of hypersensitivity pneumonitis

Symptoms of hypersensitivity pneumonitis are non-specific and similar to manifestations of many other bronchopulmonary diseases: cough, exertional dyspnea (initially at higher exertion levels, then, as the disease progresses, at lower exertion levels), fatigue, sometimes weight loss, and fever. The disease may begin acutely over several days or weeks, or insidiously over months or years. Often, initial manifestations spontaneously disappear or decrease without treatment within a few days or weeks, but over time may recur or intensify. Relapses are also possible after successful treatment.

To confirm the diagnosis, it is necessary to recall all potential adverse exposures, even those you experienced quite a long time ago. In addition, to clarify the nature and severity of lung involvement, it is necessary to perform:

When hypersensitivity pneumonitis is suspected, the minimum diagnostic workup includes:

- pulmonary function testing (spirometry, and when possible, body plethysmography and diffusing capacity of the lungs);

- computed tomography of the lungs. A conventional chest X-ray is inadequate for diagnosing any interstitial lung diseases, including hypersensitivity pneumonitis, as it lacks sufficient resolution.

If, after a thorough history taking, physical examination, and tests, the physician remains in doubt about the diagnosis, a lung biopsy is performed. A biopsy is a procedure in which a surgeon obtains a small fragment of lung tissue during surgery, which is then examined under a microscope. Sometimes a biopsy can be obtained by a simpler and less invasive method—during bronchoscopy; however, lung tissue fragments obtained this way are very small and do not always allow for the assessment of lung changes.

Treatment of hypersensitivity pneumonitis

Treatment of hypersensitivity pneumonitis begins with the elimination of the suspected exposure and systemic anti-inflammatory therapy, the drugs for which in this case include systemic corticosteroids, mycophenolic acid**, azathioprine**, and rituximab**. If, despite such treatment, dyspnea progresses, pulmonary function continues to decline, and CT scans show an increase in pulmonary fibrotic changes, nintedanib (antifibrotic therapy) is added to the treatment, which can slow further clinical deterioration. Ask your attending physician about the possibility of follow-up and treatment at a research institution with expertise in interstitial lung diseases, where modern medications may be available.

When chronic respiratory failure develops along with hypoxemia (low blood oxygen levels), long-term oxygen therapy using oxygen concentrators is prescribed. In addition to stationary oxygen concentrators, which are large and heavy, portable concentrators are available today, allowing patients to leave the house for walks.

All patients with hypersensitivity pneumonitis require pulmonary rehabilitation involving breathing exercises, which help reduce dyspnea and improve overall condition.

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

Appendix G1. Questionnaire for establishing a potential etiological factor of chronic HP

Title: Chronic Hypersensitivity Pneumonitis Exposure Questionnaire

Original title: Chronic Hypersensitivity Pneumonitis Exposure Questionnaire

Source: Barnes Y., Morisset J., Molyneaux Ph. et al. A systematically derived exposure assessment instrument for chronic hypersensitivity pneumonitis. Chest 2020; 157(6):1506-1512. doi: 10.1016/j.chest.2019.12.018.

Type (underline):

- rating scale

- score

- questionnaire

- other (specify):_____________________________________________________________

Purpose: to identify a potential etiological factor of chronic HP in this patient

Chronic Hypersensitivity Pneumonitis Exposure Questionnaire

Part 1. Recall the places where you regularly spend time (home, work, other places, e.g., garage, basement) and check the exposures you experience on a regular basis.

Have you been exposed to any other agents?

Part 2. For each exposure checked in Part 1, specify the following details:

Interpretation key: exposures identified by the patient, considering timing, duration of exposure, and relationship to disease symptoms, may be considered as potential etiological factors of hypersensitivity pneumonitis in this patient.

Explanations: The questionnaire helps the patient recall exposures they were regularly subjected to, establish the timing and duration of these exposures, and assess their potential role in the development of the disease in this patient.

Appendix G2. Medical Research Council (MRC) Dyspnea Scale

Source: Medical Research Council. Committee on research into chronic bronchitis: instruction for use on the questionnaire on respiratory symptoms. Devan, England: WJ. Holman, 1966.

Type (underline):

- assessment scale

- score

- questionnaire

- other (specify):

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

Content (template):

Interpretation key: a higher score corresponds to more severe dyspnea during daily physical activity.

Explanations: The MRC scale is used to assess the patient's dyspnea and monitor their condition during treatment, particularly pulmonary rehabilitation.