The diagnosis of orphan lung diseases often requires specific tests, and treatment is difficult due to problems in understanding the mechanisms of disease development and low incidence. When a therapy is developed, it is very expensive.

The aim of the article was to present modern approaches for the genetic diagnosis of hereditary respiratory diseases.

Conclusion. A physician of any specialty can encounter an orphan disease in clinical practice. The emergence of new methods for the maintenance and targeted therapy of orphan lung diseases necessitates allertness of both pediatric and adult pulmonologists. Competent management of such patients requires knowledge of the basics of genetics and the modern possibilities of DNA diagnostics, as well as close interdisciplinary cooperation between physicians of different specialties and laboratories.

Bronchiectasis, ICD-10 – J47, (BE) is a chronic respiratory disease characterized clinically by cough, sputum production and bronchial infection, and radiographically by abnormal and persistent dilation of the bronchi. Common causes include cystic fibrosis, primary ciliary dyskinesia, immune disorders, systemic inflammatory diseases and infections, and other factors. However, some cases are idiopathic, when the cause cannot be identified. In practice, patients with bronchiectasis are divided into two groups: associated and not associated with cystic fibrosis. The prevalence of the disease varies significantly worldwide; it is not reliably known in the Russian Federation.

The aim of the review is to analyze the literature data on modern approaches to the diagnosis of BE and to familiarize readers with diagnostic methods and basic approaches to the treatment.

Methods. Data from 77 articles and the expert opinion of specialists providing care to patients with BE were used.

Results. The main causes, frequency of occurrence, clinical phenotypes and treatment approaches for BE are described. There are many clinical, laboratory, instrumental and radiological features that provide insight into the etiology of BE. The European consensus is that the goal of treating BE is to restore or maintain normal lung function. There are no randomized trials on the treatment of BE, so all treatment guidelines are based on very low-level evidence or extrapolated from cystic fibrosis guidelines. Recommendations for mucolytic, antibacterial and anti-inflammatory therapy for BE are described, taking into account international and national experience.

Conclusion. The development of a new version of clinical guidelines with modern relevant information will improve the diagnosis and treatment of BE in the Russian Federation.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder that leads to chronic inflammatory damage to the airways and auditory organs. This article presents current information and a study aimed at investigating parallels between the course of PCD and clinical and genetic variant of the disease, which contributes to a timely diagnosis and enables personalized treatment approach.

The aim of the study was to identify phenotypic characteristics and chronological patterns of PCD course depending on the genotype.

Methods. The study was conducted at the Veltischev Research Clinical Institute of Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University (Pirogov Medical University), Ministry of Health of Russia. The study included children with PCD who underwent next generation sequencing (NGS) of the exome.

Results. Significant differences were found in the course of PCD based on clinical and genetic characteristics. Children with defects in the genes encoding central pair proteins are characterized by an earlier onset of daily productive cough and recurrent respiratory infections. A similar pattern is typical for patients with defects in the genes encoding the cilia assembly proteins. The first episode of respiratory infection occurs later in patients with defects in the genes encoding dynein handle proteins. Patients who do not have defects in PCD-associated genes are characterized by a late onset of persistent difficulty in nasal breathing, productive cough and respiratory diseases.

Conclusion. Identification of clinical and genetic variants of PCD allows prediction of chronological features of the course of the disease.

Primary ciliary dyskinesia (PCD) is a rare hereditary disease. In this ciliopathy, the disturbed structure and motility of the ciliary epithelium negatively affects the ciliary function and leads to prominent decrease or absence of mucociliary clearance. The European guidelines recommend analyzing the cilia beat frequency (СBF) in a native preparation or in ALI culture using light microscopy as one of the methods to confirm the diagnosis of PCD.

The aim of this project was to create software for automated analysis of the movement/beating of the ciliary epithelium of the respiratory tract for the diagnosis of primary ciliary dyskinesia using digital high-speed video microscopy in vivo and in vitro.

Methods. Five healthy donors and 10 patients with suspected PCD underwent nasal epithelial brush biopsy. The preparations were examined with a transmission electron microscope in vivo. Epithelial cells were also isolated from the nasal biopsy specimen, and ciliogenesis of these cells was performed by ALI-culturing, followed by digital high-speed video microscopy and assessment of the number of active cells and cilia beating frequency. The resulting video images were used to create the software.

Results. Software for determination of ciliary epithelium beat frequency in primary ciliary dyskinesia (PCD HighSpeed Video Microscopy Analysis – PCD HSVMA) was created to optimize the diagnosis of PCD by light microscopy (software registration number 2023687245). The software is designed to count the number of active cells of ciliary epithelium and CBF (Hz) by digital high-speed video microscopy in vivo and in vitro in ALI-culture. PCD HSVMA software features storage of patient data, display of heat map, formation of a large server database of patients and video files, building of color and static histograms, processing of several areas in one video. Our software has a number of advantages over CiliarMove and Cilialyzer and has high correlation of CFB (Hz) estimation with these products.

Conclusion. Our software can be used for improvement of PCD diagnostics in laboratories of healthcare institutions, in scientific institutions and can be included in specialist educational programs for laboratory doctors, pediatricians, general practitioners, pulmonologists, diagnosticians (endoscopists).

Primary ciliary dyskinesia (PCD) is a rare hereditary disease, a ciliopathy that is based on a defect in the ultrastructure of the cilia of the epithelium of the respiratory tract and similar structures. All parts of the respiratory tract are affected. About half of the patients with PCD have transposition of the internal organs (Kartagener syndrome – KS).

The aim was to investigate the clinical and genetic characteristics of patients with PCD with and without KS.

Methods. An assessment of clinical and genetic characteristics was performed in a sample of 127 patients with PCD, who were divided into 2 groups: patients with KS (n = 60) and without KS (n = 67). The groups were compared on the basis of their medical history (according to the PICADAR scale), clinical, instrumental and laboratory data, including the results of light and video microscopy, transmission electron microscopy (TEM) and genetic testing.

Results. According to the results of comparative characterization of patients with PCD with and without KS, there were similarities in the medical history, decreased lung function indices, videomicroscopy results – ciliated epithelium beating below 6 Hz, TEM – predominance of dynein arm defect. The PICADAR score was higher in the group with KS than in the group without it; congenital heart defects and renal pathology were found more frequently in patients with KS, while hearing loss and nasal polyposis were found more frequently in patients without KS. Electron microscopy revealed defects in the outer and inner dynein arms of the cilia in 50% of patients in both groups, and a tendency to lack of the central pair of microtubules in 18% of patients without KS. The following genes responsible for PCD were found in both groups: DNAH5, CFAP300 and HYDIN. DNAH5 gene variants were more common for KS patients (61.1%), while HYDIN gene variants were only found in patients with PCD without KS (15.8%).

Conclusion. The identified differences may help in the diagnosis of the groups studied.

The article discusses results of a prospective observational study of long-term use of the biosimilar dornase alfa (Tigerase) (Generium, Russia) as part of complex therapy in patients with cystic fibrosis in real clinical practice.

The aim was to analyze the outcomes of long-term use of the dornase alfa dornase alfa as part of complex therapy in patients with CF (protocol #DRN-CFR-N01).

Methods. The study included patients (n = 165) aged 5 years and older from 11 centers for treatment of cystic fibrosis in the Russian Federation with a confirmed diagnosis of cystic fibrosis who were prescribed dornase alfa by their attending physician.

Results. The analysis revealed that exacerbations of chronic pulmonary disease during the treatment with dornase alfa were observed in 29 (17.58%) patients included in the study. At the same time, there were no statistically significant changes in FEV₁ and FVC (%) against baseline during the treatment in the study population. Adverse events related to the study drug were recorded in 9 (5.45%) patients.

Conclusion. Biosimilar dornase alfa demonstrated a favorable efficacy and safety profile in routine clinical practice, which confirms the results of previously published studies.

The most effective drug for targeted therapy of cystic fibrosis (CF) today is the CFTR modulator elexacaftor/tezacaftor/ivacaftor. It is a combination of two CFTR correctors and a CFTR potentiator that correct the main genetic defect in patients with CF who carry at least one genetic variant specified in the instructions for use of the drug. In the Russian Federation, children with CF at the age of 6 years and older are provided with a targeted drug at the expense of the Circle of Kindness Charitable Foundation.

The aim of the study was to investigate the efficacy and safety of therapy with the CFTR modulator elexacaftor/thezacaftor/ivacaftor in children with cystic fibrosis during 12 months of follow-up.

Methods. The data of 48 patients aged 6 to 18 years who received targeted therapy with elexacaftor/tezacaftor/ivacaftor in 2021 and were included in the “Targeted therapy” section of the Register of Patients with Cystic Fibrosis in the Russian Federation, were analyzed. To study the effectiveness and safety of the therapy, the patients’ nutritional status, sweat test, respiratory function, blood chemistry, blood pressure, and lens condition were monitored during the therapy.

Results. During therapy, an increase in body weight was noted from 44.1 (± 8.8) to 50.1 (± 7.8) kg (M ± SD) (p < 0.001); height, from 158.2 (± 9.1) to 161.9 (± 8.7) cm (p < 0.001); and BMI, from 17.5 (± 2.3) to 19 (± 1.9) kg / m2 (p < 0.001). The conductivity of sweat decreased from 114.8 (± 17.4) at the start of triple therapy to 73.9 (± 20.6) mmol/l NaCl (p < 0.001) after 12 months of treatment. In 28.5%, the sweat test results returned to normal (the sweat conductivity was equivalent to < 50 mmol / l NaCl). Statistically significant changes in the indices of respiratory function were obtained: the forced vital capacity increased from 72.8%pred. (± 21.7) to 86.6%pred. (± 24.4) (p < 0.001), FEV1 – from 67.2%pred. (± 21.7) to 84.9%pred. (± 28.9) (p < 0.001).

Conclusion. Analysis of the tolerability showed a consistent safety profile of the triple therapy.

α₁-Antitrypsin deficiency is classified as an orphan disease. The main target organs are the lungs, liver and skin. Typical respiratory manifestations are emphysema and bronchiectasis, which often lead to disability as the disease progresses. To slow the progression of lung pathology, replacement therapy with an α1-proteinase inhibitor is used worldwide.

The aim of this article is to familiarize physicians with a rare lung disease that leads to the early development of emphysema and chronic obstructive pulmonary disease.

Conclusion. Early detection of lung pathology associated with α₁-antitrypsin deficiency allows timely prescription of the necessary replacement therapy, which in turn leads to an increase in the duration and improvement in the quality of life of patients with this pathology.

Cystic fibrosis is an autosomal recessive disease caused by pathogenic variants in the nucleotide sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. As the disease affects multiple organs, an integrated approach to the treatment is essential. The most effective model of providing medical care to patients with cystic fibrosis is the organization of specialized centers.

Aim. To assess the effectiveness of specialized medical care for patients with cystic fibrosis in the Children’s Center for Cystic Fibrosis from 2011 to 2023.

Methods. A comparative analysis of the Center’s activities was carried out using the National Register of Cystic Fibrosis Patients for 2011 and the medical records of patients registered for follow-up in 2023.

Results. The average age of the children followed at the Center increased from 7.1 to 10.4 years (Mann – Whitney; p = 0.004). In 2023, cystic fibrosis was diagnosed primarily through newborn screening (Fisher; p = 0.000). The most common clinical picture was the mixed form of cystic fibrosis. 100% of pathological alleles were identified, the frequency of the F508del allele was 57.8 – 58.9%. A predominance of “severe” genotypes was noted. The incidence of chronic infection with P. aeruginosa decreased significantly (Fisher; p = 0.002) due to the optimization of antibacterial treatment regimens, strict adherence to the sanitary and epidemiological regulations, and the use of hospitalreplacement technologies. CFTR modulators have been used in patient care since 2021. The greatest clinical efficacy was observed with the use of elexacaftor/tezacaftor/ivacaftor + ivacaftor. By the 180th day of use in children, forced expiratory volume in 1 second improved from 63.3% to 84.2% (Wilcoxon; p = 0.001), and sweat chlorides decreased by 33 mmol/l (Wilcoxon; p = 0.0001). The results of the Center’s work in 2011 – 2023 are a consequence of improved approaches to specialized medical care for cystic fibrosis.

Conclusion. The creation of a multidisciplinary team for the treatment of patients with cystic fibrosis can significantly increase the level of care and improve the quality of life of patients.

Congenital alveolar dysplasia (СAD) and alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) are rare genetically determined interstitial lung diseases in infants that manifest in the first hours to days after birth, have fatal outcome and are usually diagnosed at autopsy.

The aim of this work was to consider the clinical manifestations and pathomorphologic picture of CAD and ACD/MPV based on clinical observations of newborns who were on a ventilator, received therapy for high pulmonary hypertension and extracorporeal membrane oxygenation (ECMO). The clinical characteristics and medical history of the patients are described. The results of lifetime imaging methods, autopsy examinations with light microscopy and the use of routine staining methods of micro-preparations as well as immunohistochemical methods are considered. Morphologic changes in the lungs characteristic of CAD and ACD/MPV are described in detail in the analysis of histologic examination data.

Conclusion. The pathoanatomical examination data are of crucial importance for the diagnosis of CAD and ACD/MPV, which must be suspected in newborns with respiratory insufficiency and severe pulmonary hypertension when ventilation, inhalation of nitric oxide and ECMO are ineffective.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease that develops as a result of an ultrastructural defect of the cilia and flagella. The symptoms are non-specific, especially in childhood, and are characterized by recurrent rhinitis and bronchitis, often with obstruction. Half of the patients with PCD are diagnosed with such clear clinical manifestation as Kartagener’s syndrome (chronic bronchitis, chronic sinusitis, reverse position of internal organs (situs inversus), but even in these cases the diagnosis can be difficult.

The aim of this paper was to demonstrate a clinical case of late diagnosis of PCD in a child with classic Kartagener syndrome and concomitant atopy, and the results of 11 years of follow-up and microbiological monitoring. The stages of the diagnostic search are presented in detail and typical errors on the way to diagnosis are analyzed.

Conclusion. This clinical observation demonstrates the difficulties of diagnosing PCD in a patient with concomitant atopy. It is noted that appropriate continued monitoring and timely therapy are crucial for children with PCD. The need to standardize approaches to the diagnosis and management of patients with PCD, including continuity during transfer to the adult healthcare network, is emphasized.

Cystic fibrosis-associated chronic rhinosinusitis (CRS) is a separate form of CRS that progresses gradually over the course of patient’s life and worsens with age. The reasons for this are the mechanical congestion of mucus in the paranasal sinuses and the persistence of colonies of pathogenic antibiotic-resistant microorganisms. Therapy with CFTR modulators has resulted in a significant reduction in the severity of CRS. The nature of these changes and the dynamics in the microbial landscape of the upper respiratory tract are not sufficiently explored.

Aim of the article is to highlight various aspects of the impact of CFTR modulators on the course of CRS in adult patients with cystic fibrosis (CF) based on literature data and a number of our own clinical observations. The article presents a series of clinical cases of CRS in adult CF patients treated with CFTR modulators for different periods of time.

Conclusion. During targeted therapy with CFTR modulators, the symptoms of CRS are reversed due to the restoration of normal rheological properties of nasal secretions, the clinical picture improves, and the severity of CRS decreases. However, this type of treatment has no direct effect on the microbial landscape of the respiratory tract and requires additional interventions in the form of local and systemic antibacterial therapy. Therapy with CFTR modulators alters the course of CF in the nasal cavity, as well as in the pharynx and larynx.

An important factor influencing the severity of cystic fibrosis (CF) and the effectiveness of treatment is the presence of complex alleles in the CFTR gene ≥ 2 variants in one allele. The influence of such alleles on the manifestations of CF has not been sufficiently studied.

The aim of this study was to investigate the effect of the complex allele [L467F;F508del] on the phenotypic manifestations of CF and the efficacy of targeted therapy in an intestinal organoid (IO) model in a patient with the [L467F;F508del]/W1310X genotype.

Methods. Methods for determining the difference in intestinal potentials (IDP), the KO method, and the forskolin test are presented using the medical history of a patient with the [L467F;F508del]/ W1310X genotype as an example.

Results. The patient was diagnosed with progressive disease with obvious deterioration of pulmonary function. The ORKP method showed the absence of chlorine channel function. An assay with a KO culture from intestinal tissue showed a complete loss of functional activity of the chloride channel. In addition, the complex allele [L467F;F508del] is not sensitive to the effect of all tested CFTR modulators.

Conclusion. The complex allele [L467F;F508del] causes a complete loss of functional CFTR protein and is not sensitive to the effect of any of the registered targeted drugs.

Cystic fibrosis (CF) is a hereditary disease associated with systemic failure of the exocrine glands. In 95% of the cases, progressive damage to the lung tissue occurs that requires follow-up. The main imaging methods are radiography and computed tomography (CT). Both methods involve ionizing radiation. According to clinical guidelines, a chest X-ray is performed no more than once every 2 years. However, given the high risk of developing inflammatory processes in children with CF, the frequency of radiological examinations may increase significantly. The search for alternative methods without ionizing radiation is in great demand among children with CF. One of these methods is magnetic resonance imaging (MRI).

The aim was to explore the capabilities of MRI for imaging lung tissue in children with CF.

Methods. The study included 12 patients aged 7 to 18 years with newly diagnosed and previously diagnosed CF. All children underwent CT and MRI of the chest.

Results. In all children (100%), chest CT revealed a complex of changes typical of CF: signs of chronic bronchitis, widespread saccular and cylindrical bronchiectasis of various localizations, areas of pulmonary fibrosis, infiltrative changes in the lung tissue. Chest MRI is most effective (100%) in identifying areas of pulmonary fibrosis (thickening of the lung tissue), accumulation of exudate in the lumen of bronchiectasis, and infiltrative changes. In contrast to CT, MRI is less effective in the assessment of bronchitis changes with thickening of the bronchial walls without exudate (83%). A low efficiency of MRI is observed in the visualization of bronchiectasis with a free lumen (without signs of mucostasis).

Conclusion. Radiography and computed tomography remain the main methods for lung imaging in children with CF. However, taking into account the absence of ionizing radiation, the development of the method and the emergence of new sequences, chest MRI can be used effectively for follow-up instead of radiography and CT, reducing the radiation dose received.

In connection with the introduction of targeted therapy for cystic fibrosis (CF) into clinical practice, there is a need to study the clinical effectiveness of these drugs and to record their possible side effects in children.

The aim was to present the regional experience of the Republic of Tatarstan in the use of etiopathogenetic therapy (ivacaftor + tezacaftor + elexacaftor) in 41 children diagnosed with CF.

Methods. Before initiation of triple therapy, a comprehensive assessment of body functions was carried out. Monitoring of safety and effectiveness was carried out at 14 days, 1 month, 3 months, 6 months, and 12 months after from the start of therapy.

Results. In the first 2 weeks from the start of therapy, 10 (27%) patients reported mild side effects in the form of increased cough, sputum, and rhinorrhea, 2 (5,4%) patients had skin rashes, and 3 (8,1%) patients had elevated blood aminotransferases. One child developed encephalopathy due to arterial hypertension several months after starting therapy.

Conclusion. Monitoring of the safety of the therapy over 12 months in children with CF showed a satisfactory profile. The therapy was associated with an improvement in the body functions, nutritional status, and quality of life.

Cystic fibrosis (CF) is a disease caused by pathogenic variants of the CFTR gene. In the last decade, the treatment algorithm has entered a new era as several drugs have become available that restore the function of the CFTR chloride channel and are called CFTR modulators. The efficacy and safety of targeted drugs in cystic fibrosis needs to be further investigated using additional assessment methods.

The aim of this study was to investigate the role of intestinal current measurement (ICM) in assessing the efficacy of targeted therapy for cystic fibrosis.

Methods. The efficacy of CFTR modulator therapy was evaluated in 15 patients, of which 10 were children and 5 were adults. In addition to the ICM method, patients’ clinical parameters, sweat test, and pulmonary function were also evaluated according to clinical guidelines.

Results. Patients with genotypes 2143delT/7121G>T and G542X/R785X had no restoration of chloride channel function with elexacaftor + tezacaftor + ivacaftor therapy, and patients with the L467F;F508del genotype with lumacaftor + ivacaftor therapy. In patients with the F508del/F508del, N1303K/G461E, N1303K/3321delG genotype, improvements were noted in terms of the restoration of CFTR channel function during therapy with elexacaftor + tezacaftor + ivacaftor therapy, and in patients with the F508del/F508del genotype during therapy with tezacaftor + ivacaftor therapy and lumacaftor + ivacaftor.

Conclusion. Restoring the function of the epithelial chloride channel (CFTR) is the basis for increasing life expectancy in CF. The crucial role of the ICM method in determining the efficacy of CFTR modulators is shown.

Osteoporosis is a metabolic disease of the skeleton characterized by a decrease in bone mass, a disruption of the microarchitecture of bone tissue and, as a result, fractures with minimal trauma. The urgency of the problem of osteoporosis in children with cystic fibrosis arises from the high risk of a decrease in bone mineral density (BMD) in this category of patients.

The aim is to investigate the patterns and mechanisms of bone mineral density reduction in children with cystic fibrosis.

Methods. 100 patients with cystic fibrosis were examined. The control group included 61 healthy children aged 6 to 17 years. Alimentary and biochemical risk factors for the decrease in BMD were analyzed. X-ray densitometry was performed in children over 6 years of age using a DEXXUM device (South Korea). The concentration of calcidiol 25(OH)D and other biochemical parameters in blood were determined using the enzyme immunoassay method.

Results. 62% of patients with CF and 82% of healthy children had normal BMD. The leading factors affecting BMD in patients with cystic fibrosis are: history of meconium ileus, chronic infection with Pseudomonas aeruginosa, lower indicators of nutritional status, and lower lung function (FEV₁, %pred). The biochemical markers of osteoremodeling that determine the risk group for osteoporosis in patients with CF are osteocalcin and acid phosphatase. Healthy children who consumed more dietary calcium had better BMD. The effect of dietary calcium intake and vitamin D dose on BMD in patients with CF was not observed.

Conclusion. The features of inflammatory and catabolic processes in cystic fibrosis influence the remodeling processes by reducing osteosynthesis and activating osteoresorption. In both groups of children studied, low nutritional status had a negative effect on BMD.

Cystic fibrosis (CF) is characterized by the development of a severe nutritional deficiency. A low BMI directly correlates with low lung function and requires active nutritional support. Pathogenetic (targeted) therapy aimed at restoring the chlorine channel function also leads to weight gain. The effects of CFTR modulators on extrapulmonary pathology in adult CF patients in Russia have been described very little.

Aim. To evaluate the sequential impact of two targeted drugs – the potentiator ivacaftor and the triple combination of CF transmembrane regulator modulators elexacaftor/tezacaftor/ivacaftor – on the nutritional status of an adult patient with cystic fibrosis receiving nutritional support.

Conclusion. Therapy with CFTR modulator in combination with sipping nutritional support promotes significant weight gain in adult CF patients. The triple combination of elexacaftor/tezacaftor/ivacaftor has a more active effect on nutritional status than ivacaftor alone. The targeted therapy requires supervision by a nutritionist.