Safety and efficacy of mesenchymal/ stromal stem cells in treatment of acute respiratory distress syndrome and COVID-19 patients: Systematic review of published studies and meta-analysis

Ozadje: Kljub stalnim napredkom pri podporni oskrbi bolnikov s sindromom akutne dihalne stiske je njihova umrljivost še vedno zelo visoka. Za to patologijo je značilna huda poškodba pljuč, ki jo karakterizira odpoved oksigenacije in hipoksemija, pljučni edem, ter nato odpoved več organskih sistemov. Najpogosteje je posledica virusnih ali bakterijskih okužb, zaradi katerih pride do zapoznelega imunskega odziva oz. citokinske nevihte. Raziskave so pokazale, da mezenhimske/ stromalne matične celice uravnavajo imunske odzive, izboljšajo obnavljanje pljučnega epitela in endotela, spodbujajo mikrobni očistek in očistek alveolarne tekočine, ter tako pripomorejo k izboljšani funkciji pljuč, distalnih organov ter preživetja bolnikov. Z namenom potrditve učinkovitosti in varnosti tovrstnega celičnega zdravljenja smo izvedli sistematični pregled in meta-analizo z že objavljenimi raziskavami. Metode: Sistematični pregled literature smo izvedli po prosto dostopnih bibliografskih spletnih bazah MEDLINE, Clinicaltrials.gov, EU Clinical trials register in Google Scholar. Izbrali smo raziskave, pri katerih so za zdravljenje sindroma akutne dihalne stiske in bolezni covid-19 uporabljali mezenhimske/ stromalne matične celice ali njihove eksosome. Načrta vključenih raziskav nismo definirali, prav tako nismo postavili omejitev pri standardni oskrbi bolnikov in načinu aplikacije celične terapije. S podatki, ki smo jih pridobili iz kliničnih raziskav s kontrolno skupino, smo izvedli meta-analizo s pomočjo programa RevMan. Rezultati: S sistematičnim pregledom smo pridobili 1 že izvedeno meta-analizo in skupno 16 raziskav. Med temi je bilo 5 kliničnih raziskav s kontrolno skupino, 2 s povečevanjem odmerka, 6 serij poročil primerov in 3 poročila posameznih primerov. Z meta-analizo smo dokazali zmanjšanje smrtnosti bolnikov s sindromom akutne dihalne stiske in boleznijo covid-19 v eksperimentalni skupini v primerjavi s kontrolno skupino, RR= 0,43, 95 % CI (0,22-0,85). Statistično pomembnih razlik v številu dni izven intenzivne nege in brez mehanske ventilacije med skupinama nismo dokazali. Prav tako nismo dokazali razlik v učinkovitosti različnih uporabljenih odmerkov celičnih pripravkov. Nobena od raziskav, ki smo jih pridobili, ni poročala o pojavu resnih neželenih učinkov, ki bi bili povezani s celičnim zdravljenjem. V vseh raziskavah, v katerih so spremljali koncentracije topnih dejavnikov vnetja, so dokazali znižanje njihovih koncentracij, vendar meta-analiza zaradi heterogenosti raziskav ni bila možna. Sklep: Rezultati, ki smo jih pridobili, potrjujejo varnost uporabe mezenhimskih/ stromalnih matičnih celic in nakazujejo učinkovitost tovrstnega zdravljenja sindroma akutne dihalne stiske in covid-19.Background: Despite constant advances in the supportive care of patients with acute respiratory distress syndrome, their mortality rate is still very high. This pathology is defined by severe lung damage characterized by failure of oxygenation and hypoxemia, pulmonary oedema, and then multiorgan failure. It is most often the result of viral or bacterial infections, which lead to a delayed immune response or. cytokine storms. Research has shown that mesenchymal / stromal stem cells regulate immune responses, improve lung epithelial and endothelial regeneration, promote microbial clearance and alveolar fluid clearance, and thus contribute to improved lung, distal organ function, and patient survival. To confirm the efficacy and safety of this type of cell therapy, we performed a systematic review and meta-analysis with studies published so far. Methods: A systematic review of the literature was performed using the free bibliographic online databases MEDLINE, Clinicaltrials.gov, the EU Clinical trials register and Google Scholar. We selected studies where mesenchymal/ stromal stem cells or their exosomes were used to treat acute respiratory distress syndrome and COVID-19 disease. We did not define the plan of the included studies, nor did we set any restrictions on standard patient care and the method of cell therapy application. Using data obtained from clinical trials with a control group, we performed a meta-analysis using the RevMan program. Results: With a systematic review, we obtained one already performed meta-analysis and a total of 16 studies. Of these, 5 were clinical trials with a control group, 2 with dose escalation, 6 case series and 3 case reports. Meta-analysis showed a reduction in mortality in patients with acute respiratory distress syndrome and COVID-19 disease in the experimental group, compared with the control group, RR = 0,43, 95% CI (0.22-0.85). We did not prove statistically significant differences in the number of intensive care free days and ventilator free days between the groups. We also did not demonstrate differences in the efficacy of the different doses of cellular preparations used. None of the studies we obtained reported the occurrence of serious adverse effects associated with cell therapy. In all studies where the concentrations of soluble inflammatory factors were monitored, a decrease in their concentrations was demonstrated but meta-analysis was not possible due to the heterogeneity of the studies. Conclusion: The obtained results confirm the safety of the use of mesenchymal/ stromal stem cells and indicate the effectiveness of this type of treatment for acute respiratory distress and COVID-19