One-year follow-up study after patients with severe COVID-19 received human umbilical cord mesenchymal stem cells treatment.

BACKGROUND: The novel coronavirus is still mutating, and the pandemic continues. Meanwhile, many COVID-19 survivors have residual postinfection clinical manifestations. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been shown to be effective in the early stages of COVID-19. OBJECTIVES: The aim of this study was to investigate long-term safety and efficacy of treatment in patients with severe COVID-19 patients who had received hUC-MSCs therapy. METHODS: Twenty-five discharged patients who had severe COVID-19 (including the standard treatment group and the standard treatment plus hUC-MSCs group) were enrolled in a 1-year follow-up. The assessment considered adverse effects (including effects on liver and kidney function, coagulation, ECG, tumor marker, and so on), pulmonary function, St George's Respiratory Questionnaire (SGRQ), postinfection sequelae and serum concentration of Krebs von den Lungen-6 (KL-6), malondialdehyde (MDA), H2S, carnitine, and N-6 long-chain polyunsaturated fatty acids (N-6 LC-PUFAs). MEASUREMENTS AND MAIN RESULTS: Pulmonary ventilation function had significantly improved at the 1-year follow-up in both the hUC-MSCs group and the control group compared with the 3-month follow-up (P < 0.01). Fatigue (60% [15/25]) remained the most common symptom at the 1-year follow-up. The rate of fatigue relief was significantly reduced in the hUC-MSCs group (25% [2/8]) compared to the control group (76.5% [13/17]) (P = 0.028). The level of KL-6 was significantly lower in the hUC-MSCs group (2585.5 ± 186.5 U/ml) than in the control group (3120.7 ± 158.3 U/ml) (P < 0.001). Compared with the control group, the hUC-MSCs group had a lower level of MDA (9.27 ± 0.54 vs. 9.91 ± 0.72 nmol/ml, P = 0.036). No obvious adverse effects were observed in the hUC-MSCs treatment group at 1 year after discharge. CONCLUSIONS: Intravenous transplantation of hUC-MSCs was a safe approach in the long term in the treatment of patients with severe COVID-19. In addition, hUC-MSCs had a positive effect on postinfection sequelae in COVID-19 survivors. TRIAL REGISTRATION: Chinese Clinical Trial Registration; ChiCTR2000031494; Registered 02 April 2020-Retrospectively registered, http://www.medresman.org.

Clinical significance of serum IgM and IgG levels in COVID-19 patients in Hubei Province, China.

Background: There have been many studies about coronavirus disease 2019 (COVID-19), but the clinical significance of quantitative serum severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-specific IgM and IgG levels of COVID-19 patients have not been exhaustively analyzed. We aimed to investigate the time profiles of these IgM/IgG levels in COVID-19 patients and their correlations with clinical features. Methods: A multicenter clinical study was conducted from February 20 to March 5 2020. It involved 179 COVID-19 patients (108 males and 71 females) from five hospitals in Huangshi in Hubei Province, China. To detect SARS-CoV-2-specific IgM/IgG, quantitative antibody assays (two-step indirect immunoassays with direct chemiluminescence technology) based on the nucleocapsid protein (NP) and spike protein 1 (S1) were used. For normally distributed data, means were compared using the t-test, χ 2-test, or exact probability method. For categorical data, medians were compared using Mann-Whitney U test. Results: The median age was 57 (44-69) years (58 [38-69] for males and 57 [49-68] for females). The median duration of positive nucleic acid test was 22.32 (17.34-27.43) days. The mortality rate was relatively low (3/179, 1.68%). Serum SARS-CoV-2-specific IgG was detected around week 1 after illness onset, gradually increased until peaking in weeks 4 and 5, and then declined. Serum IgM peaked in weeks 2 and 3, then gradually declined and returned to its normal range by week 7 in all patients. Notably, children had milder respiratory symptoms with lower SARS-CoV-2-specific IgM/IgG levels. The duration of positive nucleic acid test in the chronic obstructive pulmonary disease (COPD) group was 30.36 (18.99-34.76) days, which was significantly longer than that in the non-COPD group (21.52 [16.75-26.51] days; P = 0.025). The peak serum SARS-CoV-2-specific IgG was significantly positively correlated with the duration of positive nucleic acid test. The incidence rate of severe and critical cases in the IgMhi group (using the median IgM level of 29.95 AU/mL as the cutoff for grouping) was about 38.0% (19/50), which was twice as much as that in the IgMlo group (18.4%; 9/49). The patients with positive chest imaging and lymphocytopenia (<1 × 109/L) had a higher SARS-CoV-2-specific IgM level. Conclusions: Quantitative SARS-CoV-2-specific IgM and IgG levels are helpful for the diagnosis, severity classification, and management of COVID-19 patients, and they should be monitored in each stage of this disease.

Human Umbilical Cord Mesenchymal Stromal Cell Treatment of Severe COVID-19 Patients: A 3-Month Follow-Up Study Following Hospital Discharge.

Previously, we demonstrated the therapeutic effects of human umbilical cord mesenchymal stromal cells (hUC-MSCs) in severe coronavirus disease 2019 (COVID-19) patients. In this 3-month follow-up study, we examined discharged patients who had received hUC-MSC therapy to assess the safety of this therapy and the health-related quality of life (HRQL) of these patients. The follow-up cohort consisted of 28 discharged severe COVID-19 patients who received either the standard treatment (the control group) or the standard treatment plus hUC-MSC therapy. We examined liver function, kidney function, pulmonary function, coagulation, tumor markers, and vision. We also conducted electrocardiography (ECG) analysis, let the patients answer the St. George's Respiratory Questionnaire (SGRQ), and performed computed tomography (CT) imaging for assessing the lung changes. No obvious adverse effects were observed in the hUC-MSC group after 3 months. Measurements of blood routine index, C-reactive protein and procalcitonin, liver and kidney function, coagulation, ECG, tumor markers, and vision were almost within the normal ranges in both the treatment and control groups. Forced expiratory volumes in 1 s (FEV1) (% of predicted) were 71.88% ± 8.46% and 59.45% ± 27.45% in the hUC-MSC and control groups (P < 0.01), respectively, and FEV1/forced vital capacity (FEV1/FVC) ratios were 79.95% ± 8.00% and 58.97% ± 19.16% in the hUC-MSC and control groups, respectively (P < 0.05). SGRQ scores were lower in the hUC-MSC group than in the control group (15.25 ± 3.69 vs. 31.9 ± 8.78, P < 0.05). The rate of wheezing in the hUC-MSC group was also significantly lower than that in the control group (37.5% vs. 75%, P < 0.05). There were no significant differences in CT scores between the two groups (0.60 ± 0.88 vs. 1.00 ± 1.31, P = 0.917). Overall, the intravenous transplantation of hUC-MSCs accelerated partial pulmonary function recovery and improved HRQL, indicating relative safety and preliminary efficacy of this treatment for patients with severe COVID-19.

Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells.

BACKGROUND: COVID-19 is a highly infectious respiratory disease. No therapeutics have yet been proven effective for treating severe COVID-19. OBJECTIVES: To determine whether human umbilical cord mesenchymal stem cell infusion may be effective and safe for the treatment of severe COVID-19. METHODS: Patients with severe COVID-19 were randomly divided into 2 groups: the standard treatment group and the standard treatment plus hUC-MSC infusion group. The incidence of progression from severe to critical illness, 28-day mortality, clinical symptom improvement, time to clinical symptom improvement, hematologic indicators including C-reactive protein, lymphocyte number, and interleukin 6, and imaging changes were observed and compared between the two groups. MEASUREMENTS AND MAIN RESULTS: The incidence of progression from severe to critical illness and the 28-day mortality rate were 0 in the hUC-MSC treatment group, while 4 patients in the control group deteriorated to critical condition and received invasive ventilation; 3 of them died, and the 28-day mortality rate was 10.34%. In the hUC-MSC treatment group, the time to clinical improvement was shorter than that in the control group. Clinical symptoms of weakness and fatigue, shortness of breath, and low oxygen saturation obviously improved beginning on the third day of stem cell infusion and reached a significant difference on day 7. CRP and IL-6 levels were significantly lower from day 3 of infusion, the time for the lymphocyte count to return to the normal range was significantly faster, and lung inflammation absorption was significantly shorter on CT imaging in the hUC-MSC group than in the control group. CONCLUSIONS: Intravenous transplantation of hUC-MSCs is a safe and effective method that can be considered a salvage and priority treatment option for severe COVID-19. TRIAL REGISTRATION: Chinese Clinical Trial Registration; ChiCTR2000031494; Registered on 2 April 2020; http:// www.medresman.org.

[Continuous renal replacement therapy and negative fluid balance improves renal function and prognosis of patients with acute kidney injury in sepsis].

OBJECTIVE: To investigate the influence of fluid balance and model of renal replacement therapy (RRT) on renal function and prognosis of patients suffering from septic acute kidney injury (AKI). METHODS: A retrospective cohort analysis of 117 septic AKI patients who had undergone RRT between January 2009 and December 2014 was performed in the Second Affiliated Hospital of Nanjing Medical University. The patients were divided into positive fluid balance group (n = 52) and negative fluid balance group (n = 65) according to the total amount of fluid calculated from the difference between fluid administered and fluid lost during the first 1 week of RRT. The incidence of renal recovery and death of the patients by 60 days as the endpoint events were taken to judge the prognosis of two groups. RRT strategies included continuous renal replacement therapy (CRRT) and intermittent renal replacement therapy (IRRT). Multiple factors including estimated glomerular filtration rate (eGFR), sequential organ failure assessment (SOFA) score, RRT model, the accumulation of fluid before initiation of RRT, and negative fluid balance during RRT were analyzed for outcome predictors by Cox proportional hazards model. RESULTS: There were no differences between two groups regarding clinical characteristics. The percentage of receiving CRRT in the negative fluid balance group was slightly higher than that of the positive fluid balance group (52.31% vs. 36.54%, χ² = 2.899, P = 0.089). With Kaplan-Meier survival curves, it was shown that the patients of negative fluid balance group had a higher rate of recovery of renal function (χ² = 4.803, P = 0.028) and significantly lower mortality rate (χ² = 9.505, P = 0.002). The rate of recovery of renal function by 60 days was higher in the negative fluid balance group than that in the positive fluid balance group (47.69% vs. 28.85%, χ² = 3.991, P = 0.046), while the mortality rate was significantly lowered in the negative fluid balance group compared with that of the positive fluid balance group (40.00% vs. 67.31%, χ² = 4.378, P = 0.036). Cox multivariate regression was used for excluding confounding factors. After adjusting for the clinically relevant variables, RRT negative fluid balance was significantly associated with recovery of renal function [ hazard ratios (HR) = 2.440, 95% confidence intervals (95%CI) = 1.089-5.464, P = 0.030] and mortality (HR = 0.443, 95%CI = 0.238-0.822, P = 0.010]. Higher eGFR before RRT and CRRT were independent favorable factors for recovery of renal function (HR = 1.014, 95%CI = 1.003-1.026, P = 0.012; HR = 3.138, 95%CI = 1.765-7.461, P = 0.002), and higher SOFA score was associated with a significantly higher risk of death (HR = 1.115, 95%CI = 1.057-1.177, P < 0.001). CONCLUSIONS: Once the patients with septic AKI showed the signs of fluid overload, timely RRT and effective removal of excessive liquid may reverse the adverse prognosis. RRT with negative fluid balance is beneficial for the recovery of renal function, and reduce the mortality in patients with septic AKI, and CRRT model is a good choice.