Idiopathic pulmonary fibrosis clinic. Idiopathic pulmonary fibrosis (IPF): a modern approach to classification and diagnosis

Pulmonary fibrosis is a pathology characterized by the appearance of fibrous tissue in the organ. The latter is otherwise called fibrous. It is quite strong and in the course of the disease replaces the lung tissue. The disease is also characterized by the obstructed movement of oxygen through the alveoli. A patient with fibrosis has serious respiratory failures.

The consequences of this disease are quite unpredictable. The patient should carefully understand what pulmonary fibrosis is, what are the symptoms of the disease and how to treat it.

Varieties of the disease

The classification of pathology in the lungs is extensive.

Judging by the reasons for its formation, two types of ailment can be distinguished:

  • Idiopathic.
  • Interstitial.

The idiopathic form of the disease is the most common. Moreover, the exact reasons for its occurrence remain a mystery. According to statistical data, one can only judge the influence of genetics and adverse environmental conditions.

Typically, idiopathic fibrosis affects the lungs of males. The age category of the latter is 50-60 years. Treatment is based on nintedanib (Vargatef), which only a doctor can prescribe.

Negative factors serve as a catalyst for the development of interstitial fibrosis. This form of the disease has its subspecies. You can see the reasons for their occurrence in the table below.

Name of the disease

Reasons for development

Post-radiation fibrosis of the lungs

 The impact of radiation therapy

dusty

 Regular intake of dust in the respiratory tract

connective tissue

 Connective tissue pathology
Infectious

Transferred infectious disease
Drug

Regular intake of medications
peribronchial

Inflammatory processes in the chronic stage
By the amount of pronounced fibrous tissue, the pathology is as follows:
  • Pneumofibrosis. The disease is characterized by a moderate alternation of connective tissue with lung tissue.
  • Pneumosclerosis. In addition to explicit substitution, organ compaction is diagnosed.
  • Cirrhosis of the lung. Fibrous tissue completely replaced the lung tissue. Vessels and bronchi are damaged.

Pneumofibrosis of the lungs can be local or diffuse species. Local pneumofibrosis is characterized by the presence of individual foci in the affected organ. With a diffuse variety of pathology, there is a violation of lung ventilation, the density of the latter increases, and their shape and structure change.

Another classification of the disease is linear and basal. Linear pulmonary fibrosis develops as a result of past infections, tuberculosis, etc.

Why fibrosis of the roots of the lungs occurs is not completely understood. It is usually diagnosed against the background of pneumonia or bronchitis. As an independent disease, it is quite rare.

Note: regardless of the type of disease, transform fibrous tissue back to the lung is impossible.

Signs of pathology

With pulmonary fibrosis, symptoms appear gradually as the disease progresses. If fibrosis affects a specific area (left or right), the pathology proceeds without any signs. For other cases, the main symptom that can be diagnosed almost immediately is shortness of breath. Difficulty breathing at first after exercise. Over time, even at rest, it is difficult for a patient with pulmonary fibrosis to breathe.

The following symptoms gradually develop:

  • Cough (at first dry, then secretion begins).
  • Cyanosis skin(most of all on the fingers and oral mucosa).
  • Deformity of the fingers (occasionally).

With a prolonged course of the disease from the heart and blood vessels, some symptoms also occur.

Here they are:

  • Swelling of the lower extremities.
  • Increased heartbeat.
  • Bulging of the veins in the neck.
  • Pain in the chest.
  • Listening to pulmonary rales.
  • Excessive sweating.
  • Excessive fatigue, increased fatigue.

At an early stage, lung fibrosis is diagnosed in only 20% of patients. If you find any of these symptoms, you should get the advice of a competent specialist.

Diagnostic methods

To identify the pathology, the doctor will need to perform the following actions:
  • Collect and analyze history.
  • Check the available signs.
  • Assess the current state of the patient.
  • Conduct a full inspection.

Not the last role is played laboratory research. To check the amount of oxygen contained in the patient's blood, the specialist will perform oximetry. General analysis blood will help to identify the leukocytosis that has developed due to a secondary infection.

The clinical picture of the disease will become more apparent when using various diagnostic methods.

These are:

  • Radiography.
  • Taking a biopsy of the affected organ.
  • CT scan.

The doctor also performs auscultation of the thoracic region. Conducting fluorography allows you to identify focal or diffuse enhancement of the pulmonary pattern. Sometimes there are cystic lucencies on the pictures. Reveal pulmonary hypertension succeeds through ECHO KG.

Video

Video - idiopathic pulmonary fibrosis

Getting rid of pathology

Treatment of pulmonary fibrosis should be carried out under the supervision of a physician. At the first stage, an integrated approach is needed, consisting of medicines, physiotherapy exercises, and diet. All activities are carried out in order to stop the signs of pneumofibrosis and make life easier for the patient. If the disease is detected at a late stage, the prognosis is disappointing. It is important to understand that it is impossible to completely cure this type of pathology.

Only a specialist can explain how to treat pneumofibrosis. If the problem arose as a result of inflammatory processes, the patient is prescribed antibiotics and drugs that stop inflammation. To reduce the rate of formation of connective tissue, Veroshpiron is prescribed.. Its reception is designed for a long period. Careful study of the instructions for use is necessary.

Treatment of pneumofibrosis sometimes comes down to surgical intervention, namely, to a lung transplant.

Be sure to reduce the impact of factors that can provoke deterioration. The workplace of the patient must be equipped with high-quality ventilation.

Breathing exercises

Physical activity within reasonable limits contributes to the speedy relief of the symptoms of the disease.

  • regular cycling;
  • morning run;
  • hiking in the open air;
  • breathing exercises.

The latter saturates the blood with oxygen and normalizes the work. respiratory system. A set of exercises helps to improve sputum discharge and relax the muscles that are involved in breathing.

Respiratory gymnastics for pulmonary fibrosis is performed in a standing position.

The main exercises of this warm-up are:

  1. It is necessary to inhale slowly, while sticking out the stomach. On exhalation, it should be pulled in as much as possible. The chest is calm.
  2. Inhale deeply and smoothly so that the stomach remains motionless. On exhalation, the sternum descends, on inhalation it rises.
  3. The full breathing exercise is the final one. Inhalation begins with the involvement of the peritoneum. With the abdomen fully bulging, continue to inhale using chest. Exhalation occurs in the same order: first the abdominal region, then the sternum. All transitions are slow and smooth.

It will be possible to achieve the desired effect with the daily repetition of each exercise 5-6 times.

Folk remedies

Apart from drug therapy, it makes sense to try home methods. Treatment folk remedies effective in many diseases. It is important not to forget about the need to take medications in parallel.

Only a doctor can designate the means of adjuvant therapy. Otherwise, the appearance of allergic reactions is not excluded, which will only make pulmonary fibrosis even more dangerous.

Treatment is based on the maximum removal of sputum and mucus from the respiratory system. This can help infusions and decoctions of medicinal herbs.

It is advisable to get rid of pneumosclerosis with the help of wild rose and elecampane roots, which will help cleanse the lungs and restore lung tissue. To prepare a decoction, mix herbs in equal proportions (1 tablespoon each) and pour water (about 1.5 cups). Boil the resulting mixture for 10-20 minutes, cool and strain. Take the decoction daily for at least 2 months.

Normalize lung function and prevent the development of cancer in a state of rosemary. It is necessary to grind the branches and fill them with clean water (in equal amounts). Hold the resulting mixture in the oven for about 45-60 minutes, then add a little honey. Take twice a day for 1 tsp.

You can get rid of shortness of breath and minimize coughing with the help of flax seeds. It is necessary to mix the main ingredient and boiling water in equal amounts, let it brew for 30 minutes. Take 1/3 cup three times a day for a week.

Proven effectiveness folk therapy exclusively on early stage lung pathology. In more advanced cases, only medicines can alleviate the situation.

How many people live with the disease

By how severe the disease is, one can judge the overall prognosis. In a patient with pulmonary fibrosis, life expectancy depends on the stage at which the pathology was detected.

The acute form of the disease is almost not amenable to any conservative therapy. Fatal outcome comes just a couple of months later.

Pathology in a child

Pulmonary fibrosis in children under 3 years of age is quite rare. The causes of the development of the disease are similar to those that provoke the disease in adults.

It is possible to diagnose pathology in the lungs by using the usual methods ( x-ray, biopsy, MRI, CT). Sometimes you may additionally need to consult a pediatric pulmonologist.

Self-treatment can be based only on the elimination of the main irritants (dust, sand, etc.). The doctor will recommend antibiotic therapy to prevent infections in the lungs.

Inhalation procedures that increase the oxygen content in the patient's blood are also important. Only the doctor decides which inhalers can be used.

Candidiasis of the lungs

This is the name of the defeat of the organ tissue by yeast-like fungi. The disease often occurs against the background of lung cancer.

The disease is characterized by the formation of small foci of inflammation. Their main localization is the middle and lower parts of the body. There is a lesion of the lumen of the small bronchi, the accumulation of leukocyte inflammatory fluid in them.

The patient is concerned about:

  • Severe cough (usually dry).
  • Dyspnea.
  • Increase in basal body temperature.
  • Soreness of the chest.

Getting rid of the disease is based on the use of antimycotic drugs.

More about medicines

Treatment of idiopathic pulmonary fibrosis is usually based on the use of a drug such as Vargatef. This drug is a triple angiokinase inhibitor. A number of clinical research confirmed the effectiveness of this tool.

Some time later, Vargatef successfully established itself as a drug to combat lung cancer. However, nintedanib must be used in conjunction with docetaxel. Evaluation of the effectiveness of Vargatef was carried out on the basis of many studies in which about 1.5 thousand patients participated. According to the results, life expectancy and overall survival rate among patients increased significantly.

Of course, only a competent specialist is entitled to prescribe such a drug, based on the results of the examination.

Note: Vargatef is quite expensive. medicines. It is not always possible to find it in pharmacies of our country.

With pulmonary fibrosis, treatment can only be prescribed by a qualified doctor, taking into account the patient's age and symptoms. Self-medication is extremely unacceptable! The key to successful therapy is timely access to a doctor.

In which, due to fibrotic changes(scarring) and lung tissue seals disrupt the normal functioning of the lungs. As the disease progresses, the lung tissue becomes more and 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 introduction of antifibrotic therapy not so long ago 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 - often not only patients, but also medical specialists do not know about it. Now in Russia only a few hundred cases of the disease have been officially registered, but according to experts, there are more than 10 thousand such patients in the country.

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

“Diagnosis of IPF is objectively difficult,” says Alexander Averyanov, Director of the Research Institute of Pulmonology of the Federal Medical and Biological Agency of Russia, Doctor of Medical Sciences, Professor. – On the one hand, its symptoms: dry cough, shortness of breath on exertion, and pulmonary murmurs during auscultation, reminiscent of the crunch of cellophane, are characteristic of many other respiratory and cardiovascular diseases. However, due to the rarity and lack of knowledge 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 prescribed therapy that does not help and cannot help, and in some cases even harms. From the moment you go to the doctor until the correct diagnosis is made, on average, more than a year passes, and during this time the disease progresses, fibrous 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 a correct diagnosis throughout the patient's life - this leads to the fact that the disease is considered more rare disease than it really is. As a result, the funding allocated for the treatment of patients with IPF is not enough to provide effective therapy for all patients. Traditional schemes with the use of 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 patient care, from 16 to 23 September all over the world, including Russia, the International IPF Week is being held. Representatives of the medical community and patient organizations are interested in how more people knew about the symptoms of the disease, its dangers and possible treatment. Timely appointment 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 (and those who quit) with the appearance of shortness of breath and cough, should contact a specialized pulmonology center for an examination that excludes IPF.

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

RCHD (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols MH RK - 2013

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

Pulmonology

general information

Short description

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

No. 23 dated 12/12/2013

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


Protocol name: Diagnosis and treatment of idiopathic pulmonary fibrosis.

Protocol code:


ICD-10 code(s):

J84.1 Other interstitial lung diseases with mention of fibrosis

Diffuse pulmonary fibrosis. Fibrosing alveolitis (cryptogenic). Hamman-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 (UIP) - Common Interstitial Pneumonia

SDLA - mean pressure in pulmonary artery

FBS - fibrobronchoscopy

ECG - electrocardiography

ECHO-KG - echocardiography

DLCO - diffusive capacity of the lungs


Protocol development date: 04.2013


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 course options, it is recommended to distinguish
- rapidly progressive
- slowly progressive and
- recurrent course (phase of exacerbation and stabilization).
The median survival is 2 to 5 years from the time of 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 deterioration in respiratory function 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 may occur secondary to pneumonia, pulmonary embolism, or heart failure.

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

Unless another cause is identified, the presence of any of the following changes should be regarded as disease progression:

Progressive dyspnea (preferably use a scoring scale of some kind, such as the Borg scale)

Progressive, steady decline in absolute FVC values ​​from baseline.

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

Fibrosis progression on HRCT.


Monitoring of disease progression should be carried out over a period of 4 to 6 months, but if necessary, in a shorter period.

Diagnostics


II. METHODS, APPROACHES, DIAGNOSIS AND TREATMENT PROCEDURES

List of basic and additional diagnostic measures


Before planned hospitalization:


Main:

General blood analysis;

Coagulogram;

Spirometry;

Echo-KG (with SAP assessment)


Additional:

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

Blood test with proteinogram evaluation

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

Pulse oximetry;

gases arterial blood;

FBS (according to indications);

DLCO definition,

Videothoracoscopic lung biopsy (if indicated)


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

Diagnostic criteria:

Rule out other known causes of interstitial lung disease (ILD) (eg, home or occupational exposures environment, connective tissue diseases, toxic effects of drugs).

Presence of UIP picture (UIP) according to computed tomography high resolution (HRCT) in patients who have not undergone surgical lung biopsy.

Combination of the pattern of AIP on HRCT and the specific pattern of AIP in lung biopsy material in patients undergoing surgical lung biopsy.

Accuracy diagnosis of IPF increases with interdisciplinary discussion between pulmonologists, radiologists, and pathologists with experience in diagnosing IPF.

The IPF major and minor 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 an unproductive cough, increased fatigue, occasional sweating, fever, and weight loss. Not characteristic: hemoptysis, pleural lesions, severe bronchial obstruction. The likelihood of the disease increases with age, typically onset in the sixth or seventh decade of life. IPF rarely occurs before age 50; such patients may subsequently manifest symptoms of a connective tissue disease that proceeded in a subclinical form at the time of diagnosis of IPF. IPF is almost equally common 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 ILF: based on characteristics usual interstitial pneumonia (OIP) according to HRCT (Table 1), histopathological criteria for UIP (Table 2), functional study data.

Table 1. HRCT criteria for an RIP picture.

IIP pattern (All four features) Possible IPR pattern (all three criteria) Contradicts the IPR (any of the seven signs)


Reticular deformity

- Honeycomb lung with or without traction bronchiectasis

The predominance of subpleural and basal localization

Reticular deformity

No features consistent with UIP pattern (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 in the form of "ground glass" (the area of ​​"ground glass" is greater than the reticular deformity)

Abundance of nodules (bilaterally, predominantly in the upper lobe)

Separately located cysts (multiple, bilateral, separate from areas of the “honeycomb” lung)

Diffuse mosaic weakening of the lung pattern / air traps (bilateral, in three or more lobes)

Consolidation in the bronchopulmonary segment/segments of the lobe/lobes

Table 2. Histopathological criteria specific for AIP

IIP painting

(all 4 criteria)

 Probable AIP Possible AIP (all three criteria) Non-PIU (any of the six criteria)

Evidence of fibrosis/architectural abnormalities,  "honeycombs" located predominantly subpleural/paraseptally

Heterogeneous involvement of the lung parenchyma in fibrosis

Accumulations of fibroblasts

There are no signs against the diagnosis of AIP suggesting an alternative diagnosis (see column 4).

Evidence of fibrosis/architectural abnormality,  "honeycomb"

No evidence of patchy fibrosis or fibroblast aggregations, but neither

No evidence against the diagnosis of AIP suggesting an alternative diagnosis (see column 4) or

Only honeycomb changes***

Heterogeneous or diffuse involvement of the lung parenchyma in fibrosis, with or without interstitial inflammation

Absence of other criteria for IPR (see column "Pattern of IPR")

No evidence against the diagnosis of AIP suggesting an alternative diagnosis (see column 4)

Hyaline membranes*

Organizing pneumonia**

Granulomas

Interstitial inflammatory cell infiltrates outside the honeycomb

Changes are predominantly localized peribronchially

Other features supporting an alternative diagnosis

Spirometry: signs of restrictive violations of the function of external respiration - a decrease in VC (FVC)<80% от должных величин.


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

Basic factors*:

Breathlessness level**

Dlco  40% of due

Desaturation ≤ 88% during 6-minute walk test (6MWT)

"Cellular Lung" at HRCT

Pulmonary hypertension

Temporary change of factors:

Increase in breathlessness**

Decrease in Forced Vital Lung Capacity (FVC) ≥ 10% absolute value

Decrease in Dlco ≥ 15% of absolute value

Worsening of fibrosis on HRCT

*Basic forced vital capacity - predictive value unclear.

** There is currently no single approach to quantify

Indications for expert advice:

A consultation of pulmonologists, radiologists, pathologists 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:


Nonspecific interstitial pneumonia (NSIP)

Compared to IPF, NSIP develops at a younger age (average 40 to 50 years) with equal 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 dyspnea and cough are less pronounced and do not grow as steadily. Approximately half of the patients have 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 respiratory function, minor or moderately pronounced restrictive disorders of pulmonary ventilation, a decrease in DLCO, hypoxemia may occur during exercise. In most cases, NSIP responds well to treatment with glucocorticosteroids (GCS) and has a favorable prognosis up to a clinical cure. On HRCT, symmetrical subpleural ground-glass areas 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 a "honeycomb lung", areas of compaction of the lung tissue are relatively rare. With repeated studies in the course of treatment, most patients have a positive x-ray dynamics. On histological examination, the cellular pattern is consistent with mild to moderate chronic interstitial inflammation; hyperplasia of type II pneumocytes in areas of inflammation Characterized by homogeneity of changes with a predominance of inflammation and fibrosis, in contrast to heterogeneity in AIP, 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 cough gradually increase over 3 years or more. Characterized by fever, chest pain, arthralgia, weight loss. Crackling rales are heard in the lungs. Anemia and hypergammaglobulinemia may occur. The disease is amenable to corticosteroid therapy and has a favorable prognosis, however, diffuse interstitial fibrosis develops in about 1/3 of patients. Two types of changes can be observed on lung radiography: lower lobe mixed alveolar-interstitial infiltrates and diffuse lesions with the formation of a "honeycomb lung". On HRCT, areas of "ground glass" are usually determined. Sometimes perivascular cysts and areas of the "honeycomb lung" are determined. Reticular changes are observed in approximately 50% of cases. Histology - diffuse interstitial infiltration of the affected areas; distribution mainly in the alveolar septa. Infiltrates include T-lymphocytes, plasma cells, and macrophages. Lymphoid hyperplasia.

Treatment abroad

Get treatment in Korea, Israel, Germany, USA

Get advice on medical tourism

Treatment


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


Treatment tactics

Non-drug treatment


oxygen therapy in patients with a clinically significant degree of hypoxemia (usually defined by Sp02 88% or PaO2 60 mm Hg).

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


Pulmonary rehabilitation: with the development of an individual patient management plan, 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 shown in a small number of patients.

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

Medical 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. Currently, there are no drugs that can stop the inflammatory process or fibrosis in IPF.

Only in 10-40% of patients with IPF, initial therapy with the use of corticosteroids 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 expectancy, according to the latest data, is from 2 to 4 years from the moment of diagnosis. Despite a poor prognosis, treatment should be considered in all patients with a progressive course who have no contraindications to corticosteroids or cytostatics.

However, it must be taken into account 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 diseases of the heart and blood vessels, diabetes mellitus, osteoporosis, severe respiratory failure, in the presence of a "honeycomb lung" in x-ray examination.

Before starting therapy, patients should be informed about the potential risks and side effects of corticosteroid and cytostatic therapy. Only after the consent of the patient can treatment be started.


Recommended doses of corticosteroids: 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. followed by a decrease to maintenance - 15-20 mg / day. Cytostatic therapy (cyclophosphamide and azathioprine) was previously used in patients with IPF who did not respond to corticosteroid therapy, in patients with complications or a high risk of complications from corticosteroids. Currently, it is believed that the combined treatment of corticosteroids and cytostatics increases efficiency and at the same time can significantly reduce the total doses of both drugs. Usually prednisolone 15-25 mg daily and cyclophosphamide 200 mg 2 times a week are used. The use of GCS monotherapy is not recommended for stable IPF.

Corticosteroid (prednisolone or equivalent) 0.5 mg/kg body weight per day orally for 4 weeks; 0.25 mg/kg daily for 8 weeks. Gradual reduction 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 per day, increasing the dose 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 continue for at least 6 months. Efficacy is determined monthly by clinical, radiological and functional data. The most important component of the treatment process is the monitoring of 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 platelets fall below 100,000/mm3, stop treatment or immediately reduce the dose by 50%. Monitoring the recovery of the number of leukocytes and platelets is carried out weekly. If recovery is not observed, cytostatics should be canceled until normalization of the cellular composition of the blood is achieved.


Azathioprine also has a hepatotoxic effect. In this regard, patients taking azathioprine, it is necessary to determine the level of transaminases monthly. Treatment is suspended or the dose is reduced if the content of alanine aminotransferase is more than 3 times higher than normal.

When using cyclophosphamide, hemorrhagic cystitis may develop. For prevention, it is recommended to drink plenty of water 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 summarized results of the randomized, double-blind, placebo-controlled study IFIGENIA demonstrated the advisability of adding high-dose N-acetylcysteine ​​(1800 mg per day) to corticosteroid therapy in patients with IPF. N-acetylcysteine ​​slows down the decline in VC and DLCO. The drug allows, more successfully than immunosuppressive therapy alone, to stabilize clinical and functional parameters in patients with IPF and mitigate the undesirable effects caused by corticosteroids and cytostatics. At the same time, monotherapy with N-acetylcysteine ​​is not indicated due to the lack of effect.

Other types of treatment: no (subject to evidence base)

In some cases, the use of PDE-5 inhibitors (sildenafil) may be considered to reduce mean pulmonary artery pressure in some patients with MAP >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 started 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 progression of the disease (taking into account the indicators of efficacy and safety), the decision on the advisability of lung transplantation;

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


Indicators of treatment efficacy and 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 in IPF:

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

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

Radiological improvement: reduction of parenchymal changes according to radiography 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 the exercise test.

Absence of serious undesirable effects of the therapy.


Hospitalization


Indications for hospitalization:

Conducting a lung biopsy to clarify the diagnosis (planned)

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

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

Information

Sources and literature

  1. Minutes of the meetings of the Expert Commission on Health 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 E. N. Idiopathic interstitial pneumonia: clinic, diagnosis, treatment // Attending physician. - 2005.- № 9. 11. Feshchenko Yu. I., Gavrisyuk V. K., Monogarova N. E. Idiopathic interstitial pneumonia: classification, differential diagnosis // Ukrainian Journal of Pulmonology, 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 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 for Improving Primary Health Care of the Republican State Enterprise on the REM "RCHR"


Reviewers:
Ainabekova B.A. - Doctor of Medical Sciences, Professor, Head. Department of Internal Diseases for internship and residency of JSC "MUA"

Indication of no conflict of interest: The developers of this protocol confirm that there is no conflict of interest associated with the preferred attitude to one or another group of pharmaceuticals, methods of examination or treatment of patients with idiopathic pulmonary fibrosis.

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

Attached files

Attention!

  • By self-medicating, you can cause irreparable harm to your health.
  • The information posted on the MedElement website and in the mobile applications "MedElement (MedElement)", "Lekar Pro", "Dariger Pro", "Diseases: a therapist's guide" cannot and should not replace an in-person consultation with a doctor. Be sure to contact medical facilities if you have any diseases or symptoms that bother you.
  • The choice of drugs and their dosage should be discussed with a specialist. Only a doctor can prescribe the right medicine and its dosage, taking into account the disease and the condition of the patient's body.
  • The MedElement website and mobile applications "MedElement (MedElement)", "Lekar Pro", "Dariger Pro", "Diseases: Therapist's Handbook" are exclusively information and reference resources. The information posted on this site should not be used to arbitrarily change the doctor's prescriptions.
  • The editors of MedElement are not responsible for any damage to health or material damage resulting from the use of this site.

The article is devoted to the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the role of biomarkers in the diagnosis and assessment of the severity of the disease. IPF is a specific form of chronic progressive fibrosing interstitial pneumonia of unknown etiology. It has been shown that IPF is a disease of the lung epithelium, which manifests itself with the same symptoms as fibrosis, i.e., is a consequence of dysfunction of its lung epithelium. The theory of 3-stage development of IPF is considered. From a diagnostic and differential diagnostic point of view, it is important to determine the level of serum SP-A when IPF is suspected. The diagnostic role of other biomarkers (evaluated 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 MMP-7 and KL-6 biomarkers 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 this disease. The diagnostic and prognostic significance of biomarkers in patients with IPF can only be established taking into account clinical, anamnestic, radiological, and, in some cases, morphological research methods.

Keywords: idiopathic pulmonary fibrosis, pathogenesis, biomarkers.

For citation: Leshchenko I.V., Zherebtsov A.D. Idiopathic pulmonary fibrosis: a modern view on pathogenesis and the role of biomarkers // BC. 2018. No. 10(I). pp. 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 only be established taking into account clinico-anamnestic, radiological and, in some cases, morphological methods of investigation.

key words: idiopathic pulmonary fibrosis, pathogenesis, biomarkers.
For quote: 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 to the determination of the role of biomarkers in the diagnosis and assessment of the severity of the disease.

Introduction

Interstitial lung diseases (ILD) in general, including idiopathic pulmonary fibrosis (IPF), are pulmonary pathologies that are multifaceted in nature. It is believed that the first description of interstitial lung disease was made by G. E. Rindfleisch in 1897, calling the disease cirrhosis cystica, and a year later P. von Hansemann in his observation used the term lymphangitis reticularis. From a more modern position, the first description of interstitial lung damage was presented by Hamman and Rich, who gave their case the name "fulminant diffuse interstitial fibrosis of the lungs", later changed to "Hamman-Rich syndrome". Although the name is not currently used, the discovery of Hammann-Rich syndrome has 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 looked like 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 has been recognized.
According to the modern understanding, IPF is defined as a special form of chronic progressive fibrosing interstitial pneumonia of unknown etiology, which occurs predominantly in older people, affects only the lungs and is associated with the histological and / or radiological pattern of ordinary interstitial pneumonia. A number of modern researchers believe that this name does not correspond to current discoveries in the study of IPF. The accumulated information allows us to identify many causes of the development of this disease, which makes the term "idiopathic" no longer appropriate.

Modern issues of pathogenesis

It quickly became clear that the basis of IPF is the proliferation of connective tissue. The first concept of the pathogenesis of IPF 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 a 3-stage development of IPF (Fig. 1).

Stage I - predisposition (predisposition). Its essence lies in the presence of factors that cause 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 unfolded 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. Abnormalities in the surfactant proteins SP-A and SP-D may 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 lung epithelium (bronchoalveolar and alveolar): reprogramming of the physiological aging of cells and the release of profibrotic mediators by the alveolar epithelium, such as transforming growth factor β (Tβ) and platelet-derived growth factor ligand α (PDGFα) . These mediators directly or indirectly through leukocytes activate fibroblasts, which begin to produce an abnormal extracellular matrix (intercellular substance).
Stage III - progression. The intercellular substance promotes additional differentiation of fibroblasts into myofibroblasts, which deposit even more matrix and additionally 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 in IPF acquire destructive properties, which may 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, prognosis of the development of the disease and response to treatment.
There is currently no generally accepted classification of biomarkers of pulmonary fibrosis. We have divided all the main biomarkers into three large groups based on their significance:
– for the diagnosis and differential diagnosis of IPF;
– determination of IPF prognosis;
– evaluation of the effectiveness of targeted antifibrotic 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. Surfactant proteins are the first and most studied. Serum levels of SP-A in patients with IPF were significantly higher than in patients with other ILDs. Also, the level of SP-A was significantly higher in patients with IPF than in patients with pulmonary sarcoidosis and pneumonia. The level of SP-D in the serum of patients with IPF, similar to SP-A, also turned out to be significantly higher than in patients with pneumonia, pulmonary sarcoidosis and patients in the control group. Unlike SP-A, there is no significant difference in SP-D levels between patients with IPF and other ILDs (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 disease. The level of MMP in healthy lung tissue is lower than in 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 more likely to be released by inflammatory cells and may be associated with tissue remodeling-induced inflammation, 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, strongly express it. Apparently, this process, at least in part, is associated with the secretion of MMP-2 and MMP-9 gelatinases. 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, indicating that these MMPs may play a role in the migration of myofibroblasts into the alveolar spaces. MMP-7 is expressed in normal and pathologically altered 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 patients with IPF, but its sources and mechanisms of action remain unclear. The authors found that serum periostin levels are elevated in patients with IPF, which correlates with a decrease in forced vital capacity (FVC) and lung diffusing capacity (DLco). It has been established that periostin predominantly exists in the oligomeric form in serum and monomeric periostin is presented as a minor fraction of it. It is the monomeric periostin that is given diagnostic value, the level of which is significantly increased in IPF compared with other diseases also associated with the level of periostin (Alzheimer's disease, systemic scleroderma and bronchial asthma).

Biomarkers for determining IPF prognosis

An increase in surfactant levels may indicate an exacerbation of IPF. Studies have noted an association between a high level of SP-A and a significantly higher risk of death in patients with IPF. A similar strong association has also been found 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. recommend using as a predictor of death in patients with IPF the GAP index, which includes gender, age, and 2 lung function variables (FVC and DLco), based on a simple scoring system and developed from a study of 558 patients with IPF. Only the GAP index, radiodiagnosis, and blood serum biomarkers in combination can increase the accuracy and sensitivity of determining the prognosis of patients with IPF.
In a study conducted by Japanese scientists, 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 group 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) by analyzing the ROC curve in patients with IPF (n=65), patients with bacterial pneumonia (n=31) and healthy individuals ( n=101) are shown in table 2.


Statistically significant significant differences in the levels of biomarkers MMP-7, CCL18, KL-6, SP-A and SP-D in patients with IPF, bacterial pneumonia and the 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 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. These results 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 survival prognosis 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.
Survival correlations of patients with IPF, divided into 3 groups according to the ratio of various biomarkers and survival, are shown in Figure 3.

The present results confirm that IPF patients with elevated levels of both MMP-7 and KL-6 had lower survival rates, suggesting that assessment of both factors is more effective in identifying a high-risk subgroup than individual assessments of both biomarkers. . It is proposed that MMP-7, a family of zinc-containing enzymes with proteolytic activity, and KL-6, a high molecular weight glycoprotein classified as mucin MUC1, are involved in the progression of IPF with different mechanisms and require further prospective studies.

Biomarkers for evaluating the effectiveness of targeted antifibrotic 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). Because the combined activity of these two enzymes can degrade fibrillar fibers and collagen basement membranes of the lung interstitium, their increased activity will promote matrix breakdown 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 the treatment of patients with IPF and pulmonary sarcoidosis in the future.
It is interesting to analyze whether monomeric periostin can predict the efficacy of two antifibrotic drugs approved by the International Committee for IPF ATS/ERS/JRS/ALAT, pirfenidone and nintadanib. Although it has been proven that these drugs are effective in the treatment of patients with IPF, the corresponding biomarkers for predicting the effectiveness of these drugs have not yet been found, 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 pulmonary fibrosis develops due to dysfunction of the lung epithelium (bronchoalveolar and alveolar).
Concerning IPF biomarkers the following is established. 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 inverse relationship has been established between the concentration of MMP-7 and KL-6 biomarkers and the prognosis of 5-year survival in patients with IPF, but their diagnostic and prognostic role remains to be reliably established. It is of interest to study the changes and ratio of IPF biomarkers not separately, but in combination. There is little serious work in the field of evaluating the effectiveness of treatment by changing the concentration of biomarkers, and the available data are not enough even to isolate a potentially suitable biomarker for such purposes. Another shortcoming of the studies published to date is their length. Prospective studies are needed to assess the predictive power of biomarkers. The diagnostic and prognostic significance of biomarkers in patients with IPF can only be established taking into account clinical, anamnestic, radiological, and, in some cases, morphological research methods.

Literature

1. Homolka J. Idiopathic pulmonary fibrosis: a historical review // CMAJ. 1987 Vol. 137. P. 1003–1005.
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 of access: 08/17/2018) . URL: www.pulmonology.ru 2016 (data obrashhenija 08/17/2018) (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.
8. Kai W., Qing J., Jing C. et al. Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis // Medicine. 2017 Vol. 96. P. 23. DOI:10.1097/MD.0000000000007083.
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.
10. Henry M. T., McMahon K., Mackarel A. J. et al. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF // Eur. Resp. J. 2002. Vol. 20. P. 1220-1227.
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.
16. Rui N., Xiaohui L., Yuan Z. et al. Potential biomarkers of idiopathic pulmonary fibrosis discovered in serum by proteomic array analysis // Int. J.Clin. Exp. Pathol. 2016. Vol. 9(9). P. 8922–8932.
17. Lagente V., Manoury B., Nenan S. et al. Role of matrix metalloproteinases in the development of airway inflammation and remodeling // Brazilian J. Med. Biol. Res. 2005 Vol. 38. P. 1521-1530.
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 (cryptogenic fibrosing alveolitis) is the most common form of idiopathic interstitial pneumonia, corresponding to progressive pulmonary fibrosis and predominant in male smokers. Symptoms of idiopathic pulmonary fibrosis develop over months to years and include dyspnoea on exertion, cough, and wheezing.

The diagnosis is established by analysis of the history, physical examination, chest x-ray, and pulmonary function tests and is confirmed by HRCT, lung biopsy, or both, if necessary. No specific treatment for idiopathic pulmonary fibrosis has been shown to be effective, but glucocorticoids, cyclophosphamide, azathioprine, or combinations of these are often prescribed. In most patients, deterioration occurs even during treatment; median survival is less than 3 years from the time of diagnosis.

ICD-10 code

J84.1 Other interstitial lung diseases with mention of fibrosis

Causes of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis, histologically defined as ordinary interstitial pneumonia, accounts for 50% of cases of idiopathic interstitial pneumonia and occurs in both men and women aged 50 to 60 years in a ratio of 2:1. Continued or past smoking is highly correlated with the disease. There is some genetic predisposition: a burdened family history is noted in 3% of cases.

Although idiopathic pulmonary fibrosis is referred to as pneumonia, inflammation probably plays a relatively minor role. Environmental, genetic, or other unknown factors are thought to initially cause damage to the alveolar epithelium, but the proliferation of specific and aberrant interstitial fibroblasts and mesenchymal cells (with collagen deposition and fibrosis) probably underlies the clinical course of the disease. The key histological criteria are subpleural fibrosis with foci of fibroblast proliferation and areas of marked fibrosis interspersed with areas of normal lung tissue. Widespread interstitial inflammation is accompanied by lymphocytic, plasmacytic and histiocytic infiltration. Cystic dilatation of the peripheral alveoli ("honeycomb lung") is found in all patients and increases as the disease progresses. This histological pattern is uncommon in IBLARB of known etiology; The term usual interstitial pneumonia is used for idiopathic lesions with no apparent cause.

Symptoms of idiopathic pulmonary fibrosis

Symptoms of idiopathic pulmonary fibrosis usually develop over 6 months to several years and include dyspnea on exertion and a non-productive cough. General symptoms (fever to subfebrile figures and myalgia) are rare. The classic sign of idiopathic pulmonary fibrosis is sonorous, dry bilateral basal inspiratory fine bubbling rales (reminiscent of the sound of opening a Velcro fastener). Thickening of the terminal phalanges of the fingers is present in approximately 50% of cases. The rest of the examination remains normal until the development of the terminal stage of the disease, when manifestations of pulmonary hypertension and right ventricular systolic dysfunction may develop.

Diagnosis of idiopathic pulmonary fibrosis

The diagnosis is based on the analysis of anamnestic data, the results of radiation methods of research, studies of lung function and biopsy. Idiopathic pulmonary fibrosis is usually misdiagnosed as other diseases that have similar clinical manifestations, such as bronchitis, bronchial asthma, or heart failure.

Treatment of idiopathic pulmonary fibrosis

None of the specific treatment options has been shown to be effective. Supportive treatment for idiopathic pulmonary fibrosis is reduced to oxygen inhalation for hypoxemia and antibiotics for the development of pneumonia. End-stage disease may require lung transplantation in some patients. Glucocorticoids and cytotoxic agents (cyclophosphamide, azathioprine) have traditionally been given empirically to patients with idiopathic pulmonary fibrosis in an attempt to stop the progression of inflammation, but there is limited evidence to support their effectiveness. However, it is common practice to try prednisolone (orally, at a dose of 0.5 mg/kg to 1.0 mg/kg, once a day for 3 months, followed by a dose reduction to 0.25 mg/kg, once per day for the next 3-6 months) in combination with cyclophosphamide or azathioprine (oral, at a dose of 1 mg/kg to 2 mg/kg, once a day and N-acetylcysteine ​​600 mg 3 times a day orally as an antioxidant ). With a frequency of every 3 months to 1 time per year, clinical, radiological and physical assessment of the condition and correction of doses of drugs are performed. Treatment of idiopathic pulmonary fibrosis is stopped in the absence of an objective response.

Pirfenidone, which is a collagen synthesis inhibitor, may stabilize lung function and reduce the risk of exacerbations. The effectiveness of other antifibrotic agents, in particular, inhibiting the synthesis of collagen (relaxin), profibrotic growth factors (suramin) and endothelin-1 (angiotensin receptor blocker) has been demonstrated only in vitro.

Interferon-y-lb showed a good effect when administered together with prednisolone in a small study, but a large double-blind multinational randomized trial showed no effect on disease-free survival, lung function or quality of life.