Epidemiology of therapeutic apheresis with a multidisciplinary approach at a high volume pediatric center.

INTRODUCTION: Therapeutic apheresis (TA) is used inconsistently in pediatric populations. We seek to define our multidisciplinary institutional practice. METHODS: We conducted a retrospective chart review of patients receiving TA from January 1, 2012 through October 31, 2015. Data collected included demographics, American Society of Apheresis (ASFA) indication, complications, and mortality. RESULTS: Over 46 months, 1198 TA procedures were conducted on 289 patients ranging in age from 5 months to 21 years with weights ranging from 4.76 to 170.3 kg (16 procedures in patients <10 kg). The procedures were 86% therapeutic plasma exchange, 10% red blood cell exchange, 4% extracorporeal photopheresis, and 5 leukocytapheresis procedures. TA was initiated in different clinical environments: 41% outpatient, 37% intensive care, 15% general inpatient, and 7% operating room. The ASFA category (6th edition) indications for the 1198 procedures included: 44% category I, 25% category II, 23% category III, a single category IV procedure, and the remainder (8%) uncategorized by ASFA. The rate of procedure failure and procedure-related mortality are 1 and 0%, respectively. Case mortality rate was 4%. CONCLUSION: At a large volume pediatric hospital, TA is commonly used and can be performed safely in a variety of settings by a multidisciplinary team. This demographic review catalogs the number and type of procedures performed as a second-line therapy or on the basis of limited evidence. Additional collaborative investigation is needed to evaluate unique implications of TA in pediatrics to maximize efficacy while preserving safety.

A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.

Neutrophils play a central role in eliminating bacterial pathogens, but may also contribute to end-organ damage in sepsis. Interleukin-8 (IL-8), a key modulator of neutrophil function, signals through neutrophil specific surface receptors CXCR-1 and CXCR-2. In this study a mechanistic computational model was used to evaluate and deploy an extracorporeal sepsis treatment which modulates CXCR-1/2 levels. First, a simplified mechanistic computational model of IL-8 mediated activation of CXCR-1/2 receptors was developed, containing 16 ODEs and 43 parameters. Receptor level dynamics and systemic parameters were coupled with multiple neutrophil phenotypes to generate dynamic populations of activated neutrophils which reduce pathogen load, and/or primed neutrophils which cause adverse tissue damage when misdirected. The mathematical model was calibrated using experimental data from baboons administered a two-hour infusion of E coli and followed for a maximum of 28 days. Ensembles of parameters were generated using a Bayesian parallel tempering approach to produce model fits that could recreate experimental outcomes. Stepwise logistic regression identified seven model parameters as key determinants of mortality. Sensitivity analysis showed that parameters controlling the level of killer cell neutrophils affected the overall systemic damage of individuals. To evaluate rescue strategies and provide probabilistic predictions of their impact on mortality, time of onset, duration, and capture efficacy of an extracorporeal device that modulated neutrophil phenotype were explored. Our findings suggest that interventions aiming to modulate phenotypic composition are time sensitive. When introduced between 3-6 hours of infection for a 72 hour duration, the survivor population increased from 31% to 40-80%. Treatment efficacy quickly diminishes if not introduced within 15 hours of infection. Significant harm is possible with treatment durations ranging from 5-24 hours, which may reduce survival to 13%. In severe sepsis, an extracorporeal treatment which modulates CXCR-1/2 levels has therapeutic potential, but also potential for harm. Further development of the computational model will help guide optimal device development and determine which patient populations should be targeted by treatment.

Treatment of minor severe acquired haemophilia. Is there a rationale for immunoadsorption?

OBJECTIVES: In Acquired Haemophilia (AH) autoantibodies against blood coagulation factors, mainly FVIII, inhibit the blood coagulation cascade. The clinical symptoms can vary from minor to severe life threatening bleedings. At present it is unclear if the intensity of the treatment needs to be adapted to the severity of the disease. METHODS: The clinical data and long term outcome from 20 patients suffering from minor severe AH were summarized. Bleedings requiring no blood transfusions were defined as less severe. In case of FVIII concentration <5% an immunosuppressive treatment (IT) consisting of cyclophosphamide 1-2 mg/kg BW/d and/or prednisolone 1-2 mg/kg BW/d was initiated. RESULTS: IT induced complete remission (CR) in only 40% of patients (8/20) after a mean time of 133.4 d (±90.7 d). Treatment associated severe side effects occurred in all patients. 15 patients required a factor substitution therapy due to proceeding bleedings. In 7 patients a partial remission (PR) of AH could be achieved; bleedings progressed in 5 of them and they underwent successfully second line immunoadsorption-based protocol. The inhibitor titer differed statistically significant between CR and PR with a mean of 3.7 BU vs. 16 BU. 5 patients had a fatal outcome mainly due to severe disease associated co morbidities. CONCLUSION: Immunosuppressive treatment failed in nearly a half of AH patients. Mortality was with 25% still high. The majority of patients required an intense long-term IT and developed severe treatment related side effect. Immediate start of IT did not control bleeding. In consequence, less severe AH also should be treated with a more rigorous regime because the occurrence of minors bleedings at initial presentation is not a predictive of clinical outcome. An Immunoadsorption-based protocol should be considered first line or even as a salvage strategy.

Immunoadsorption can improve cardiac function in transplant candidates with non-ischemic dilated cardiomyopathy associated with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) is a risk factor for death from heart failure (HF) in patients with dilated cardiomyopathy (DCM) but DM patients are less eligible for heart transplantation (HTx) and DM is a risk factor for death also after HTx. New therapies are therefore necessary to improve survival of diabetic DCM patients. Immunoadsorption (IA) can improve heart function in DCM but its usefulness for therapy of DM-associated DCM is unknown. We assessed this aspect. METHODS: Cardiac function and HTx-free survival were evaluated in diabetic HTx-candidates with DCM who underwent IA (Globaffin(®), a broadband-immunoadsorber containing synthetic peptide-GAM(®)) in 6/2003-6/2012 (follow-up 1-10 yrs). Non-diabetic HTx-candidates with DCM who received IA in the same time-period served as controls. Before and after IA patients were tested for serum ß1-autoantibodies (ß1-AABs). RESULTS: We evaluated 31 patients with and 31 without DM. Before IA there were no differences between the 2 groups in LV size, LVEF and ß1-AAB levels. However, DM patients were older, their HF duration was longer and their peak oxygen-uptake was lower (p < 0.005). During the 1st post-IA year in both groups there was a decrease in LV size and improvement in both LVEF and NYHA-class (p < 0.05). Post-IA 3-year HTx-free survival and prevalence of responders to IA in patients with and without DM was 81.3 ± 8% and 78.4 ± 8%, respectively and 73.3% and 67.7%, respectively. Post-IA 3-year freedom from ß1-AAB reappearance in patients with and without DM reached 72.1 ± 9.0% and 71.1 ± 8.6%, respectively. CONCLUSIONS: IA improves heart function, exercise tolerance and Tx-free survival in patients with DM-associated end-stage DCM. Our results also suggest that IA can delay HTx-listing, improve survival on HTx lists and even spare some diabetic patients from HTx, benefits of particular importance for these patients who are at high risk for pre-HTx and post-HTx mortality.

Efficacy, safety, and tolerability of long-term lipoprotein apheresis in patients with LDL- or Lp(a) hyperlipoproteinemia: Findings gathered from more than 36,000 treatments at one center in Germany.

LDL cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are main risk factors for cardiovascular disease (CVD). Efficacy, safety, and tolerability of lipoprotein apheresis (LA) were investigated in 36,745 LA treatments of 118 patients with CVD in a retrospective, monocentric study. Indications were severe hypercholesterolemia (n = 83) or isolated Lp(a) hyperlipoproteinemia (n = 35). Average age of patients at start of LA treatment was 58.1 years for males and 62.5 years for females. Medium interval between the first cardiovascular event and LA treatment was 6.4 ± 5.6 years and the average LA treatment period was 6.8 ± 4.9 years. On average treatments were performed once a week, via peripheral venous access in 79.3% of non-hemodialysis patients. In patients with hypercholesterolemia initial pre-LA LDL-C was lowered from 176.4 ± 67.0 mg/dL by 66.7 ± 10.8% per session, achieving a long-term interval mean value of 119.8 ± 34.7 mg/dL, i.e. reduction by 32.1 ± 19.6% (p < 0.0001). In patients with isolated elevated Lp(a) initial pre-LA Lp(a) was lowered from 127.2 ± 67.3 mg/dL by 66.8 ± 5.8% per session, achieving a long-term interval mean value of 60.0 ± 19.5 mg/dL, i.e. reduction by 52.8 ± 23.0% (p < 0.0001). After start of LA the average annual rate of major adverse coronary events (MACE) of all patients declined by 79.7% (p < 0.0001). Subgroup analysis showed decline by 73.7% (p < 0.0001) in patients with severe hypercholesterolemia, and by 90.4% (p < 0.0001) in patients with isolated elevated Lp(a). Adverse events (AE) occurred in 1.1% of treatments. LA treatment of patients with high risk for CVD due to LDL and/or Lp(a) hyperlipoproteinemia was effective, safe, and well tolerated. The number of cardiovascular events, at least during a six-year period, declined by 80%.

Long term outcome of patients with acquired haemophilia--a monocentre interim analysis of 82 patients.

BACKGROUND: Acquired haemophilia (AH) is a rare condition leading to life threatening bleedings with a mortality ranging between 7.9 and 22%. Due to the low incidence of AH, randomized studies are not available, but observational studies with a long term follow up are of high interest. METHODS: Our haemophilia centre has documented since 1994 the treatment of 82 patients with AH, suffering from severe and moderate AH. Patient's clinical data, treatment schedules and long term outcomes were analyzed. RESULTS: In 73% of patients the first manifestation of AH was a severe life threatening bleeding. These patients were successfully treated via a multimodal immunomodulating regime (Bonn Protocol) with an overall response rate of 93% after a median treatment time of 16 d (95% CI: 13-18.9 d). Solid cancer, lymphoma, surgery and an adjacent autoimmune disease were the main "associated conditions" of AH (AHSAC). In patients with less severe AH, conventional immunosuppressive treatment was successful in 11 patients after a median of 3.9 months (range 1-12), 5 patients failed and were treated successfully second line via the Bonn protocol. In both treatment groups no bleeding associated fatalities occurred. Four patients required an additional treatment of acute bleedings with bypassing agents leading to fatal thrombotic events. CONCLUSION: Our data show that an optimal treatment schedule in AH should be adapted to the patient's individual risk profile considering the severity of bleeding and comorbidities. Idiopathic AH predisposes to severe AH requiring a more intensive treatment compared to AHSAC. In the latter, the so called "bystander immunological phenomena" induced by the primary disorder might have an important impact on the inhibitor development. Therefore the differentiation between idiopathic AH and AHSAC should be considered for a treatment decision.

Septic shock with multiorgan failure: from conventional apheresis to adsorption therapies.

Septic shock is often associated with multiorgan failure, a life threatening clinical condition during which there is an imbalance in the proinflammatory and anti-inflammatory cytokines, chemokines, antigens, endotoxins, procoagulant, and anticoagulant factors and also resultant effects of therapeutic intervention like volume overload. Various extracorporeal therapies have shown some positive results as adjunctive therapeutic intervention to traditional antimicrobials in an effort to bring the inflammatory mediators to a homeostatic balance and to improve poor organ perfusion caused by hypotension and thrombosis in the microcirculation. This review focuses on current information on the use of therapeutic apheresis procedures as adjunctive therapy in such clinical situations as well as the exciting prospects for the near future. The sometimes disappointing results of early phase clinical studies may, in some cases, be related to the well known barriers to successful clinical trials in critically ill patients rather than to failure of the novel concept of adjunctive extracorporeal treatment of septic shock. It should be noted that some of the specialized apheresis technologies reviewed in this article are not yet available for clinical use in the United States as they are not yet approved for use by the US Food and Drug Administration.

Complications of apheresis.

In general, therapeutic apheresis is a relatively safe procedure with the most commonly seen complications caused by citrate-induced hypocalcemia and urticarial reactions to the protein-containing replacement fluid. Depletion coagulopathy and immunoglobulin depletion must be anticipated when albumin is used as the replacement fluid and becomes more profound as the number of treatment increases. The most serious complications are seen when there is an anaphylactoid reaction to the multiple units of fresh frozen plasma required when used as the replacement fluid. The overall incidence of death is 0.05%, but many of these deaths were in patients with severe preexisting conditions in which the apheresis procedure, itself, may not have been the precipitating cause. As with all extracorporeal treatments requiring large bore vascular access, catheter-related trauma, clotting, infection, and bleeding may also occur.

Therapeutic apheresis in children: special considerations.

The provision of therapeutic apheresis to children is a technically challenging procedure, requiring trained personnel and an understanding of the disease processes that leads to the need for apheresis. Most apheresis protocols are derived from studies in adult patients, even though most studies are of limited sample size. The focus of this review is to highlight the disease processes commonly treated with therapeutic apheresis in children, and to address the technical considerations pertinent to the provision of safe and effective apheresis in the pediatric setting.

Granulocytapheresis in the treatment of severe alcoholic hepatitis: a case series.

OBJECTIVES: The management of alcoholic hepatitis remains controversial. Anti-tumour necrosis factor treatments have been studied recently. We piloted the use of granulocytapheresis (GCAP) in the management of severe alcoholic hepatitis. METHODS: GCAP was performed on six patients with severe alcoholic hepatitis. Their clinical and laboratory progress was reviewed retrospectively. RESULTS: Six of the patients underwent at least one session of GCAP. Three of the patients had coexistent renal failure and five of the six patients were corticosteroid nonresponders. All patients tolerated the procedure. However, three of the patients died during their hospital admission within 4 days of GCAP treatment. These three patients suffered from torrential variceal haemorrhage, multiorgan failure and pneumonia, respectively. Two patients died 18 and 25 days after their GCAP treatment, both with multiorgan failure. The survivor was the sole corticosteroid responder of the group. There was a trend towards a fall in serum bilirubin level after GCAP, but this did not reach significance. CONCLUSION: GCAP is tolerated in severe alcoholic hepatitis; however, we have no evidence of survival advantage with this treatment.

Blood purification in the intensive care unit.

The cornerstone of renal replacement therapy in critically ill patients with acute renal failure (ARF) in our hospital, was intermittent bicarbonate dialysis with synthetic membranes, prescribed daily for anuric patients. Filling of the extracorporeal circuit with 5% human albumin or saline solution before the start of dialysis, as well as hypernatraemic dialysis with profiling, lower dialysate temperature and higher ionized calcium concentration have been used to prevent harmful hypotensive episodes either at the start or during dialysis. Continuous renal replacement therapy (CRRT) in adults was used primarily for anuric, hypotensive patients who might not tolerate standard haemodialysis. All newborns and infants in whom peritoneal dialysis was not possible were treated by continuous procedures. Sustained low efficiency dialysis (SLED) or extended daily dialysis (EDD) were an acceptable compromise between intermitent haemodialysis and CRRT. However, in our opinion, the most promising approach to intensive care unit (ICU) patients with ARF would be the combination of CRRT in the anuric patient followed by intermittent daily dialysis thereafter. Although the mortality rate of ARF patients was as high as 88% in adults and 73% in small children due to the lack of reliable criteria for the selection of patients with poor or good prognosis, aggressive treatment for all patients who needed dialysis was recommended recently. Apheresis has dramatically improved the prognosis and outcome in patients with myasthenia gravis, Guillain-Barré syndrome, Goodpasture syndrome and thrombotic thrombocytopenic purpura. The mortality rate of patients with septic shock and fulminant hepatic failure was still very high, and the role of apheresis and dialysis, in spite of some encouraging results, remains controversial.

Prognostic significance of the immunocytochemical detection of contaminating tumor cells (CTC) in apheresis products of patients with high-risk breast cancer treated with high-dose chemotherapy and stem cell transplantation.

The aim of this study was to determine whether the detection of CTC in the apheresis product contribute significantly to treatment failure of patients with high-risk breast carcinoma treated with high-dose chemotherapy (HDC) and stem cell transplantation (SCT). Patients were with stage II and III adenocarcinoma of the breast with > or = 10 axillary lymph nodes affected after primary surgery (> or = 10 N+) who had received HDC with SCT. We analyzed retrospectively the presence of CTC as assessed by immunocytochemistry (ICC) in the apheresis products obtained after standard adjuvant chemotherapy. We compared the clinical outcome of patients who received HDC and SCT with or without CTC-positive apheresis. One hundred and twenty-seven apheresis products samples were obtained from 51 patients. Fourteen (27.4%) of these samples were CTC positive. After a median follow-up of 4.6 years, 20 patients have relapsed, 14 died from progression of their disease and 30 patients remain alive and free of progression. For the whole group of patients the 5 year probabilities of DFS and OS were 60% (IC 95%, 47-75%) and 71% (IC 95%, 55-83%), respectively. However, the 5 year probabilities of DFS were 23% (IC 95%, 0-46) and 75% (IC 95%, 60-89) for patients with CTC positive and negative, respectively. The 5 year probabilities of OS were 42% (IC 95%, 15-68) and 83% (IC 95%, 70-95) for patients with CTC positive and negative, respectively. Both univariate and multivariate analysis showed that the presence of CTC in the apheresis product was the only prognostic factor associated with a higher incidence of clinically overt disease relapse (P = 0.002) and shorter survival (P = 0.003). The presence of cytokeratin-positive metastatic cells in the apheresis product increases the risk of relapse after HDC and SCT in patients with stage II and III adenocarcinoma of the breast with > or = 10 N+.