scholarly journals Analysis of Serum Ferritin Levels As a Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis (HLH) in Hospitalized Adult Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1014-1014
Author(s):  
Anthony Q Pham ◽  
Megan M. O'Byrne ◽  
Prashant Kapoor ◽  
Mithun Vinod Shah ◽  
Roshini S Abraham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Liver Disease ◽  
Serum Ferritin ◽  
Cardiac Disease ◽  
Pediatric Patients ◽  
Serum Bilirubin ◽  
Adult Patients ◽  
Multivariable Model ◽  
Good Discrimination ◽  
C Statistic

Abstract INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder caused by the pathologic activation of the immune system. In children, either a molecular diagnosis consistent with HLH or five out of the following eight criteria are considered necessary for a diagnosis of HLH (HLH-04 criteria): 1) fever; 2) splenomegaly; 3) cytopenia in two or more cell lines; 4) hypertriglyceridemia (≥265 mg/dL) or hypofibrinogenemia (≤150 mg/dL); 5) hemophagocytosis in the bone marrow, spleen, or lymph nodes; 6) hyperferritinemia (≥500 mcg/L); 7) impaired NK cell function; and 8) elevated soluble CD25 (sCD25). These criteria have been extrapolated to diagnose HLH in adults; however, it's unclear if these same criteria are applicable in the adult population. METHODS: We reviewed the Mayo Clinic electronic medical record for all adult (≥18 years) hospitalized patients with an admission serum ferritin of ≥500 mcg/L from January 2012 through December 2014. Patients' charts were reviewed and those who met the HLH-04 criteria were considered to have HLH. For the remainder of the patients, the etiology for hyperferritinemia was determined based on chart review and discharge diagnoses. Logistic regression models were used to assess the ability of these values in predicting a diagnosis of HLH. The Mayo Clinic IRB approved this study. RESULTS: We identified 1,329 patients with a serum ferritin ≥500 mcg/L. Of these, HLH was diagnosed in 28 (2.1%) patients (malignancy-associated HLH in 11 patients, infection-associated HLH in 4 patients, autoimmune-associated HLH in 7 patients, and idiopathic HLH in 6 patients). Table 1 describes the etiology of hyperferritinemia in the remaining 1,301 patients. In contrast to pediatric hospitalized patients (Allen, Pediatr Blood Cancer, 2008), adults are more likely to have malignancy (28.1% vs 7%; p<0.05); bacterial infection (21% vs. 13%; p=0.001); liver disease (9.9% vs. 2.7%; p<0.05); and cardiac disease (7.2% vs. 1.5%; p=0.0001) as the etiology of hyperferritinemia during their hospitalization. Among all patients in the study, the following variables were associated with higher odds of having HLH compared to hyperferritinemia due to an alternate cause: elevated ferritin (odds ratio [OR] 35.97, p<0.01); thrombocytopenia (OR 15.22, p<0.01), cytopenias defined by HLH-04 criteria (OR 8.04, p<0.01); elevated admission serum bilirubin (OR 1.05, p=0.02); and peak serum bilirubin (OR 1.05, p<0.01). After stepwise selection in multivariate analysis, serum ferritin ≥2,600 mcg/L and platelets ≤100 x 109/L were independently associated with HLH diagnosis (OR 24.9 and 7.8 respectively; p<0.01 for both). The area under the curve (AUC or c-statistic) ranges from 0.5 for no ability to discriminate, to 1.0 for perfect discrimination; this model has an AUC of 0.91, which shows very good discrimination between cases and controls. An adult hospitalized patient with a combination of serum ferritin ≥2,600 mcg/L and platelets ≤100x109/L predicts a ~200 fold increased likelihood of being diagnosed with HLH as compared to hospitalized adult meeting neither of these criteria (Figures 1 and 2). CONCLUSION: In contrast to hospitalized pediatric patients, the etiology of hyperferritinemia in adults is more likely to be malignancy, bacterial infection, liver disease, and cardiac disease. We conclude that a combination of serum ferritin ≥2,600 mcg/L and platelet count ≤100 x 109/L can be used as screening criteria to help identify adult patients most likely to have HLH. The traditional 5/8 criteria to diagnose HLH in pediatric patients do not appear necessary for establishing a diagnosis of HLH in adult patients. These observations need replication in an independent data set prior to broader applicability. Table 1.Patients with ferritin > 500 mcg/L with underlying cause for elevation.Number Diagnosed (%)Cardiac Disease95 (7.2%)Liver Disease131 (9.9%)Renal Disease87 (6.6%)Infectious343 (25.8%)Malignancy373 (28.1%)Autoimmune118 (8.9%)Solid Organ Transplant34 (2.6%)Stem Cell Transplant16 (1.2%)Bone Marrow Failure9 (0.7%)Shock39 (2.9%)Idiopathic53 (4.0%)Hemoglobinopathies3 (0.2%) Figure 1. ROC curve for the multivariable model with ferritin > 2,600 (yes/no) and platelets below 100,000 (yes/no) in the model with a very good discrimination c-statistic of 0.91. Figure 1. ROC curve for the multivariable model with ferritin > 2,600 (yes/no) and platelets below 100,000 (yes/no) in the model with a very good discrimination c-statistic of 0.91. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Human Mesenchymal Stroma Cells (hMSCs) Expanded with Human Platelets Lysate Are Safe and Effective For the Treatment of Graft Versus Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1171-1171 ◽  
Author(s):  
Martino Introna ◽  
Ettore Biagi ◽  
Chiara Capelli ◽  
Agnese Salvadè ◽  
Giovanna D’Amico ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Pediatric Patients ◽  
Human Platelets ◽  
Adult Patients ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Iii

Abstract Background Very recently, encouraging results indicate that third party human mesenchymal stromal cells (hMSCs) are a rapidly available therapeutic tool for the treatment of severe (grade III–IV), steroid resistant, acute graft versus host disease (aGVHD). In the clinical experience published so far, hMSCs have been expanded in Fetal Bovine Serum (FBS), which may constitute a problem for its antigenicity and as a possible vehicle of animal pathogens. We have established a highly efficient protocol for the in vitro expansion, under strict GMP compliance, of bone marrow derived hMSCs using human platelets lysate (PL) in place of FBS (Capelli C. et al.: BMT, 2007). In this study, upon Ethical Committee approval and patient’s informed consent, hMSCs were administered on a compassionate basis for the treatment of refractory GVHD. Methods hMSCs were prepared from washouts of bags and filters, left over at the end of the standard filtration procedures of the bone marrow harvests from third party HLA mismatched healthy donors. Cells were grown in the presence of DMEM with 5% PL obtained from the Blood Bank of our Hospitals. In a short period of time (10–33 days), low density seeding of unmanipulated cells (100–200/cm2), obtained from 7 bone marrow harvests allowed to prepare large quantities of hMSCs (median 115×106, range: 67–375), with only one in vitro passage. Twenty-three frozen bags of hMSCs (each containing approximately 1×106/kg of recipient body weight) have been quarantined until the completion of quality tests, including viability, phenotype, absence of detectable bacteria, fungi, mycoplasma or endotoxin, according to European Pharmacopea guidelines. Differentiation to osteogenic and chondrogenic cells as well as the immunosuppressive potential of these cells was confirmed when tested in mixed lymphocyte reaction (MLR). Q banding and clonogenic assays were performed for each batch and never showed abnormalities of karyotype or autonomous growth in vitro. Results Two adult and 4 pediatric patients were treated for aGVHD (grade II–IV) and 2 adults for extensive chronic GVHD (cGVHD) between January and July 2008, using 12 hMSCs bags that had completed quarantine. Before hMSCs, second or third line treatments had been given to patients with aGVHD, including Etanercept (n= 5), Mycophenolate Mofetil (MMF, n= 4) and Extracorporeal Photopheresis (ECP, n= 3), Rituximab (1 patient). Patients with cGVHD were previously treated with ECP and MMF (n= 2), Imatinib (n= 1) and Etanercept (n= 1). Each infusion contained a median dose of 1×106/kg (range, 0.7–1.2×106) hMSCs. For patients with aGVHD, a single infusion was performed in 4 pediatric patients while 1 and 3 infusions were performed in 2 adult patients. The 2 patients with cGVHD received 1 and 4 infusions, respectively. All infusions were very well tolerated with no immediate or late adverse events according to WHO common criteria. Among pediatric patients with aGVHD, 3 complete and 1 partial responses were registered and all patients are alive and in complete hematologic remission. A complete response was observed in 1 adult with grade III cutaneous aGVHD although the patient rapidly relapsed and died of leukemia progression. No response was observed in the other adult patient who died of progressive grade IV gut and liver aGVHD. The 2 adult patients with cGVHD had both a partial response and are alive. Conclusions These data show that large numbers of third party hMSCs can be expanded in vitro with PL containing medium and stored for immediate use in patients with GVHD. Moreover, the clinical results and the toxicity profile confirm those reported with hMSCs expanded in FBS containing media.

The Abrogated Thrombopoietin (TPO) Signal Transduction In Pediatric Patients Suffering From Thrombocytopenia-Absent Radii Syndrome Is Restored In Adult Patients, Suggesting An Additional, c-Mpl-Jak2-Independent Mechanism for Platelet Biogenesis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1561-1561
Author(s):  
Janine Fiedler ◽  
Gabriele Strauss ◽  
Martin Wannack ◽  
Silke Fleischhauer ◽  
Kerstin Seidel ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Bone Marrow ◽  
Platelet Count ◽  
Pediatric Patients ◽  
Precursor Cells ◽  
Adult Patients ◽  
Negative Regulator ◽  
Healthy Children ◽  
Comparable Amount ◽  
Platelet Counts

Abstract Abstract 1561 Thrombocytopenia-absent radii syndrome (TARS) is a rare congenital disorder defined by low platelet count and bilaterial aplasia of radii. Additionally, patients have perinatal eosinophilia and leukocytosis and are often anemic during the first years of life. At this time, a moderate, but enigmatic increase in platelet counts has been described, but patients remain thrombocytopenic and eventually continue to suffer from severe episodes of bleeding. Megakaryocytes, the immediate precursor cells of platelets, are scarce in the bone marrow and precursor cells fail to produce megakaryocytic colonies in response to thrombopoietin (TPO). Recently, we demonstrated that all TARS patients harbor a microdeletion on chromosome 1q21 which spans 120–200 kb, comprising 12–18 annotated genes. The deletion is also present in some unaffected parents (carriers) indicating that it is essential but not sufficient for generating the TARS phenotype. We analyzed 158 platelet counts of 33 patients over time and found that platelets increase within 2 years of life in most of our patients, but even in adult patients counts do not reach the lower norm. Thus, we performed an extended analysis of TPO signal transduction in platelets from 20 TARS patients. Overall, Jak2 kinase - despite being expressed in comparable amount - does not become phosphorylated in response to TPO when patients were below age 20, confirming our previous results also performed on young patients. Intriguingly, in platelets isolated from patients over age 20, Jak2 did become phosphorylated. As TPO activates several distinct pathways, we looked for the consequences of this bipartite TPO-responsiveness, including the activation of the alternate januskinase Tyk2, the STAT, the MAPK/ERK, and the Akt pathways. As expected, when Jak2 was not phosphorylated, Tyk2 and all downstream pathways were inactive. In contrast, in the presence of phosphorylated Jak2 (pJak2), all downstream pathways were activated, emphasizing the key role of Jak2 for TPO responsiveness. Platelets from either 20 healthy children or 11 carriers showed normal TPO signaling, excluding that the effect was due to a general age-dependence or a mere consequence of the microdeletion. Densitometric analyses confirmed our overall visual results. Expression levels of the TPO-receptor c-Mpl was not altered in 2 young and 2 adult patients compared to carriers, healthy children and adult controls, arguing against a compensatory upregulation in older patients. Furthermore, we sequenced all coding regions of Jak2 mRNA derived from patient-derived lymphoblastic cell lines (LCL) of one young and one adult patient and could not find any mutations. As bone marrow biopsies are typically not performed, changes in bone marrow cellularity or composition are not directly accessible. Recently, the immature platelet fraction (IPF) has been considered a surrogate marker for megakaryopoiesis. Interestingly, while there was no correlation between platelet count and IPF in 16 patients with TARS, we found a negative correlation between IPF with age. In 9 pediatric patients IPF was elevated (4.6%) compared to the median of 100 pediatric controls (2.7%), while in 7 adult TARS patients the mean IPF was 2.4%. These data provide circumstantial evidence that changes in megakaryopoiesis might drive the change in platelet biogenesis and TPO signaling. Plasma levels of stromal derived factor 1, a chemokine that contributes to restore platelet production in the absence of functional TPO signaling, were within the normal range in 6 patients with TARS. Real-time analysis of mRNA expression in LCL of genes within the microdeleted region indicates comparable expression in 2 unaffected parents with 2 controls, while 3 patients and 2 carriers showed the expected reduced expression. This includes the expression of PIAS3, a negative regulator of the Jak-STAT pathway. PIAS3 protein level, however, was normal in platelet lysates of TARS patients, making a key function for thrombocytopenia in TARS unlikely. Taken together, our data show an unexpected age-dependent change in TPO-signaling in platelets of TARS patients. As this change occurs much later than the amelioration of platelet counts, we suggest that an unknown factor influences platelet biogenesis during childhood. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2292-2292 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Adult Patients ◽  
Off Label Use ◽  
Employment Equity ◽  
Hematopoietic Stem ◽  
Off Label ◽  
Equity Ownership ◽  
Label Use

Abstract Introduction: Blinatumomab, an investigational bispecific T-cell engager (BiTE®) antibody construct, has been shown to induce remission in adult patients with relapsed/refractory BCP-ALL. Medically important adverse events (AEs) related to blinatumomab treatment in adults are cytokine release syndrome (CRS) and neurological events. We report the primary analysis of the phase 1 portion of a multicenter phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods: In this continuing study, eligible patients are <18 years old and must have BCP-ALL that is in second or later bone marrow relapse, in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or refractory to induction or reinduction therapy. Patients receive blinatumomab for 28 days by continuous intravenous infusion followed by a 14-day treatment-free period (for up to five cycles). Escalating dosing levels of 5, 15, and 30 μg/m²/day and stepwise dosing of 5–15 or 15–30 μg/m²/day were evaluated. The primary endpoint of the phase 1 portion of the study was maximum tolerated dose (MTD). Secondary endpoints included toxicity, complete remission (CR) rate, overall survival (OS), relapse-free survival (RFS), pharmacokinetics evaluation, and cytokine measurement. Results: In the phase 1 portion, 41 patients received a total of 73 cycles (median of 2 cycles received, range of 1 to 5). Eight (20%) patients had refractory disease and seven (17%) had experienced at least two bone marrow relapses. Twenty-six (63%) patients had relapsed following HSCT. Dose-limiting toxicities (DLTs) are listed in Table 1. The MTD was established at 15 µg/m²/day. To decrease the risk of CRS, a stepwise dose of 5–15 μg/m²/day was recommended for the phase 2 part of the study (5 µg/m²/day for 7 days, then 15 µg/m²/day). This dose was subsequently assessed in two age groups (2–6 and 7–17 years) in the phase 1 expansion part with one of 18 patients developing grade 3 CRS. No patient in the expansion cohort developed grade 4 or 5 CRS. Across all dosing levels, 13 (32%) patients had CR with 10 (77%) achieving minimal residual disease (MRD) negativity. Of these 13 patients, nine (69%) underwent HSCT. Among patients who achieved CR, median RFS was 8.3 months (95% CI: 3.0–16.0 months). Median OS was 5.7 months (95% CI: 3.3–9.7 months; Figure 1) with a median follow-up time of 12.4 months. Across all dosing levels, the most common AEs regardless of causality were pyrexia (78%), headache (37%), hypertension (32%), nausea (29%), abdominal pain (27%), pain in the extremity (27%), and anemia (27%). Pharmacokinetic parameters, including steady-state concentration (Css), clearance, and half-life were similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mostly within the first two days after starting blinatumomab, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions: In the phase 1 portion of this study in pediatric patients with relapsed/refractory BCP-ALL, the MTD was 15 µg/m²/day. CRS was dose-limiting, but stepwise dosing of 5–15 μg/m²/day has been effective in ameliorating CRS. Thirty-two percent of patients achieved CR and more than half were able to proceed to allogeneic HSCT. Figure 1 Figure 1. Disclosures von Stackelberg: Amgen: Consultancy, Honoraria. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Rheingold:Novartis: Consultancy. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhu:Amgen Inc.: Employment, Equity Ownership. Hijazi:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Gore:Amgen Inc.: Travel Support Other.

scholarly journals Bone marrow fat change in pediatric patients with non-alcoholic fatty liver disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. e0234096
Author(s):  
Salman S. Albakheet ◽  
Haesung Yoon ◽  
Hyun Joo Shin ◽  
Hong Koh ◽  
Seung Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Pediatric Patients ◽  
Marrow Fat ◽  
Alcoholic Fatty Liver ◽  
Bone Marrow Fat ◽  
Alcoholic Fatty Liver Disease

scholarly journals Determinants of Erythrocyte Size in Chronic Liver Disease

Blood ◽  
1969 ◽  
Vol 34 (6) ◽  
pp. 739-746 ◽  
Author(s):  
THOMAS M. KILBRIDGE ◽  
PAUL HELLER
Keyword(s):  
Bone Marrow ◽  
Liver Disease ◽  
Chronic Liver Disease ◽  
Peripheral Blood ◽  
Hepatic Cirrhosis ◽  
Alcoholic Cirrhosis ◽  
Clinical Findings ◽  
Red Cells ◽  
Red Cell ◽  
Cell Volumes

Abstract Serial determinations of red cell volumes were made with an electronic sizing device in 30 patients with hepatic cirrhosis. Variations in red cell volumes were correlated with other hematologic and clinical findings. The results of these studies suggest that volume macrocytosis in patients with alcoholic cirrhosis is either due to megaloblastosis of the bone marrow or to an accelerated influx of young red cells into the peripheral blood.

scholarly journals Macrophage Activation Syndrome in Adults: A Retrospective Case Series

2021 ◽  
Vol 9 ◽  
pp. 232470962110264
Author(s):  
Taylor Warmoth ◽  
Malvika Ramesh ◽  
Kenneth Iwuji ◽  
John S. Pixley
Keyword(s):  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Pediatric Patients ◽  
Inflammatory Diseases ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Case Series ◽  
Adult Patients ◽  
Retrospective Case ◽  
Life Threatening ◽  
Activation Syndrome

Macrophage activation syndrome (MAS) is a form of hemophagocytic lymphohistocytosis that occurs in patients with a variety of inflammatory rheumatologic conditions. Traditionally, it is noted in pediatric patients with systemic juvenile idiopathic arthritis and systemic lupus erythematous. It is a rapidly progressive and life-threatening syndrome of excess immune activation with an estimated mortality rate of 40% in children. It has become clear recently that MAS occurs in adult patients with underlying rheumatic inflammatory diseases. In this article, we describe 6 adult patients with likely underlying MAS. This case series will outline factors related to diagnosis, pathophysiology, and review present therapeutic strategies.

Sign in / Sign up

Export Citation Format

Share Document