Invasive mycoses in patients with hematological malignancies and recipients of hematopoietic stem cell transplantation: results of a systematic review, literature review and meta-analysis

Background. Invasive mycoses (IM) are one of the most severe infectious complications in oncohematology. The etiological structure of IM is a rather heterogeneous group of microorganisms and undergoes changes over time. Understanding the IM etiological structure is the basis for choosing an effective IM prevention and treatment strategy.
Aim. To conduct a systematic review with a meta-analysis of data on the IM etiological structure in patients of all ages receiving therapy for oncohematological diseases, including patients who underwent hematopoietic stem cell transplantation. The analytical hypothesis was the assumption of an increase in caused by rare pathogens IM proportion in the overall IM structure over the past few years. Clinical manifestations, affected organs, risk factors and outcomes were analyzed using the literature review method.
Materials and methods. A systematic search was carried out for publications with data on the IM species structure available for analysis until February 10, 2022 in 3 databases (PubMed (Medline), Embase and eLibrary.ru). All IM were divided into 11 groups. The IM species structure was constructed in several patient subgroups in 2 time ranges – in studies before 2010 and after 2010, and they were compared. Results from individual studies were pooled by metaanalysis. Data from selected publications were reviewed to analyze the IM clinical manifestations, risk factors for their development and outcomes.
Results. Thirty-four publications were selected using a systematic search. The meta-analysis included 43 cohorts of patients with 2771 samples of IM pathogens. The time period up to 2010 included 16 cohorts with a total number of IM pathogens of 1158 samples; in the time interval after 2010 – 27 cohorts with a total number of IM pathogens of 1613 samples. Analysis of total group showed that the proportion of rare IM among all patients increased from 29 to 39 %. In the subgroup of patients with oncohematological diseases, it increased from 28 to 33 %. For total group of patients, the in‑ crease in rare IM proportion is due to an increase in rare yeasts (from 3.0 to 4.1 %) and a significant increase in the proportion of unidentified species (from 3.2 to 19.8 %). In children, the frequency of rare IM increased from 26 to 28 % among all nosologies. For total children group, the increase in rare IM proportion is due to an increase in mucormycosis (from 1.3 to 1.6 %), rare yeasts (from 4.7 to 7.9 %) and unidentified species (from 4.5 to 12.2 %). In total adult patients group, the frequency of rare IM increased from 24 to 35 %, in adult patients with oncohematological diseases – from 23 to 40 %. For total adult patients group, the increase in rare IM proportion is due to an increase in cryptococcosis (from 1.3 to 2.4 %), hyalohyphomycosis (from 3.4 to 4.8 %), rare yeast (from 1.6 to 1.9 %) and unidentified species (from 1.9 to 16.6 %); for a group of patients with oncohematological diseases – an increase in cryptococcosis (from 1.3 to 2.1 %), rare yeast (from 1.6 to 2.6 %) and unidentified species (from 1.9 to 23.1 %). There is no specific clinical manifestations characteristic of IM, the symptoms are associated with the affected organ. Febrile fever is the only IM systemic clinical manifestation, independent of localization. The lungs were the most common IM localization. The main IM risk factors are prolonged blood cell deficiency, uncontrolled underlying disease, concomitant conditions: comorbidity, diabetes mellitus, mucositis, graft-versus-host disease, infections caused by other pathogens, and a history of IM. IM increases the risk of death, attributable mortality is variable and ranged from 13 to 72 %. The most common cause of death in oncohematological patients with IM is the progression of the underlying disease, in patients after hematopoietic stem cell transplantation – graft-versus-host disease, cardiovascular complications.
Conclusion. In IM structure in oncohematological patients and hematopoietic stem cell transplant recipients, the proportion of rare IM increased markedly, mainly due to an increase in their proportion in adult patients with oncohematological diseases. The increase in rare IM proportion is mainly due to the increase in unidentified species, hyalohyphomycosis, rare yeast and cryptococcosis. Clinical manifestations are due to the localization, the main of which is the lungs. The development of IM increases the risk of death, but attributable mortality is about 50 %.

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