.: ORİJİNAL ARAŞTIRMA
Mesenchymal Stem Cell Therapy in COVID-19 Pneumonia: A Prospective, Randomized Clinical Research
COVID-19 Pnömonisinde Mezenkimal Kök Hücre Tedavisi: Prospektif, Randomize Klinik Araştırma
Turkiye Klinikleri J Med Sci. 2022;42(1):5-13
doi: 10.5336/medsci.2021-85395
Makale Dili: EN
Tam Metin
ABSTRACT
Objective: Deficiencies in immune-regulatory mechanisms such as immune activation and T-regulatory cells are classically referred to as cytokine storms. Mesenchymal stem cells (MSCs) act as living anti-inflammatory cells that can rebalance cytokine/immune responses to restore balance in patients with coronavirus disease-2019 (COVID-19) acute respiratory distress syndrome by reducing the activation of T and B cells, and dendritic and natural killer cells. The aim of this study is to provide immune modulation with stem cell transplantation by reducing the damage caused and COVID-19 infection to tissues and organs. Material and Methods: In this prospective randomized single-center clinical trial, patients were divided into 3 groups: intubated without comorbidity (n=7); intubated with comorbidity (n=7); not intubated (n=7). Dosage of MSCs transplantation for each group was 1 million cell/kg intravenous at days 0, 2, and 4. age, gender, APACHE II scores, procalcitonin, C-reactive protein (CRP) and leukocyte values, and cluster of difference 4 (CD4), CD8, interleukin 2 (IL-2), and IL-6 levels, morbidities, number of days in intensive care unit, mortality were recorded. Clinical results, changes in inflammatory and immune function levels, and side effects were evaluated. Each patient's improvement in oxygenation and symptoms were recorded in the days after MSC transplantation. After treatment, lymphocyte, CRP, tumor necrosis factor-α level, and IL-6 levels were recorded. Results: There was no statistically significant difference between the three groups in terms of stem cell therapy patients' age and exit/discharge days and mortality. Patients who were in the group of 'intubated, no comorbidity' had significantly higher CD19 and CD19+HLA-DR+ values compared with patients in the groups of 'intubated with comorbidity' and 'not intubated.' CRP, FiO2, IL-6 and SpO2 values were significantly different across periods. Conclusion: Our study may found a useful effect of MSCs on severe COVID-19 pneumonia and showed reversal of hypoxia and downregulation of cytokine storm in patients with severe COVID-19 following 3 intravenous doses with no adverse effects assignable to the treatment.
Keywords: Mesenchymal stem cell; COVID-19; pneumonia
Objective: Deficiencies in immune-regulatory mechanisms such as immune activation and T-regulatory cells are classically referred to as cytokine storms. Mesenchymal stem cells (MSCs) act as living anti-inflammatory cells that can rebalance cytokine/immune responses to restore balance in patients with coronavirus disease-2019 (COVID-19) acute respiratory distress syndrome by reducing the activation of T and B cells, and dendritic and natural killer cells. The aim of this study is to provide immune modulation with stem cell transplantation by reducing the damage caused and COVID-19 infection to tissues and organs. Material and Methods: In this prospective randomized single-center clinical trial, patients were divided into 3 groups: intubated without comorbidity (n=7); intubated with comorbidity (n=7); not intubated (n=7). Dosage of MSCs transplantation for each group was 1 million cell/kg intravenous at days 0, 2, and 4. age, gender, APACHE II scores, procalcitonin, C-reactive protein (CRP) and leukocyte values, and cluster of difference 4 (CD4), CD8, interleukin 2 (IL-2), and IL-6 levels, morbidities, number of days in intensive care unit, mortality were recorded. Clinical results, changes in inflammatory and immune function levels, and side effects were evaluated. Each patient's improvement in oxygenation and symptoms were recorded in the days after MSC transplantation. After treatment, lymphocyte, CRP, tumor necrosis factor-α level, and IL-6 levels were recorded. Results: There was no statistically significant difference between the three groups in terms of stem cell therapy patients' age and exit/discharge days and mortality. Patients who were in the group of 'intubated, no comorbidity' had significantly higher CD19 and CD19+HLA-DR+ values compared with patients in the groups of 'intubated with comorbidity' and 'not intubated.' CRP, FiO2, IL-6 and SpO2 values were significantly different across periods. Conclusion: Our study may found a useful effect of MSCs on severe COVID-19 pneumonia and showed reversal of hypoxia and downregulation of cytokine storm in patients with severe COVID-19 following 3 intravenous doses with no adverse effects assignable to the treatment.
Keywords: Mesenchymal stem cell; COVID-19; pneumonia
ÖZET
Amaç: Mezenkimal kök hücreler [mesenchymal stem cell (MSC)], T ve B hücrelerinin, dendritik ve doğal öldürücü hücrelerin aktivasyonunu azaltarak, koronavirüs hastalığı-2019 [coronavirus disease-2019 (COVID-19)] sitokin/bağışıklık tepkilerini yeniden dengeleyebilen canlı bir antiinflamatuar görevi görür. Bu çalışmanın amacı, kök hücre nakli ile immün modülasyonu sağlayarak, COVID19 enfeksiyonun doku ve organlara verdiği zararı azaltmaktır. Gereç ve Yöntemler: Bu prospektif randomize tek merkezli klinik araştırmada hastalar 3 gruba ayrıldı: Komorbiditesi olmayan entübe (n=7); komorbidite ile entübe (n=7); entübe edilmemiş (n=7). Her grup için MSC transplantasyonunun dozu 0, 2 ve 4. günlerde 1 milyon hücre/kg intravenöz olarak verildi. Yaş, cinsiyet, APACHE II skoru, prokalsitonin, C-reaktif protein (CRP) ve lökosit değerleri, farklılaşma kümesi 4 [cluster of difference 4 (CD4)], CD8, interlökin 2 (IL-2), IL-6 seviyeleri, morbiditeler, yoğun bakımda geçen gün sayısı, mortalite kaydedildi. Klinik sonuçlar, inflamatuar ve immün fonksiyon düzeylerindeki değişiklikler ve yan etkiler değerlendirildi. MSC transplantasyonundan sonraki günlerde hastanın oksijenizasyonundaki iyileşme ve semptomları kaydedildi. Tedaviden sonra lenfosit, CRP, tümör nekrozis faktör-α düzeyi, IL-6 düzeyleri kaydedildi. Bulgular: Kök hücre tedavisi uygulanan hastaların yaşı, çıkış/taburcu olma günleri ve mortalite açısından 3 grup arasında istatistiksel olarak anlamlı fark yoktu. Sonuçlara göre entübe komorbidite yok grubunda yer alan hastaların CD19 ve CD19+HLA-DR+ değerleri, entübe ek hastalık eşlik eden ve entübe olmayan hastalara göre anlamlı olarak daha yüksek bulundu. CRP, FiO2, IL-6 ve SpO2 değerleri, zaman periyotları arasında önemli ölçüde farklılık gösterdi. Sonuç: Bu çalışma, MSC'lerin şiddetli COVID-19 pnömonisinde tedaviyle ilişkili hiçbir yan etki olmaksızın, şiddetli COVID-19'lu hastalarda 3 intravenöz dozun ardından hipoksinin tersine çevrildiğini ve sitokin fırtınasının olumsuz etkilerinin azaldığını gösterebilir.
Anahtar Kelimeler: Mezenkimal kök hücre; COVID-19; pnömoni
Amaç: Mezenkimal kök hücreler [mesenchymal stem cell (MSC)], T ve B hücrelerinin, dendritik ve doğal öldürücü hücrelerin aktivasyonunu azaltarak, koronavirüs hastalığı-2019 [coronavirus disease-2019 (COVID-19)] sitokin/bağışıklık tepkilerini yeniden dengeleyebilen canlı bir antiinflamatuar görevi görür. Bu çalışmanın amacı, kök hücre nakli ile immün modülasyonu sağlayarak, COVID19 enfeksiyonun doku ve organlara verdiği zararı azaltmaktır. Gereç ve Yöntemler: Bu prospektif randomize tek merkezli klinik araştırmada hastalar 3 gruba ayrıldı: Komorbiditesi olmayan entübe (n=7); komorbidite ile entübe (n=7); entübe edilmemiş (n=7). Her grup için MSC transplantasyonunun dozu 0, 2 ve 4. günlerde 1 milyon hücre/kg intravenöz olarak verildi. Yaş, cinsiyet, APACHE II skoru, prokalsitonin, C-reaktif protein (CRP) ve lökosit değerleri, farklılaşma kümesi 4 [cluster of difference 4 (CD4)], CD8, interlökin 2 (IL-2), IL-6 seviyeleri, morbiditeler, yoğun bakımda geçen gün sayısı, mortalite kaydedildi. Klinik sonuçlar, inflamatuar ve immün fonksiyon düzeylerindeki değişiklikler ve yan etkiler değerlendirildi. MSC transplantasyonundan sonraki günlerde hastanın oksijenizasyonundaki iyileşme ve semptomları kaydedildi. Tedaviden sonra lenfosit, CRP, tümör nekrozis faktör-α düzeyi, IL-6 düzeyleri kaydedildi. Bulgular: Kök hücre tedavisi uygulanan hastaların yaşı, çıkış/taburcu olma günleri ve mortalite açısından 3 grup arasında istatistiksel olarak anlamlı fark yoktu. Sonuçlara göre entübe komorbidite yok grubunda yer alan hastaların CD19 ve CD19+HLA-DR+ değerleri, entübe ek hastalık eşlik eden ve entübe olmayan hastalara göre anlamlı olarak daha yüksek bulundu. CRP, FiO2, IL-6 ve SpO2 değerleri, zaman periyotları arasında önemli ölçüde farklılık gösterdi. Sonuç: Bu çalışma, MSC'lerin şiddetli COVID-19 pnömonisinde tedaviyle ilişkili hiçbir yan etki olmaksızın, şiddetli COVID-19'lu hastalarda 3 intravenöz dozun ardından hipoksinin tersine çevrildiğini ve sitokin fırtınasının olumsuz etkilerinin azaldığını gösterebilir.
Anahtar Kelimeler: Mezenkimal kök hücre; COVID-19; pnömoni
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