Idiopathic pulmonary fibrosis with cellular lung formation. Idiopathic pulmonary fibrosis - treatment and recommendations. Pulmonary Fibrosis Causes

In which, due to fibrous changes (scars) and compaction of the lung tissue, the normal functioning of the lungs is disrupted. As the disease progresses, the lung tissue becomes more scarred, which leads to a decrease in the amount of oxygen entering the blood.

The five-year survival rate of patients with IPF does not exceed 30%, and only the recent appearance of anti-fibrotic therapy has made it possible to slow down the progression of the disease and prolong the life of patients. Unfortunately, such therapy is not available to every Russian patient: this is due to the low level of awareness about the disease - not only patients but also medical specialists often do not know about it. Now in Russia, only a few hundred cases of the disease have been officially registered, but according to the estimates of specialists, there are more than 10 thousand such patients in the country.

Difficulties in diagnosing IPF are due to the fact that symptoms of the disease are also found in other diseases - patients are misdiagnosed and prescribed therapy that does not alleviate their condition in any way. About 60% of patients with IPF do not receive treatment on time.

“The diagnosis of IPF is objectively difficult,” says Alexander Averyanov, director of the Federal State Budgetary Institution Research Institute of Pulmonology, FMBA of Russia, MD, professor. - On the one hand, its symptoms: dry cough, shortness of breath on exertion and pulmonary noises on auscultation, reminiscent of the crunch of cellophane, are characteristic of many other respiratory and cardiovascular diseases. However, due to the rarity and poor understanding of the disease, most therapists and even pulmonologists do not have sufficient experience in diagnosing and treating this disease. As a result, in more than 50% of cases, patients with idiopathic pulmonary fibrosis are initially diagnosed with a completely different diagnosis: COPD, heart failure - and are prescribed therapy that does not help and cannot help, and in some cases even hurts. On average, more than a year passes from the moment of going to the doctor until the correct diagnosis is made, and during this time the disease progresses, fibrotic processes in the lungs increase, making breathing more and more difficult, leading to disability and early death. "

In some cases, it is not possible to make the correct diagnosis throughout the patient's life - this leads to the fact that the disease is considered a rarer disease than it actually is. As a result, funding for IPF patients is insufficient to ensure effective therapy for all patients. Traditional regimens using glucocorticosteroids and cytostatics do not give the expected result, and innovative drugs that can really prolong life are not paid for by the state.

To raise awareness of idiopathic pulmonary fibrosis and provide patient care, International IPF Week is taking place from 16 to 23 September around the world, including Russia. Representatives of the medical community and patient organizations are interested in making as many people as possible aware of the symptoms of the disease, its danger and possible treatment. Timely administration of therapy soon after diagnosis will help prevent the rapid progression of the disease and prolong the period of active life.

Men suffer from idiopathic pulmonary fibrosis much more often than women, and mortality from this disease exceeds mortality from many types of cancer. Men over 60 years of age, smokers (as well as those who quit) with shortness of breath and coughing should contact a specialized pulmonary center for an examination that excludes IPF.

The diagnosis of "pulmonary fibrosis" for many patients means the beginning of a difficult fight against the disease, requiring tremendous efforts.

How dangerous this disease is, is it really that an effective cure for it has not been invented, and what is the life expectancy for this disease - these questions concern the patient in the first place.

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Life expectancy at different stages of the disease

Fibrosis of the lungs has several stages and forms of the course, which directly affect the prognosis of the disease, the quality and duration of life. Doctors tend to classify the disease into early and late stages, in which the existing symptoms differ in intensity.

• The early stage is characterized by a slight deterioration in the general well-being of a person. Most often, respiratory failure of the first or second degree is diagnosed, the patient complains of shortness of breath, prolonged weakness and apathy, night sweats, pain in the joints in the morning. Laboratory studies show small changes in the composition of the blood, changes are clearly visible on radiographs of the lungs.
• The late stage is manifested by severe, prolonged shortness of breath, increased respiratory failure to the third or fourth degree. Cyanosis of the skin appears, mucous membranes acquire a bluish-ash color. Changes in the shape of the fingers are increasing, the nails become convex, the fingers are shaped like drumsticks.

Fibrosis, depending on the course and duration of the disease, is divided into chronic and acute.

• The acute type of the disease develops rapidly, complicated by hypoxemic coma, and acute respiratory failure, which are fatal;
• the chronic form has a slow course, gradually decreasing the duration of activity. This form of the disease is subdivided into: aggressive, focal, slowly progressive and persistent.

The increase in symptoms in the aggressive type of chronic pulmonary fibrosis occurs much more slowly than in the acute form of the disease. Persistent chronic fibrosis is characterized by a gradual, prolonged increase in the intensity of symptoms. The most gradual development of the disease is observed with slowly progressive chronic fibrosis.

In what cases is an unfavorable outcome possible?

• The acute form is relatively rare, in only twenty percent of cases. It is characterized by a sudden onset with rapidly increasing symptoms. The degrees of respiratory failure quickly replace each other, the patient suffers from severe shortness of breath. Acute progressive fibrosis practically does not lend itself to the methods of conservative therapy; the patient dies after a couple of months.
• Chronic fibrosis of an aggressive form sharply reduces the duration of the necessary movements and leads the patient to death within a year, with conservative treatment. Shortness of breath and heart failure aggravate the patient's condition, since the symmetrical growth of fibrous tissue in the lungs cannot be controlled by the administration of drugs.

Chronic persistent pulmonary fibrosis allows a patient with a similar diagnosis to live for no more than three to five years.

Surgical treatment, lung transplantation with this pathology in half of the cases gives the patient a chance to continue life. Statistics show that timely surgery can help prolong the duration of activity by about five years.

Weight loss, low-grade fever indicate serious problems in the lungs. For the timely organization of therapeutic events, find out how early is carried out.

Working in a workplace with permanently polluted air can lead to the development of silicosis. on measures to prevent this disease.

In what cases is a favorable outcome possible

Slowly progressive chronic disease is characterized by a fairly smooth, prolonged development of the disease. A patient, with adequate treatment and the absence of concomitant pathologies of the cardiovascular system, can live for ten or more years.

Doctors can give a favorable prognosis when diagnosing focal fibrosis in a patient. If the disease does not progress, then there are no symptoms that worsen the quality and duration of life and lead to the death of the patient.

How to improve the condition and prognosis of life

Therapeutic measures in the treatment of pulmonary fibrosis are aimed at restoring normal breathing and gas exchange, stopping the pathological process of proliferation of fibrous formations and stabilizing disorders associated with the respiratory system. The methods are classified into:

• Drug therapy;
• non-drug therapy;
• rehabilitation measures;
• surgery.

The main goal of drug therapy is to reduce the formation of growths in the lungs and increase life expectancy. The termination of the pathological process gives hope to patients, since concomitant therapy of disorders of the heart and respiratory system has only an auxiliary effect.

Since the drugs used to treat fibrosis negatively affect the body, reducing immunity, patients are prescribed an annual influenza vaccination, and it is also recommended to administer the pneumococcal vaccine once every five years. Treatment is long-term, carried out under the obligatory regular supervision of a doctor.

Non-drug treatment includes oxygen therapy, which is carried out both in a hospital setting and in outpatient treatment. Inhalation of oxygen allows you to normalize gas exchange, reduces shortness of breath and allows you to increase physical activity. According to the doctor's prescription, plasmaphoresis and hemosorption are performed.

Rehabilitation measures are needed to prevent metabolic disorders associated with the disease. To improve the quality and duration of life, help:

• Physiotherapy exercises, walks and jogging in the fresh air;
• sleeping in the fresh air is especially recommended for pulmonary fibrosis, as well as being in nature;
• - one of the most powerful remedies for pulmonary diseases;
• high-quality, nutritious food, excluding the use of products that contain preservatives and chemicals. The body must be supported, food must be gentle, light, nutritious and rich in vitamins;
• taking various vitamin complexes recommended by your doctor.

Unfortunately, this is a serious illness that in most cases leads to the death of the patient. But adherence to medical recommendations, the desire to stop the disease, the desire to increase life expectancy, become the factors that help a person in the fight against a serious illness.

The video shows a set of 13 breathing exercises.

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The article is devoted to the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the determination of the role of biomarkers in the diagnosis and assessment of the severity of the disease. IPF is a special form of chronic progressive fibrosing interstitial pneumonia of unknown etiology. It has been shown that IPF is a disease of the pulmonary epithelium, which manifests itself in the same symptoms as fibrosis, i.e., is a consequence of dysfunction of its pulmonary epithelium. The theory of 3-stage development of IPF is considered. From a diagnostic and differential diagnostic point of view, if IPF is suspected, it is important to determine the serum SP-A level. The diagnostic role of other biomarkers (assessed in these studies) has not been established. Studies have also found that serum biomarkers SP-A,
MMP-7 and KL-6 play a diagnostic and prognostic role: studies have shown an inverse relationship between the concentration of biomarkers MMP-7 and KL-6 and the prognosis of 5-year survival in patients with IPF. For the prognosis of IPF, the level of interleukin-8 is important, which correlates with the severity of the disease. The diagnostic and prognostic significance of biomarkers in patients with IPF can be established only taking into account clinical-anamnestic, radiological and, in some cases, morphological research methods.

Keywords: idiopathic pulmonary fibrosis, pathogenesis, biomarkers.

For citation: I.V. Leshchenko, A.D. Zherebtsov Idiopathic pulmonary fibrosis: a modern view of the pathogenesis and the role of biomarkers // BC. 2018. No. 10 (I). S. 6-10

Idiopathic pulmonary fibrosis: modern view of pathogenesis and the role of biomarkers
I.V. Leshchenko 1,2, A.D. Zherebtsov 1

1 Ural State Medical University, Yekaterinburg
2 Medical Association “Novaya Bolnitsa”, Yekaterinburg

The article is devoted to the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the role of biomarkers in the diagnosis and asssessing of the severity of the disease. IPF is a special form of chronic progressive fibrosing interstitial pneumonia of unknown etiology. It is shown that IPF is a disease of the pulmonary epithelium, which manifests itself as fibrosis, i. e.it is caused by dysfunction of the pulmonary epithelium. The theory of the three-stage development of the IPF is considered. From a diagnostic and differential diagnostic point of view, at suspicion on IPF it is important to determine the level of serum SP-A. The diagnostic role of other biomarkers (evaluated in these studies) is not established. When determining the prognosis, IPF can have the value of IL-8, the level of which correlates with the severity of the disease. Studies have shown that the serum biomarkers SP-A, MMP-7 and KL-6 can play a diagnostic and prognostic role for IPF patients. An inverse relationship was found between the concentration of biomarkers MMP-7 and KL-6 and the prognosis of 5-year survival in patients with IPF. Diagnostic and prognostic significance of biomarkers in IPF patients can be established only taking into account clinico-anamnestic, radiological and, in some cases, morphological methods of investigation.

Key words: idiopathic pulmonary fibrosis, pathogenesis, biomarkers.
For citation: Leshchenko I. V., Zherebtsov A. D. Idiopathic pulmonary fibrosis: modern view of pathogenesis and the role of biomarkers // RMJ. 2018. No. 10 (I). P. 6-10.

The article is devoted to the pathogenesis of idiopathic pulmonary fibrosis and the determination of the role of biomarkers in the diagnosis and assessment of the severity of the disease.

Introduction

Interstitial lung disease (ILD) in general, including idiopathic pulmonary fibrosis (IPF), is a multifaceted pulmonary pathology. It is believed that the first description of interstitial lung lesions was made by G. E. Rindfleisch in 1897, calling the disease cirrhosis cystica, and a year later P. von Hansemann used the term lymphangitis reticularis... From a more modern point of view, the first description of interstitial lung lesions was presented by Hamman and Rich, who gave their case the name "fulminating diffuse interstitial fibrosis of the lungs", later changed to "Hamman-Rich syndrome". Despite the fact that this name is not currently used, the discovery of the Hamman-Rich syndrome made an important contribution to the understanding of interstitial lung lesions. Firstly, based on observations of patients with this syndrome, the first histological pattern associated with a specific interstitial lung lesion was identified, and, secondly, it became clear that some patients may respond to corticosteroid therapy, while in others this group of drugs causes an exacerbation. illness. In 1948, Robbins first used the term "idiopathic pulmonary fibrosis" to describe patients with interstitial changes on chest radiographs that were similar to pulmonary fibrosis, but without an identified cause. At the same time, the relationship between pulmonary fibrosis and post-infectious fibrosis, pneumoconiosis, the effects of radiation therapy, autoimmune diseases such as rheumatoid arthritis or systemic sclerosis was recognized.
According to the modern understanding, IPF is defined as a special form of chronic progressive fibrosing interstitial pneumonia of unknown etiology, which occurs mainly in older people, affects only the lungs and is associated with the histological and / or radiological pattern of common interstitial pneumonia. A number of modern researchers believe that this name does not correspond to the current discoveries in the study of IPF. The accumulated information allows us to identify many reasons for the development of this disease, which makes the term "idiopathic" no longer appropriate.

Modern issues of pathogenesis

It quickly became clear that IPF is based on an overgrowth of connective tissue. The first concept of IPF pathogenesis was the concept of inflammation of the alveolar wall, leading to the production of fibrogenic mediators. However, the use of steroidal anti-inflammatory drugs did not give the desired results and only led to the progression of the disease. Gradually, the concept of damage to the alveolar epithelium resulted in the theory of the 3-stage development of IPF (Fig. 1).

Stage I - predisposition (predisposition). Its essence lies in the presence of factors that determine the increased sensitivity of the alveolar epithelium to the alleged etiological agents. Viruses such as Epstein-Barr virus, cytomegalovirus, hepatitis C virus, influenza, as well as tobacco smoke, wood dust, livestock, environmental factors that lead to accelerated division of type II alveolocytes in genetically predisposed individuals, mediated by the endoplasmic reticulum (ER-stress), activation of the expanded protein response (UPR), apoptosis, which ultimately leads to progressive depletion (shortening) of telomeres. At this stage, the state of the surfactant acquires a certain significance, since damaging factors come into contact with it. Anomalies in the surfactant proteins SP-A and SP-D can determine the strength of the damaging factor of the above antigens.
Stage II - activation.

Accumulated environmental factors in genetically predisposed individuals lead to pathological changes in the pulmonary epithelium (bronchoalveolar and alveolar): reprogramming of physiological aging of cells and the release of profibrotic mediators by the alveolar epithelium, such as transforming growth factor β (TGFβ) and platelet-derived growth factor α PDG ... These mediators, directly or indirectly through leukocytes, activate fibroblasts, which begin to produce abnormal extracellular matrix (extracellular substance).
Stage III - progression. The extracellular substance promotes additional differentiation of fibroblasts into myofibroblasts, which deposit even more matrix and further activate fibroblasts, which leads to remodeling of lung tissue. Lung tissue remodeling alters the expression of a number of extracellular matrix substances, many of which are capable of activating profibrotic signaling pathways in mesenchymal cells. Fibroblasts with IPF acquire destructive properties, which can contribute to chronic remodeling.

The role of biomarkers in the diagnosis and treatment, assessment of the prognosis of IPF

In studies, IPF biomarkers are considered as a necessary tool for differential diagnosis, predicting disease progression and response to treatment.
There is currently no generally accepted classification of biomarkers of pulmonary fibrosis. We have divided all major biomarkers into three large groups based on their significance:
- for the diagnosis and differential diagnosis of IPF;
- determining the prognosis of the ILF;
- evaluating the effectiveness of targeted anti-fibrotic therapy.

Biomarkers for the diagnosis and differential diagnosis of IPF

The largest number of studies has been carried out in the field of biomarker assessment as a method for diagnosing IPF and its differential diagnosis with other lung diseases. The first and most studied are surfactant proteins. Serum SP-A levels in IPF patients were significantly higher than in patients with other IPL. Also, SP-A levels were significantly higher in IPF patients than in patients with pulmonary sarcoidosis and pneumonia. The level of SP-D in the serum of IPF patients, similar to SP-A, was also significantly higher than in patients with pneumonia, sarcoidosis of the lungs and patients of the control group. In contrast to SP-A, no significant difference was found in the content of SP-D in patients with IPF and other IPL (including progressive systemic sclerosis, pulmonary alveolar proteinosis, idiopathic nonspecific interstitial pneumonia, and sarcoidosis).
Matrix metalloproteinases(MMR). They are a family of zinc and calcium-dependent endopeptidases. They play an important role in many normal physiological processes, such as embryonic development, morphogenesis, reproduction and tissue remodeling, as well as in various pathological processes: arthritis, malignant growth and cardiovascular diseases. The level of MMP in healthy lung tissue is lower than in the lung with IPF. According to their specificity, MMPs are divided into collagenases (MMP-1, -8 and -13), gelatinases (MMP-2 and -9) and stromelysins (MMP-3 and -10). Gelatinase A (MMP-2) and gelatinase B (MMP-9) appear to be involved in pulmonary fibrosis, but their specific role in this process remains unclear. While MMP-9 is rather released by inflammatory cells and may be associated with an inflammatory process caused by tissue remodeling, MMP-2 is synthesized by structural cells, including fibroblasts, endothelial and epithelial cells, and may be associated with chronically impaired tissue remodeling, resulting in to abnormal collagen deposition.
Normal lung fibroblasts do not express MMP-9 in vitro, while fibroblasts from lungs affected by IPF, on the contrary, express it intensely. This process appears to be, at least in part, associated with the secretion of gelatinases MMP-2 and MMP-9. In this context, both MMP-2 and MMP-9 have been observed in subepithelially located myofibroblasts and sometimes in areas of exposed alveolar basement membrane, suggesting that these MMPs may play a role in the migration of myofibroblasts into alveolar spaces. MMP-7 is expressed in normal and abnormal epithelial cells. MMP-7 is synthesized by various tumors: breast, colon, prostate, stomach, upper respiratory tract and esophagus, lungs and skin.
Periostin... Periostin has been reported to be elevated in IPF patients, but its sources and mechanisms of action remain unclear. The authors found that serum periostin levels increased in IPF patients, which correlated with decreased forced vital capacity (FVC) and lung diffusion capacity (DLco). It was found that predominantly periostin exists in oligomeric form in serum and monomeric periostin is presented as its insignificant fraction. It is monomeric periostin that is given diagnostic value, the level of which is significantly increased in IPF in comparison with other diseases also associated with the level of periostin (Alzheimer's disease, systemic scleroderma and bronchial asthma).

Biomarkers for determining the prognosis of IPF

An exacerbation of IPF may be indicated by an increase in surfactant levels. Studies have noted the association of high SP-A levels with a significantly higher risk of death in IPF patients. There was also a similar strong association between high SP-D levels and an increased risk of death. One study showed that IL-8 mRNA and IL-8 protein correlated with disease severity. Ley et al. It is recommended to use the GAP index, which includes gender, age, and 2 pulmonary function variables (FVC and DLco), as a predictor of death in patients with IPF, based on a simple scoring system and developed as a result of a study of 558 patients with IPF. Only the GAP index, radiation diagnostics and serum biomarkers in the complex can increase the accuracy and sensitivity of determining the prognosis of patients with IPF.
In a Japanese study, the authors compared the diagnostic and prognostic value of a number of serum biomarkers (MMP-7, CCL18, KL-6, SP-A, and SP-D) in the IPF and comparison groups. Table 1 presents the characteristics of the subjects participating in the study.


Differences in the values ​​of five biomarkers (MMP-7, CCL18, KL-6, SP-A and SP-D) using the ROC curve analysis method in patients with IPF (n = 65), patients with bacterial pneumonia (n = 31) and healthy individuals ( n = 101) are reflected in table 2.


Statistically significant differences in the levels of biomarkers MMP-7, CCL18, KL-6, SP-A and SP-D in patients with IPF, bacterial pneumonia and control group (healthy individuals) are shown in Figure 2.

It was also determined which biomarkers are independent predictors of prognosis in patients with IPF. Multivariate Cox analysis of the sensitivity and specificity studied in this study of biomarkers in the IPF, pneumonia and control groups showed that the levels of biomarkers MMP-7 and KL-6 are independent predictors of prognosis in patients with IPF. In addition, IPF patients with elevated MMP-7 and KL-6 levels had lower survival rates, and the combination of the two markers corresponded to the highest mortality rate. The results obtained indicate that both MMP-7 and KL-6 are promising prognostic markers of IPF, and the combination of the two markers can improve the assessment of the prognosis of survival in patients with IPF. In addition, the authors of this study showed that MMP-7 and KL-6 can clearly differentiate patients with IPF from patients with bacterial pneumonia and healthy individuals, further indicating their potential as diagnostic biomarkers.
Correlations of the survival of patients with IPF, divided into 3 groups according to the ratio of different biomarkers and survival, are shown in Figure 3.

These results confirm that IPF patients with elevated levels of both MMP-7 and KL-6 had lower survival rates, suggesting that assessing both factors is more effective in identifying the high-risk subgroup than individual assessments of both biomarkers. ... MMP-7, a family of zinc-containing enzymes with proteolytic activity, and KL-6, a high molecular weight glycoprotein classified as mucin MUC1, are thought to be involved in the progression of IPF by different mechanisms and require further promising research.

Biomarkers for evaluating the effectiveness of targeted anti-fibrotic therapy

The increase in the production of MMP-8 and MMP-9 is not accompanied by a compensatory increase in their main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1). Since the combined activity of these two enzymes can destroy fibrillar fibers and basement membranes of collagen in the pulmonary interstitium, their increased activity will promote matrix destruction and remodeling in the development of fibrosis. Analysis of MMP-8 and MMP-9 from bronchoalveolar lavage fluid may provide useful biochemical markers for monitoring efficacy and adverse events in future treatment of patients with IPF and pulmonary sarcoidosis.
It is interesting to analyze whether monomeric periostin can predict the efficacy of two antifibrotic drugs, pirfenidone and nintadanib, approved by the International IPF Committee ATS / ERS / JRS / ALAT. Although it has been proven that these drugs are effective in treating patients with IPF, no corresponding biomarkers have been found to predict the effectiveness of these drugs, which would allow developing the necessary tactics for managing patients with IPF.

Conclusion

Thus, from modern scientific positions, the pathogenesis of IPF is considered as a 3-stage process, as a result of which, due to dysfunction of the pulmonary epithelium (bronchoalveolar and alveolar), pulmonary fibrosis develops.
The following has been established regarding IPF biomarkers. From a diagnostic and differential diagnostic point of view, if IPF is suspected, it is necessary to determine the level of serum SP-A. The diagnostic role of other biomarkers has not been established. In determining the prognosis of IPF, IL-8 may have a value, the level of which correlates with the severity of the disease. An inversely proportional relationship was established between the concentration of biomarkers MMP-7 and KL-6 and the prognosis of 5-year survival in patients with IPF; however, their diagnostic and prognostic role remains to be reliably established. It is of interest to study changes and the ratio of IPF biomarkers not individually, but in aggregate. There are few serious works in the field of evaluating the effectiveness of treatment on changes in the concentration of biomarkers, and the available data are insufficient even to isolate a potentially useful biomarker for such purposes. Another disadvantage of the studies published to date is their duration. Prospective studies are needed to assess the predictive power of biomarkers. The diagnostic and prognostic significance of biomarkers in patients with IPF can be established only taking into account clinical-anamnestic, radiological and, in some cases, morphological research methods.

Literature

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2. Interstitial Lung Diseases / Edit. by Du Bois R. M., Richeldi L. Eur. Respir. Monograph, M: ERS. 2009.395 p.
3. Diagnosis and treatment of idiopathic pulmonary fibrosis. Federal clinical guidelines [Electronic resource]. URL: www.pulmonology.ru. 2016 (date accessed: 17.08.2018). URL: www.pulmonology.ru. 2016 (data obrashhenija 17.08.2018) (in Russian)].
4. Qiang D., Tracy L., Louise H. et al. New Insights into the Pathogenesis and Treatment of IPF: An Update // Drugs. 2011. Vol. 71 (8). P. 981-1001.
5. Paul J. W., Timothy S. B. Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? // Lancet Respir. Med. 2018. Vol. 6. P. 154-160.
6. Giacomo S., Bruno I., Mariarosaria C. et al. Idiopathic pulmonary fibrosis: pathogenesis and management // Respir. Res. 2018. Vol. 19 (1). P. 32. DOI: 10.1186 / s12931-018-0730-2.
7. Luca R., Harold R. C., Mark G. J. Idiopathic pulmonary fibrosis // Lancet. 2017. Vol. 389 (10082). P. 1941-1952.
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9. Bhattacharyya P., Acharya D., Roychowdhury S. Role of matrix metalloproteinases in the pathophysiology of idiopathic pulmonary fibrosis // Lung India. 2007. Vol. 24. P. 61–65.
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11. Shoichiro O., Masaki O., Kiminori F. et al. The usefulness of monomeric periostin as a biomarker for idiopathic pulmonary fibrosis // PLOS ONE. 2017. Vol. 12 (3). P. 1-17.
12. Guiot J., Henket M., Corhay J. - L. et. al. Sputum biomarkers in IPF: Evidence for raised gene expression and protein level of IGFBP-2, IL-8 and MMP-7 // PLOS ONE. 2017. Vol. 12 (2). P. 1-2.
13. Bentley J. B., Naik P. K., Bozyk P. D., Moore B. B. Periostin promotes fibrosis and predicts progression in patients with Idiopathic Pulmonary Fibrosis // AJP Lung Cell / Mol. Physiol. 2012. Vol. 303. P. 12. DOI: 10.1152 / ajplung.00139.2012. Epub 2012 Oct 5.
14. Ley B. A multidimensional index and staging system for idiopathic pulmonary fibrosis // Ann. Intern. Med. 2012. Vol. 15, 156 (10). P. 684-691.
15. Hamai K., Iwamoto H., Ishikawa N. et al. Comparative Study of Circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as Disease Markers of Idiopathic Pulmonary Fibrosis // Disease Markers. 2016. Vol. 3. P. 1–8. http://dx.doi.org/10.1155/2016/4759040.
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18. Raghu G., Collard H. R., Egan J. J. et al. ATS / ERS / JRS / ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS / ERS / JRS / ALAT statement: idiopathic pulmonary fibrosis; evidence-based guidelines for diagnosis and management // Am. J. Respir. Crit. Care Med. 2011. Vol. 183. P. 788-824.

Idiopathic pulmonary fibrosis, Hammen-Rich syndrome, Diffuse pulmonary fibrosis, Fibrosing cryptogenic alveolitis, Idiopathic fibrosing alveolitis

RCHD (Republican Center for Healthcare Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical Protocols of the Ministry of Health of the Republic of Kazakhstan - 2013

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

Pulmonology

general information

Short description

Approved by the minutes of the meeting
Expert Commission on the Development of Healthcare of the Ministry of Health of the Republic of Kazakhstan

No.23 on 12/12/2013

Definition: idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown etiology, occurring mainly in the elderly, limited to the lungs, and associated with the histopathological and / or radiological picture of common interstitial pneumonia.

Former name: idiopathic fibrosing alveolitis is not recommended for use due to the pathomorphological features of the disease - the rapid formation of fibrosis.

I. INTRODUCTORY PART

Protocol name: Diagnosis and treatment of idiopathic pulmonary fibrosis.

Protocol code:

ICD-10 code (s):

J84.1 Other interstitial pulmonary diseases with mention of fibrosis:

Diffuse pulmonary fibrosis. Fibrosing alveolitis (cryptogenic). Hammen-Rich Syndrome. Idiopathic pulmonary fibrosis

Abbreviations used in the protocol:

DIP - Desquamative Interstitial Pneumonia

IIP - Idiopathic Interstitial Pneumonia

IPF - Idiopathic Pulmonary Fibrosis

ILD - Interstitial Lung Disease

HRCT - high resolution computed tomography

LIP - lymphoid interstitial pneumonia

NSIP - nonspecific interstitial pneumonia

UIP - common interstitial pneumonia

SDPA - mean pulmonary artery pressure

FBS - fibrobronchoscopy

ECG - electrocardiography

ECHO-KG - echocardiography

DLCO - Lung Diffusion Capacity

Date of protocol development: 04.2013 r.

Protocol users: General practitioners, therapists, pulmonologists, executive managers, nursing staff

Classification

Clinical classification

IPF is a fatal lung disease with a variable and unpredictable course. Despite the fact that there is no generally accepted classification by stages and flow options, it is recommended to distinguish
- rapidly progressing,
- slowly progressive and
- recurrent course (phase of exacerbation and stabilization).
Median survival is 2 to 5 years from diagnosis.

In most patients with IPF, lung function gradually deteriorates over time; in a minority of patients, lung function remains stable or deteriorates rapidly.

In a relapsing course, patients may experience episodes of acute respiratory deterioration despite prior stability. Observations have shown that acute deterioration of respiratory function occurs in a small number of patients with IPF (approximately 5-10%).

These episodes can occur secondary to pneumonia, pulmonary embolism, or heart failure.

If the cause of an acute decrease in respiratory function cannot be determined, the term "exacerbation of IPF" is used. It is currently unclear whether the exacerbation of IPF is simply a manifestation of an unidentified respiratory complication (eg, pulmonary embolism, infection) that caused an acute deterioration in the patient's IPF, or is the acceleration of the pathobiological processes involved in IPF inherent in the disease itself.

If no other cause is identified, the presence of any of the subsequent changes should be regarded as the progression of the disease:

Progressive dyspnea (preferably using a grading scale, such as the Borg scale)

Progressive, steady decrease in absolute FVC values ​​compared to baseline.

Progressive, steady decrease in the absolute values ​​of Dlco compared to the baseline.

Fibrosis progression on HRCT.

Disease progression should be monitored over a period of 4 to 6 months, but for a shorter period if necessary.

Diagnostics

II. METHODS, APPROACHES, PROCEDURES OF DIAGNOSTICS AND TREATMENT

List of basic and additional diagnostic measures

Before planned hospitalization:

Basic:

General blood analysis;

Coagulogram;

Spirometry;

Echo-KG (with SDL score)

Additional:

In the hospital, in addition to the above, the following are carried out:

Blood test with proteinogram assessment

Blood test for the presence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpeviruses, hepatitis viruses

Pulse oximetry;

Arterial blood gases;

FBS (according to indications);

DLCO definition,

Videothoracoscopic lung biopsy (if indicated)

Emergency hospitalization is performed without preliminary (outpatient) laboratory and instrumental research.

Diagnostic criteria:

Eliminate other known causes of interstitial lung disease (ILD) (eg, household or occupational exposure to the environment, connective tissue disorders, drug toxicity).

Presence of a UIP pattern on high-resolution computed tomography (HRCT) in patients who have not undergone surgical lung biopsy.

Combination of RIP pattern on HRCT and a specific pattern of RIP of lung biopsy material in patients undergoing surgical lung biopsy.

The accuracy of the diagnosis of IPF is enhanced by interdisciplinary discussion between pulmonologists, radiologists, and pathologists with experience in the diagnosis of IPF.

The large and small IPF criteria proposed by the 2000 ATS / ERS Consensus have been eliminated.

IPF should be considered in all adult patients with progressive, unexplained dyspnea on exertion. Other common manifestations are unproductive cough, increased fatigue, sometimes sweating, fever, and weight loss. Not typical: hemoptysis, pleural involvement, severe bronchial obstruction. The likelihood of the disease increases with age, typically the onset of the disease in the sixth or seventh decade of life. IPF is rare before age 50; such patients may subsequently manifest symptoms of connective tissue disease, which proceeded in a subclinical form at the time of IPF diagnosis. IPF occurs almost equally in men and women.

At physical examination the leading criteria are bilateral basal inspiratory crepitus, changes in the fingers in the form of "drumsticks".

Typical laboratory criteria no. Perhaps a moderate increase in the level of leukocytes, ESR, dysproteinemia.

Instrumental criteria IPF: based on the characteristic signs of common interstitial pneumonia (IPP) according to HRCT (Table 1), histopathological criteria for IPP (Table 2), and functional study data.

Table 1. HRCT criteria for the OIP pattern.

The picture of the OIP (All four signs)	Possible drawing of the OIP (all three criteria)	Contradicts the IPR (any of the seven signs)
Reticular deformity - "Cell lung" with / or without traction bronchiectasis	The predominance of subpleural and basal localization Reticular deformity No signs contradicting the UIP picture (see third column)	The predominance of damage to the upper or middle lobe of the lung Predominantly peribronchovascular localization Extensive decrease in the transparency of the lungs by the type of "ground glass" (the area of ​​"ground glass" is larger than reticular deformity) Abundance of nodules (bilaterally, predominantly in the upper lobe) Separately located cysts (multiple, bilateral, separate from areas of the "cellular" lung) Diffuse mosaic attenuation of pulmonary pattern / air traps (bilateral, in three or more lobes) Consolidation in bronchopulmonary segment / lobe / lobe segments

Table 2. Histopathological criteria specific to OIP

OIP painting (all 4 criteria)	Probable IPR	Potential IPR (all three criteria)	Not an IPR (any of the six criteria)
Evidence of fibrosis / architectural abnormalities,  honeycomb predominantly subpleural / paraseptal Heterogeneous involvement of the pulmonary parenchyma in fibrosis Clusters of fibroblasts There are no indications against a diagnosis of AIP suggesting an alternative diagnosis (see column 4).	Evidence of fibrosis / architectural abnormalities,  honeycomb Absence of signs of heterogeneous fibrosis or accumulations of fibroblasts, but neither at the same time There are no indications against a diagnosis of AIE suggesting an alternative diagnosis (see column 4) or Honeycomb changes only ***	Heterogeneous or diffuse involvement of the pulmonary parenchyma in fibrosis, with or without interstitial inflammation Absence of other IPR criteria (see the column “IPR picture) There are no indications against a diagnosis of AIE suggesting an alternative diagnosis (see column 4)	Hyaline membranes * Organizing pneumonia ** Granulomas Interstitial inflammatory cell infiltrates outside the honeycomb Changes are mainly localized peribronchial Other signs supporting an alternative diagnosis

Spirometry: signs of restrictive respiratory dysfunctions - decreased VC (FVC)<80% от должных величин.

Table 3. Signs associated with increased mortality risk in IPF.

Basic factors *: Shortness of breath ** Dlco  40% of due Desaturation ≤ 88% during 6-minute walk test (6MWT) "Cellular lung" at HRCT Pulmonary hypertension Temporary change of factors: Increased dyspnea ** Decreased Forced Vital Capacity (FVC) ≥ 10% of absolute value Decrease in Dlco ≥ 15% of absolute value Worsening fibrosis on HRCT

* Baseline forced vital capacity - predictive value unclear. ** Currently there is no uniform approach to quantification

Indications for specialist consultation:

A consultation of pulmonologists, radiologists, pathomorphologists is required to establish a diagnosis.

Differential diagnosis

Differential diagnosis, first of all, it should be carried out with other forms of idiopathic interstitial pneumonia:

Non-specific interstitial pneumonia (NISP)

Compared to IPF, NSIP develops at a younger age (on average, 40 to 50 years) with the same frequency in men and women. The disease begins gradually, in a small part of patients, a subacute onset is possible. The clinical picture of NSIP is similar to that of IPF, but shortness of breath and cough are less pronounced and do not increase so steadily. In about half of the patients, there is a decrease in body weight (on average, up to 6 kg). An increase in body temperature and changes in the nail phalanges are relatively rare. In the study of FVD, insignificant or moderately pronounced restrictive disorders of pulmonary ventilation, a decrease in DLCO are determined, and hypoxemia may occur during exercise. In most cases, NSIP responds well to treatment with glucocorticosteroids (GCS) and has a favorable prognosis up to clinical cure. On HRCT, symmetrical subpleurally located areas of "frosted glass" are most often determined. In one third of patients, this symptom is the only manifestation of the disease. Reticular changes are observed in about half of the cases. Signs of "honeycomb lung", areas of compaction of lung tissue are relatively rare. With repeated studies in the course of treatment, most patients show positive X-ray dynamics. On histological examination, the cellular pattern corresponds to mild or moderate interstitial chronic inflammation; hyperplasia of type II pneumocytes in the zones of inflammation Homogeneity of changes with a predominance of inflammation and fibrosis is characteristic, in contrast to heterogeneity in OIP, coarse fibrosis is usually absent, fibroblast foci are few or absent.

Desquamative interstitial pneumonia (DIP)

DIP is rare (<3 % всех случаев ИИП), преимущественно у курящих мужчин 40-50 лет. У большинства пациентов заболевание протекает подостро в течение нескольких недель или месяцев, проявляется сухим кашлем и нарастающей одышкой. При исследовании ФВД выявляются умереные рестриктивные нарушения, снижение DLCO. ГКС-терапия достаточно эффективна, прогноз благоприятен. На рентгенограмме преобладает симптом "матового стекла" преимущественно в нижних отделах легких. Описана также узелковая текстура участков "матового стекла". При КТВР участки "матового стекла" определяются во всех случаях. В нижних зонах довольно часто определяются линейные и ретикулярные тени, возможно формирование ограниченных субплевральных участков "сотового легкого". При гистологии - однородное поражение легочной паренхимы, накопление альвеолярных макрофагов. Незначительное или умеренное утолщение альвеолярных перегородок, маловыраженное интерстициальное хроническое воспаление (лимфоидные агрегаты), фокусы фибробластов, признаки "сотового легкого" отсутствуют.

Lymphoid interstitial pneumonia (LIP)

LIP is rare, usually in women, more often after 40 years. The disease develops slowly, shortness of breath and coughing gradually increase over 3 years or more. Fever, chest pain, arthralgia, weight loss are characteristic. Cracking rales are heard in the lungs. Anemia, hypergammaglobulinemia may occur. The disease is amenable to GCS therapy and has a favorable prognosis, but about 1/3 of patients develop diffuse interstitial fibrosis. On radiography of the lungs, two types of changes can be observed: lower lobe mixed alveolar-interstitial infiltrates and diffuse lesions with the formation of a "honeycomb lung". HRCT usually identifies areas of "frosted glass". Sometimes perivascular cysts and areas of the "cellular lung" are determined. Changes of the reticular nature are observed in about 50% of cases. In histology, diffuse interstitial infiltration of the affected areas; distribution predominantly in the alveolar septa. Infiltrates include T lymphocytes, plasma cells, and macrophages. Lymphoid hyperplasia.

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Treatment

Treatment goals:
- slow down the rate of progression of pulmonary interstitial fibrosis,
- to prevent life-threatening complications.

Treatment tactics

Non-drug treatment

Oxygen therapy in patients with a clinically significant degree of hypoxemia (usually defined by SpO2 88% or PaO2 60 mm Hg).

Purpose: to increase physical tolerance, improve the survival of patients with clinically significant resting hypoxemia.

Pulmonary rehabilitation: with the development of a plan for the individual management of the patient, including educational lectures, the development of a nutrition plan, physical training with the inclusion of individually selected strength exercises, psychological support. Recommended for most patients with IPF. Not indicated for a small number of patients.

The role of pulmonary rehabilitation: improving the functional status and individual characteristics of the course of the disease.

Drug treatment

Glucocorticosteroids (GCS) and cytostatics- the main drugs for the treatment of patients with IPF, although in most patients these drugs do not have a significant effect on life expectancy. There are currently no drugs that can stop inflammation or fibrosis in IPF.

Only in 10-40% of patients with IPF, initial therapy with GCS leads to a partial improvement in the condition, while complete remission of the disease is observed in isolated cases. With IPF, spontaneous remissions are not observed, and the average life span, according to the latest data, ranges from 2 to 4 years from the moment of diagnosis. Despite the poor prognosis, treatment should be prescribed to all patients with a progressive course who have no contraindications to GCS or cytostatics.

However, it should be borne in mind that the expected therapeutic effect should outweigh the risk of complications from therapy. First of all, this applies to patients over the age of 70, patients with extreme obesity, concomitant severe heart and vascular diseases, diabetes mellitus, osteoporosis, severe respiratory failure, in the presence of a "cellular lung" in the X-ray examination.

Before starting therapy, patients should be informed about the potential risks and side effects of therapy with corticosteroids and cytostatics. Only after the patient's consent can treatment be started.

Recommended doses of GCS: 1 mg of prednisolone per 1 kg of body weight orally, but not more than 60 mg per day. This dose is prescribed for 2-4 months. with a subsequent decrease to maintenance - 15-20 mg / day. Cytostatic therapy (cyclophosphamide and azathioprine) was previously used in patients with IPF who did not respond to GCS therapy, in patients with complications or a high risk of complications from GCS. At present, it is believed that the combined treatment of corticosteroids and cytostatics increases the effectiveness and at the same time can significantly reduce the total doses of those and other drugs. Usually 15-25 mg of prednisolone is used daily and 200 mg of cyclophosphamide 2 times a week. The use of corticosteroids monotherapy in case of stable IPF is not recommended.

Corticosteroid (prednisone or equivalent) - 0.5 mg / kg body weight per day orally for 4 weeks; 0.25 mg / kg daily for 8 weeks. A gradual decrease to 0.125 mg / kg per day or 0.25 mg / kg every other day;

Plus azathioprine - 2-3 mg / kg per day; the maximum dose is 150 mg per day. Treatment begins with 25-50 mg daily, increasing by 25 mg every 1-2 weeks until the maximum dose is reached;

Or cyclophosphamide 2 mg / kg per day. The maximum dose is 150 mg per day. Treatment begins with 25-50 mg per day, increasing the dose by 25 mg every 1-2 weeks until the maximum dose is reached.

Therapy should be continued for at least 6 months. Efficacy is determined monthly based on clinical, radiological and functional data. The most important component of the treatment process is monitoring the unwanted effects of therapy.

Treatment with cyclophosphamide and azathioprine requires weekly monitoring of leukocytes and platelets in the blood. If the leukocyte count decreases ≤ 4000 / mm3, and the platelet count falls below 100,000 / mm3, treatment is stopped or the dose is immediately reduced by 50%. Control of the restoration of the number of leukocytes and platelets is carried out weekly. If recovery is not observed, cytostatics should be canceled until the normalization of the cellular composition of the blood is achieved.

Azathioprine also has hepatotoxic effects. In this regard, patients taking azathioprine need to determine the level of transaminases on a monthly basis. Treatment is stopped or the dose is reduced if the content of alanine aminotransferase is more than 3 times higher than the norm.

When using cyclophosphamide, hemorrhagic cystitis can develop. For prevention, it is recommended to drink plenty of fluids with monthly monitoring of the number of red blood cells in the urine.

The effectiveness of drugs that inhibit collagen synthesis and fibrosis (D-penicillamine, colchicine, interferons) has not yet been proven. D-penicillamine (cuprenil), which was widely used earlier, causes serious side effects in more than half of patients, which compete with the underlying disease in severity.

The pooled results of the randomized, double-blind, placebo-controlled study IFIGENIA demonstrated the feasibility of joining GCS therapy in patients with IPF of N-acetylcysteine ​​in high doses (1800 mg per day). N-acetylcysteine ​​slows down the decrease in VC and DLCO. The drug allows more successfully than only immunosuppressive therapy, to stabilize the clinical and functional parameters in patients with IPF and to mitigate the undesirable effects caused by GCS and cytostatics. At the same time, monotherapy with N-acetylcysteine ​​is not indicated due to the lack of effect.

Other treatments: no (taking into account the evidence base)

In some cases, the use of PDE-5 inhibitors (sildenafil) can be considered to reduce the mean pressure in the pulmonary artery in some patients with PAPA> 25 mm / h.

Surgical intervention: lung transplantation (with the ineffectiveness of drug treatment for a certain period, in the absence of positive dynamics of the main indicators of the effectiveness of treatment), etc.

Preventive actions: not developed

Further management:

With the effectiveness of the begun drug therapy, its continuation according to an individually developed program, taking into account the response to treatment and side effects;

In the absence of the effect of the therapy and / or the progression of the disease (taking into account the indicators of efficacy and safety), the decision on the expediency of lung transplantation;

Solving the issue of the patient's ability to work, taking into account the severity of respiratory failure.

Indicators of the effectiveness of treatment and the safety of diagnostic and treatment methods described in the protocol:

The ERS and ATS experts have developed the following criteria for the effectiveness of therapy for IPF:

Clinical improvement: presence of at least two of the following criteria during two consecutive visits in the period from 3 to 6 months of treatment:

Reducing the degree of shortness of breath and the severity of the cough;

X-ray improvement: reduction of parenchymal changes according to X-ray or HRCT of the lungs;

Functional improvement: the presence of at least two criteria: - ≥ 10% increase in TLC or FVC (minimum 200 ml); - ≥ 15% increase in DLco (minimum 3 ml / min / mm Hg); - significant improvement (≥ 4% units, ≥ 4 mm Hg) in SaO2 or PaO2 measured during exercise test.

Absence of serious undesirable effects of the therapy.

Hospitalization

Indications for hospitalization:

Lung biopsy to clarify the diagnosis (planned)

Initiation of immunosuppressive therapy, selection of drugs, pulse therapy (planned)

Sharp progression or exacerbation with the development of life-threatening complications: an increase in respiratory failure, progression of pulmonary hypertension, the appearance of signs of decompensation of the pulmonary heart, the appearance of signs of infection (emergency)

Information

Sources and Literature

1. Minutes of meetings of the Expert Commission on Healthcare Development of the Ministry of Health of the Republic of Kazakhstan, 2013
   1. 1. An official ATS / ERS / JRS / ALAT statement: Idiopathic Pulmonary fibrosis: evidence-based guidelines for diagnosis and management./ Am J Respir Crit Care Med. - 2011.- Vol. 183. 2. American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias // Am J Respir Crit Care Med. - 2002. - Vol. 165: 277-304. 3. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis // Am J Respir Crit Care Med 2006; 174: 810-816. 4. Lynch DA, Godwin JD, Safrin S, Starko KM, Hormel P, Brown KK, Raghu G, King TE Jr, Bradford WZ, Schwartz DA, et al., Idiopathic Pulmonary Fibrosis Study Group. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis // Am J Respir Crit Care Med 2005; 172: 488–493. 5. Shin KM, Lee KS, Chung MP, Han J, Bae YA, Kim TS, Chung MJ. Prognostic determinants among clinical, thin-section CT, and histopathologic findings for fibrotic idiopathic interstitial pneumonias: tertiary hospital study // Radiology 2008; 249: 328–337. 6. Visscher DW, Myers JL. Histologic spectrum of idiopathic interstitial pneumonias // Proc Am Thorac Soc 2006; 3: 322–329. 7. Best AC, Meng J, Lynch AM, Bozic CM, Miller D, Grunwald GK, Lynch DA. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality // Radiology 2008; 246: 935-940. 8. Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival // Am J Respir Crit Care Med 2000; 161: 1172-1178. 9. Flaherty KR, Toews GB, Lynch JP III, Kazerooni EA, Gross BH, Strawderman RL, Hariharan K, Flint A, Martinez FJ. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival // Am. J. Med., 2001. - Vol. 110. - R. 278-282. 10. Popova EN Idiopathic interstitial pneumonia: clinical picture, diagnosis, treatment // Attending physician. - 2005.- № 9. 11. Feschenko Yu. I., Gavrisyuk VK, Monogarova N. Ye. Idiopathic interstitial pneumonia: classification, differential diagnosis // Ukrainian pulmonological journal, 2007. - № 2. 12. American Thorecis Society, European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement // Am. J. Respir. Crit. Care Med. -2000. - Vol. 161. - P.646-664. 13. Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, MacNee W, Thomeer M, Wallaert B, Laurent F, et al; IFIGENIA Study Group. High-dose acetylcysteine ​​in idiopathic pulmonary fibrosis // N Engl J Med, 2005. - Vol. 353. - P. 2229-2242.

Information

III. ORGANIZATIONAL ASPECTS OF THE PROTOCOL IMPLEMENTATION

List of protocol developers with qualification data:

Kozlova I.Yu. - Doctor of Medical Sciences, Professor, Head. Department of Pulmonology and Phthisiology, Astana Medical University;

Latypova N.A. - Doctor of Medical Sciences, Associate Professor of the Department of Internal Medicine, Astana Medical University;

Bakenova R.A. - Doctor of Medical Sciences, Professor of the Medical University of Astana, chief therapist of the MC UDP RK;

Garkalov K.A. - Candidate of Medical Sciences, Head of the Department of Improvement of Primary Healthcare of the Republican State Enterprise on the RCC "RTSRZ"

Reviewers:
Ainabekova B.A. - Doctor of Medical Sciences, Professor, Head. Department of Internal Medicine for Internship and Residency of JSC "MUA"

No Conflict of Interest Statement: The developers of this protocol confirm that there is no conflict of interest related to the preferred attitude to a particular group of pharmaceuticals, methods of examination or treatment of patients with idiopathic pulmonary fibrosis.

Indication of the conditions for revision of the protocol: the revision of the protocol is carried out as new information on the IPF becomes available, but at least once every 2 years.

Attached files

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M.Yu. Brovko, L.A. Akulkina, V.I. Sholomova, M.V. Lebedeva

Idiopathic pulmonary fibrosis (IPF) is a variant of idiopathic interstitial pneumonia (IIP) characterized by a steady progressive course and high mortality. Unlike most IIPs, immunosuppressive therapy does not affect the rate of progression of IPF. Over the past decade, the effectiveness of two antifibrotic drugs in the treatment of IPF - pirfenidone and nintedanib - has been established. To start pathogenetic therapy in a timely manner, it is necessary to establish a diagnosis of IPF as soon as possible based on a diagnostic algorithm that involves the analysis of clinical, laboratory and instrumental data, primarily the results of high-resolution computed tomography (HRCT). With insufficient information content of the latter, minimally invasive transbronchial cryobiopsy of the lung can be used, which is comparable in accuracy to surgical lung biopsy. The search continues for molecular biological and genetic markers of IPF.

Table of contents

American Thoracic Society / European Respiratory Society (ATS) classification: 1-112. / ERS): 1-112.), Idiopathic pulmonary fibrosis (IPF) is a form of idiopathic interstitial pneumonia (IIP) (Table 1). The share of IPF is 20-30% in the structure of all IIP, and the incidence is from 7 to 17 cases per 100,000 population. Men get sick more often than women (male / female ratio approximately 1.5: 1). IPF develops mainly in middle-aged and elderly people: the age of 65% of patients at the time of diagnosis is 60 years or more.

TABLE 1. Classification of idiopathic interstitial pneumonia (IIP) ATS / ERS (2013)

Frequent forms of SMPS

Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic nonspecific interstitial pneumonia

Respiratory bronchiolitis associated with interstitial lung disease

Desquamative interstitial pneumonia

Cryptogenic organizing pneumonia

Acute interstitial pneumonia

Rare forms of SMPS

Idiopathic lymphocytic interstitial pneumonia

Idiopathic pleuroparenchymal fibroelastosis

Unclassifiable forms (UIS)

In 2018 P. Wolters et al. proposed to distinguish 4 variants of pulmonary fibrosis, depending on the pathogenesis of the disease (Table 2). IPF is characterized by a progressive course with the development of respiratory failure and among all IIPs it has the most unfavorable prognosis: the average survival rate is from 2 to 5 years. The high mortality rate of patients with IPF is explained by the peculiarities of the pathogenesis of the disease - the predominance of fibrosis with a slight severity of inflammatory changes. The main mechanism leading to the development of progressive pulmonary fibrosis is persistent damage to the alveolar epithelium with subsequent disruption of the processes of its regeneration, excessive deposition of extracellular matrix components, activation of fibroblasts and myofibroblasts. These changes determine the ineffectiveness of traditional immunosuppressive therapy in patients with IPF. Nevertheless, significant advances have now been made in the treatment of IPF associated with the use of antifibrotic drugs - pirfenidone (an antagonist of transforming growth factor beta - TGF β) and nintedanib (a multiple inhibitor of tyrosine kinases), which slow down the decrease in lung volumes, primarily, forced vital lung capacity (FVC), and improve progression-free survival. In the absence of contraindications, lung transplantation is also considered as a treatment option in patients with progressive IPF complicated by severe respiratory failure.

TABLE 2. Pathogenetic variants of pulmonary fibrosis

Group 1: Lf induced by epithelial cell dysfunction	ILF
Group 2: Lf induced by dysfunction of inflammatory cells	Systemic scleroderma, rheumatoid arthritis, Sjogren's syndrome, exogenous allergic alveolitis, sarcoidosis, NSIP
Group 3: DF caused by medication or occupational exposure	Asbestosis, silicosis, drug damage to the lungs
Group 4: DF associated with smoking	Desquamative interstitial pneumonia, respiratory bronchiolitis associated with interstitial lung disease, Langerhans cell histiocytosis

Clinical picture

The main complaints in patients with IPF are progressive dyspnea and dry cough, aggravated by exertion. Less commonly, there is pain and discomfort in the chest, increased fatigue, general weakness, and weight loss. In some cases, the disease at the initial stages is asymptomatic, and the first manifestations are changes in the functional pulmonary parameters. A typical auscultatory phenomenon in IPF is crepitus, predominantly in the posterior-basal regions of the lungs. In patients with an advanced stage of IPF, there may be signs of secondary arterial pulmonary hypertension with the development of cor pulmonale and right ventricular heart failure.

With IPF, a slight increase in ESR may be detected. Despite the presence of progressive respiratory failure, a pronounced increase in hemoglobin concentration is extremely rare. a decrease in all lung volumes in combination with a decrease in lung diffusion capacity (DLCO). One of the early manifestations of IPF may be an isolated decrease in DLCO with a relative preservation of lung volumes. The early manifestations of IPF also include an increase in the alveoloarterial oxygen gradient, which is often characterized by normal blood saturation at rest and desaturation during exercise.

Diagnostic algorithm

The diagnosis of IPF is based on the absence of known causes of pulmonary fibrosis and the presence of a pattern of common interstitial pneumonia (IPP). Even in the presence of a histological picture of acute respiratory tract infection during surgical lung biopsy (CLL), the final diagnosis requires exclusion of other pathological conditions associated with the development of acute respiratory tract infections, including diffuse connective tissue diseases, pneumoconiosis, drug-related pulmonary disease, and familial pulmonary fibrosis. In the absence of data for an alternative diagnosis, according to current clinical guidelines, IPF is diagnosed on the basis of characteristic high-resolution computed tomography (HRCT) data and, if necessary, lung biopsy results (Table 3). It should be noted that in the presented histological classification, "possible IPF" and "probable IPF" are highlighted when it is impossible to unambiguously confirm or exclude the presence of IPF. In this case, reevaluation of HRCT data and lung biopsy is shown to clarify the diagnosis.

TABLE 3. Combination of HRCT and lung biopsy for the diagnosis of IPF

CT picture	Histological data	Diagnosis
OIP	OIP	ILF
	Probable IPR
	Possible IPR
	Unclassified fibrosis
	Does not comply with the OIP	Non-ILF
Possible IPR	RRP Probable RRP	ILF
	Possible IPR	Likely ILF
	Unclassified fibrosis
	Does not comply with the OIP	Non-ILF
Does not comply with the OIP	OIP	Potential ILF
	Probable IPR	Non-ILF
	Possible IPR
	Unclassified fibrosis
	Does not comply with the OIP

CT diagnostics

HRCT plays a key role in the diagnosis of IPF and allows the diagnosis to be made in approximately 2/3 of cases. A number of studies have shown that the CT picture of a typical RIP according to HRCT data is consistent with the presence of a histological picture of a typical RIP according to lung biopsy data in 90-100% of cases. The presence of reliable CT signs of TIP is currently considered sufficient for the diagnosis of IPF without a lung biopsy. Surgical lung biopsy (CLL) is recommended if a CT scan is not typical of a PIU. In such cases, the diagnosis is made on the basis of a combination of HRCT data and the histological picture (Table 3). Thus, accurate interpretation of HRCT data is a prerequisite for diagnosis.

At present, there are three CT-variants of the OIP "typical OIP", which eliminates the need for HLD, "possible OIP" and "does not correspond to the OIP". With the latter two options, CBD is required.

The CT picture of a typical RIP includes predominantly basal and peripheral reticular changes with the formation of a cellular lung in combination with or without traction bronchiectasis. The criteria for "cellular lung" are mainly subpleural cysts with a diameter of 3-10 mm with clear, relatively thick walls (1-3 mm), located in layers. All CT signs considered as "non-conforming" to the RIP should be absent (Fig. 1). If all of the above criteria are met, HRCT readings are sufficient to diagnose AIP, and there is no need for a lung biopsy. As for the features of a typical IPR, the conclusions of different specialists usually agree well. Nevertheless, it should be noted that OIP and IPF are not synonymous, since CT changes characteristic of OIP can be observed in a number of other diseases, primarily diffuse connective tissue diseases.

Rice. 1. CT picture of a typical RIP in a 77-year-old woman.

With a possible RIP, predominantly basal and peripheral reticular changes are observed without the formation of zones of the cellular lung. At the same time, there are no changes that do not correspond to the OIP (Fig. 2). The pattern of a possible TTI is less specific to IPF than the pattern of a typical TIA. In this case, the differential diagnosis should be carried out, first of all, with nonspecific interstitial pneumonia (NISP), which is characterized by the absence of areas of the cellular lung, the predominance of "ground glass" opacities over reticular changes, and the relative safety of the subpleural zones. Areas of cellular transformation are rare in NSPI. In one study, they were found in less than 5% of patients with idiopathic NISP.

Rice. 2. CT picture of a possible IUP in a 75-year-old man.(A) On the axial section, reticular changes, traction bronchoectases, zones of the "cellular lung" are determined. (B) Coronal reconstruction shows an apicobasal gradient in lung tissue lesions.

Changes according to HRCT data, which are considered not to be consistent with AIP, include the following: a) the predominance of changes in the upper and middle parts of the lungs; b) predominantly peribronchovascular changes; c) zones of darkening of the "ground glass" type, significant in size, the prevalence of which exceeds that of reticular changes; d) bilateral focal changes, mainly in the upper parts of the lungs; e) the presence of cysts (multiple, bilateral) outside the zones of fibrosis; f) picture of mosaic darkening of lung tissue / presence of "air traps" (bilateral changes in three or more lobes); g) the presence of consolidation zones (Fig. 3).

Fig. 3. CT picture that does not correspond to RIP in a 61-year-old patient with chronic exogenous allergic alveolitis. On the axial section, reticular changes are revealed in combination with mosaic distribution of darkened zones of the "ground glass" type.

Despite the high likelihood of the presence of IPF in a typical IPF according to HRCT, the absence of a transcendental CT picture should not serve as a basis for excluding the diagnosis of IPF. In 2017 D. Lynch et al. proposed a new CT-classification of RIP, in which for the first time a group of undefined RIP was distinguished (Table 4).

TABLE 4. Diagnostic groups of RIP according to CT data

Typical IPP	Probable IPR	Undefined IPR	Least likely to meet the IPR
Prevalence in the basal and subpleural regions (rarely diffuse changes); often inhomogeneous distribution of the "cellular lung" area; reticular changes with peripheral traction bronchoectases and bronchioectases; lack of data for an alternative diagnosis	Predominance in the basal and subpleural regions; often inhomogeneous distribution Reticular changes with peripheral traction bronchiectasis and bronchioectasis; lack of "cellular lung" zones; lack of data for an alternative diagnosis	Variable or diffuse distribution The presence of fibrosis in combination with small changes in volume that do not correspond to the IUI	Predominance in the upper and middle parts of the lungs; peribronchovascular distribution with relative preservation of subpleural zones Any of the following: predominance of consolidation zones; Significant "frosted glass" blackout zones (in the absence of exacerbation of IPF); diffuse focal or cystic changes; pronounced mosaic darkening of the lung tissue with the presence of "air traps"

The clinical course of IPF can vary. Most patients have a slowly progressive course, however, in some patients, the pathological process stabilizes, while in others, a rather rapid progression of the disease is noted. As for the severity of pulmonary changes according to HRCT data, the "ground glass" darkening zones are most often transformed into reticular changes, which, in turn, can progress and form the "cellular lung" zones, the size of which usually increases with time. It should be noted that the general pattern of pulmonary changes can also change: for example, the CT pattern of a possible TIA can transform into a typical TIA.

Lung biopsy

If there are no unambiguous data on the presence of IPF in HRCT, then surgical biopsy of the lungs, which is more often performed using a videothoracoscopic technique, is indicated to confirm the diagnosis. In order to be more effective, lung biopsies should be performed from different lobes of the lungs. Although CPD is the most reliable method for determining the histological picture of IIP, its implementation is associated with the risk of a number of complications, the most severe of which is an exacerbation of IPF, especially in patients with severe respiratory and / or heart failure. In this regard, the decision to conduct it should be made individually, taking into account the clinical picture, the possible advantages for making an accurate diagnosis, as well as the patient's consent.

Over the past decade, the method of transbronchial cryobiopsy of the lung (TBCLB) has been developed for histological confirmation of the diagnosis of IPF and other types of IIP. Its main advantages are minimally invasiveness, no need for intubation and inhalation anesthesia and, as a result, a low incidence of complications in combination with the possibility of obtaining a large lung biopsy sample, sufficient, in the vast majority of cases, for histological verification of the diagnosis. Thus, in patients without a typical picture of RIP according to HRCT, TBKLD allowed to establish the diagnosis in approximately 2/3 of cases, which is comparable to the effectiveness of CKD in a similar situation. At the same time, TBKLD is characterized by a lower risk of perioperative complications (most often the development of pneumothorax and non-life-threatening bleeding at the biopsy site) and death, a shorter period of hospitalization, which allows TBKLD to be performed in patients with a high level of anesthetic risk and the presence of contraindications to CPD. Thus, the introduction of TBKLD into clinical practice can expand the indications for lung biopsy and increase the diagnostic accuracy of the algorithm for examining patients with suspected IPF.

In a morphological study in patients with suspected IPF, G. Raghu et al. there are five possible histological patterns of the disease (Table 5). In combination with radiological data, they are used to confirm / exclude the diagnosis of IPF (Table 3).

Differential diagnosis

In patients with suspected IPF, a careful differential diagnosis should be made. When a CT picture is detected that corresponds to a probable or possible IUP, which happens quite often, the range of differential diagnosis should include, first of all, chronic exogenous allergic alveolitis and the fibrotic variant of NIPI. Nevertheless, in some patients, the CKD recommended in this case is not performed due to the presence of contraindications (severe respiratory failure, concomitant diseases, age restrictions) or the patient's unwillingness.

When carrying out a differential diagnosis, it is also important to exclude lung damage within the framework of a systemic connective tissue disease, in particular, rheumatoid arthritis, systemic scleroderma, dermatomyositis, Sjogren's syndrome, including in the presence of a CT picture of a typical OIP. If a patient has individual clinical manifestations or an increase in the level of laboratory autoimmune markers that do not correspond to a specific systemic connective tissue disease, a diagnosis of interstitial pneumonia with autoimmune features can be made.

IPF genetic markers

Currently, a number of mutations and polymorphisms of genes involved in the remodeling of lung tissue and the regulation of innate and acquired immunity associated with the development of IPF have been identified. These include, in particular, mutations in genes encoding surfactant proteins A and D (S): 1–112. P-A and S): 1-112. PD) described in familial IPF. A number of studies have revealed an association of genetic polymorphisms with the prognosis of the disease: in particular, the presence of individual single nucleotide polymorphisms in the TLR-3 gene (Toll-like receptor type 3) is associated with a faster progression of the disease. Also, with IPF, a number of polymorphisms have been described in the genes of mucin 5B (MUC5B) and TOLLIP (a protein that interacts with the Toll-like receptor). Although the study of genetic polymorphisms is not part of the diagnostic algorithm for IPF, the search for genetic markers that can serve as predictors of various variants of the course of the disease and response to therapy continues.

Exacerbation of IPF

An exacerbation of IPF is a severe life-threatening condition that manifests itself in the form of a rapid increase in respiratory failure in patients with a previously established diagnosis of IPF. As a rule, it is characterized by an extremely severe course; mortality in a number of studies reached 85%. In contrast to the stable or slowly progressive course of IPF, the criteria for diagnosing its exacerbation are less clearly defined. According to N. Collard et al. , criteria for exacerbation of IPF include the presence of previous or newly diagnosed IPF with a sharp increase in shortness of breath, the development of respiratory failure in the previous 30 days without an established cause, as well as the appearance of new areas of darkening of lung tissue like "ground glass" and / or consolidation against the background of existing earlier changes corresponding to RIP - zones of reticular changes and "honeycomb lung" (Fig. 4). Nevertheless, the above criteria have low specificity, and therefore, if an exacerbation of IPF is suspected, a differential diagnosis should be made with an infectious process, thromboembolism of the pulmonary artery and its branches, pneumothorax, as well as acute left ventricular failure with the development of pulmonary edema.

Rice. 4. Multifocal exacerbation of IPF. According to HRCT data, the darkening of the lung tissue of the "ground glass" type and consolidation in the central and peripheral parts of the lung in combination with subpleural changes of the "cell lung" type are determined

Conclusion

The emergence of new therapies, in particular antifibrotic drugs, and the ineffectiveness of traditional immunosuppressive therapy for IPF, underscore the importance of early diagnosis and initiation of therapy. Over the past decade, significant progress has been made in the development of diagnostic algorithms for patients with IPF. This was facilitated by improved imaging techniques, a better understanding of the role of lung biopsy, and the development of histological criteria for IPF. All of the above parameters should be examined by a multidisciplinary team of specialists, which is currently the standard for the diagnosis of IPF. Despite the successes achieved, in the diagnosis of IPF there are unresolved issues, mainly related to the use of invasive diagnostic methods, in particular, surgical biopsy of the lung. It is necessary to continue the search for molecular biological and genetic markers of IPF and the development of minimally invasive biopsy methods for the earliest possible diagnosis, prognosis and development of a strategy for IPF therapy.

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