RU2749489C1 - Method of treatment of disintegration cavities in the lungs, complicated by chronic aspergillosis (mycosis) - Google Patents

Abstract

FIELD: medicine; endoscopy; pulmonology; phthisiology.

SUBSTANCE: diagnostic bronchoscopy is performed to assess the condition of the bronchi in the affected area, while taking bronchial flushes to confirm fungal invasion and determine drug sensitivity. In the absence of contraindications to the installation of the endobronchial valve at the next fiber-optic bronchoscopy, the endobronchial valve is installed in the lobar, zonal or segmental bronchus, ventilating section of the lung in which the cavity with the mycetoma is located. After 3-5 days during bronchoscopy, a plastic catheter is inserted between the wall of the endobronchial valve and the wall of the bronchus in which the valve is installed until the distal end of the catheter exits the valve. An aqueous solution of an antifungal drug for intravenous injection containing a single dose of the drug is injected through the catheter. After that, the catheter is released from the solution by the introduction of injection water. Then, the catheter is removed into the channel of the fiber-optic bronchoscope and together with it from the respiratory tract.

EFFECT: method allows providing a high concentration of the drug in the affected area, destroying the mycetoma after a single injection of an antifungal drug, promoting rapid and effective healing of the cavity, reducing the risk of relapse and complications.

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Description

The technical field to which the invention relates

The invention relates to medicine, namely, endoscopy, pulmonology and phthisiology, and can be used for quick and effective healing of cavities in the lung with damage to their inner wall by chronic pulmonary mycosis (aspergillosis).

State of the art

Chronic mycosis of the lungs, most often in the form of chronic pulmonary aspergillosis (CPA) (Chronic pulmonary aspergillosis (CPA)) is common throughout the world and is often a complication of other acute and chronic lung diseases [Maghrabi F, Denning DW. The Management of Chronic Pulmonary Aspergillosis: The UK National Aspergillosis Center Approach. Curr Fungal Infect Rep. 2017; 11 (4): 242-251. Epub 2017 Nov 13. PubMed PMID: 29213345; PubMed Central PMCID: PMC5705730].

So aspergillosis can affect cavities in the lungs, resulting from another infectious disease, often tuberculosis. The conidia of the fungus germinate and form a network of hyphae on the inner surface of the cavity, damaging the surrounding parenchyma [Latgé JP. Aspergillus fumigatus, a saprotrophic pathogenic fungus. Mycologist. 2003; 17 (2): 56-61. doi: 10.1017 / S0269915X0300209X]. In some patients, the growth of fungi in the cavity progresses to the formation of a "fungal body" - aspergilloma (mycetoma), which prevents the healing of the cavity formation, even if the previous process ended favorably. At the same time, patients may experience various respiratory and constitutional symptoms: shortness of breath, chronic cough, sputum production, chest discomfort, weight loss, fatigue and fatigue [Godet C, Laurent F, Beraud G., et al. Phenotyping chronic pulmonary aspergillosis by cluster analysis. Eur Respir J. 2015; 46 (5): 1509-1512. doi: 10.1183 / 13993003.00869-2015; Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003; 37 (Suppl 3 (s3)): S265-S280. doi: 10.1086 / 376526; Al-Shair K, Muldoon EG, Morris J, Atherton GT, Kosmidis C, Denning DW. Characterization of fatigue and its substantial impact on health status in a large cohort of patients with chronic pulmonary aspergillosis (CPA) Respir Med. 2016; 114: 117-122. doi: 10.1016 / j.rmed.2016.03.020]. Patients with CPA also often have recurrent hemoptysis and even life-threatening bleeding (> 150 ml / day), which is the main cause of mortality in CPA [Betancourt BY, Garofoli AC, Sandhu JS, Boma N, Sy AM. Pulmonary aspergillosis presenting with recurrent haemoptysis. BMJ Case Rep. 2015: bcr2015211249. doi: 10.1136 / bcr-2015-211249; Farid S, Mohamed S, Devbhandari M, et al. Results of surgery for chronic pulmonary Aspergillosis, optimal antifungal therapy and proposed high risk factors for recurrence. National Center's experience. J Cardiothorac Surg . 2013; 8: 180. Published 2013 Aug 5. doi: 10.1186 / 1749-8090-8-180]. All of the above necessitates the treatment of this pathology.

The main method of treatment of CPA is the systemic use of various antifungal drugs with a course duration of 4-12 months, often accompanied by manifestations of drug toxicity, intolerance to their patient, especially when interacting with drugs prescribed for concomitant pathology [David W. Denning, Jacques Cadranel, Catherine Beigelman -Aubry, Florence Ader, Arunaloke Chakrabarti, Stijn Blot, Andrew J. Ullmann, George Dimopoulos, Christoph. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Lange on behalf of the European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society European Respiratory Journal 2016 47: 45-68; DOI: 10.1183 / 13993003.00583-2015].

The group of researchers found that the drugs itraconazole and voriconazole are moderately effective in CPA if they are prescribed for 12 months (the dose of voriconazole is on average 400 mg / day (from 200-500 mg), while less than 50% of patients manage to carry out such Adverse events in more than a third of patients are the reason for stopping therapy [Bongomin F, Harris C, Hayes G, Kosmidis C, Denning DW. Twelve-month clinical outcomes of 206 patients with chronic pulmonary aspergillosis. PLoS One. 2018 Apr 10; 13 (4): e0193732. Doi: 10.1371 / journal.pone.0193732. eCollection 2018] Adverse reactions with azoles are common, including peripheral neuropathy, heart failure, elevated hepatic enzymes, and prolonged QTc interval seen on electrocardiography.

In case of ineffectiveness of conservative treatment, the method of choice at the moment is surgical treatment - resection of the lung of various volumes. [David W. Denning, Jacques Cadranel, Catherine Beigelman-Aubry, Florence Ader, Arunaloke Chakrabarti, Stijn Blot, Andrew J. Ullmann, George Dimopoulos, Christoph. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Lange on behalf of the European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society European Respiratory Journal 2016 47: 45-68; DOI: 10.1183 / 13993003.00583-2015]. At the same time, surgical treatment is associated with the risk of complications such as ineffectiveness of aerostasis, wound infection, the occurrence of a residual pleural cavity, the development of pleural empyema and bronchopleural fistulas [Kim YT, Kang MC, Sung SW, et al. Good long-term outcomes after surgical treatment of simple and complex pulmonary aspergilloma. Ann Thorac Surg 2005; 79 : 294-298 .; Akbari JG, Varma PK, Neema PK, et al. Clinical profile and surgical outcome for pulmonary aspergilloma: a single center experience. Ann Thorac Surg 2005; 80 : 1067-1072.]. And only if it is impossible to use surgical treatment for various reasons, other methods are recommended.

The literature describes methods of treating CPA (in the form of aspergilloma within the cavity formation of the lungs) with its complication by bleeding with the use of local administration of antifungal drugs and / or hemostatic agents [Rumbak M, Kohler G, Eastrige C, et al. Topical treatment of life threatening haemoptysis from aspergillomas. Thorax 1996; 51 : 253-255].

Used such antifungal drugs as amphotericin B, nystatin, drugs of the triazole group. Delivery to the bronchial tree of the drug solution was carried out during bronchoscopy through a catheter inserted into the bronchus, rarely into the affected cavity [Yamada H, Kohno S, Koga H, et al. Topical treatment of pulmonary aspergilloma by antifungals: relationship between duration of the disease and efficacy of therapy. Chest 1993; 103 : 1421-1425; David W. Denning, Jacques Cadranel, Catherine Beigelman-Aubry, Florence Ader, Arunaloke Chakrabarti, Stijn Blot, Andrew J. Ullmann, George Dimopoulos, Christoph. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Lange on behalf of the European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society European Respiratory Journal 2016 47: 45-68; DOI: 10.1183 / 13993003.00583-2015]. The disadvantage of this method is the inevitable partial reflux of the drug from the injection site into the larger bronchi, which cannot even prevent a special positioning of the patient. Constant respiratory movements, mucociliary clearance, changes in the patient's body position lead to a sharp decrease in the concentration of the drug and its exposure in the focus of the fungal infection. The oxygen concentration in the inhaled air also contributes to the inactivation of the administered drug. Such administration of the drug in the cited sources was carried out in courses of 1-5 times until the cessation of pulmonary bleeding, while the destruction of the aspergilloma and the healing of the cavity containing it were not analyzed.

The known method of percutaneous intracavitary administration of antifungal drugs through a catheter for the treatment of aspergilloma located in the cavity formation of the lung. Under local anesthesia with X-ray control, a needle is inserted through the chest wall and lung tissue into the cavity, a catheter is passed through this needle, and then the needle is removed. Through such a catheter, an antifungal drug was injected repeatedly [Jackson M, Flower CD, Shneerson JM. Treatment of symptomatic pulmonary aspergillomas with intracavitary instillation of amphotericin B through an indwelling catheter. Thorax 1993; 48 : 928-930 .; Munk PL, Vellet AD, Rankin RN, et al. Intracavitary aspergilloma: transthoracic percutaneous injection of amphotericin gelatin solution. Radiology 1993; 188 : 821-823.]. The administration of the drug was continued until the cessation of bleeding (hemoptysis). It was reported that the recurrence of serious hemoptysis occurred in 6 cases out of 18. The disadvantages of the method include: impossibility of long-term (several weeks) use of a percutaneous catheter due to the high probability of its infection, probably for this reason there is no data on the healing of cavities; when the drug is injected through a catheter into the cavity, a significant part of it enters the respiratory tract through the draining bronchus, which is manifested by the onset of coughing upon administration; percutaneous installation of a catheter into the cavity is impossible when the cavity is small or deep in relation to the chest wall; when installing a percutaneous catheter, complications are possible - especially often, pneumothorax (up to 26% of cases [Shapiro MJ, Albelda SM, Mayock RL, et al. Severe hemoptysis associated with pulmonary aspergilloma: percutaneous intracavitary treatment. Chest 1988; 94 : 1225-1231]) ...

There are reports that to increase the concentration of the drug into the cavity through a percutaneous catheter, a paste with amphotericin was injected, while in 26 of 40 patients aspergilloma disappeared radiographically, and in 3 (7.5%) the cavity also healed [Giron J, Poey C, Fajadet P , et al. CT-guided percutaneous treatment of inoperable pulmonary aspergillomas: a study of 40 cases. Eur J Radiol 1998; 28 : 235-242]. The authors managed to overcome the loss of its concentration by changing the consistency of the drug, but the healing rate of the cavity affected by aspergilloma was only 7.5%. Preservation of the same cavity is the possibility of recurrence of aspergilloma.

A known method of endoscopic removal of intracavitary lung aspergilloma using rigid and flexible bronchoscopy [Stather DR, Tremblay A, MacEachern P., et al., Bronchoscopic removal of a large intracavitary pulmonary aspergilloma. Chest 2013; 143 : 238-241; Stather D, Tremblay A, MacEachern P., et al., Intracavitary pulmonary aspergilloma removal using combined virtual, ultrathin, and rigid bronchoscopy-a case series. Chest 2013; 144 : 817A.]. However, this method is applicable only for large cavities with aspergillomas with a large draining bronchus, the method requires the use of expensive equipment (several types of bronchoscopes, including ultrathin ones), the use of anesthesia and mechanical ventilation, and is associated with the risk of complications, primarily bleeding.

Installation of a specially designed endobronchial valve in the bronchus, which creates a local collapse of the affected area of the lungs, is successfully used to stop pulmonary bleeding and heal cavities in destructive forms of pulmonary tuberculosis [Levin A.V., Tseimakh E.A., Zimonin P.E. and others. The use of valvular bronchial blocking in the complex treatment of patients with widespread destructive pulmonary tuberculosis complicated by pulmonary hemorrhage // Probl. tub. -2007. -No. 9. -C. 13-16; Levin, A., Sklyuev, S., Felker, I .; Tceymach, E., Krasnov, D. Endobronchial valve treatment of destructive multidrug-resistant tuberculosis The International Journal of Tuberculosis and Lung Disease, 2016, 20: 1539-1545]. However, no cases of successful use of an endobronchial valve in intracavitary mycetoma developed in a cavity formed as a result of another disease, including tuberculosis, have been described in the literature.

Disclosure of invention

A method of treating decay cavities in the lung, complicated by chronic aspergillosis, is that after a diagnostic bronchoscopy to assess the condition of the bronchi in the affected area with simultaneous taking of bronchial washings to determine drug sensitivity and in the absence of contraindications with repeated fibrobronchoscopy, an endobronchial valve is installed in the lobar or segmental bronchus, ventilating part of the lung, in which there is a cavity with a mycetoma, then between the wall of the endobronchial valve and the wall of the bronchus, in which the valve is installed, a thin plastic catheter is passed until the distal end of the catheter exits the valve and an aqueous solution of an antifungal drug for intravenous administration is injected through it administration, containing a single dose of the drug, after which the catheter is released from the solution by the introduction of water for injection, and then the catheter is removed into the channel of the fiberoptic bronchoscope and together with it from the respiratory tract. In this case, the introduction of an antifungal drug is preferably carried out immediately after the installation of the endobronchial valve, and repeated fibrobronchoscopy is performed 3-5 days after the diagnostic fibrobronchoscopy. As an antifungal drug, a drug is used, to which the sensitivity of the fungus is established when performing diagnostic bronchoscopy. It is preferable to use voriconazole at a dose of 200 mg as an antifungal drug, and 1-2 ml of water for injection is injected to release the lumen of the catheter from the drug.

The inventive method has the following advantages:

1. Installation of an endobronchial valve reduces the volume and airiness of the affected segment or lobe of the lung, reducing the activity of respiratory movements in it, and does not allow the drug to flow out of the affected area of the lung, all this contributes to a high concentration of the drug in the affected area. In addition, in the collapsed area of the lung, the drug comes into contact with air with a low oxygen content before absorption, which slows down its oxidation and loss of activity.

2. The method is minimally invasive and can be performed under local anesthesia. There is no risk of pneumothorax and other complications associated with surgery and percutaneous catheter placement. There is no violation of the integrity and structure of the lung, as in resection operations.

3. It is not necessary that the instrument (catheter) accurately hit the cavity formation with the mycetoma, this makes our method suitable for the treatment of cavities of any size, including small and located in any parts of the lung. As a rule, a single injection of the drug in a single dose is enough, but in the absence of an X-ray effect, after 2 months, the administration of the drug can be repeated using the already established EC.

4. It does not require daily infusions of antimycotic drugs, which avoids undesirable reactions and drug interactions arising from its systemic (intravenous) daily many months of use. Does not require a long time from the patient for repeated drip infusions. The patient's activity is practically not limited, treatment can be carried out on an outpatient basis.

5. Material costs for the treatment of mycetoma are sharply reduced - the total dose of the drug required for the course of treatment is minimized to 1 single dose administered once.

6. The method is complex, as it destroys the mycetome (the action of the drug under improved conditions for compliance with the dosage and the effect on the mycetome) and promotes the healing of the cavity (collapse therapy under prolonged exposure to the endobronchial valve), excluding the possibility of recurrence of the fungus in the preserved cavity.

The cavity cleared of mycetoma can heal up to 4-6 months, but all this time the patient does not need inpatient treatment and does not require the introduction of antifungal drugs. Also, there are no undesirable effects on the administration of antifungal drugs due to the timing of their administration. A test for allergic reactions to the drug is made to patients before its administration, by applying the drug to the mucous membrane of the lips.

Brief Description of Drawings

FIG. 1 shows a diagram of the introduction of an antifungal drug into the bronchus distal to the installed endobronchial valve, where A is the distal end of the fiberoptic bronchoscope; B - endobronchial valve (EC); B - a catheter inserted into the channel of the fiberoptic bronchoscope, and then passed between the EC and the wall of the bronchus, a medicinal solution is injected through it; D - the wall of the bronchus.

FIG. 2 shows the data of patient N. - MSCT OGK (a) reconstruction b - sagittal and c - frontal at the time of admission to the Federal State Budgetary Institution "NMITs FPI" of the Ministry of Health of Russia. In C10 of the right lung, a focus with irregular heavy contours measuring 37 × 37 × 27 mm with a decay cavity 28 × 35 × 17 mm was determined, in the lumen of which a rounded shadow characteristic of an aspergilloma was determined.

FIG. 3 shows photographs of methods for studying bronchial lavage of patient N. for mushrooms and the duration from the beginning of the study to the readiness of the result: a - the result of microscopy (duration 1 hour), b - photo of the growth of Aspergillus fungus on Chapek Dox agar (duration 1-2 days), c - identification of Aspergillus fumigatus to species (duration 3-5 days).

FIG. 4 shows the data of patient N. - MSCT OGK (a) and reconstruction b - frontal and c - sagittal before removal of the endobronchial valve - healing of mycetoma by the focus.

FIG. 5 shows the data of patient C. MSCT of the OGC and reconstructions b, c - frontal and d - sagittal upon admission to the FGBI "NMITs FPI" of the Ministry of Health of the Russian Federation. Mycetoma C-2 of the left lung, post-tuberculous foci in the right and left lungs.

FIG. 6 shows the data of patient B after applying the method of treatment of mycetoma. MSCT OGK (a) and frontal reconstruction (b) - segments C-1-2 and 3 of the left lung are in atelectasis. Mycetoma is not detected. On the sagittal reconstruction (c) in the lumen of the left main bronchus (indicated by the arrow), the tail part of the endobronchial valve is visible, which is indicated by the arrow in the enlarged fragment (d).

FIG. 7 shows the data of patient B. long-term results after successful completion of treatment of mycetoma and removal of EC. MSCT OGK (a), sagittal reconstruction (b) and frontal reconstruction (c) - after treatment of mycetoma: the upper lobe of the left lung is straightened, cavity formation with mycetoma is not detected, in its place is a large dense focus, in the lungs there are multiple dense post-tuberculous foci.

FIG. 8 shows the results of CT examination of patient N. before (A) - a cavity with an uneven inner surface and (B) 4 months after the placement of EC on 09/11/19 - segments in atelectasis, the cavity with mycetoma decreased, but did not close.

FIG. 9 shows the results of the frontal CT examination of patient N. before (A) - a cavity with an uneven inner surface and (B) after the installation of EC on 09/11/19 - segments in atelectasis, the cavity with mycetoma decreased, but did not close.

Implementation of the invention

Diagnosis of intracavitary aspergilloma (mycetoma) occurs during X-ray examination (as a rule, MSCT OGK (multislice computed tomography of the chest organs) - sometimes the pathology has a characteristic appearance, in the form of a rounded formation filling the cavity - the "rattle" syndrome, but more often these are areas of thickened of the inner lining of the cavity, protruding into its lumen.In this case, the exact topic of the cavity formation is determined - up to the segment.In such patients, the presence of a pathogenic fungus is determined by mycological examination: mainly (especially with small dimensions of the cavity) from the bronchial lavage of the affected segment of the lung, obtained with bronchoscopy, rarely sputum (rarely). In mycological examination, not only the presence of fungal invasion is determined, but also the drug sensitivity of the fungus. Any of the drugs to which sensitivity is preserved and there is a dosage form for intravenous administration can be used. Avilo, this is a drug - voriconazole lyophilisate for intravenous administration. During bronchoscopy, the condition of the bronchus is also assessed for the possibility of installing a valve bronchoblocker.

In the absence of changes in the bronchus that impede the installation of the endobronchial valve (pronounced deformation, the presence of an inflammatory process on its mucosa) and obtaining data on the presence of invasion of the fungus and its drug sensitivity, the proposed method of treatment is used.

With fibrobronchoscopy (as a rule, this is fibrobronchoscopy under local anesthesia, but, according to indications, anesthesia can be used, as well as rigid bronchoscopy under anesthesia), an endobronchial valve (EC) is installed (the technique is approved by the Ministry of Health of the Russian Federation for use [Lovacheva O. V., Elkin A.V., Zimonin P.E., Krasnov D.V., Krasnov V.A., Levin A.V., Sklyuev S.V., Skornyakov S.N., Stepanov D.V., Tseimakh E. A., Shumskaya I.Yu., Federal clinical guidelines for the use of the valve bronchoblocking method in the treatment of pulmonary tuberculosis and its complications, New Terra Publishing House, Moscow, 2015, p. 24 http://roftb.ru/netcat_files /doks2015/rec7.pdf]). The endobronchial valve was installed in the lobar or segmental bronchus, the ventilating part of the lung, in which the cavity with the mycetoma is located. EC is a device that allows air, bronchial contents to escape from the blocked area when coughing, but prevents the flow of air during inhalation into the blocked area. In the Russian Federation, the EC of the company "Medlang" of the Russian Federation is registered and approved for use.

After the installation of the endobronchial valve (EC), an aqueous solution of an antifungal drug can be injected immediately after its installation, or better after 3-5 days, when the blocked area of the lung reduces its airiness, respectively, the volume, participation in the respiratory function, and the EC is tight due to mucosal edema will be fixed in the bronchus and the patient will get used to his condition and will not cough, repeat bronchoscopy. For the introduction of an antifungal drug between the endobronchial valve and the wall of the bronchus, which encompasses it, a thin plastic catheter is inserted until the distal end of the catheter goes beyond the valve into the distal bronchi (Fig. 1), which is easily controlled along the length of the catheter part, which is wound parallel to the head of the EC, length which is known. 10 ml of a solution of the drug for intravenous administration (to which the sensitivity of the fungus has been established), containing one single dose of the drug (for voriconazole lyophilisate, this is 200 mg dissolved in water for injection), is slowly injected through the catheter. After the completion of the administration of the drug, another 1-2 ml of water for injection is injected into the catheter to free the lumen of the catheter from the drug (this depends on the volume of fluid required to fill the catheter, that is, on its diameter and length), and then the catheter is removed into the channel of the fiberoptic bronchoscope and along with it from the respiratory tract. After removing the catheter from the space between the valve and the wall of the bronchus, the channel of its penetration is instantly closed due to the elasticity of the material of the endobronchial valve and the drug does not flow back. For endobronchial administration, the drug is prepared according to the instructions for the drug, which indicates the single and daily doses, as well as the solvent, we introduced one single dose of the drug voriconazole lyophilisate, dissolved in water for injection. We did not observe any adverse events following the administration of antifungal drugs. A test for allergic reactions to the drug is done to patients before its administration, by applying the drug to the mucous membrane of the lips.

The localization and size of the cavity with mycetoma in the blocked area of the lung does not matter, since it is not necessary to get the drug directly into the cavity, which is impossible with its small size, it is enough to saturate the surrounding tissue with a high dose of the drug, which always happens. If necessary, EC installation and drug administration can be carried out during one bronchoscopy, but this lengthens the manipulation time, which is worse tolerated by the patient and the drug enters the area of the lung filled with air with an oxygen content, as in the inhaled air, in addition, the patient can cough violently after installing the EC, which will lead to the loss of part of the drug.

As a rule, one injection of the drug in a single dose is enough, but in the absence of an X-ray effect, after 2-3 weeks, the administration of the drug can be repeated using the already established EC.

EC remains in the bronchi until the full desired effect of “destruction of the mycetoma and closure of the decay cavity” is obtained, which can take from 2 to 12 months. The destruction of mycetoma was usually recorded by us during the first control MSCT, carried out 2 months after the drug administration procedure (control X-ray studies are usually recommended no more than 2 months later). If the cavity is preserved, then the EC should not be removed until the positive X-ray dynamics has ceased, in order to reduce the frequency of cases of “cure of mycetoma while maintaining the cavity”.

The valve prevents new portions of air from entering the blocked area of the lung, and the existing in the lung contains significantly less oxygen and with each exhalation of air it becomes less and less - the area of the lung begins to collapse, producing compression of the cavity, which contributes to its healing. But healing will not occur as long as there is a mycetoma in the cavity. The introduction of a topical drug in a high concentration has a detrimental effect on fungi, which destroys the mycetoma, its adhesion to the walls of the cavity disappears, it is fragmented and enters the bronchi from the cavity, and then through the valve with sputum is excreted from the respiratory tract. Patients sometimes note the presence of dark, dense lumps in the sputum. The cavity released from the mycetoma is compressed as a result of collapse due to EC, its walls join and grow together, forming a scar, or the reduced cavity is filled, turning into a dense focus.

Voriconazole is an antifungal agent for systemic use from the group of triazoles. Voriconazole is active (both in vitro and according to the results of clinical studies in the treatment of a number of infections) against most strains of the following microorganisms: Aspergillus spp. (including A. flavus, A. fumigatus, A. terreus, A. niger), Candida spp. (including strains of C. krusei resistant to fluconazole, resistant strains of C. glabrata and C. albicans, as well as C. parapsilosis and C. tropicalis ) and in relation to pathogenic fungi that have become relevant recently, incl. Scedosporium apiospermum (asexual form of Pseudallescheria boydii ) and Fusarium spp., Including Fusarium solani, which have limited sensitivity to existing antifungal agents. The course of treatment requires at least 42-84 daily doses of the drug (with a recommended duration of treatment of at least 6-12 weeks [Patterson TF, Thompson GR 3 ^rd , Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15; 63 (4): e1-e60. doi: 10.1093 / cid / ciw326. Epub 2016 Jun 29].

Valvular bronchial blocking is a minimally invasive non-drug method for treating certain types of cavities in the lung, including tuberculous cavities, based on the creation of therapeutic hypoventilation in the affected area of the lung while maintaining the drainage function of the blocked bronchus. With intensive exhalation and coughing through the EC, air and bronchial contents come out of the lesion. At the same time, on inhalation, the EC does not allow the entry of atmospheric air through the blocked bronchus, thereby achieving a gradual state of therapeutic hypoventilation, in some cases up to atelectasis of the lung tissue. The method is certified and approved for the treatment of tuberculosis and its complications.

A feature of the proposed method, causing the death of mycetoma and healing of the cavity, is a combination of local endobronchial and intracavitary administration of a solution of an antifungal drug (for example, voriconazole) and a device that prevents the removal of the drug from the affected area (endobronchial valve) and causes a decrease in ventilation and a decrease in the volume of the affected area of the lung ...

After installing the endobronchial valve (EC) during bronchoscopy, it is possible immediately after performing, or better after a few days with repeated bronchoscopy, a thin plastic catheter is inserted through the flexible bronchoscope channel, which is inserted into the blocked space between the bronchus wall and the EC. An aqueous solution of an antifungal drug is injected through the catheter (for example, voriconazole lyophilisate in 10 ml of water for injection at a dosage recommended by the manufacturer for a single injection - 200 mg), after which the catheter is released from the solution by introducing 2 ml of water for injection.

Examples of implementation of the invention

Example 1

Patient N., 43 years old, was admitted to the Federal State Budgetary Institution "NMITs FPI" of the Ministry of Health of Russia with complaints of cough with a large amount of mucopurulent sputum, an increase in body temperature to 38.2 ° C, shortness of breath with little physical exertion, poor appetite. It is known from the anamnesis that treatment for this episode of tuberculosis has been taking place since 2016 in a hospital at the place of residence. The patient was in the hospital for 2.5 years, received a treatment regimen of 5 anti-tuberculosis drugs. The last episode of bacterial excretion ( M. tuberculosis ) was recorded 6 months before admission to the Federal State Budgetary Institution “NMITs FPI” of the Ministry of Health of Russia, where he was sent, since the cavity, regarded as a tuberculous cavity, did not heal. On admission, the clinical diagnosis was: Cavernous tuberculosis of the lower lobe of the right lung in the phase of decay and seeding. Office (+). XDR MBT. Concomitant: Type 1 diabetes mellitus. Diabetic angiopathy in both eyes. Chronic hepatitis C. Chronic pancreatitis. Complications: - Respiratory failure (DN) 1-2.

Upon receipt of MSCT WGC in the S10 of the right lung, a focus with irregular heavy contours measuring 37 × 37 × 27 mm with a disintegration cavity of 28 × 35 × 17 mm was determined, in the lumen of which a rounded shadow characteristic of aspergilloma was determined (Fig. 2). In S2,9,10, three foci of compaction of lung tissue up to 14 mm and small delimited foci are identified. Diagnostic bronchoscopy was performed, in which pathology in the bronchi was not detected. A bronchial lavage was taken from B-10 of the right lung, in which the growth of the fungus was detected in the mycological laboratoryAspergillus fumigatus(fig. 3) and its drug sensitivity to voricanazole was established. The growth of the fungus was also found in the sputum donated after bronchoscopy.Aspergillus fumigatuswith similar drug sensitivity... Analysis of the material on the office (M. tuberculosis) by all methods turned out to be negative. Clinical diagnosis changed: post-tuberculous changes, CLA (cavity with mycetoma (aspergilloma) C10 of the right lung), Concomitant: Type 1 diabetes mellitus. Diabetic angiopathy in both eyes. Chronic hepatitis C. Chronic pancreatitis. Complications: - Respiratory failure (DN) 1-2.

Given the presence of several concomitant diseases, it was decided not to use surgical resection methods for the treatment of aspergilloma and to use a combined local treatment (the claimed method). Under local anesthesia (2% lidocaine solution - 6.0 ml + lidocaine spray 10% - 6 doses) with fibrobronchoscopy, EC was installed in B-10 of the right lung. After 4 days, during bronchoscopy, 10 ml of voriconazole lyophilisate solution (200 mg of active ingredient) was introduced into the blocked space through the catheter. The patient tolerated manipulations well, there were no complications. Further, the patient did not receive antifungal drugs. After 2 months, the control MSCT of the OGC was performed: the lower lobe of the right lung is slightly reduced in volume, multiple small foci are preserved in it, however, the decay cavity in which the mycetoma was located is not determined, a dense foci of irregular shape was formed in its place (Fig. 4). To consolidate the effect and given the good tolerance of the treatment by the patient, it was decided to remove the EC in a month, which was done during bronchoscopy under local anesthesia. When observed for a year, there is no recurrence of the cavity and mycetoma.

Comment. The patient has a cavity in the right lung as a result of pulmonary tuberculosis. With long-term treatment - more than 2 years, the tuberculous process ended, and in the preserved post-tuberculous cavity against the background of prolonged use of antibiotics included in the tuberculosis treatment regimen, the invasion of the fungus Aspergillus fumigatus , which formed the mycetoma - aspergilloma, occurred. Considering the presence of several concomitant diseases and the frequent complication of mycetomas with bleeding, it was decided to apply the combined treatment proposed for patenting. The treatment had a good effect - the death of the aspergilloma and the healing of the cavity. This was recorded during the first control X-ray examination. Then the EC was removed.

Clinical example 2

Patient V., 40 years old. From the anamnesis it is known that since December 2017 the patient has been registered with a phthisiatrician with a diagnosis of Fibrous-cavernous tuberculosis of the upper lobe of the left lung in the phase of infiltration and seeding of MBT (+) pre XDR MBT. Within 5 months, the patient was treated in a hospital, then on an outpatient basis. She received treatment with 7 anti-TB drugs for a year, including the antibiotics linezolid and levofloxacin. During treatment, positive X-ray dynamics of pulmonary tuberculosis was noted in the form of resorption of focal infiltrative changes and healing of several decay cavities, but some cavities remained in the upper lobe of the left lung. Bacterial excretion ( M. tuberculosis ) stopped 4 months (from March 2018) after the start of treatment. She was consulted by a thoracic surgeon. Due to the presence of decay cavities, surgical treatment is recommended.

In April 2019, the patient was admitted to the Federal State Budgetary Institution "NMITs FPI" of the Ministry of Health of Russia, an additional examination was carried out. The condition upon admission is satisfactory, no complaints. MSCT of WGC revealed decay cavities in the upper lobe of the left lung. Inside the largest of them, located in segment 2 of the left lung, there was a rounded formation, which is characteristic of mycetoma (Fig. 5). Bronchoscopy revealed no pathology in the bronchi; in the bronchial lavage from the b-zonal bronchus during sowing on mushrooms, Aspergillus flavus was found with preserved sensitivity to voricanazole. Given the bilateral tuberculous process, pronounced post-tuberculous changes, including in the area of the lung surrounding the cavity with mycetoma and the planned large volume of surgery, the patient expressed a desire to try a non-surgical method of treatment (proposed for patenting).

During fibrobronchoscopy, EC was installed in the upper zonal bronchus of the left lung, and after 5 days, a solution of voricanazole was administered at a dosage of 200 mg. The patient endured the manipulation well, there were no complications, was discharged at the place of residence, did not take antifungal drugs, the control MSCT of the OGC was performed after 3 months - three segments of the upper lobe of the left lung are in atelectasis, cavities, including mycetoma, are not detected, in the lumen of the left main the bronchus is visible the tail of the EC (Fig. 6). The treatment of the cavity with mycetoma was recognized as completed and the EC was removed. At control MSCT after 6 months: the upper lobe of the left lung is straightened, along its entire length there are sclerotic changes, dense foci of different sizes. A cavity formation with a mycetoma is not detected, in its place there is a large dense focus (Fig. 7), in the lower lobe of the left lung there are single post-tuberculosis partially calcified foci of 10 and 13 mm, in the upper lobe and segments 6, 8 of the right lung - sclerotic changes and a few post-tuberculous dense foci.

Comment: a patient with fibrous-cavernous tuberculosis was successful as a result of long-term treatment - tuberculosis was cured (cessation of bacterial excretion, resorption of infiltration, closure of several cavities), while the invasion of the fungus Aspergillus flavus with the formation of mycetoma occurred in the wall of one of the post-tubercular cavities. The application of the method proposed for patenting led to the death of the mycetoma and the closure of the decay cavity by a large focus. The last control study showed the stability of the achieved result. The patient was able to preserve the entire volume of functioning lung tissue, while during surgical treatment it was planned to remove the entire upper lobe of the left lung.

Clinical example 3 (comparative example of treatment of a cavity with a mycetoma, when only the EC device was used, but the antifungal drug was not administered).

Patient N., 17 years old. Ill since early January 2019, when cough and fever appeared. On January 15, 19, an X-ray examination revealed infiltration in the lower lobe of the left lung, then a computed tomography from February 25, 19: in the lower lobe of the left lung, multiple focal changes were detected, in places merging into extensive areas of consolidation of lung tissue with decay cavities. In the study of sputum from 20.02.19 by the PCR method, the presence of MBT DNA was established, the diagnosis was made "infiltrative pulmonary tuberculosis in the disintegration phase", the patient was transferred to a tuberculosis hospital.

Received treatment: 6 anti-tuberculosis drugs. CT of the lungs and mediastinum from 05/27/19: resorption and consolidation of the foci, but one of the decay cavities remained. Treatment from 05/31/19 to 09/30/2019 was already carried out with 3 anti-tuberculosis drugs. After 02/20/19, all sputum tests for the office and DNA for the office were negative. CT from 07/29/19 (Fig. 8 (A) and Fig. 9 (A)) - further resorption of changes in the lower lobe of the left lung, the decay cavity 24.3 × 20, l mm was preserved, the contour of its inner wall was uneven with a section that bulged out into the lumen in the form of a rounded thickening. In September 2019, he was consulted in absentia at the Federal State Budgetary Institution "NMITs FPI" of the Ministry of Health of Russia, and then on 10.09.19 he was hospitalized. A decision was made to close the decay cavity in the lung to carry out the EC installation. The general condition of the patient is satisfactory. There is no pathology for other organs and systems. During bronchoscopy on September 11, 19, a bronchial lavage was taken from the area of the lung with the above-described cavity on the MBT and fungi, and then the EC was installed in the lower zonal bronchus of the left lung, which blocked the flow of air into the area of the lung with the decay cavity. The patient tolerated the manipulation satisfactorily, he feels good, does not feel the presence of a valve in the bronchus. Auscultation - in the lower parts of the left lung, breathing is weakened, no wheezing. A few days later, the laboratory received results on the detection of the growth of the fungus Aspergillus fumigatus in the bronchial lavage, MBT and MBT DNA were not detected.

Discharged on September 19, 2019 at the place of residence with a recommendation to perform a control CT scan in 4 months. Computed tomography was performed on January 16, 2020 (Fig. 8 (B), Fig. 9 (B) - segments 7, 8, 9, 10 of the left lung in atelectasis, reduced transparency, which is the result of EC installation, but the decay cavity in the zone atelectasis persists, it has changed its configuration, inside it a mycetoma is clearly defined. A decision was made to remove the valve due to its ineffectiveness in closing the decay cavity with mycetoma. The application of the method proposed for patenting to this patient was not considered, since the parents were determined to undergo surgical treatment. removed during bronchoscopy The patient was recommended for surgery - resection of the segments of the n-lobe of the left lung with the final clarification of the volume during the operation Diagnosis of post-tuberculous changes in the n-lobe of the left lung, CLA with the presence of cavity formation, with invasion of the wall by the fungus Aspergillus fumigatus.

Installation of EC caused atelectasis of the segments of the lower lobe of the left lung, but the cavity with the presence of mycetoma did not heal over the next 4 months.

Claims (5)

1. A method of treating decay cavities in the lung, complicated by chronic aspergillosis, characterized by the fact that after diagnostic bronchoscopy to assess the condition of the bronchi in the affected area with simultaneous taking of bronchial washings to confirm fungal invasion and determine drug sensitivity, and in the absence of contraindications to the installation of an endobronchial valve , at the next fibrobronchoscopy, an endobronchial valve is installed in the lobar, zonal or segmental bronchus, the ventilating part of the lung, in which the cavity with the mycetoma is located, after 3-5 days during bronchoscopy between the wall of the endobronchial valve and the wall of the bronchus, in which the valve is installed, a plastic catheter is inserted before the distal end of the catheter leaves the valve and through it, an aqueous solution of an antifungal drug for intravenous administration is injected, containing a single dose of the drug; after which the catheter is freed from the solution by the introduction of water for injection, and then the catheter is removed into the channel of the fiberoptic bronchoscope and together with it from the respiratory tract. 2. The method according to claim 1, characterized in that the antifungal drug is a drug to which the sensitivity of fungal invasion is established when performing diagnostic bronchoscopy. 3. The method according to claim 2, characterized in that voriconazole is used as the antifungal drug. 4. The method according to claim 3, characterized in that a single dose of voriconazole for administration is 200 mg. 5. The method according to claim 1, characterized in that 1-2 ml of water for injection is injected to free the catheter from the drug solution.

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