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Background and ObjectivesThe novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS).MethodsOn Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed.ResultsNone of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray’s lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy.Conclusionpc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.

Chun-Yu Lin,1,2 Yu-Chen Huang,1,2 Hung-Yu Huang,1,2 Fu-Tsai Chung,1,2 Yu-Lun Lo,1,2 Shu-Min Lin,1,2 Chun-Hua Wang,1,2 Han-Pin Kuo3 1Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3College of Medicine, Taipei Medical University, Taipei, TaiwanCorrespondence: Chun-Hua WangDepartment of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, 5 Fu-Hsing Street, Kweishan, Taoyuan 33305, TaiwanTel +8863-3281200 ext.8467Fax +8863-3287787Email wchunhua@ms7.hinet.netBackground: The efficacy of antifungal therapy in fungal-associated severe asthma remains controversial.Objective: We aimed to evaluate the differences in the clinical presentation and response to antifungal therapy between severe asthmatics with fungal sensitization and positive fungal isolates.Methods: This retrospective study included 73 patients with severe asthma from January 2004 to December 2017. We examined the presentation, medication, exacerbations, pulmonary function, serum IgE, blood eosinophils, and sputum culture results. Follow-up care was provided to each patient for minimum 3 years.Results: We classified the patients into four groups: group 1, neither fungal sensitization nor fungal isolates in the sputum (n=16); group 2, positive fungal sensitization (n=16); group 3, positive fungal isolates (n=31); and group 4, concomitant positive fungal sensitization and positive fungal isolates (n=10). There were four participants in group 2, 15 in group 3, and 6 in group 4 had received itraconazole therapy for 3 months. Patients in group 3 presented with lower serum IgE level than those in groups 2 and 4. Antifungal therapy significantly improved ACT score during the first year in groups 3 (from 18 [15– 22] to 24 [23– 24], p=0.0004) and resulted in a long-lasting ACT improvement till the third year in group 3 (from 18 [15– 22] to 24 [22– 24], p=0.0013).Conclusion: Antifungal therapy could effectively control the symptoms in patients with severe asthma with positive fungal isolates, contrary to those with merely fungal sensitization; therefore, highlighting the need for a more precise treatment strategy in future for fungal-associated severe asthma.Keywords: fungal-associated asthma, severe asthma, fungal sensitization, antifungal therapy, itraconazole