Potential of therapeutic plasmapheresis in treatment of COVID-19 patients: Immunopathogenesis and coagulopathy.

Therapeutic plasmapheresis (TP) is the process of the separation and removal of plasma from other blood components and is considered as an adjunctive treatment strategy to the discarded abnormal agent in the management of respiratory viral pandemics. This article reviews the mechanisms of immunopathogenesis and coagulopathy induced by SARS-CoV-2 and the potential benefits of TP as adjunctive treatment in critically COVID-19 patients.

An alternative test for determining autologous stem cell transplantation cell harvesting outcome: Comparison between predictive values of two tests.

Daily CD34+ cells enumeration as a success indicator of stem cell pheresis procedure using flow cytometry is costly, lengthy, and labor-intensive. Thus, finding a simpler method to achieve the optimum time for harvesting the minimum required stem cells for transplantation could be helpful. The aim of this study was to evaluate the predictive value of reticulocytes fractions and their sensesivity and specificity in guiding CD34+ cell harvesting by G-CSF mobilization strategy. In this study, 49 candidates for autologous peripheral blood stem cell transplantation were enrolled. Before leukapheresis, the immature reticulocytes fraction (IRF) and CD34+ cell count were measured. Moreover, patients were evaluated for leukapheresis outcomes in two MNC and cMNC groups. Here we demonstrated that IRF, LFR, and MFR with the associated criterion of >17.3, ≤82.5, and >15.9, respectively, earned 100 % specificity and 47.2 %, 47.22 %, and 41.46 % sensitivity to predict the minimum required CD34+ cell count. Furthermore, IRF-V (Value) and MFR-V with the associated criterion of >0.77 and >0.55, respectively, earned 58.33 %, 66.67 % sensitivity and 84.62 %, 69.23 % of specificity, separately. As only MFR-V was able to predict the platelet engraftment (P-value = 0.014), none of the other above mentioned factors were not able to predict the neutrophil engraftment. Likewise, it was shown that patients who underwent MNC leukapheresis had a statistically significantly higher total WBC, harvested CD34+ cells, MNCs/ kg, and lower apheresis durations (P-values<0.05). Taken together, using IRF and its maturity stages seems to be a compelling predictor of minimal required CD34+ cells in autologous peripheral blood stem cell transplantation.

Peripheral blood stem cell apheresis in low-weight children: A single centre study.

Peripheral blood stem cell transplantation (PBSCT) is now widely used in both malignant and non-malignant hematologic diseases as a treatment strategy. Using this approach, a controversial group of donors is children weighing 20 kg or less. The aim of this study was to evaluate results of allogeneic and autologous PBSCT and also the efficacy of our suggested alternative method for a custom prime in cell harvesting of this group. All the participants' demographic and laboratory data were collected before apheresis. A total of 37 individuals participated in this study of which 12 and 25 of them were categorized in autologous and allogeneic groups respectively. For the apheresis procedure, a central venous access was used as well as the custom prime method with some changes. Apheresis details, as well as CD34 and CD3 cell counts in the allogeneic and autologous groups, were calculated. In this study, 91.9% (N = 34) of all individuals achieved the minimal amount of cells for PBSCT (2 × 106 CD34+ cells/kg) in one session. On the other hand, 12% (N = 3) of donors in the allogeneic group achieved the minimal threshold in 2 apheresis sessions. During the leukapheresis a total processed blood volume/total blood volume ratio (TPBV/TBV) was calculated as 4.64 ± 1.06 and 5.18 ± 0.73 fold in the allogeneic and autologous groups respectively. The mean of harvested CD34 cells in allogeneic and autologous groups was 5.28 ± 3.47 × 106 and 3.57 ± 2.9 × 106 cells/kg respectively. Likewise, in the allogeneic group, the mean of the harvested CD3 cell count was 339 ± 141 × 106/kg. Also, the median day of white blood cell (WBC) engraftment was 14 and 13 for allogeneic and autologous groups respectively. Furthermore, the median day of platelet engraftment was 19.5 for both allogeneic and autologous groups. Among the recipients of the allogeneic group, acute graft versus host disease (aGVHD) was detected in 56% (N = 14) of patients and this was also correct for chronic GVHD. Taken together, it was shown, despite the probable complications of peripheral blood stem cell apheresis in donors weighing less than 20 kg; that it is possible to perform this procedure without any complication during the leukapheresis.

Effect of plasma exchange in acute respiratory failure due to Anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Acute respiratory failure related to diffuse alveolar hemorrhage (DAH) is a typical presentation of small-vessel vasculitis that requires prompt multidisciplinary management. The primary treatment is based on immunosuppressive drugs, whereas urgent plasma exchange has been proposed in case of life-threatening complications. We addressed the course of respiratory failure in 12 patients with ANCA-associated vasculitis-related DAH. PATIENTS AND METHODS: Observational retrospective case series performed in the medical ICU of a tertiary hospital in Paris, France. Consecutive patients with ANCA-associated DAH admitted to our ICU for acute respiratory failure and treated by plasmapheresis were included in the analysis. We evaluated the SpO2/FiO2 ratio and assessed the mechanical ventilation mode hourly for 7 days. RESULTS: Twelve patients were included. Five of them required invasive mechanical ventilation. All patients were treated by plasma exchange in addition to a combination of glucocorticoids and immunosuppressive agents. Oxygenation improved over the first 7 days following initiation of plasma exchange, as shown by a dramatic increase in the median SpO2/FiO2 ratio from 183 [interquartile 137-321] to 353 [239-432] (p = 0.003), along with a decrease in the level of ventilatory support. All but one patient survived. CONCLUSIONS: A multimodal induction regimen combining immunosuppressants and plasma exchange may rapidly reverse the respiratory dysfunction in ANCA-associated vasculitis-related DAH.

Low-volume standardized ECP for children and adults.

This manuscript highlights a new ANSM (French security agency for food & drug) approved method of ECP in order to render ECP easier and more secure for children and adults, with shorter time of procedure and lower final volume of cells (100 ml) and lower injected 8-MOP. This modified procedure is appropriately called "a Low Volume ECP (LV-ECP)".

Photopheresis of a less than 10-kg child with acute graft versus host disease accompanied with hyperbilirubinemia: A case report.

Hematopoietic stem cell transplantation is a curative treatment for many hematologic malignancies with its most important side effect being graft-versus-host disease (GVHD). Herein, we present a 3.5 year-old male with weight of 9.8 kg with acute GVHD (grade IV gastrointestinal and cutaneous) who did not respond to the first line therapies (corticosteroids). Thus, the patient was a candidate for extracorporeal photochemotherapy (ECP). Due to the hyperbilirubinemia, two sessions of ECP every week as well as one session of plasmapheresis 24 h before each ECP session were performed (Spectra™Optia® apheresis system). The procedures were performed successfully without any side effects and the GVHD manifestations of skin and GI responded perfectly to the treatment after 12 and 14 sessions of ECP, respectively. According to the results, it seems that ECP could be successfully performed in even less than 10-kg patients.

Extra corporeal photochemotherapy in steroid refractory graft versus host disease: A review of guidelines and recommendations.

Regardless of remarkable progresses in prevention and treatment approaches, graft versus host disease (GVHD) remains a major impediment for successful allogeneic hematopoietic stem cells transplantation (HSCT) and leads to morbidity and mortality in transplanted patients. Corticosteroids are the standard therapy for GVHD; however, a great number of patients will not respond sufficiently and others will be significantly affected by adverse effects of steroids. Extracorporeal photochemotherapy (ECP), as one of the numerous second line therapies, through modulation of immune cells may improves GVHD affected organ function in steroid-refractory forms. Considering to widespread utilization of ECP as a therapeutic strategy, we performed review on current literature of ECP, regarding the treatment strategies, monitoring protocols and technical aspects in chronic and acute GVHD.

An alternative method for custom prime: A case report of successful peripheral blood stem cell harvesting from two low-weight child donors.

Allogeneic peripheral blood stem cell (APBSCs) transplantation is an effective treatment for hematological malignancies. However low-weight donor children meet some complications. In the current report, PBSCs were harvested from a 14-month-old child (9.8Kg) for a 6years old sibling recipient suffering from pre-B type of acute lymphoblastic leukemia (ALL) and also 24 months old male child donor (12Kg) for a haploidentical recipient suffering from acute myeloid leukemia (AML-M4EO). The PBSC harvesting was performed using Spectra™ Optia® apheresis software with continuous mononuclear cell (CMNC) procedure. The results were completely promising and both recipients underwent an acceptable transplantation.

Outcomes of patients with Goodpasture syndrome: A nationwide cohort-based study from the French Society of Hemapheresis.

The overall and renal outcomes of patients with Goodpasture syndrome (GS), a rare autoimmune disorder characterized by circulating anti-GBM antibodies and rapidly progressive glomerulonephritis and/or pulmonary hemorrhage, have mostly been reported in small-sized cohorts or by aggregating patients receiving a variety of therapies that include aggressive (i.e., combined plasma exchanges, corticosteroids, and cyclophosphamide) and less aggressive (i.e., either plasma exchanges or immunosuppressive drugs, or no treatment). To address the prognosis of GS patients with relatively homogeneous management including plasma exchanges, we conducted a multicenter retrospective study on GS patients included in the registry of the French Society of Hemapheresis. 122 patients were included (kidney alone (n = 28), lung alone (n = 5), or combined involvement (n = 89)). All 122 patients received plasma exchanges (median number of sessions: 13 [9-17]), either alone (n = 8) or associated with combined corticosteroids and oral or IV cyclophosphamide (n = 101) or with corticosteroids alone (n = 12) or cyclophosphamide alone (n = 2). One-year survival was 86.9%. 7/16 patients died from severe infection. In multivariate analyses (Cox's regression model), being aged <60 years, and number of plasma exchanges were correlated to overall survival. The use of alternative immunosuppressive drugs (because of refractory or relapsing GS) was correlated to mortality at one year. Superiority of oral cyclophosphamide compared to intravenous intake was close to significant. Using a logistic regression model, renal survival in patients alive at 1 year was only predicted by serum creatinine <500 µmol/L at presentation. This large series describes the predictive factors for overall and renal survival of GS patients treated by plasma exchanges. Interventional studies that compare oral and intravenous cyclophosphamide, as well as testing new immunosuppressive therapies, are warranted.

Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group.

The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications.

Updating ECP action mechanisms.

Extracorporeal Photochemotherapy (ECP) consists in illumination of the patient's leukocytes in the presence of 8-Methoxy Psoralen (8-MOP) and its reinjection to the same patient. ECP is responsible for many cellular events, the most important being the induction of cell apoptosis. Apoptosis appears first in lymphocytes and activated lymphocytes (allo or auto) which are more sensitive and undergo faster apoptosis rather than other cells. Monocytes develop apoptosis later. The injection of apoptotic cells induces tolerance in patients with graft versus host disease (GvHD) and acute heart or lung graft rejection. In these patients, phagocytosis of apoptotic cells by antigen-presenting cells (APCs) and in particular dendritic cells is responsible for a shift from Th1 to Th2 immune response, an increase in anti-inflammatory cytokines such as interleukine 10 (IL-10) and Tumor Growth Factor Beta (TGF-ß), a decrease in pro-inflammatory cytokines and finally, for the proliferation of regulatory cells. Among CD4/CD25 positive cells, only CD4(+)CD25(hi) are T-regulatory cells (T-regs). One subpopulation of T-regs produces IL-10 and inhibits Th1 CD4 cells, whereas other populations act as suppressors and inhibit the cytotoxic T-cells responsible for organ rejection and GvHD in an antigen specific fashion. It is not clear why the injection of early apoptotic cells induces tolerance in GvHD and organ graft rejection, but in Sézary syndrome, it induces up-regulation of anti-tumor immune response. Immune response modulation (up- or down-regulation) after ECP depends on many factors: early apoptotic cell injection; anti-inflammatory environment; impaired function of dendritic cells; dendritic type 2 cell dominance, lead to immune tolerance, whereas late apoptotic or necrotic cell injection and pro-inflammatory cytokines enhance immune response. Therefore, immune response to ECP depends on various factors responsible for the diversity of its mode of action in different diseases and further investigations are required.

Non-interventional Study Evaluating the Mobilization of Stem Cells by Plerixafor Before Salvage Autologous Stem Cell Transplant in Relapsed Multiple Myeloma (IFM-2015-03).

INTRODUCTION: Despite the implementation of new therapeutic agents, management of relapsed multiple myeloma (MM) remains a challenge. Salvage autologous hematopoietic cell transplant (AHCT) remains a valid therapeutic option for eligible patients who achieve prolonged response after a first AHCT. However, a second graft is not always available, and these patients may need a second mobilization. PATIENTS AND METHODS: This prospective, non-interventional, multicenter study aimed to collect data on the feasibility of salvage AHCT using a plerixafor-based hematopoietic cell mobilization in relapsed MM, according to the plerixafor label in France. Adult patients with relapsed MM eligible for a second AHCT and mobilized using granulocyte- colony stimulating factor (G-CSF) and plerixafor were included. RESULTS: Of the 23 patients, 17 achieved a successful hematopoietic cell mobilization and 13 were able to proceed to a second AHCT. Median age was 62.9 years (min-max 51-71). Ten patients (77%) were male. Eleven (85%) received AHCT as a third-line treatment or more. Median time between first and second AHCT was 5.4 years (range, 2.6-16.3). Among 18 evaluable patients, mobilization was successful for 17 (94%) of them [95% CI 84-100], with no reported side effects. Among the 13 patients who underwent salvage AHCT, the median time to engraftment was 14 days (min-max 11-29). One-year progression-free and overall survival were 88.9% [95% CI 43.3-98.4] and 100%, respectively. CONCLUSION: This study demonstrated that plerixafor allows safe and efficient mobilization in relapsed MM patients who are candidates for a salvage AHCT. TRIAL REGISTRATION: NCT02439476 Registered 8 May 2015, https://clinicaltrials.gov/ct2/show/NCT02439476 .

Delayed recovery after autologous peripheral hematopoietic cell transplantation: potential effect of a high number of total nucleated cells in the graft.

BACKGROUND: Some patients demonstrate delayed recoveries after autologous hematopoietic stem cell transplantation despite infusion of an adequate number of CD34+ cells/kg and clinically stable status. Factors considered being possible predictors of this outcome in this context were explored. STUDY DESIGN AND METHODS: A total of 246 patients were evaluated in terms of engraftment. Delayed recovery was defined by white blood cell recovery time exceeding mean+1 SEM. Clinical factors and graft characteristics were examined. Comparisons between patients with normal or delayed engraftment were made. Proinflammatory cytokines and proteolytic enzyme quantification and CXCR4+ and CD44+ cell enumeration were performed on peripheral hematopoietic stem cells (PHSC) product samples of patients with delayed engraftment and patients with usual engraftment time. RESULTS: Sixteen patients, who received at least 3 × 10(6) CD34+ cells/kg without known clinical factors likely to affect engraftment, demonstrated a delayed recovery time of over 20 days. Some graft variables were found to be significantly increased in these patients by univariate analysis. One variable was the total number of nucleated cells cryopreserved and infused. Among the nucleated cells, the absolute number of granulocytes before and after cryopreservation also differed significantly between the two groups. A multivariate analysis showed that the main predictive factor for delayed recovery was the number of nucleated cells in the graft (p=0.0044). The influence of contaminating cells might be related to the release of elastase, matrix metalloproteinase-9, interleukin (IL)-1ß, and IL-6 involved in stem cell homing. CONCLUSION: Therefore, the numeration of total nucleated cells and granulocytes should be considered as a possible quality control variable of PHSCs submitted for cryopreservation.

Intraoperative minimal acute normovolemic hemodilution in patients undergoing coronary artery bypass surgery.

BACKGROUND & OBJECTIVE: Efficacy of minimal acute normovolemic hemodilution (ANH) in avoiding homologous blood transfusion during cardiovascular surgery remains controversial. Postoperative bleeding and transfusion remain a source of morbidity and cost after open heart operations. Our objective was to evaluate the impact of minimal ANH on blood transfusion requirements during open cardiovascular surgery using cardiopulmonary bypass (CPB). METHODS: This study was a randomized controlled trial. One hundred one patients scheduled for elective coronary artery bypass graft (CABG) under cardiopulmonary bypass in October 2007 through March 2008 in Imam Khomeini hospital were randomly assigned to a control group (standard care, no = 47) or an ANH or study group (no = 54). We used minimal ANH (representing 10% of patients' blood volume). Mean 490 +/- 50 mL of fresh autologous blood was removed after induction of anesthesia and reinfused at the end of CPB. The blood transfusion guidelines were uniformly applied to all patients. RESULTS: Significant decrease in the number of red blood cell units transfused per patient per group (1.39 +/- 1.0 and 2.551.9 +/- units; p < 0.0001) in the ANH group versus the control group was observed. Conversely, chest tube output, postoperative hematocrits, and platelet count did not differ between two groups. Percentage of patients in whom allogeneic red blood cells were transfused was 44% in study group versus 76% in control group; (p < 0.01). No patient was transfused with platelet concentrates or fresh frozen plasma. CONCLUSIONS: Minimal ANH is safe and cost effective and its routine use in eligible patients is therefore justified. Intraoperative autologous blood donation in CABG surgery decreased perioperative allogeneic blood requirement. However, the removal and reinfusion of about one unit autologous blood had no effect on postoperative bleeding or platelet count.

Marked efficacy of a therapeutic strategy associating prednisone and plasma exchange followed by rituximab in two patients with refractory myopathy associated with antibodies to the signal recognition particle (SRP).

We report two patients with myopathy associated with anti-signal recognition particle Ab, refractory to conventional therapy, who were treated with prednisone and plasma exchange, followed by rituximab. A marked response was observed in both patients, with partial to complete recovery of muscle strength, which was sustained.

Outcome of severe adult thrombotic microangiopathies in the intensive care unit.

OBJECTIVE: Thrombotic microangiopathies, namely thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, are uncommon microvascular occlusive diseases. Despite the dramatic improvement in the outcome by exogenous plasma supply, either through plasma infusion or through plasma exchange, patients frequently require support in the intensive care unit. In the present study, we evaluated the outcome of a large cohort of patients with severe thrombotic microangiopathies. DESIGN: A retrospective multicenter study from January 1998 to June 2001. SETTING: Fourteen French university hospital medical intensive care units. PATIENTS: Sixty three adult patients with severe thrombotic microangiopathies. MEASUREMENTS AND RESULTS: Of the 63 patients, 19 had a clinical presentation of thrombotic thrombocytopenic purpura, 18 had hemolytic uremic syndrome and 26 had combined neurologic and renal failures. Infections were the main etiology associated with thrombotic microangiopathies. The mortality rate was 35%. Of the survivors, all achieved complete remission. Whereas neurologic failure assessed through the Glasgow coma scale was an independent predictor of mortality [HR=0.845 (CI 95%: 0.759-0.940), P=0.002], renal impairment did not appear to be an adverse prognostic factor. The use of plasma exchange was independently associated with survival [HR=0.269 (CI 95%: 0.104-0.691), P=0.006]. CONCLUSIONS: Thrombotic microangiopathies with severe organ dysfunctions leading to hospitalization in the intensive care unit are associated with high mortality. Neurologic impairment appears to be the main adverse prognostic factor correlated to mortality, and the study confirms the importance of plasma exchange in the treatment of high-risk patients.